Volume 5 - 2023 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fclim.2023.1038883">https://doi.org/10.3389/fclim.2023.1038883</a>
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Floods disproportionately affect disadvantaged groups
Social vulnerability assessments are the first step in designing just and equitable flood risk reduction strategies
earlier social vulnerability indices apply top-down approaches
we develop and apply a combined bottom-up and top-down approach to assess social vulnerability to flooding at a sub-municipal level in Sweden
We tested an indicator-based climate risk and vulnerability framework
more specifically the impact chain method suggested by the Vulnerability Sourcebook
We involved stakeholders using various participatory methods in three workshops
and informal exchanges to identify variables and indicators for social vulnerability
The Indicators were aggregated into a composite social vulnerability index using exploratory factor analysis
We thereafter mapped the social vulnerability index scores to uncover spatial injustices
We found that the proposed social vulnerability index captures municipal nuances better than national-level approaches
Our findings indicate an uneven spatial distribution of social vulnerability that mimics the overall patterns of income segregation found in the municipality
Many areas that score low in social vulnerability endure high exposure to floods
The social vulnerability index can support municipalities in designing just and equitable interventions toward flood risk reduction by serving as an input to policymaking
The study includes both municipal census areal units and RegSO-areas
we wish to further advance the current state of the art by presenting and applying a combined bottom-up and top-down social vulnerability assessment process with an emphasis on local injustices and thereby enable policymakers to design socially-just flood protection
we aim to design and test a social vulnerability index to floods at a sub-municipal level in Sweden
We combine a bottom-up stakeholder involvement and top-down statistical analysis to derive a social vulnerability index
We use the smallest census areal unit (DeSO-areas)
This allows us to study social vulnerability in depth and context to form an understanding of how social vulnerability varies within the same municipality
We also map the social vulnerability index scores to uncover potential spatial injustices
To meet these objectives, we run a pilot study in which we zoom into Halmstad Municipality. Halmstad Municipality makes an interesting case as it endures significant exposure to coastal and river flooding while also battling with substantial socioeconomic inequalities (<a href="#B77">National Board of Housing Building Planning, 2020</a>)
which allows us to study the interaction between exposure and societal inequality and its effects on social vulnerability
It allows us to explore whether disadvantaged and marginalized areas suffer from higher flood exposure or not
The remainder of the paper is organized as follows: First
we delve into the concept of social vulnerability
The following section presents the results starting with the variables determining social vulnerability
followed by an analysis of the spatial distribution of vulnerability to flooding
We thereafter discuss the implications for research and practice and juxtapose our findings with previous research
Factors and variables for assessing social vulnerability
we applied an exploratory mix-method approach combining stakeholder engagement and statistical analysis
We structured the social vulnerability index around (i) factors describing a group of interdependent variables
(ii) variables describing a characteristic that determines social vulnerability
and (iii) indicators describing the metrics that measure the variables
In this study, we followed the indicator-based climate risk and vulnerability assessment approach the &#x0201C;impact chain&#x0201D; method outlined in the Vulnerability Sourcebook (<a href="#B46">Fritzsche et al., 2014</a>)
The impact chain method draws on the definitions provided by the IPCC AR4
and breaks vulnerability into its components of exposure
The impact chain illustrates the main cause-effect relationships behind climate change and its impacts on people: climate change exposure (e.g.
heavy precipitation or meteorological drought) interacts with the system&#x00027;s sensitivity (e.g.
population pressure or resource depletion) and adaptive capacity (e.g.
financial resources or risk awareness) to produce potential impacts and vulnerabilities
and informal exchanges during the scoping phase
Stakeholders were not involved in the statistical analysis
in which we instead departed from methods found in the academic literature
The scoping phase included several steps to further specify our aims and research questions and to inform the design of the case study and the participatory process
To gain a better understanding of the context
we first conducted a brief document study reviewing available documentation on climate risk and disaster risk reduction in Halmstad Municipality
Key documents included a flood risk and impact assessment
It allowed us to tap into ongoing work in the municipality
and ensure relevance for policy and practice
broadened the search to include studies from similar contexts in Northwestern Europe
We identified literature by applying intuitive Boolean searches in Scopus
Keywords included &#x0201C;social vulnerability&#x0201D;
The search period was set to 2005&#x02013;2020
Variables were noted and clustered into themes
In close dialogue with our contact person in Halmstad Municipality
we invited 17 stakeholders to an online scoping workshop about capacity needs
Ten stakeholders participated representing different areas of work: climate adaptation
The workshop aimed to establish collaboration and partnership
we co-explored current and future challenges and risks in the municipality
We thereby gained an initial understanding of relevant hazards
We defined the scope of the social vulnerability assessment together as a group
The researchers then further refined the aims and research questions based on the stakeholder input in order to boost the relevance and usefulness of the research to the problem context
We engaged stakeholders in a collaborative process to identify variables and indicators for social vulnerability in Halmstad Municipality
The Halmstad Municipality climate adaptation plan and stakeholder inputs from the workshop served as a point of departure in order to ensure context and location-specific relevance
It was an iterative feedback process that built on a close collaboration between the researchers and stakeholders
in which the list of variables and indicators was refined as the process moved along
We invited 16 representatives from Halmstad Municipality to a second online workshop
The aim was to continue to co-explore drivers of social vulnerability
We used the digital tools Miro and MentiMeter to support the stakeholder dialogue
We asked the participants to brainstorm about what social groups might render vulnerable in the case of river flooding and coastal inundation in Halmstad Municipality
We divided the participants into smaller groups in which they discussed the political
and institutional factors that determine sensitivity and adaptive capacity in Halmstad Municipality
The participants were brought back to the full group to share their main points from their discussions
We asked the participants to justify and elaborate their answers to challenge underlying assumptions
the research team extracted an initial list of variables for social vulnerability
we added variables found in the academic literature to identify gaps that the upcoming data collection had to address
This formed the basis for a survey consisting of 19 variables
The survey consisted of four-point Likert-scale questions
The survey delved into two questions: What social groups are vulnerable in the case of a disruptive event
What social groups might need assistance in the case of a disruptive event
We shared the survey with the same group of stakeholders in online interviews
Five group interviews were conducted virtually
The interviews aimed to further refine the list of variables for social vulnerability
the survey served as a basis for discussion
Participants were first asked to individually fill out the survey and informed that the results would not be included in the formal analysis but support the full group discussion
We thereafter shared the results with the full group
It was followed by a discussion about the results in which the participants elaborated and justified their answers
No quantitative data were included for analysis
we extracted variables for social vulnerability from the interview notes and transcripts
Findings were thereafter consolidated by the researchers into a list of contextually relevant variables for further analysis
We assigned quantitative indicators to the variables
Data was collected for the indicators from Statistics Sweden and the Delegation against Segregation (Delmos)
Data was gathered for DeSO-areas that consist of 700-2700 inhabitants for 2018
From a total of 56 DeSO-areas in Halmstad Municipality
We then collected data for flood exposure. A coastal inundation map was generated for Halmstad Municipality using the results from the NEMO-Nordic model (<a href="#B59">Hordoir et al., 2018</a>)
A flooding map along the Nissan River was obtained from the Swedish Civil Contingencies Agency
Both maps corresponded to storms of a 100-year return period
with sea level rise and land uplift assumed for the year 2,100 under the RCP8.5 climate change scenario
The data reduction was realized by investigating whether the collected indicators were linearly related to a smaller number of factors that account for a particular amount of variance in the observed data
The exploratory factor analysis was conducted in three steps: (i) testing of data adequacy
(ii) determination of the number of factors
Each factor score was then comprised of a sum of indicators that increase or decrease vulnerability
representing either sensitivity or adaptive capacity
We normalized the data from zero to one using a minimum-maximum scaling technique
To account for flood exposure, we added a factor representing the average distance to areas exposed to inundation. Exposure was not included in the exploratory factor analysis as it is possible to be exposed but not sensitive (<a href="#B60">IPCC, 2007</a>)
We calculated the distance from inundated areas due to extreme storm surges or river discharge by using the buffer tool in ArcMap 10.8
The distances were averaged within each demographic area
Averaging has the limitation that smaller demographic areas near inundation maps are more exposed than larger areas
To find social vulnerability index values, individual factor scores were added together. In line with previous research (<a href="#B111">Tate, 2012</a>)
We presented the standardized normal variables (Z-scores) to highlight the data variability relative to the mean value
We assumed that the results were normally distributed
Areas corresponding to one standard deviation above the mean were considered the most vulnerable
We then presented the results in a geospatial format. We retrieved the latest GIS layer containing DeSO boundaries from February 2020 from Statistics Sweden (<a href="#B101">SCB, 2022a</a>)
Using Python&#x00027;s libraries GeoPandas and GeoViews
the Z-Score results for each demographic area were merged into their corresponding boundaries in the DeSO geodata and plotted as choropleth maps
Geographic visualizations were produced for the aggregated social vulnerability index values
we conducted fieldwork in Halmstad Municipality to collect observations of the neighborhoods that scored high and low in the social vulnerability index
and helped us to justify the selection of variables and indicators
an interactive validation workshop was held with seven representatives from Halmstad Municipality
The aim was to share the findings with the stakeholders and gather their feedback for further improvement
in which the participants provided additional information for areas that scored high and low in the social vulnerability index
We then provided the participants with printed impact chains for them to elaborate on the findings and make changes as deemed appropriate
the stakeholders commended the quality of the results and validated them
No changes were made to the selected variables and indicators
the factors were renamed based on stakeholder input
the stakeholders provided additional input to the justification of variables and indicators based on their local expertise and experience
It anchored the findings in the local context and improved the accuracy and transparency of the information
we present the social vulnerability index and its application in Halmstad Municipality
The results section is structured around the impact chain method
We first present findings from the scoping phase
and provide a brief description of Halmstad Municipality
We proceed with introducing the results from the impact chain development process
Variables and indicators were interpreted and extracted from the stakeholder dialogues
the aggregation of indicators is presented followed by the aggregation of vulnerability components
The aggregation of indicators and vulnerability components is accompanied by a visual representation to showcase the spatial distribution of social vulnerability
We integrate secondary data from the scoping phase throughout the results section
It allows for the empirical data to be presented in a wider societal context
and reduces the risk of individual biases interfering with the results
Figure 2. Halmstad municipality (<a style="color:grey;" href="#B22">Copernicus, 2018</a>)
From the stakeholder dialogues and interviews, we extracted ten variables for social vulnerability to flooding in Halmstad Municipality. The variables represent human and social capital, access to resources, and exposure. Some variables represent sensitivity (increase vulnerability), whereas others represent adaptive capacity (decrease vulnerability). We assigned one or more indicators for all variables (see <a href="#T2">Table 2</a> for an overview)
Overview of variables and indicators for social vulnerability to flood hazards in Halmstad Municipality
From the stakeholder discussions we identified language as a variable for social vulnerability. It was, for example, argued that language barriers inhibit information access as witnessed during the COVID-19 pandemic. There is, however, no data on language proficiency in Sweden. In line with previous research (<a href="#B45">Fielding, 2012</a>; <a href="#B68">Kazmierczak et al., 2015</a>; <a href="#B71">Koks et al., 2015</a>; <a href="#B70">Kirby et al., 2019</a>)
the percentage of foreign-born persons is used as a proxy indicator for language proficiency
Foreign-born persons may also lack an understanding of the Swedish crisis management system
It was noted during the stakeholder dialogue that foreign-born persons comprise a diverse group with different capacities and sensitivities depending on other intersecting variables such as housing
In line with previous research (<a href="#B118">Vink et al., 2014</a>; <a href="#B122">Welle et al., 2014</a>)
the stakeholder dialogues revealed that health conditions and impairments increase vulnerability
Some groups depend on others for safety including people with significant mobility impairments
Further, it was noted during the dialogues that adults with lower levels of educational attainment have less access to information. Low educational attainment correlates with low income (<a href="#B24">Cutter et al., 2003</a>; <a href="#B43">Fekete, 2010</a>; <a href="#B122">Welle et al., 2014</a>). In line with previous research (<a href="#B13">Bremberg et al., 2015</a>)
two indicators are included: (i) the percentage of people who have completed primary education or less and (ii) the percentage of people who have an educational attainment of at least 2 years of university or similar
In line with previous research (<a href="#B49">Garbutt et al., 2015</a>; <a href="#B96">Sayers et al., 2018</a>)
it was noted during the participatory process that single parent households are a potentially vulnerable group
Extreme weather events impose increased demands on parents
Single parents are less likely to share the responsibility with another adult in comparison to co-habiting parents
It increases the dependency on childcare services
The number of single parent households in an area serves as an indicator for this group
As suggested by previous research (<a href="#B68">Kazmierczak et al., 2015</a>; <a href="#B96">Sayers et al., 2018</a>)
insights from the stakeholder dialogue suggested that owning a vehicle reduces social vulnerability as it can facilitate the evacuation of people and goods
We use the number of vehicles per capita in an area as an indicator
House owners have greater responsibilities than apartment dwellers in the case of flooding
Apartment dwellers can rely on their housing association for proactive and reactive flood risk management
Costs and benefits are shared in a larger group compared to house owners
who have the legal responsibility for protecting their property against natural hazards
We used an indicator that includes the percentage of house owners in an area
In line with previous research (<a href="#B58">Holand et al., 2011</a>; <a href="#B91">R&#x000F8;d et al., 2012</a>; <a href="#B12">Breil et al., 2018</a>; <a href="#B44">Fekete, 2019</a>)
income was identified as a critical variable for determining social vulnerability
Households below average income have less capacity to cope in the case of a crisis as they have fewer financial resources to invest in efforts toward flood risk management
we included four indicators: (i) households with an income &#x0003C;60% of the national median
(ii) households with an income &#x0003E;200% of the national median
and (iv) children living in households below the poverty threshold
In line with previous research (<a href="#B5">Aroca-Jimenez et al., 2017</a>; <a href="#B12">Breil et al., 2018</a>; <a href="#B83">Nikkanen et al., 2021</a>), insights from the stakeholder dialogue suggested that people in long-term unemployment are less likely to have the financial resources to cope in the event of a flood. To assess long-term unemployment, we included an indicator that considered those unemployed longer than 6 months [as defined by <a href="#B97">SCB (2020a)</a>]
Human exposure to flooding was highlighted as an important variable for social vulnerability
Flood exposure can translate to social and economic impacts
we use the average distance to areas exposed to river floods and coastal inundation as an indicator
it was noted that men are overrepresented in flood-related causalities due to risk-taking behavior
We performed a scree test to generate a composite index from the selected variables and indicators. The scree plot identified three factors according to the Kaiser criterion for retaining factors. This amount was applied to generate a loading table for further analysis (see <a href="#T3">Table 3</a>)
The analysis reduces the indicators into three factors consisting of correlated indicators for sensitivity and adaptive capacity
<a href="#T3">Table 3</a> shows the social vulnerability index and its factor labels
The factors account for 70% of the cumulative variability
which we named &#x0201C;House-owners with children&#x0201D;
explains 32% of the dataset variability and is characterized by a high incidence of single-family houses
and low presence of households with income below 60% national median
which we called &#x0201C;People outside the labor force&#x0201D;
explains 23% of the variance found in the dataset and is dominated by a large number of sick leave days
highest educational attainment primary school or less
households with income below 60% national median
The third factor was labeled &#x0201C;Elderly with accumulated wealth&#x0201D;
and represents 15% of the dataset variability
It consists of households with an income of &#x0003E;200% of the national median
The spatial distribution for each factor is illustrated in <a href="#F3">Figure 3</a>
Even though the adopted indicators characterize vulnerability
factor labels are considered neutral and describe major societal groups in the municipality
These groups could be more or less vulnerable depending on their specific indicators
vulnerability results are interpreted according to their absolute numerical values
where positive values are more vulnerable and negative numbers are less vulnerable
The main characteristics of each factor and their vulnerability hotspots within municipality areas are described next
Separate factor relative vulnerability distributions in Halmstad Municipality
due to the long distance to municipal services and employment opportunities
Oskarstr&#x000F6;m also scored high. With a population of 4,157 (<a href="#B98">SCB, 2020b</a>), Oskarstr&#x000F6;m is the second-largest locality in the municipality. Around 17% have an income &#x0003C;60% of the national median income (<a href="#B31">Delmos, 2020a</a>). Most have completed upper-secondary education, whereas few have a post-secondary education from a university or similar (<a href="#B34">Delmos, 2020d</a>). Most inhabitants are born in Sweden (<a href="#B100">SCB, 2021b</a>)
As expected, we found that flood exposure within Halmstad Municipality was higher in areas near the coast and the Nissan River (<a href="#F5">Figures 4A</a>, <a href="#F4">B</a>)
the most populated neighborhoods are located in these risk areas and host major residential and commercial activities
Touristic beaches are subject to coastal inundation
Surrounding rural areas stand out as the least exposed to flooding
The aggregated social vulnerability index score is illustrated in <a href="#F5">Figure 5</a>, visualizing the spatial distribution of social vulnerability in Halmstad Municipality. The Nissan River runs through Halmstad, dividing the city into two areas with clear socioeconomic differences. Citizens residing in the eastern neighborhoods have less education, income, and employment opportunities in comparison to those living in their western counterparts (<a href="#B35">Delmos, 2020e</a>)
Social vulnerability index distribution in Halmstad Municipality
The results vary from &#x02212;1.7 standard deviations to 2.1 standard deviations
Eleven DeSO-areas are considered the most vulnerable as they have standard deviations &#x0003E; &#x0002B;1
Neighborhoods with high levels of vulnerability have 21,910 inhabitants
and account for 22% of the total population
we discuss the findings and research process
we juxtapose the findings from developing and applying a social vulnerability index to floods at a sub-municipal level in Sweden against earlier social vulnerability and justice research
We pay special attention to the exposure and vulnerability paradox
we proceed with discussing the methodological contributions of combining bottom-up stakeholder involvement and top-down statistical analysis
In Sweden, the social dimension of flood risk remains understudied despite that growing socioeconomic inequality is expected to spur increases in social vulnerability. We address this gap by developing and applying a local social vulnerability index. In line with previous research (<a href="#B93">Roncancio and Nardocci, 2016</a>; <a href="#B96">Sayers et al., 2018</a>; <a href="#B69">Kim and Bostwick, 2020</a>)
the application of the social vulnerability index shows an uneven spatial distribution of social vulnerability that reflects the overall pattern of societal inequality and development
It uncovers injustices faced by the vulnerable segments of the population
and acknowledges the importance of considering the social dimension for flood risk management and climate adaptation to be effective
House owners are alone bearing the financial burden in the case of a flood whereas renters or apartment dwellers can share the cost
evaluations are recommended to investigate the participatory process and its impact on procedural justice and whether any intangible co-benefits emerge
We also suggest that future research engages disadvantaged groups when constructing social vulnerability indices and impact chains to prompt procedural justice for the most vulnerable segments of the population
As noted in the section above, identifying social vulnerability indicators from the bottom-up produces different results compared to top-down approaches. It challenges previous top-down assessments building on academic literature, and highlights differences between countries and their vulnerability contexts. In line with previous research (<a href="#B57">Holand and Lujala, 2013</a>)
we argue that social vulnerability indices must be carefully modified and contextualized through close dialogue with local stakeholders before being replicated in a new context
we find that larger census areal units produce ecological fallacy i.e.
attributing group characteristics to an individual
It can spur discrimination and injustices if assuming that individuals have certain characteristics or behaviors due to the group they belong to
It can produce an unjust and inefficient distribution of resources for flood risk management
ultimately entrenching vulnerabilities and inequalities
using fine-grained spatial data also comes with challenges
We encountered limitations regarding the data input
The social vulnerability index builds on open access data to ensure procedural justice and transparency
as well as stimulate further refinement and application
data on specific indicators were missing for some DeSO-areas
Census data only include registered citizens
hence excluding potential vulnerable groups such as tourists
census data show where citizens have their residence not their actual location in the case of a disruptive event
The question also remains as to whether the suggested social vulnerability index can explain situations beyond Halmstad Municipality
Future research is needed to test the social vulnerability index across spatial scales and contribute to further refinement and validation
at the end supporting the implementation of socially-just flood risk management and climate adaptation
To develop the social vulnerability index we followed the impact chain method outlined in the Vulnerability Sourcebook (<a href="#B46">Fritzsche et al., 2014</a>). While the method identifies knowledge, technology, institutions, and the economy as drivers of vulnerability, it provides limited attention to disadvantaged and marginalized groups (<a href="#B46">Fritzsche et al., 2014</a>)
This study shows that it can support social vulnerability assessment processes by capturing the multidimensional
and situational factors that determine social vulnerability
and thus go beyond climatic and technical factors
The practical and standardized step-by-step approach thus appear to be applicable for various sectors and topics
and it can help stakeholders and researchers to disentangle social vulnerability and its complexities
The impact chain method can anchor the social vulnerability index in the local context
describe and visualize vulnerability pathways
and provide a sound knowledge base for disaster risk reduction and climate adaptation
we present a social vulnerability index for flooding in Sweden
We complement earlier research by assessing social vulnerability using a combined bottom-up and top-down approach with an emphasis on stakeholder involvement and local context
When mapping the social vulnerability index scores
we find pronounced injustices arising from the uneven distribution of social vulnerability across neighborhoods and groups
It highlights that flood risk assessments must go beyond climatic and technical parameters and consider people and their vulnerabilities
in order to design just risk reduction strategies and avoid reproducing inequalities
The social vulnerability index can support Swedish flood risk management policy and practice
and prompt socially just-informed decision-making processes
Social vulnerability indices can guide decisions and investments in disaster risk reduction by identifying and locating vulnerable populations
It can shed light on distributional injustices
and spur actions toward just and equitable flood risk management in which no one is left behind
The social vulnerability index can also support monitoring and evaluation
and provide conclusions on whether policies and actions are effective&#x02013;or not&#x02014;in addressing the vulnerability of different social groups
It can help to avoid producing or reproducing injustices
and prevent other maladaptive outcomes such as gentrification and entrenched inequalities
Our findings add to the body of research investigating social vulnerability
We make a significant contribution to Swedish flood risk management
by shedding light on the social dimension that constitutes flood risk
this can strengthen the justice and disaster risk reduction nexus and improve overall flood risk management
The raw data supporting the conclusions of this article will be made available by the authors
&#x000C5;G and KB: writing&#x02014;review and editing
All authors contributed to the article and approved the submitted version
This work derives from the projects HydroHazards
HydroHazards was funded by the Swedish Civil Contingencies Agency (MSB) and FORMAS
CrisAct was funded by the Swedish Research Council&#x02014;VR project 2021-06309
UNCHAIN: Unpacking Climate Impact Chains was funded through the EU funding mechanisms Joint Programming Initiative (JPI) and Assessment of Cross (X)-sectoral climate impacts and pathways for Sustainable transformation (AXIS)
All UNCHAIN partners are granted financial support through their national funding agency
of which the Stockholm Environment Institute received support from FORMAS (SE) (2018-02737) and the EU (Grant No
We thank Hanna Billmayer from Halmstad Municipality for her support and input
We thank Aline Regnell for her support in collecting data
We are grateful to all informants who participated in the study
We also thank the three reviewers for their valuable feedback
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations
Any product that may be evaluated in this article
or claim that may be made by its manufacturer
is not guaranteed or endorsed by the publisher
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Received: 07 September 2022; Accepted: 24 April 2023; Published: 18 May 2023
Copyright &#x000A9; 2023 Englund, Vieira Passos, Andr&#x000E9;, Gerger Swartling, Segnestam and Barquet. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
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a column of stockquotations rubbed out and written in by a Western Union boy on a blackboard
a public-library full of old newspapers and dogeared historybooks with protests scrawled on the margins in pencil
is the world’s greatest rivervalley fringed with mountains and hills
is a set of bigmouthed officials with too many bankaccounts
is a lot of men buried in their uniforms in Arlington Cemetery
is the letters at the end of an address when you are away from home
In the “Newsreel” sections, text from actual newsreels flows together with snippets from newspaper articles, lines from popular songs, and excerpts from radio broadcasts. These bursts of information seem random but were carefully selected for maximum effect. Hurtling themselves at the reader, they are too brief to be fully explicable, but too portentous to be ignored:
It is difficult to realize the colossal scale upon which Europe will have to borrow in order to make good the destruction of warBAGS 28 HUNS SINGLEHANDEDPeace Talk Beginning To Have Its Effect On Southern Iron MarketLOCAL BOY CAPTURES OFFICERONE THIRD WAR ALLOTMENTS FRAUDULENTThere are smiles that make us happyThere are smiles that make us blue . . . .
In the “Camera Eye” sections, we move from the media to memory. Dos Passos grew up largely in European hotel rooms, as the lonely bastard son of a wealthy Portuguese-American lawyer. (At the time, this status carried real social stigma.) He then attended élite institutions—Choate, Harvard—before volunteering as an ambulance driver in the First World War. The “Camera Eye” interludes make the fleeting bits of information we encounter in the media  (“BAGS 28 HUNS SINGLEHANDED”) visceral and real:
  remembering the grey crooked fingers the thick drip of blood off the canvas the bubbling when the lungcases try to breathe the muddy scraps of flesh you put in the ambulance alive and haul out dead  three of us sit in the dry cement fountain of the little garden with the pink walls in RécicourtNo  there must be some way  they taught us Land of the Freeconscience  Give me liberty or give me  Well they give us death
Dos Passos was often an early reader of manuscripts by Hemingway, Fitzgerald, and other writers; they’ve since gone on to be more famous than he is. Perhaps his peers trusted him because he perceived, with special clarity, the conflicting sociopolitical forces that were shaping modern life and giving it its texture—forces that are still at work in our digitized Gilded Age.
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<a href="#commentDiv" aria-label="View article comments" title="View article comments" class="dist__Box-sc-1fnzlkn-0 edNRfi"></a>MIAMI BEACH, Fla. – Local 10 News exclusively obtained video Thursday of the moments when a transgender woman was <a href="https://www.local10.com/news/local/2024/04/25/man-accused-of-brutally-murdering-trans-woman-in-miami-beach-to-remain-jailed/" target="_blank">beaten to death with a metal pipe</a> last month
a transgender woman who was experiencing homelessness at the time
was sleeping outside the Miami City Ballet building when she was struck repeatedly with a metal pipe on April 23
Miami Beach police said Dos Passos was pronounced dead at the scene at 6:56 a.m
said he had known her since she was 10 years old and described her as “wonderful.” He said she had been struggling with mental health issues for the last five to 10 years
sitting on a bench before walking up to Dos Passos and striking her 11 times with what appeared to be a metal pipe before throwing it in a nearby trash can and walking away
The video also showed Gibert shaking Dos Passos’ head just moments after the attack
Jail records show Gibert faces a charge of second-degree murder
He is being held without bond at the Miami-Dade County Pre-Trial Detention Center
Gibert has a long criminal history in Miami-Dade County
he was out on probation after pleading guilty to attempted armed robbery and aggravated battery
A close-out memo provided by the Miami-Dade State Attorney’s Office details the crime
The state says Gibert approached a man in May of last year while carrying something sharp and demanded he get off a scooter
Gibert allegedly threw rocks at the victim
The state cites multiple reasons for why the case collapsed
“the civilian witness failed to appear for three separate depositions” and that
“due to statements made by the victim during deposition concerning identification and his testimony of the incident in conjunction with the evidence collected by law enforcement…”
Judge Andrea Wolfson ruled he should get credit for the year he spent behind bars
Eight days after the deal went into effect
A vigil was held for Dos Passos at Pridelines in Miami Beach on April 25
“We had no idea she connected with you guys
It gave me so much peace that she had a community,” Ana Van Gilst
told those who were gathered at the vigil last month
“You don’t expect something...It’s like things you see in the movies
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Hannah Yechivi joined the Local 10 News team in May of 2024
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Does anybody at MSNBC even listen to their own shows
We just went through a brutal election season and MSNBC
made the case ( endlessly) that nothing less than DEMOCRACY was on the line.&nbsp;
they managed to miss the actual temperature of the electorate
That’s a different subject for another day
You might think that the imminent end of democracy and constitutional governance they anticipated and forecasted would be the main
perhaps the ONLY topic they’d be interested in
as if we’re just in another chaotic political period
Lawrence O’Donnell actually said that perhaps Mitch McConnell is the guy who will turn back Trump’s worse impulses legislatively
O’Donnell ( who I will refer to henceforth here as “OD”) also said that there appear to be Republican senators who are positioned to thwart Trump’s agenda
trying to “poli-sci” the coming Trump term into politics as usual
The slow motion coup has hit warp speed and OD is strolling down memory lane
He’s serving as Trump and if you don’t know that now
MSNBC has hit rock-bottom if they actually think we didn’t hear them the last year and a half
Maybe they should be required to listen to their broadcasts from that period
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the 42nd John Dos Passos Prize was awarded to novelist and short story writer Patricia Engel (Vida; The Veins of the Ocean; Infinite Country; The Faraway World) by Longwood University
The Dos Passos Prize is the oldest literary award given by a Virginia college or university
and every year honors an “American writer who experiments with form
explores a range of voices and deserves more recognition.”
Patricia Engel illuminates those dimensions of the human experience that often go unnoticed and unsung,” said Dr
associate professor of early American literature in the English department at Longwood and chair of the selection jury
she imagines America on a scale broader than its national boundaries.”
“Patricia Engel’s fiction plumbs the depths of human consciousness even as it renders visible the complex ramifications of societal realities in the U.S. and across the globe,” said Caro De Robertis, <a href="https://lithub.com/carolina-de-robertis-has-won-the-2022-john-dos-passos-prize/" rel="noopener" target="_blank">last year&#8217;s winner</a>
“The aesthetic scope of her work is vast—from stories to novels
intimate portraits to sweeping epics—yet they are all powered by breathtaking prose
extraordinary vision and an almost preternatural compassion
Her voice is essential to the future of literature.”
Engel will receive an honorarium and medal
and will visit Longwood’s campus for a public event on Wednesday
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On Wednesday, the <a href="http://www.longwood.edu/news/2023/carolina-de-robertis-named-41st-john-dos-passos/" target="_blank" rel="noopener" class="external">41st John Dos Passos Prize</a> was awarded to Uruguayan American writer Carolina De Robertis (The President and the Frog; Cantoras; The Gods of Tango) by Longwood University
and every year honors an &#8220;American writer who experiments with form
explores a range of voices and deserves more recognition.&#8221;
“In clear, precise prose, De Robertis makes audible the beating hearts of people navigating a terrifying world,” said Dos Passos Prize committee chair Brandon Haffner <a href="http://www.longwood.edu/news/2023/carolina-de-robertis-named-41st-john-dos-passos/" target="_blank" rel="noopener" class="external">said in a statement</a>
“But De Robertis’ stories aren’t so much interested in exploiting that terror for narrative suspense as they are in interrogating what compassion and resilience look like in the face of confounding policies and state violence.”
“There’s a distillation of narrative and language there that I find particularly impressive,” said Monique Truong
who won the 2021 prize and served on the jury this year
“The prose—so spare and yet emotionally engaging—brings us into a narrative world that verges on fable and myth and yet is damningly just about us humans and our capacity for grotesque cruelty on the one hand and our boundless will to survive on the other.”
De Robertis, who was chosen from <a href="https://lithub.com/are-these-americas-most-talented-but-underappreciated-writers/" target="_blank" rel="noopener">a shortlist of four</a>
will receive an honorarium and will read from their work on Longwood’s campus in April
he served as an ambulance driver) and communist revolution
to which he was passionately attached as a young man
was to become a novelist with the instincts of a journalist
and a fictional reporter with the insight of a storyteller
wrote that Dos Passos was “the first American novelist to make the people of our generation talk as they actually did”
is a massive (1,300-page) trilogy that recounts the evolution of American society during the first three decades of the 20th century
the thrills and glamour of the jazz age had become soured by the crash
was still a committed communist who wanted to depict the gulf between rich and poor in America
as well as to explore the lives of ordinary people in the aftermath of the great war
which is partly set in the Paris of the 1920s
develops the narrative techniques of the first volume
devices inspired by modernist innovation and emerging mass communications
like his innovative contemporary EE Cummings
Dos Passos also painted his own book jackets
Some sections (Camera Eye) are stream-of-consciousness evocations of mood and place
and intercut with biographical essays on contemporary American figures
USA is as jerky and authentic as an old newsreel
mainstream attempt to explore aspects of the American century from the point of view of an Iowa farming family
Smiley’s book is an unconscious tribute to John Dos Passos
Dos Passos and Hemingway fell out over their differing responses to this
the author of For Whom the Bell Tolls wrote to his friend F Scott Fitzgerald that Dos Passos was a second-rate writer with no ear
Houghton Mifflin published USA in a deluxe edition in three volumes with colour endpapers and illustrations by Reginald Marsh
(I have a cheap paperback version of this in which the majesty of Dos Passos’s intentions is still evident.) The first printing of the illustrated edition was fewer than 1,000 copies
but in due course the mass-market edition sold in thousands
Dos Passos’s masterpiece found its permanent home
Manhattan Transfer (1925); The 42nd Parallel (1930); The Big Money (1936)
This is the archive of The Observer up until 21/04/2025
The Observer is now owned and operated by Tortoise Media
<a href="/articles/s41586-023-06621-4/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics details</a>
An <a href="https://doi.org/10.1038/s41586-023-07002-7" class="relation-link" data-track="click" data-track-action="view linked article" data-track-label="link">Author Correction</a> to this article was published on 02 January 2024
This article has been <a href="#change-history">updated</a>
Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence
requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol
Cytosolic mtDNA in turn activates the cGAS–STING pathway
We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice
Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP
We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan
These cells therefore represent promising therapeutic targets to prevent age-related disorders
we found that inhibition of miMOMP in vivo decreases inflammatory markers and improves multiple healthspan parameters in aged mice
Our data support the concept that apoptosis and senescence are regulated by similar mitochondrial-dependent mechanisms and miMOMP is a major contributor to senescence and the SASP
Our results suggest that targeting miMOMP-induced inflammation may be a therapeutic route to improve healthspan
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM4">Source data</a>
Statistical significance was assessed using one-way ANOVA followed by Tukey’s multiple-comparison test (b) and two-sided Student’s unpaired t-tests (b
Individual data points are from biological replicates
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM5">Source data</a>
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM6">Source data</a>
These results indicate that miMOMP-dependent caspase activation does not affect SASP activation under these conditions
Schematic of the experimental procedure (top)
representative immunohistochemical image showing successful deletion of Bax in the liver after AAV injection
Quantification of mRNA levels of the indicated SASP genes in the livers of Sham- and 4-Gy-irradiated Baxfl/flBak−/− and Bak−/−Bax−/− mice
n = 5 (sham-IR Baxfl/flBak−/− and 4Gy-IR Bak−/−Bax−/−) and n = 4 (sham-IR Bak−/−Bax−/− and 4-Gy-IR Baxfl/flBak−/−) mice
Values are expressed as the fold change compared with sham-irradiated Baxfl/flBak−/− mice
Quantification of mRNA levels of Bax in the livers of aged Baxfl/flBak−/− mice after tail-vein injection of AAV-Cre virus
n = 5 (Baxfl/flBak−/−) and n = 4 (Bak−/−Bax−/−) mice
Quantification of mRNA expression of the indicated SASP genes (e) and of Cdkn2a and Cdkn1a (f) in young (y; n = 5) and old (n = 5) wild-type mice and aged Baxfl/flBak−/− mice (n = 5) after AAV-Cre virus injection (n = 4)
Representative immunofluorescence image of CD45 (red) and CD68 (green) in the livers of aged Baxfl/flBak−/− (n = 5) and Bax−/−Bak−/− mice (n = 4)
The correlation coefficient between expression levels of Bax and different SASP factors in the livers of aged Baxfl/flBak−/− and Bax−/−Bak−/− mice
Statistical significance was assessed using two-way ANOVA followed by Tukey’s multiple-comparison test (b
two-sided Student’s unpaired t-tests (d and h) and Pearson’s correlation coefficient (i); *P &lt; 0.05
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM7">Source data</a>
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM8">Source data</a>
Mean cytosolic DNA foci in human fibroblasts treated with BAI1
n = 14 (senescent) and n = 17 (senescent + BAI1) cells analysed
representative of 2 independent experiments
The mRNA levels of IL6 and IL8 in proliferating and senescent (IR) human fibroblasts with or without BAI1 treatment
rotarod latency in vehicle-treated (n = 13) and BAI1-treated (n = 17) aged mice
The average time spent on the pole (d) and forelimb grip strength (the number of trials required to remain hanging for a total of 90 s; percentage success is shown in green) (e) in vehicle-treated (n = 7) or BAI1-treated (n = 8) mice
2 and 4 months after treatment with vehicle (n = 14) or BAI1 (n = 15)
The linear regression of the mean frailty index at each timepoint is shown
Representative μCT images of bone microarchitecture at the lumbar spine and femur of vehicle- and BAI1-treated mice
Quantification of μCT-derived trabecular number (Tb.N; per mm) (h) and trabecular separation (Tb.Sp; mm) (i) and bone volume fraction (BV/TV; percentage) (j)
The mRNA expression of SASP genes was assessed using qPCR with reverse transcription (RT–qPCR) in the femur of vehicle- or BAI1-treated mice
Values are the fold change (FC) compared with the vehicle
n = 6 (vehicle) and n = 10 (BAI1-treated) mice
Single-nucleus suspensions from vehicle-treated and BAI1-treated aged mice were prepared from whole brains for RNA-seq analysis
The t-distributed stochastic neighbour embedding (t-SNE) plots indicate the separation of different cell populations
BAI1 reduced the fraction of p16INK4a-expressing cells across cell populations
BAI1 significantly reduced the expression of the SenMayo gene set in oligodendrocytes and microglia
Two vehicle-treated and two BAI1-treated mice were pooled for analysis
Statistical significance was assessed using one-way ANOVA followed by Tukey’s multiple-comparison test (a and b)
h–k and n) and two-way ANOVA followed by Sidak’s multiple-comparison test (d)
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM9">Source data</a>
These findings highlight the potential of targeting miMOMP as a therapeutic strategy for mitigating inflammation and cellular senescence in the ageing brain
we found that caspase activation due to miMOMP
is insufficient to dampen cGAS–STING signalling and activation of the SASP in senescent cells
We demonstrate that mtDNA is present in the cytosol of senescent cells and can also engage this pathway
We found that pharmacological inhibition of miMOMP (through BAX inhibition) inhibits the SASP and improves various parameters of healthspan
Although inhibitors have potential off-target effects
we found that genetic inhibition of miMOMP also inhibits the SASP in vivo
MOMP is often essential for apoptotic cell death
a terminal cell fate that is considered to be independent from cellular senescence and immunologically silent
Our findings indicate that miMOMP occurs during cellular senescence and can drive the SASP through the release of mtDNA into the cytosol
we show that inhibition of miMOMP may be a therapeutic target to counteract age-associated sterile inflammation and improve healthspan
Human embryonic lung MRC5 fibroblasts (ATCC) and IMR90 fibroblasts (ATCC) were grown in Dulbecco’s modified Eagle’s medium (Sigma-Aldrich
D5796) supplemented with 10% heat-inactivated fetal bovine serum (FBS)
100 μg ml−1 streptomycin and 2 mM l-glutamine and maintained at 37 °C under 5% CO2
MRC5 fibroblasts were cultured in atmospheric oxygen conditions and IMR90 fibroblasts were cultured under low-oxygen (3%) conditions
HEK293T cells (ATCC) were used for lentiviral transduction and were cultured in DMEM as described above and further supplemented with 1% non-essential amino acids (Sigma-Aldrich
500 μg ml–1 G418 antibiotic (Sigma-Aldrich
A1720) and 1 mM sodium pyruvate (Sigma-Aldrich
Parental and Rho0 osteosarcoma 143B cells were grown in DMEM as described above with further supplementation using 5% non-essential amino acids and 25 μg ml−1 of uridine
MAFs were isolated from ear clippings and cultured in DMEM/F12 (Thermo Fisher Scientific
12634010) supplemented with 10% heat-inactivated FBS
P4333) and 2 mM l-glutamine (Sigma-Aldrich
and maintained at 37 °C under low-oxygen conditions (3% oxygen) with 5% CO2
Human osteosarcoma U2OS cells (ATCC) were grown in DMEM with 10% FBS
1 mM sodium pyruvate and 5 mM 2-β-mercaptoethanol
Cells were maintained at 37 °C with 5% CO2
Stress-induced senescence was achieved by exposing cells to X-ray irradiation at 10 Gy (MAFs) or 20 Gy (human fibroblasts)
Replicative senescence was achieved by serially passaging cells until they reached their replicative potential and performed less than 0.5 population doublings for at least 4 weeks
Senescence was confirmed by the presence of p16 and p21
and the absence of proliferation markers Ki-67 or EdU incorporation
OIS was achieved in ER-RAS-IMR90 fibroblasts by treating cells with 100 nM 4-hydroxy-tamoxifen (4-OHT)
4-OHT was maintained in the culture medium until the cells were collected
proliferating cells were treated with 2.5 μM ABT-737 (Abcam
cells were irradiated with 20 Gy X-ray irradiation and treated with 1 μM cyclosporin A (Sigma-Aldrich
MRC5 fibroblasts were irradiated with 20 Gy X-ray irradiation and treated with BAX inhibitor (BAI1) (Adooq Biosciences
Cyclosporin A and BAI1 were added straight after irradiation and maintained in the cell culture medium for 10 days (refreshed every 48–72 h)
cells were treated with ABT-263 at the indicated concentrations for 24 h before assessment of cytotoxicity
cells were treated with either 250 nM of doxorubicin or 50 µM etoposide for 24 h
Cells were maintained in culture and collected at days 10 and 8 after treatment
X-ray-irradiated cells were treated with 10 µM eltrombopag (provided by E
Gavathiotis) for 10 days (treatment was added immediately after irradiation)
Cells were collected at 10 days after irradiation for analysis
cells were treated with 12.5 µM CCCP at days 2 and 3 after irradiation
and the cells were maintained in culture until day 10 after irradiation
Cells were collected at day 10 for analysis
U2OS cells were pre-incubated for 1–2 h with 2.5 μM BAI1 before apoptosis was induced
cells were treated with 10 μM ABT-737 (Abcam
MRC5 fibroblasts were first transfected with the pFU-GEV16 construct (expression vector that contains the transcriptional activator)
Cells were selected with hygromycin and were then infected with lentivirus containing the UL12.5 sequence (tamoxifen inducible) followed by puromycin selection
cells were treated with 100 nM 4-hydroxytamoxifen for 48 h
Mitochondrial DNA was assessed by qPCR using the Absolute Human Mitochondrial DNA Copy Number Quantification qPCR Kit (ScienCell
8948) according to the manufacturer’s instructions
All of the cell lines used have been regularly tested for mycoplasma contamination
The cell lines have not been authenticated
proliferating or irradiated Parkin-expressing IMR90 fibroblasts were treated with 12.5 μM CCCP (Sigma-Aldrich
C2759) (3 days after irradiation) for 48 h (CCCP was refreshed every 24 h)
Mitochondria-depleted cells were then transfected with isolated mitochondrial DNA (as described below) at 7 days after irradiation and collected at 10 days after irradiation
Parkin-expressing IMR90 fibroblasts were transfected with 15 μg of isolated mitochondrial DNA
7 days after irradiation using DharmaFECT kb DNA transfection reagent (Horizon
according to the manufacturer’s instructions
a total of 7 × 106 cells was collected and centrifuged at 900g for 5 min
cells were resuspended in PBS and then divided into two 1.5 ml Eppendorf tubes
After another centrifugation at 600g for 5 min
the pellet from one tube was frozen and considered as the whole-cell fraction
The pellet from the other tube was incubated in 500 μl of buffer 1 (150 mM NaCl
The supernatant was next centrifuged twice at 150g at 4 °C and once at 17,000g for 10 min
Extraction of DNA from the whole-cell fraction was performed using the DNeasy Blood &amp; Tissue Kit (Qiagen
69504) according to the manufacturer’s instructions
The cytosolic fraction was cleaned up using the Qiaquick Nucleotide Removal Kit (Qiagen
28115) according to manufacturer’s instructions and the DNA concentration was measured using the Nanodrop ND-1000 Spectrophotometer
cells were collected by scraping the flask with 5 ml of ice-cold PBS
Cells were centrifuged at 800g for 5 min at 4 °C and resuspended in mitochondrial isolation solution (MIS) (20 mM HEPES-KOH pH 7
The samples were transferred to a glass homogenizer and cells were broken open using 60 strokes
The homogenate was centrifuged at 800g for 5 min at 4 °C
The supernatant was further centrifuged at 800g for 5 min at 4 °C
An aliquot of the supernatant was collected and stored as the whole-cell extract
The remaining was centrifuged at 16,100g for 10 min at 4 °C
The supernatant was collected as the cytosolic fraction
The pellet containing mitochondria was resuspended in 1 ml of MIS and centrifuged again at 16,100g for 10 min at 4 °C
and the resulting pellet was resuspended in 100 μl of MIS
the mitochondrial pellet was centrifuged at 16,100g for 10 min at 4 °C and the pellet was resuspended in 200 μl PBS
DNA extraction was performed using the DNeasy Blood &amp; Tissue Kit (Qiagen
Cellular oxygen consumption rate was measured using Agilent Seahorse XFe96 Analyzer
The cell culture medium was replaced with unbuffered basic medium
The following compounds were added to test mitochondrial activity: 0.5 μM oligomycin
The resulting oxygen consumption rate values were normalized to cell numbers quantified after the assay using an automated cell counter
The following plasmids were used: LentiCRISPR v2 hBAK (Addgene
Lentiviral pLKO.1 Empty Vector Control (Horizon
The following sequences were used to create CRISPR–Cas9-mediated deletion of STING
APAF1 and CGAS: hTMEM173_1 5′-GCAAGCATCCAAGTGAAGGG-3′; hTMEM173_2 5′-CGGGCCGACCGCATTTGGGA-3′; APAF1 5′-ACAGCCTGCCATTCCATGTA-3′; CGAS 5′-AAAGTAATATGCACGAGTGT-3′
HEK293FT cells were transfected with the plasmids above together with the packaging and envelope plasmids VSVG and Gag-Pol (Sigma-Aldrich) using Lipofectamine 3000 (Invitrogen
L3000015) according to the manufacturer’s instructions
the supernatant from the transfected HEK293FT cells containing viral particles was filtered using a 0.45 μm pore PVDF filter
mixed with 10 μg ml−1 polybrene and used to infect the cells of interest
cells were selected for successful CRISPR–Cas9 deletion using the following antibiotics: 1 μg ml−1 puromycin (for BAX
BAK and cGAS) or blasticidin 10 μg ml−1 (for APAF1 and STING)
Detection of cytokines and chemokines in the cell culture supernatant and mouse plasma was performed by Eve Technologies
The following assays were used: Human Cytokine/Chemokine 41-Plex Discovery Assay (HD41) and Mouse Cytokine/Chemokine 31-Ples Discovery Assay Array (MD31)
Confirmatory ELISAs were performed using the following kits: Human IL-6 DuoSet ELISA (R&amp;D Systems
DY208) and Human CXCL10/IP-10 DuoSet ELISA
The optical density at 450 nm was determined using the Multiskan FC microplate reader (Thermo Fisher Scientific) and corrected by subtracting the readings at 540 nm
Cells grown on coverslips were fixed in 0.2% glutaraldehyde in 2% PFA in PBS for 5 min
Sen-β-Gal staining solution (150 mM sodium chloride
1 mg ml−1 5-bromo-4-chloro-3-inolyl-β-d-galactosidase (X-gal)
5 mM potassium hexacyanoferrate(ii) trihydrate
5 mM potassium hexacyanoferrate(iii) trihydrate) (pH 6.0) was applied and incubated overnight at 37 °C in the dark overnight
Cells were washed in PBS three times and were then mounted onto glass microscope slides using ProLong Gold Antifade Mountant with DAPI (Invitrogen)
The signal intensity of protein bands was analysed using ImageJ
Cells grown in 150 cm2 flasks were trypsinized and pooled to obtain sufficient material for the assay
Cell pellets were then lysed using CHAPS lysis buffer (1% (w/v) CHAPS
1 mM sodium vanadate and 20 nM microcystin) for 30 min at 4 °C
The samples were diluted to contain 10 mg ml−1 of protein and 200 μl was injected onto a Superdex S200 size-exclusion column
Protein precipitation using trichloroacetic acid (TCA) was then performed
the samples were incubated with one-tenth sample volume of 10% Triton X-100 and one-fifth sample volume of 100% ice-cold TCA for 20 min on ice
The samples were then centrifuged for 5 min at 800g at 4 °C
the supernatant was discarded and the pellet was washed once with 1 ml ice-cold 10% TCA and twice with 1 ml acetone at −20 °C
The pellets were left to air dry at room temperature and were then solubilized in sample buffer (4× Laemmli Sample Buffer
1610747) with 1% 2-mercaptoethanol (Bio-Rad
Protein was separated using 4–20% gradient acrylamide Tris-Glycine gel generated using Gradient Former (Bio-Rad
Protein was transferred to BioTrace NT nitrocellulose membrane (Pall Corporation
66485) and immunoblotted according to the method described above
Sequencing libraries were made from poly(A) RNA
and sequenced using either the Illumina GAIIX or a NextSeq 500 sequencer
RNA-seq paired-end reads were assessed for quality using the FastQC algorithm
then aligned to the human genome using the splice-aware aligner STAR with a two-pass alignment pipeline
Reference splice junctions were provided by a reference transcriptome from the Gencode GRCh38 (hg38) build
BigWig files were generated using DeepTools
Raw read counts per gene were calculated using htseq-count
The read count matrix was then used for differential expression analysis with the linear modelling tool DESeq2
Significantly changing expression was defined as a false-discovery-rate-corrected P ≤ 0.05
Fragments per kilobase of transcript per million mapped reads (FPKM) values were generated using Cufflinks
Gene Ontology analysis was performed using Gene Set enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software
All of the animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Mayo Clinic
Male and female aged wild-type C57BL/6 mice (aged 18–20 months) were acquired from the National Institute on Aging (NIA) and were maintained in a pathogen-free facility under a 12 h–12 h light–dark cycle at 23–24 °C with free access to regular chow and water
The mice were housed in same-sex cages in groups of 3–5
The animals were randomly assigned into the vehicle or treatment group
Mice were injected intraperitoneally with 10 mg per kg of BAI1 (Tocris Bioscience
at which point the animals were euthanized and tissues were collected for analysis
BAI1 injections were administered three times weekly until death
Frailty assessment was conducted every 2 months because these measurements are non-invasive
The mice were euthanized and considered to be dead if they met humane end points
Survival was assessed by right-censored Kaplan–Meier curve analysis using the log-rank test
Bak−/−;Baxfl/fl mice (mixed background; male and female) were donated by O
Mice were monitored daily and kept in conventional animal facilities
Experiments conducted with Bak−/−;Baxfl/fl mice were performed under UK Home Office license and approved by the University of Glasgow Animal Welfare and Ethical Review Board
AAV-Cre virus in 100 μl PBS (AAV8.TBG.PI.Cre.rBG
AV-8-PV1091) was delivered by tail-vein injection (2 × 1011 plaque-forming units (PFU) per mouse) in 8-week-old mice
and the livers were collected in 10% neutral-buffered formalin
Aged (17–20 months) Baxfl/flBak−/− (mixed background; male and female) were administered either AAV9-CAG-eGFP or AAV9-CAG-iCre/eGFP virus (in 100 µl PBS; Vector BioLabs) through tail injection (2 × 1012 PFU per mouse)
The mice were euthanized 3 weeks after injection
The animals were randomly assigned numbers at weaning
the genotype or treatment group was not linked to the numbers until data analysis after completion of all studies
Group size estimates were based on power analyses and previous experiences
Investigators were blinded to allocation during experiments and outcome assessments
and data were collected and analysed in a blinded manner
Assessment of maximal walking speed and latency was performed using an accelerating rotarod system (Ugo Basile
Mice were trained on the rotarod for 3 consecutive days before the test day
Training consisted of mice remaining on a rotarod at speeds of 4
mice were placed onto the rotating cylinder
which increased in speed from 4 to 40 rpm over a 200 s interval
The speed and latency at which a mouse fell off the cylinder were recorded
The results were the average of three trials
Assessment of neuromuscular coordination was performed using the tightrope test<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Correia-Melo, C. et al. Rapamycin improves healthspan but not inflammaging in nfκb1−/− mice. Aging Cell 18, e12882 (2019)." href="/articles/s41586-023-06621-4#ref-CR44" id="ref-link-section-d372269590e3785">44</a>
which was 1.5 cm in diameter and situated 60 cm off the ground
The time that the mice were able to spend on top of the bar was recorded
A trial was deemed to be successful if a mouse could remain on top of the bar for 60 s without falling
Each mouse was given five trials with a 30 s rest between trials
Assessment of forelimb grip strength was performed by allowing the mice to grip a suspended wire coat hanger
which was 2 mm in diameter and 30 cm in length
The time that a mouse was able to hang from the wire following grip was recorded
and each mouse was given 10 attempts (with a 20 s rest in between) up to a total of 90 s
Success was defined as being able to hang for a total sum of 90 s
The trial was defined as failure if the animal fell from the wire
Frailty was assessed using a 30-parameter index based on a previous study<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Whitehead, J. C. et al. A clinical frailty index in aging mice: comparisons with frailty index data in humans. J. Gerontol A 69, 621–632 (2014)." href="/articles/s41586-023-06621-4#ref-CR33" id="ref-link-section-d372269590e3805">33</a>
and the surface body temperature was measured using an infrared temperature probe
where a score of 1 was equivalent to clasping with one limb whereas a score of 4 was given if the animal showed clasping with all four limbs
All bone imaging and analysis was performed in a blinded manner
Quantitative ex vivo analyses of bone microarchitecture of the lumbar vertebrae (L5) and femur (proximal metaphysis/mid-shaft diaphysis) were performed using a µCT system (Skyscan 1276 Scanner
0.4° rotation steps for 360° and 4 frames average imaging with a 0.25 mm A1 filter
Skyscan NRecon software was used to reconstruct scans and for post-alignment and beam hardening corrections
µCT parameters were derived using the manufacturer’s protocols for Bruker CtAN software
which permits assessments of trabecular and cortical bone parameters
The trabecular bone volume fraction (BV/TV; percentage) was assessed at the lumbar spine (200 slices) and proximal metaphysis (100 slices) of the femur
at the proximal metaphysis and mid-diaphysis (50 slices) of the femur
an estimate of bone torsional strength (that is
cells were fixed in 0.02% glutaraldehyde in 4% paraformaldehyde for 10 min
washed in PBS and permeabilized in 0.5% Triton X-100 in PBS for 10 min
Cells were blocked in 5% normal goat serum (NGS) for 1 h
Incubation with primary and secondary antibodies was performed as described above
Labeling of mitochondria using CellLight Mitochondria-RFP BacMam 2.0 (Thermo Fisher
C10601) was performed following manufacturer’s instructions
Formalin-fixed paraffin-embedded tissue sections were deparaffinized in 100% Histoclear
hydrated through a graded ethanol series of 100
and washed twice for 5 min in distilled water
Antigen retrieval was performed by placing the sections in 0.01 M citrate buffer (pH 6.0) and heating it until boiling for 10 min
The sections were allowed to cool to room temperature and then washed in distilled water for 5 min
Blocking was then performed using normal goat serum (1:60) in BSA/PBS for 30 min followed by overnight incubation with rabbit monoclonal anti-γH2AX antibodies (1:400
the tissues were incubated with a goat anti-rabbit biotinylated secondary antibody (1:200
PK-6101; Vector Labs) for 30 min at room temperature
The sections were then washed three times in PBS and incubated with fluorescein avidin DCS (1:500
A-2011; Vector Labs) for 30 min at room temperature
The tissues were then washed three times in PBS and incubated in 4% paraformaldehyde in PBS for 20 min for cross-linking
the sections were dehydrated in graded cold ethanol solutions (70
100%) for 3 min each and were then allowed to air dry
10 μl of PNA hybridization mix (70% deionized formamide (Sigma-Aldrich)
5% blocking reagent (Roche) containing 2.5 μg ml–1 Cy-3-labelled telomere-specific (CCCTAA) peptide nucleic acid probe (PANAGENE)) was added to sections and denaturation was allowed to occur for 10 min at 80 °C
The sections were then incubated in PNA hybridization mix for 2 h at room temperature in the dark to allow hybridization to occur
Tissues were washed in 70% formamide in 2× SSC for 10 min
followed by one wash in 2× SSC for 10 minutes and a PBS wash for 10 min
Tissues were mounted using ProLong Gold Antifade Mountant with DAPI (Invitrogen) and imaged using in-depth z stacking (a minimum of 40 optical slices with a ×63 objective)
Cells were fixed in 0.1% glutaraldehyde and 4% paraformaldehyde in 0.1 mol l−1 phosphate buffer for 2 h and were then collected and centrifuged at 900g for 5 min
cells were incubated with 2.3 mol l−1 sucrose in 0.1 mol l−1 phosphate buffer overnight and then frozen in liquid nitrogen
Thin cryosections (60 nm) were cut using the Leica cryo-microtome
The sections were incubated with primary antibodies (1:20) at 4 °C overnight
The sections were then incubated with a 10 nm anti-mouse IgG gold secondary antibody (Sigma-Aldrich
the sections were fixed in 1% glutaraldehyde and embedded in 2% methyl cellulose solution containing 0.3% uranyl acetate
The samples were imaged using the Jeol 1200 electron microscope (Mayo Clinic Core Microscopy Facility) operating at 60 to 80 kV
Cytotoxicity was assessed using the lactate dehydrogenase assay (Abcam
ab65939) according to the manufacturer’s instructions
cells were grown in 24-well plates and treated as indicated
On the day on which the assay was performed
50 µl of cell culture medium was mixed with 50 µl of LDH reaction mix and pipetted into a 96-well plate
The absorbance was measured using a plate reader with a 450 nm filter
U2OS cells were seeded at approximately 20,000 cells per well in a 24-well plate
Cell death assays were performed using Incucyte S3 software (Sartorius) and Sytox Green at 30 nM as cell death readout
which is taken up into cells after cell death
Cell death was induced using ABT-737 and S63845 at 10 μM and 2 μM
Images (four images per well) were taken every hour for 24 h at ×10 magnification
Analysis was performed using Incucyte S3 2022 software with Sytox count per well normalized to cell confluency
Proliferating pLenti or Bax−/−Bak−/− cells were transfected with herring testes DNA (HT-DNA; 1 µg ml−1; Sigma-Aldrich
D6898) using Lipofectamine 3000 Reagent (Thermo Fisher Scientific
cells were treated with either DMSO or BAI-1 (2.5 µM) 24 h before transfection
Cells were collected for analysis 20 h after transfection with HT-DNA
Cellular senescence was induced with 200 nM doxorubicin for 24 h and developed for 9 days
A small fraction of proliferative and senescent cells was pelleted and kept for MS analysis (total cell control samples)
The remaining cells were resuspended in mitochondria isolation buffer (MIB: 20 mM HEPES pH 7.6
1 mM EDTA) and homogenized with a Dounce homogenizer followed by centrifugation at 850g for 5 min
Crude mitochondria were pelleted at 10,000g for 5 min at 4 °C and washed once more
A total of 50 µg of mitochondria was kept for further MS analysis (crude mitochondria control samples)
A total of 400 µg of mitochondria was resuspended in ice-cold co-IP buffer (20 mM HEPES pH 7.6
lysed on ice for 30 min and cleared from insoluble material at 10,000g
A total of 1 µg of anti-BAX6A7 antibody (NBP1-28566
Novus Biologicals) was immobilized on Protein G-coupled Dynabeads (Invitrogen)
The beads were washed twice with co-IP buffer and combined with cleared mitochondrial extracts
Activated BAX complexes were immunoprecipitated overnight at 4 °C with gentle rocking
The beads were washed three times with ice-cold co-IP buffer and twice with CHAPS-free co-IP buffer
The beads were resuspended in the 2 M urea
50 mM triethylammonium bicarbonate and 50 ng trypsin (Promega)
and incubated for 30 min at room temperature with gentle agitation
The samples were mixed with 40 mM chloroacetamide and incubated for 30 min at room temperature with gentle agitation
The supernatants with eluted proteins were collected
A total of 50 ng of LysC (Promega) was added to protein eluates and supplemented with 100 ng of trypsin
Proteins were digested overnight at 37 °C with vigorous shaking
Peptides were desalted on the Affinisep SPE-Disks-C18 and separated by liquid chromatography
Cell and mitochondrial pellets were resuspended in 8 M urea
50 mM triethylammonium bicarbonate and protease inhibitor cocktail
Chromatin was degraded in a water bath sonicator (10 min
followed by benzonase HC nuclease treatment
Insoluble material was removed by centrifugation at 20,000g
A total of 50 µg of proteins was reduced for 1 h in 5 mM dithiothreitol and incubated with 40 mM chloroacetamide for 30 min
The samples were subjected to sequential LysC and trypsin digestion (1:75 enzyme to substrate ratio
The measurements were performed at the Proteomic Core Facility of IMol Polish Academy of Sciences using the Dionex UltiMate 3000 nano-LC system coupled to a Q-Exactive HF-X through an EASY-Spray ion source (Thermo Fisher Scientific)
The data were processed with MaxQuant 1.6.17.0
and the peptides were identified from the MS/MS spectra searched against human reference proteome UP00000564 using the built-in Andromeda search engine
The data were subjected to non-quantitative analysis
Aged (&gt;16 months old) C57BL/6 J male mice were fasted overnight and water was available ad libitum
The mice had access to certified rodent diet ad libitum 4 h after dosing
The mice were housed in a controlled environment
under the following target conditions: temperature
The temperature and relative humidity were monitored daily
An electronic time-controlled lighting system was used to provide a 12 h–12 h light–dark cycle
Three mice for each indicated timepoint were administered BAI1(10 mg per kg) in 3.5% DMSO
75% gamma-cyclodextrin (20%) in 0.1 M citrate buffer pH 6
7.5% 0.1 M citrate buffer pH 6 through the intraperitoneal route
The mice were euthanized and brain tissue was collected at 0 h
Sample collection at 0 h was to collect brain tissue immediately after dose administration
Brain homogenates were prepared by homogenizing tissue with 4 volumes (w/v) of homogenizing solution (MeOH/15 mM PBS 1:2) and analysed for BAI1 concentration using liquid chromatography coupled with tandem MS bioanalysis
Imaging was performed using confocal microscopes (SP8 Leica and LSM780 Zeiss) and super-resolution microscopes (confocal microscopy using the AiryScan type detector LSM800 Zeiss AiryScan;and SIM using the Zeiss Elyra PS.1 Super Resolution system)
Analysis of extramitochondrial DNA foci and mitochondria positive for BAX(6A7) was performed manually using ImageJ
CLSM images were processed for deconvolution using AutoQuant X3 Deconvolution
The Pearson’s R value was subsequently determined for each cell using the Coloc2 ImageJ plugin
For the 3D visualization of mitochondrial leakage
Imaris 9.6 Image Visualization and Analysis Software was used
Images for miMOMP analysis were acquired from cells labelled with antibodies against Cyt c and TOM20 by 3D imaging using z-stacks on the Leica SP8 Confocal microscope
Approximately 30 z-stacks were acquired for each coverslip imaged
micrographs were processed using the Huygens Deconvolution Software
The level of colocalization was assessed using the colocalization tool within the Huygens Deconvolution Software
single-cell suspensions were prepared from flash-frozen mouse brain tissue using the Chromium Next GEM Single Cell Fixed RNA Preparation kit (10x Genomics) according to the user guide (CG000553
Minced tissues were fixed for 24 h at 4 °C
Cell dissociation was performed using the gentleMACS Octo Dissociator (Miltenyi)
Libraries were constructed using the single-plex Chromium Fixed RNA Profiling kit (CG000477
Probes were incubated for 20 h at 42 °C and 9 cycles were performed for the indexing PCR
Libraries were sequenced on the NextSeq500 (Illumina) system
GraphPad Prism v.9.0 was used for statistical analysis; the results were considered to be statistically significant when P ≤ 0.05
the differences between two groups were tested for statistical significance using an independent-sample two-tailed t-tests
For data that were normally distributed and when there was more than one group
Mann–Whitney U-tests were used to determine statistical significance
All animal experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Mayo Clinic
Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM2">Nature Portfolio Reporting Summary</a> linked to this article
A Correction to this paper has been published: <a href="https://doi.org/10.1038/s41586-023-07002-7">https://doi.org/10.1038/s41586-023-07002-7</a>
Cellular senescence: defining a path forward
Mitochondria are required for pro-ageing features of the senescent phenotype
Mitochondria as multifaceted regulators of cell death
The serial cultivation of human diploid cell strains
Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor
Reducing senescent cell burden in aging and disease
Feedback between p21 and reactive oxygen production is necessary for cell senescence
Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence
Birch, J. &amp; Passos, J. F. Targeting the SASP to combat ageing: mitochondria as possible intracellular allies? BioEssays <a href="https://doi.org/10.1002/bies.201600235" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/bies.201600235">https://doi.org/10.1002/bies.201600235</a> (2017)
BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis
Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis
Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Nonionic detergents induce dimerization among members of the Bcl-2 family
cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders
The BH3 mimetic ABT-737 induces cancer cell senescence
Mitochondrial permeability transition triggers the release of mtDNA fragments
Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence
Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production
Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA
Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency
Depletion of mitochondria in mammalian cells through induction of widespread mitophagy
Mitochondrial DNA stress primes the antiviral innate immune response
Herpes simplex virus UL12.5 targets mitochondria through a mitochondrial localization sequence proximal to the N terminus
T cells with dysfunctional mitochondria induce multimorbidity and premature senescence
Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions
Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage
Small-molecule allosteric inhibitors of BAX
3,6-Dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation
A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy
Eltrombopag directly inhibits BAX and prevents cell death
A clinical frailty index in aging mice: comparisons with frailty index data in humans
Targeting cellular senescence prevents age-related bone loss in mice
A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues
Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs
Senescent human fibroblasts resist programmed cell death
L1 drives IFN in senescent cells and promotes age-associated inflammation
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
Activated mitofusin 2 signals mitochondrial fusion
and reduces susceptibility to radical induced depolarization
A non-death function of the mitochondrial apoptosis apparatus in immunity
Rapamycin improves healthspan but not inflammaging in nfκb1−/− mice
Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes
<a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41586-023-06621-4?format=refman&amp;flavour=references">Download references</a>
This work was funded by NIH grants R01AG068048 (to J.F.P.)
R01AG071861 (to P.D.A.) and R33AG61456-4 and R01AG064165; Department of Defense grant W81XWH-20-1-0792 (to E.G.); U54 AG79754 (to S.K
and N.K.L.); Cancer Research UK grants C40872/A2014
DRCNPG-Jun22\100011 (to S.W.G.T.); the Ted Nash Long Life Foundation (to J.F.P
and D.J.); The Glenn Foundation For Medical Research (to J.F.P
and N.K.L.); Hevolution/AFAR (to D.J.); a Robert and Arlene Kogod Center on Aging Career Development Award (to S.V.); a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (Capes)—Finance Code 001 and by the Universidade Federal do Rio de Janeiro (to C.A.M.); Cancer Research UK grant DRCPFA-Nov22/100001 and Wellcome grant 203105/Z/16/Z0 to L.C.G.
BBSRC PhD studentship BB/R506345/1 (to G.K
and V.I.K.); UKRI cross-council Newcastle University Centre for Ageing and Vitality Ph.D
studentship MR/L016354/1 (to J.C.) and CRUK Awards C18342/A23390 and DRCRPG-Nov22/100007 and MRC MR/R023026/1 (to D.A.M.)
holds the Audrey Geisel Chair in Biomedical Science
MS interactome analysis was performed at the Proteomic Core Facility of IMol Polish Academy of Sciences and supported by ReMedy International Research Agenda (Foundation of Polish Science
MAB/2017/2) and EMBO Installation Grant 5040-2022 (to K.S.)
scRNA-seq was performed by the Sanford Burnham Prebys Genomics Core
holds the Audrey Geisel Chair in Biomedical Science and is supported by P30AG068635 as director of the San Diego Nathan Shock Center
Nelson and the members of the Newcastle University Bioimaging Unit for technical support
These authors contributed equally: Stella Victorelli
Department of Physiology and Biomedical Engineering
Hanna Salmonowicz &amp; Karolina Szczepanowska
Wellcome Centre for Mitochondrial Research
Sanford Burnham Prebys Medical Discovery Institute
Department of Gastroenterology and Hepatology
Instituto de Bioquímica Médica Leopoldo de Meis
Division of Oncology Research and Department of Molecular Pharmacology and Experimental Therapeutics
Wilf Family Cardiovascular Research Institute
Emmanouil Zacharioudakis &amp; Evripidis Gavathiotis
was involved in mouse and cell culture experiments
conceptualization and interpretation of data
were involved in cell culture experiments and analysis of end points
were involved in animal experiments and analysis of end points
were involved in conceptualization and functional assessment of bone function
conducted analyses of BAX oligomerization through FPLC under the supervision of S.H.K
conceptualized and supervised BAX6A7 co-IP and subsequent proteomics analysis
oversaw animal experiments and analysis of end points
performed scRNA-seq analysis of the mouse brain
conducted pharmacological analyses of BAI1 in the brain under the supervision of E.G
oversaw cell culture and microscopy experiments performed by H.S
supervised cell culture studies involving Tfam+/− fibroblasts performed by A.G.S
provided the CGAS shRNA lentiviral construct
oversaw the study and wrote the manuscript
All of the authors contributed to reviewing or editing the manuscript
is a scientific advisor for Longaevus Technologies
The other authors declare no competing interests
Nature thanks the anonymous reviewers for their contribution to the peer review of this work.<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM3"> Peer reviewer reports</a> are available
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
(a) Scheme representing the mechanism by which ABT-737 induces miMOMP
representative Western blot showing cleaved caspase 3 in proliferating and ABT-737- treated MRC5 fibroblasts
(b) Absorbance values (at 450 nm) as a measure for lactate dehydrogenase (LDH) release from proliferating MRC5 fibroblasts treated with vehicle or ABT-737 for 72 h (n = 3 independent experiments)
Levels of secreted (c) IL-6 (n = 2 and n = 3 independent experiments
respectively) and (d) IL-8 in control and MRC5 fibroblasts treated with ABT-737 for 9 (n = 4 independent experiments) and 23 days (n = 3 independent experiments)
Quantification of mRNA expression levels of interleukins (IL-1α,β
interferon genes (IFN-α and β) in MRC5 (n = 5 independent experiments) (e-f) and IMR90 fibroblasts (n = 3 independent experiments) (g) 23 days after ABT-737 treatment
(h) Graph showing population doublings of control and ABT-737-treated MRC5 fibroblasts
Quantification of (i) mean number of γH2AX foci
(j) percentage of Sen-β-Gal-positive cells and (k) mean number of DNA nucleoids located outside of the mitochondrial network in control and MRC5 fibroblasts treated with ABT-737 for 9 and 23 days (n = 3 independent experiments; n = 4 for day 0)
Statistical significance was assessed using one-way ANOVA followed by Tukey’s multiple comparison test (k)
two-way ANOVA followed by Sidak’s multiple comparison test (c
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM10">Source data</a>
Levels of secreted (a) IL-6 and (b) IL-8 in proliferating and senescent (IR) EV and BAX/BAK-/- cells (n = 6 independent experiments)
Data are expressed as fold change to proliferating EV cells (n = 6 independent experiments)
(g) Percentage of cells containing DNA foci located outside of mitochondrial network
and (h) Levels of secreted IL-6 and IL-8 in proliferating and senescent cells treated with DMSO or 1 μM Cyclosporin A (n = 4 independent experiments)
(i) Graph showing the energy production by glycolysis or oxidative phosphorylation normalized to total ATP production and expressed as a percentage (n = 5 independent experiments; n = 4 Sen BAK/BAXCRISPR)
(j) Quantification of MitoSOX fluorescence intensity in proliferating and senescent EV and BAX/BAK−/− cells (n = 4 independent experiments for Prol and Sen EV and Prol BAX/BAK−/− cells; n = 3 independent experiment for Sen BAX/BAK−/− cells)
(k) Quantification of the percentage of EV and BAX/BAK−/− cells displaying Cytoplasmic chromatin Fragments (CCF) (n = 7 independent experiments)
(l) Column clustered heatmap of OXPHOS genes that are differentially expressed in senescent cells and are not changed by BAX/BAK deletion
The colour intensity represents column Z-score
where red and blue indicate high and low expression
Statistical significance was assessed using one-way ANOVA followed by Tukey’s multiple comparison test (a-k)
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM11">Source data</a>
Quantification of mRNA expression levels of (a) p16INK4A
(e) IL-6 and (f) IL-8 in proliferating and doxorubicin-induced senescent (n = 3 independent experiments) BAX/BAK−/− MRC5 human fibroblasts
Quantification of mRNA levels of (g) p16INK4A
(k) IL-6 and (l) IL-8 in proliferating and etoposide-induced senescent (n = 3 independent experiments) BAX/BAK−/− MRC5 human fibroblasts
Data are expressed as fold change to proliferating EmptyCRISPR cells
Statistical significance was assessed using one-way ANOVA followed by Tukey’s multiple comparison test (a-l)
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM12">Source data</a>
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM13">Source data</a>
(a) Column clustered heatmap of SASP genes that are differentially expressed in senescent IMR90 fibroblasts
down-regulated upon mitochondria clearance and are rescued by mtDNA transfection
(b) Gene members of two hallmark signatures
TNFA-signalling via NFKB (M5890) and Hecker IFNB1 targets (M3010)
were upregulated in senescent cells and downregulated after CCCP
Subsequent addition of mtDNA rescued this phenotype
Parkin Prol display an enrichment for the TNFA-signalling via NF-κB (M5890) and Hecker IFNB1 targets (M3010) pathways in the senescent cell population
Addition of mtDNA led to a significant enrichment compared to CCCP alone in senescent cells
(d) Venn diagram depicting a substantial overlap of enriched pathways in all three conditions (FWER p-value &lt; 0.25)
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM14">Source data</a>
a) Relative mtDNA copy number of MRC5-UL12.5 fibroblasts with and without tamoxifen treatment (100 nM
(b-e) mRNA expression levels of SASP genes
Ccl2 and IL-1α in proliferating and senescent (IR) MRC5-UL12.5 fibroblasts with and without tamoxifen treatment (48 h)
Statistical significance was assessed using two-sided Student’s unpaired t-test (a)
one-way ANOVA followed by Tukey’s multiple comparison test (b-e)
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM15">Source data</a>
(a) Representative immunofluorescence image of cGAS–GFP fusion protein (green) co-localizing with TFAM (red) in senescent cells
Magnification at the bottom shows cGAS–GFP reporter colocalizing with TFAM foci in the absence of TOM20 (white) (scale bar is 20 µm)
Graph represents quantification of cGAS and TFAM signals in selected linear region indicated in a
(b) Quantification of the percentage of proliferating and senescent cells (IR) containing cGAS co-localizing with cytosolic TFAM foci (n = 5 independent experiments)
(c) Western blot showing the level of cGAS upon CRISPR/Cas9-mediated cGAS deletion
Representative blot of n = 1 independent experiment
Secreted levels of (d) IL-6 and (e) IL-8 in proliferating and senescent EV and cGAS-deficient MRC5 human fibroblasts (n = 3 independent experiments)
(f) Representative Western blot showing the level of STING upon CRISPR/Cas9-mediated STING deletion using two different gRNAs
Blot is representative of n = 2 independent experiments
Secreted levels of (g) IL-6 and (h) IL-8 in proliferating (n = 4 independent experiments) and senescent (n = 6 independent experiments) EV and STING-deficient MRC5 human fibroblasts
Secreted levels of (i) IL-6 and (j) IL-8 in EV and STING-deficient MRC5 human fibroblasts upon mtDNA transfection (n = 4 for control
n = 6 independent experiments for +mtDNA condition)
Statistical significance was assessed using two-sided Student’s unpaired t-test (b)
one-way ANOVA followed by Tukey’s multiple comparison test (d
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM16">Source data</a>
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM17">Source data</a>
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM18">Source data</a>
(a) Neuromuscular coordination shown as a percentage number of successful attempts (green) to remain on a straight rod for 60 s (n = 7 vehicle and n = 8 BAI1-treated mice)
(b) Kaplan-Meier survival curves of animals treated with vehicle (n = 38) or Bax inhibitor (n = 39) from 18–20 months old until death
(c) Heatmap showing levels of cytokines found in plasma from mice treated with vehicle or BAI1
Values are shown as fold change compared to vehicle-treated animals
Red denotes high expression and blue indicates low expression
d) Table summarizing μCT-derived parameters obtained for the spine and femur from vehicle (n = 6) and BAI1-treated mice (n = 10)
p21 and p53 in control (n = 6) and BAI-1 treated mice (n = 10)
f) (left) Heatmap showing mRNA expression of the indicated SASP factors in the brain from aged animals treated with BAI1 (p = 0.04)
(right) Graphs showing quantification of levels of mRNA of the indicated genes in brains from aged mice treated with BAI1 (n = 8 vehicle- and n = 7 BAI1-treated mice)
Statistical significance was assessed using two-sided Student’s unpaired t-test (d
<a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-023-06621-4#MOESM19">Source data</a>
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hundreds of young Americans volunteered to serve ambulance drivers retrieving the dead and wounded from the front line
Among their ranks were John Dos Passos and Ernest Hemingway who briefly met near the front
both men knew they had to write about it; they had to give voice to what they felt about war and life
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WSVN was able to obtain the arrest affidavit for 53-year-old Gregory Gibert
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anybody does not deserve to die in a park like this
you know,&quot; said George Buchholz who lives near the scene
See also: <a href="https://cbs12.com/news/local/florida-has-helped-700-americans-rescued-from-haiti-in-past-5-weeks-desantis-evaucation-fdem-emergency-management-israel-april-24-2024" target="_blank" title="https://cbs12.com/news/local/florida-has-helped-700-americans-rescued-from-haiti-in-past-5-weeks-desantis-evaucation-fdem-emergency-management-israel-april-24-2024" class="themeColorForLinks">Florida has helped 700+ Americans rescued from Haiti in the past 5 weeks</a>
Police said the building and a library close by have surveillance systems
and check if the victim&#x27;s tragic death was captured on the cameras
&quot;Our organization is very confident that we&#x27;ll be able to identify and arrest the subject responsible for this heinous crime,&quot; said MDPD officerChristopher Bess
police have arrested someone in connection to Dos Passos&#x27; death on Wednesday
WSVN was able to obtain the arrest affidavit for 53-year-oldGregory Gibert
Police said while Dos Passos was lying down on the steps sleeping,Gibert was spotted surveying the area
In the report police noted the severity of the beating
In addition to the trauma to her head and face
two wooden sticks were jammed up Dos Passos&#x27; nose
detectives said they were able to connectGilbert to the crime due to his previous arrest record and his description
Gibert was arrested and faces one count of second-degree murder
<a href="https://www.digitalpw.com/digitalpw-refurl/current" target="_offsite" referrerpolicy=”no-referrer-when-downgrade”>Read this week's magazine</a>
NEW BEDFORD – Although he is considered one of the major novelists post-World War I
John dos Passos is arguably a lost member of the ‘Lost Generation’ of writers as he was overshadowed by some of his peers
the New Bedford Whaling Museum will put a spotlight on the Portuguese-American prolific writer’s life and work as part of its Portuguese and Lusophone-World Lecture Series
and the Portuguese Heritage with Bernardo de Vasconcelos,’ the event will feature Dr
an assistant professor at University of Madeira in the Faculty of Arts and Humanities
who will speak upon the importance of Dos Passos and his work
and the inherent and binding transatlantic connection
“Dos Passos is not as well known as he should be
given the quality of his writing and his association with Hemingway
and other great writers of the 20th century
I believe that Professor Vasconcelos’ talk should illuminate his greatness,” said Gilbert Perry
who serves on the Whaling Museum’s Board of Trustees and Portuguese Advisory Committee
a series of three novels covering the historical development of American society during the first three decades of the 20th century
Vasconncelos will also shed light on Dos Passos’ thoughts concerning his Portuguese heritage and the preparation of what was to become The Portugal Story
“The talk should highlight not only his greatness as an American writer
but also his pursuit of his Portuguese identity
as well as his direct connection to this area by virtue of his summers spent in Provincetown,” Perry said
who immigrated from Ponta do Sol to the United States back in 1830
was born in Chicago to John Randolph Dos Passos
Vasconcelos will point out how Dos Passos sought to maintain ties with Portugal
“Having first visited Madeira in May 1905 for a three-week stay
as a nine-year-old and in the company of his parents
Dos Passos next stopped at Funchal in 1921
Cummings as a travel companion,” reads a press release announcing the lecture
“But it was only in July 1960 that Dos Passos fully gained perception of Madeira during his one week stay
in the company of his wife Elizabeth and his daughter Lucy
This visit was much celebrated in the Madeiran press with interviews and extensive news reports
Currently on a mobility program as Coordinator of the John Dos Passos Cultural Center
Bernardo aims his efforts at raising awareness
as well as his goal to strengthen ties with all institutions
“I’m hoping that attendees will come away with an appreciation of Dos Passos’ place in American literature
as well as a greater sense of how our Portuguese culture has influenced not only the discovery of unknown islands
but also many literary and artistic endeavors,” Perry said
This program is made possible in part by the New Bedford Whaling Museum
the Luso-American Development Foundation (FLAD)
the Department of Portuguese and Brazilian Studies at Brown University and Clube Madeirense S.S
Admission is free, but registration is requested on the Whaling Museum's website at <a href="https://buy.acmeticketing.com/orders/495/tickets?eventId=634ef6e0a74a5b4fd85e1350&date=2022-12-01T18:00:00-05:00&cart=true">https://buy.acmeticketing.com/orders/495/tickets?eventId=634ef6e0a74a5b4fd85e1350&date=2022-12-01T18:00:00-05:00&cart=true</a>
Gregory Fitzgerald Gibert, 53, was initially arrested on a second-degree murder charge in the killing of 37-year-old Andrea Dorias Dos Passos, whose body was found Tuesday near the Miami City Ballet.
After refusing to appear for a bond court appearance on Wednesday, Gibert went before Miami-Dade Judge Mindy Glazer on Thursday by video, where Glazer found there was probable cause for a more serious charge.
"I've had a chance to review the arrest affidavit, to me it looks like it should be a first-degree murder not a second-degree, based on the facts alleged in this arrest affidavit where he allegedly struck the victim with a metal pipe about the head and face, and then it looks like he defiled the body by doing other things to the victim after she was deceased," Glazer said.
Get local news you need to know to start your day with NBC 6's News Headlines newsletter.
Glazer ordered Gibert held without bond and appointed him a public defender.
An arrest report by Miami Beach Police said detectives found surveillance video that captured Gibert beating Dos Passos with a metal pipe as she was sleeping near the entrance of the building.
Police noticed lacerations to her head and face, a puncture wound to her chest, and two wooden sticks lodged in her nostrils.
The surveillance video allegedly showed Gibert throwing the metal pipe in a nearby trash can before walking away, police said.
Detectives were able to retrieve the weapon and obtain fingerprints which helped detectives identify the suspect.
They tracked Gibert down to an address in Miami where he was found with bloodstained shoes and basketball shorts, the report said.
Records show Gibert was just released from jail last Wednesday, a week before this crime, where he was being held for armed robbery and aggravated assault. He was given four years of probation.
A memo obtained by NBC6 showed Miami-Dade prosecutors were seeking to have Gibert sentenced to at least 10 years in prison for attempting to rob a man of his moped.
But the prosecutor said the victim’s deposition revealed weaknesses in the case if it were to go to trial, and a corroborating witness repeatedly failed to appear.
So last week they agreed to let Gibert plead guilty, immediately get out of jail, and go on probation. A week later, he allegedly committed the murder.
The victim's stepfather spoke to NBC6 a day after Dos Passos was killed. Victor Van Gilst said his family is devastated.
"I knew one day this could happen," he said. "I need to go through the stages of anger and grief and denial and acceptance and all that."
Police said Gibert refused to cooperate with investigators so a motive for the killing was unknown.
"No evidence alludes to the fact that this was a hate crime. The evidence does not allude to the fact that the defendant targeted the victim based off her sexual orientation and or her gender," Miami Beach Police spokesman Christopher Bess said. "What we do know is that the offender was a very violent individual and should not have been on our streets.”
Van Gilst said he would also like answers.
"I do not know if Andrea had an interaction before with this suspect and it was a revenge case, or this was a total random act. I do know that she had no chance, she was sleeping," he said.
Van Gilst said Dos Passos had struggled with mental health in recent years.
"I think that the system let her down. At this moment I also have the feeling that I let her down," he said. Nobody deserves this. "Nobody deserves this, to die like this."
Gibert, who had already been labeled a habitual violent offender, could face a possible sentence of life in prison in convicted on the first-degree murder charge.
Some in the community, like Miami Beach Commissioner Alex Fernandez, are left wondering if Gibert had not been let out of jail whether the murder could have been prevented.
"It's an alarming failure of society. A violent criminal that's been in jail over 33 times, this is a man with a horrible wrap sheet, a danger to society who should never been in probation on the streets, roaming the streets of Miami Beach or anywhere in Miami-Dade County," Fernandez said.&nbsp;"This is a dangerous man who has committed atrocities against innocent individuals in society. He had one place and that was behind bars."
Volume 2 - 2022 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fviro.2022.826393">https://doi.org/10.3389/fviro.2022.826393</a>
This article is part of the Research TopicHost Immune Responses to Retroviral Infections<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 5 articles" href="https://www.frontiersin.org/research-topics/20602/host-immune-responses-to-retroviral-infections/magazine" target="_self" data-event="customLink-linkType-a_viewAll5Articles">View all 5 articles</a>
Human Endogenous Retroviruses (HERVs) constitute up to 8% of the human genome and have been emerging as important modulators of the immune system
we investigated the expression of three HERV families in the human thymus
and -R envelope (env) and HERV-K gag transcriptional levels were quantified in the main thymocyte subsets
and Env protein expression was studied in thymic tissue
We found that HERV mRNA decreased with T cell development
which was in agreement with the identification of HERV-K Env protein in CD3 negative cortical cells
These results suggest a distinct regulation of HERV expression along T cell development
prompting us to evaluate the interplay with host restriction factors and potential underlying pathways
The transcriptional levels of some HERVs were found to positively correlate with the expression of the host restriction factors APOBEC3G and SLFN11
a negative correlation was found with SAMHD1
IFN-&#x003B1; and IFN-&#x003B3; induced the upregulation of HERV-K env and gag in purified CD4 single-positive thymocytes
we found high levels of HERV mRNAs in TECs
our data support a tight regulation of HERV expression during human T cell development
with possible implications for the process of T cell selection
but there are no detailed studies on HERV expression throughout human thymocyte development as well as on thymic stromal cells
We provide here a comprehensive evaluation of the expression of 3 major HERV families
along thymocyte differentiation and in the other main cell populations in the human thymus
in parallel with the assessment of host restriction factors
cytokine exposure and HIV infection impact on HERV expression in human thymocytes
Thymic specimens were obtained from routine thymectomy performed during pediatric (newborns to 4-year-old children) corrective cardiac surgery at Hospital de Santa Cruz
Cord blood was collected at the Obstetric Department of Hospital de Santa Maria
Pediatric tonsils were obtained from routine pediatric tonsillectomy at the Centro Hospitalar Universit&#x000E1;rio Lisboa Norte (CHULN)
Adult peripheral blood was collected from volunteer healthy donors at Instituto de Medicina Molecular Jo&#x000E3;o Lobo Antunes
All samples were collected after participants or parent&#x00027;s/legal guardians&#x00027; written informed consent
The study was approved by the Ethical Boards of Faculty of Medicine of the University of Lisbon
of the CHULN and of the Hospital de Santa Cruz
Total thymocytes and tonsillar cells were recovered by tissue dispersion using a 70&#x003BC;M filter (BD Biosciences)
cord blood and peripheral blood mononuclear cells were obtained through separation on Ficoll-Paque PLUS (GE Healthcare) density gradient
Surface staining was performed for 20 min at room temperature and always included Fixable Viability Dye (eBioscience) for dead cell exclusion. Cells were fixed, permeabilized and stained using an intracellular staining kit (eBioscience), as described (<a href="#B23">23</a>, <a href="#B24">24</a>)
Anti-human monoclonal antibodies (mAb) used were (clones in brackets): CD3 (UCHT1 or OKT3)
PD1 (MIH4) and TCR&#x003B3;&#x003B4; (B1.1) from eBioscience
Cells were acquired using LSRFortessa (BD Biosciences) and data was analyzed in FlowJo (FlowJo)
and mononuclear tonsillar cells were centrifuged and incubated at 4&#x000B0;C in the dark for 30 min with the antibodies listed above
cells were sorted to a high degree of purity (routinely &#x0003E;98%) using a FACSAria (BD Biosciences)
Total thymocytes were sorted according to human &#x003B1;&#x003B2; T-cell developmental stages: triple-negative (TN) CD34&#x0002B; (Lineage-CD4-CD8-CD3-CD34&#x0002B;)
double-positive (DP - CD4&#x0002B;CD8&#x0002B;CD3-/&#x0002B;)
CD4SP (CD4&#x0002B;CD8-CD3&#x0002B;) and CD8SP (CD4-CD8&#x0002B;CD3&#x0002B;)
The following thymic stromal populations were also sorted: B cells (CD3-CD19&#x0002B;DR&#x0002B;)
monocytes/macrophages (CD3-CD163&#x0002B;)
plasmacytoid dendritic cells (pDCs - CD3-CD8-DR&#x0002B;CD123&#x0002B;)
CD11c&#x0002B; myeloid dendritic cells (mDCs - CD3-CD8-DR&#x0002B;CD123-BDCA3-CD11c&#x0002B;)
BDCA-3&#x0002B; mDCs (CD3-CD8-DR&#x0002B;CD123-BDCA3&#x0002B;)
thymic epithelial cells (TECs - CD3-CD8-CD45-EpCAM&#x0002B;) and TCR&#x003B3;&#x003B4; T cells (CD3&#x0002B;TCR&#x003B3;&#x003B4;&#x0002B;)
Cord blood cells were sorted as CD34&#x0002B;
Adult peripheral blood T cells were sorted into CD4 (CD3&#x0002B;CD4&#x0002B;CD8-) and CD8 (CD3&#x0002B;CD4-CD8&#x0002B;) T cells
as well as na&#x000EF;ve (CCR7&#x0002B;CD45RA&#x0002B;) and effector plus central memory (CCR7-CD45RA-
CCR7&#x0002B;CD45RA- and CCR7-CD45RA&#x0002B;) T cell subsets
Memory CD4 (CD4&#x0002B;CD45RO&#x0002B;) pediatric mononuclear tonsillar cells were sorted according to the T follicular helper differentiation stages: PD1-CXCR5-
were calculated using the 2-&#x00394;CT or 2-&#x00394;&#x00394;CT method
Fixed thymic tissue was embedded in paraffin and cut into 3 &#x003BC;m sections (Minot Microtome Leica RM2145)
Epitope-retrieval was performed at pH9 (Leica Biosystems buffer) for 15 min using a microwave (800W)
Sections were stained with antibodies against HERV-K Env TM (Austral Biologicals
Samples were then incubated with a peroxidase/DAB detection system (EnVision
Dako) and counterstained with Harris&#x00027; hematoxylin (BioOptica)
Images were acquired using a Leica DM2500 microscope
After protein blocking, 3 &#x003BC;m tissue sections were stained by sequential incubations with the above mentioned anti-HERV-K Env antibody and anti-CD3 (eBioscience, OKT3) antibody and secondary antibodies as previously described (<a href="#B23">23</a>, <a href="#B24">24</a>)
and DAPI was used for nuclear counterstaining
Images were acquired with Zeiss LSM 710 confocal microscope (Carl Zeiss
Germany) using a EC Plan-Neofluar 40x/1.30 objective; Digital zoom inserts acquired with ZEN 2012 SP5 FP3 (black) software
FACS-sorted CD4SP T cells (200.000&#x02013;500.000 cells/condition) were stimulated in a 96 well U-bottom tissue culture plate at 37&#x000B0;C in the presence of complete medium alone or supplemented with Interleukin-2 (IL-2; 100 U/mL; R&#x00026;D)
Tumor Necrosis Factor-&#x003B1; (TNF-&#x003B1;
or PMA (500 ng/mL; Sigma-Aldrich) &#x0002B; Ionomycin (500 ng/mL; Calbiochem
cells were washed and cell pellets were frozen at &#x02212;80&#x000B0;C
Statistical analysis was performed using GraphPad Prism v9 (GraphPad Software Inc.)
Two-sample data were compared using Wilcoxon-matched pairs test
Data from more than two samples were compared using Friedman test or Kruskal-Wallis test with Dunn&#x00027;s multiple comparison post-test
P values &#x0003C; 0.05 were considered significant
for which we were unable to optimize a reliable quantitative assay for human thymic cells
-P and -R env normalized to &#x003B2;-actin expression levels in sort-purified: (A) CD34 &#x0002B; cells from cord blood
thymocyte subsets along T cell development (TN
CD8 Single Positive) and &#x003B3;&#x003B4; thymocytes; (B) Major non-T cell populations in the thymus
both CD11c &#x0002B; and BDCA3 &#x0002B; myeloid dendritic cells (DCs)
and thymic epithelial cells (TECs); each dot represents one different thymus; results were compared using Kruskal-Wallis with Dunn&#x00027;s multiple comparisons test; &#x0002A;P &#x0003C; 0.05; &#x0002A;&#x0002A;P &#x0003C; 0.001
(C) HERV-K Env protein expression evaluated by immunohistochemistry; left images amplification 200x; right images amplification 400x; Digital zoom insert - the image down to a centered area with the same ratio as the original; black arrows indicate positive cells stained in brown; white lines shows delimitation cortex/medulla area; C
(D) Double staining for HERV-K Env protein and CD3 by immunofluorescence; image amplification 400x; Digital zoom insert - the image down to a centered area with the same ratio as the original
Notably, we were able to quantify the HERV transcripts in the main antigen-presenting populations in the thymus, namely B cells, myeloid and plasmacytoid dendritic cells, and monocytes/macrophages, as well as in thymic epithelial cells (TECs) that featured the highest levels (<a href="#F1">Figure 1B</a>)
the expression of HERV-K (HML-2) gag was also lower than that of HERV-K (HML-2) env at all cell populations
further supporting a distinct regulation of transcription or splicing of the gag
As a validation control we quantified in parallel the HERV transcripts in purified CD4 T cell subsets from pediatric human tonsils (<a href="#SM1">Supplementary Figure 1A</a>), as well as the expression of HERV-K Env by immunohistochemistry (<a href="#SM1">Supplementary Figure 1B</a>) and by immunofluorescence (<a href="#SM1">Supplementary Figure 1C</a>)
The transcriptional levels observed tended to be lower than those observed in the thymus
though the HERV-K (HML-2) Env expression was more frequently detected
and in cells co-expressing CD3 located outside the germinal centers
raising the possibility of a translational control of HERV-K (HML-2) Env protein in the thymus
in the human thymus and show that their transcriptional levels tended to decrease along T cell development
and were highly expressed in stromal cells
Host Restriction Factor (HRF) expression in pediatric thymuses
Relative transcriptional levels of the host restriction factors APOBEC3G
SAMHD1 and SLFN11 normalized to &#x003B2;-actin expression levels in sort-purified: (A) CD34 &#x0002B; cells from cord blood
SAMHD1 and SLFN11 protein expression evaluated by immunohistochemistry in representative thymus samples; upper images amplification 100x; middle images amplification 200x; bottom images 400x - Digital zoom insert - the image down to a centered area with the same ratio as the original; Positive cells stained in brown; (D) Correlogram of the transcriptional levels of factors APOBEC3G
SAMHD1 and SLFN11 with transcriptional levels of HERV-K
and -R env in total thymocytes and in the other cells from the thymus
using non-parametric Spearman correlation test (red/negative and green/positive)
&#x0002A;p &#x0003C; 0.05; &#x0002A;&#x0002A;p &#x0003C; 0.01; &#x0002A;&#x0002A;&#x0002A;p &#x0003C; 0.001; &#x0002A;&#x0002A;&#x0002A;&#x0002A;p &#x0003C; 0.0001
Interestingly, HERV-R env levels in thymocytes significantly correlated with APOBEC3G, APOBEC3F and SLFN11 and inversely with SAMHD1 expression (<a href="#F2">Figure 2D</a>). Moreover, the APOBEC3G and APOBEC3F expression levels were also directly correlated the levels of expression of HERV- K gag and HERV-K, -R, -W env in thymic stromal cells (<a href="#F2">Figure 2D</a>)
our data support the possibility that HERVs may modulate the up-regulation of the main host restriction factors in the human thymus
HERVs levels, and specifically HERV-K (HML-2), have been shown to be modulated by cytokines, hormones and chemical agents in different types of cells, but their regulation in thymocytes has not been addressed. We thus studied the modulation of HERV-K (HML-2) env and gag by cytokines and activation conditions in CD4SP thymocytes (<a href="#F3">Figure 3A</a>)
Changes in HERV and HRF transcriptional levels upon cytokine and mitogenic stimulation of CD4SP thymocytes and upon HIV exposure
(A,B) Sorted CD4SP thymocytes were stimulated for 4 h (light green) or 23 h (dark green) with medium alone or in the presence of IL-2
and the relative expression levels of HERVs (A) and HRFs (B) calculated as the fold-change relative to the unstimulated control by &#x00394;&#x00394;CT in 3 thymuses; Bars represent mean &#x000B1; SEM
Kruskal-Wallis test with Dunn&#x00027;s multiple comparison post-test was used to compare each condition with the unstimulated control
and the significant comparisons were shown
(C,D) Sorted CD4SP thymocytes were infected by HIV-1 (triangles) with or with HIV-2 (circles) with primary isolates using CXCR4 (X4) or CCR5 (R5) as co-receptors; cells were collected after 4 h and the relative expression levels of HERVs (C) and HRFs (D) calculated as the fold-change relative to the non-infected control by &#x00394;&#x00394;CT; Each symbol represents a thymus
Of all the stimuli tested, only IFN&#x003B1; clearly increased HERV-K (HML-2) levels (<a href="#F3">Figure 3A</a>). IFN&#x003B3; also increased HERV-K (HML-2) gag but not env levels, although with slower kinetics than IFN&#x003B1;. In addition, IL-7 increased HERV-K (HML-2) gag expression. Of note, we found no evidence of increased HERV-K (HML-2) env or gag expression upon stimulation or in any of the activation conditions tested (<a href="#F3">Figure 3A</a>)
In parallel, we quantified the changes in the expression of HRFs, and found that IFN&#x003B1; stimulation induced increase in the transcriptional levels of APOBEC3G, APOBEC3F, and SAMHD1 in CD4SP, whereas IL-7 increased the levels of SAMHD1 and SLFN11 (<a href="#F3">Figure 3B</a>)
may modulate HERV-K (HML-2) env and gag expression in CD4SP thymocytes
Surprisingly we were unable to reveal an impact of either HIV-1 or HIV-2 infection in HERV expression in CD4SP thymocytes using both CCR5- and CXCR4-tropic primary isolates. Although we did not exclude a possible later up-regulation of HERV expression, these results suggest a wired control of their expression in these mature quiescent thymocytes, in contrast with peripheral and activated CD4 T cells (<a href="#B18">18</a>, <a href="#B20">20</a>, <a href="#B35">35</a>)
we found that the profile of HERV expression along human T cell development and in thymic stromal cell populations parallels the expression levels of key host restriction factors
supporting a relevant role for HERVs in human thymus biology
The studies involving human participants were reviewed and approved by Ethical boards of the Faculdade de Medicina da Universidade de Lisboa
of the Centro Hospitalar Universit&#x000E1;rio Lisboa Norte
Written informed consent to participate in this study was provided by the participants&#x00027; legal guardian/next of kin
This work was supported by Funda&#x000E7;&#x000E3;o para a Ci&#x000EA;ncia e a Tecnologia (FCT) and by Programa Operacional Ci&#x000EA;ncia e Inova&#x000E7;&#x000E3;o 2010 (POCI2010)
HN-C received a scholarship from FCT co-financed by POCI2010
Rui Anjos for human thymus sample collection; the ENT department of CHULN for tonsil collections; Dr
Francisca Matos and nurses and staff at Hospital de Santa Cruz for technical assistance; Diana Santos and Pedro Rosmaninho for technical support; Afonso Almeida and Alexandre ASF Raposo for their critical reading of the manuscript; patients and families
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fviro.2022.826393/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fviro.2022.826393/full#supplementary-material</a>
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<a href="https://pubmed.ncbi.nlm.nih.gov/27843891" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.3389/fped.2016.00119" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=SL+Silva&#x00026;author=AE+Sousa+&#x00026;publication_year=2016&#x00026;title=Establishment+and+maintenance+of+the+human+na&#x000EF;ve+CD4++T-cell+compartment&#x00026;journal=Front+Pediatr.&#x00026;volume=4&#x00026;pages=119" target="_blank">Google Scholar</a>
Molecular mechanisms by which HERV-K gag interferes with HIV-1 gag assembly and particle infectivity
Innate immune sensing of HIV-1 by dendritic cells
<a href="https://pubmed.ncbi.nlm.nih.gov/23084911" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.1016/j.chom.2012.10.002" target="_blank">CrossRef Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=J+Luban+&#x00026;publication_year=2012&#x00026;title=Innate+immune+sensing+of+HIV-1+by+dendritic+cells&#x00026;journal=Cell+Host+Microbe.&#x00026;volume=12&#x00026;pages=408-18" target="_blank">Google Scholar</a>
Nunes-Caba&#x000E7;o H and Sousa AE (2022) Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development
Received: 30 November 2021; Accepted: 17 January 2022; Published: 10 February 2022
Copyright &#x000A9; 2022 Passos, Pires, Foxall, Nunes-Caba&#x000E7;o and Sousa. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
&#x0002A;Correspondence: Ana E. Sousa, <a id="encmail">YXNvdXNhQG1lZGljaW5hLnVsaXNib2EucHQ=</a>
&#x02020;These authors have contributed equally to this work and share senior authorship
radio host and writer Xorje Olivares is speaking with fellow LGBTQ+ faithful to learn more about how they&#x27;re queering their beliefs
Vania Christian Dos Passos says her life couldn’t be more exciting right now
Not only is the Baltimore County school teacher married to the love of her life
but they’re mothers to a month-old daughter who’s now part of their “adventure,” as she puts it
It’s been quite the adventure so far for Dos Passos
who immigrated to the United States in 2011 to learn English and obtain her Bachelor&#x27;s degree after living most of her life in Latin America
Growing up in a rural part of northern Brazil
she says her family was deeply Catholic and made it known that attending Mass was a requirement
because of the lack of priests in the area
her father would preach regularly to their local congregation
Dos Passos says Catholicism was just as much of a cultural standard as it was a belief system since
you “experience Catholicism in everything.”
after working with local nuns as a way to get involved with social justice issues
she was a postulant (a prospective candidate looking to join the convent and become a nun herself)
tasked with deciding whether religious life was for her
But this eight-year-long spiritual journey also brought a sexual awakening — Dos Passos recognized that aside from loving God
So in order to stay true to herself and her same-sex desires
Dos Passos left the convent in December 2013
Dos Passos and her eventual wife went from being a part of LEAD
the LGBTQ+ ministry at Baltimore&#x27;s St
Matthew Catholic Church (even appearing in a short documentary series about it
titled The Lost Flock) to leaving the institutional Church altogether over its exclusionary policies
spoke to Dos Passos about how she navigated the sanctity of religious life while closeted
introducing her child to her former religion
and what she’d suggest to other LGBTQ+ people questioning the extent of their devotion
What were your perceptions of queerness as a young Brazilian woman
I never thought those two things were possible — you just couldn’t be Catholic and gay
And we didn’t discuss it much in my family (even though I have a gay cousin)
I always knew there was something different about me
I just knew that dating guys was not something I was very successful at
“Maybe it’s me; maybe there’s something wrong with me
Was entering the convent a way to repress your sexuality
I wanted to be a part of the sisterhood; I wanted that community life
I grew up in a struggling family — my parents were poor
But I always had the feeling that God was there
So serving God in religious life was my way of saying “thank you,” and knowing that things could’ve been worse
You came out to yourself a few years into taking your solemn religious vows
I never told anyone I was gay because it clearly wasn’t acceptable in my community
But I was satisfied knowing that was my truth
I started losing myself and my personality as a nun
And I started getting jealous watching other people live authentically
But I’m also thankful for the experience of being a sister
What experience from the religious life do you carry with you today
I would say the sense of selflessness and caring for others
I try reminding myself and my partner that on top of focusing on ourselves
we can be in touch with the community around us and be emotionally involved with those we meet
helping others experience the love of God through our gestures is one thing I don’t want to ever lose
it’s easy for us to get caught in our problems and forget that there’s always someone to help
What did you enjoy most about Catholicism before coming out
I loved going to Mass and having that shared experience of worshipping God in a common place
Because we would all gather together in church to have that special moment together; it was very important
Plus the communion was a source of strength for me
church was where I could go to as a refuge just to have that intimacy with God
Describe that process and its emotional toll considering your deep relationship to the faith
Once I met my partner and we decided we wanted to have a family
we had to think about the environment we wanted our kids to grow in
we previously found ourselves in a Catholic community that was very open and welcoming
But we knew the changes we wanted to see in the church might not happen in our lifetime
So we came to the conclusion that we needed to leave
I still do the sign of the cross before meals and pray Hail Marys
But we now go to a United Church of Christ parish that’s LGBTQ+ affirming
Is there a desire to share tenets of Catholicism with your newborn daughter
I would like her to experience what I had as a child; we actually want to baptize her soon
I want her to know that there are flaws in everything
And it’s so imperfect that we can’t even be a part of it right now
But I do want her to experience faith; we want her to one day say
“I want to go to the Catholic Church,” and I’d say
“go for it!” It’s sad that we can’t be there now since there’s so many beautiful things that can bring people together
it excludes me and my family from being a part of it
Which of your identities — sexual or spiritual — comes first
If I had to think of where I am in my life
I’ve learned to detach myself from religion and now see it as a means to experience God
What’s your advice to anyone discerning leaving the Catholic Church
and where you can grow your faith and be the best you
I needed to sit down and think: how is my faith life going to look in five years
I think I would still be fighting for the changes within the Church
It’s a very personal decision that you need to pray a lot about it
 I’ve been able to free myself from the beliefs that were ingrained in me by faith and culture
It’s now about understanding God beyond Catholicism and Christianity and seeing that He created me the way that I am
Rosa Passos is known and loved as &#8220;a feminine Joao Gilberto.&#8221; For a singer/songwriter who carries the soulful cool of bossa nova into a new age
Barroso and other masters of Brazilian song with her own enchanting works
are pleasures international audiences are now getting to know a little better
Rosa Passos grew up surrounded by music in the city of Salvador
Inspired by Joao Gilberto and Antonio Carlos Jobim &#8211; the godfathers of bossa nova &#8211; she switched from piano to guitar and began writing her own material as a teenager
Passos&#8217;s songs (written with her longtime lyricist Fernando de Oliveira) appeared on her first recording in 1979
After taking several years off to devote herself to her husband and children
she returned to performing and recording in 1985
jump-starting a career that has been on the upswing ever since
Especially since her American debut in 1996 (at the invitation of Oscar Castro Neves) with a sensational performance in a &#8220;Jazz at the Bowl&#8221; concert at the Hollywood Bowl in Los Angeles
Rosa Passos has developed an ever-growing international following
the singer/songwriter performed in Japan for the first time with saxophonist Sadao Watanabe
which led to successful appearances in Spain
collaborated with Ivan Lins and Chucho Valdes in a memorable Cubadisco show in Havana
and wowed a packed crowd at New York&#8217;s Lincoln Center for a Tribute to Elis Regina show
she was invited to perform during the 50th anniversary celebration of German democracy
joining Paquito D&#8217;Rivera and the WDR Big Band for shows in Bonn and Cologne that featured her own songs and classic Brazilian tunes
where she has built an impressive catalogue of recordings
Rosa Passos has been one of the stars of producer Almir Chediak&#8217;s &#8220;Words and Melody&#8221; project
a series of recordings honoring the legacies of the great Brazilian songwriters
Her discs of the songs of Jobim and Ary Barroso were instant hits
revelatory new interpretations of such worldwide hits as Barroso&#8217;s &#8220;Aquarela do Brasil&#8221; and Jobim&#8217;s &#8220;Desafinado,&#8221; &#8220;Samba de Uma Nota So&#8221; (One Note Samba) and &#8220;Garota de Ipanema&#8221; (The Girl From Ipanema)
Sony Classical/Odyssey signed Rosa Passos in 2004
Rosa Passos&#8217; first solo acoustic recording came out on Telarc
Rosa captures the essence of this extraordinary artist with nothing more than her voice and her acoustic guitar
The album is her first solo acoustic project since she began recording nearly three decades ago
&#8220;I think this is the kind of work every artist should make,&#8221; says Passos
&#8220;It tells a lot about my artistic personality
I realized that this was the right moment to do it
I believe I achieved my professional maturity
so this was the moment to make my solo flight.&#8221;
In keeping with this vision of a personal musical statement
Passos arranged all fifteen of the tracks on Rosa
Six of the songs are collaborations between Passos and various lyricist friends
and the remaining nine are penned by a variety of Latin songwriters
&#8220;I&#8217;m responsible for the musical part of the composing process,&#8221; says Passos
friends of mine who share with me the same thoughts and feelings about music.&#8221;
The set opens with Passos&#8217; unaccompanied
crystal clear voice singing &#8220;Duas Contas,&#8221; followed immediately by the brief but equally stirring Antonio Jobim/Vinicius de Morales piece
&#8220;Eu Nao Existo Voce.&#8221; Flowing effortlessly from these opening tracks is &#8220;Sutilezas,&#8221; a whimsical composition penned by Passos and lyricist Sergio Naturezas
The second half of the album gives more room to Passes&#8217; songwriting
with the lighthearted &#8220;Demasiado Blue&#8221; (co-written with Fernando de Oliveira)
Passos&#8217; subtly complex fingerpicking here underscores a vocal line that alternates between easygoing and earnest
&#8220;Desilusion&#8221; (co-written with Spanish singer Santiago Auseron) showcases vocal dynamics that evoke a range of emotions in a single track Passos alternates effortlessly between the high and low ends of the vocal spectrum on &#8220;Detalhe&#8221; (a second piece co-authored by Oliveira)
But it&#8217;s her guitar work rather than her vocals that drives &#8220;Fusion,&#8221; a piece that requires rhythmically complex fretwork
&#8220;Inverno,&#8221; the closing track co-written by Passes and Walmir Palma
upbeat piece that sets vocal and guitar work in near seamless counterpoint
The occasional echo effect in the vocal track sets up a subtle chorus effect that accentuates Passes&#8217; silky vocal style
Please enter an answer in digits:10 &#43; fourteen = 
The exhibit will run through May 30 in the Hollings Library
It doesn&#8217;t take long to go down the list of boys&#8217; soccer coaches in Duncanville High School&#8217;s history
and now Nuno Passos is in his 15th season at the helm
&#8220;We&#8217;re the Pittsburgh Steelers of high school soccer
and I&#8217;m Mike Tomlin,&#8221; Passos said with a chuckle
Passos won his 300th game as a head coach this season
another year in which he has the Panthers back in the postseason
&#8220;When you can hit these type of milestones you have great players
your players are committed and your coaches are loyal,&#8221; Passos said
knowing how to win consistently keeps one in the coaching business
you don&#8217;t do it (coach),&#8221; he said
&#8220;I think the hardest part about it is once you get to the success
it is so much harder to maintain that success.&#8221;
his Panthers teams had 92 victories over the past four seasons and the current one
Passos was born in Portugal and migrated to Toronto
as he had difficulty adjusting to a new language and a new country
bouncing from Santa Clara City College to Highland Community College to Ranger College and graduating from Tarleton State University
&#8220;There was no money in soccer in the 90s,&#8221; he said
But coaching his son in recreational and club soccer brought him back to the sport
which was the first sport that my dad had taught me,&#8221; he said
and the rest is history,&#8221; Passos said
Passos said his own past growing up has helped him relate to his players and has helped him be a better coach
&#8220;I was a kid that grew up on the streets of Toronto
which was an unbelievable experience of a melting pot of cultures from all over the world,&#8221; he said
Passos attended Central Tech High School in Toronto
which is the largest high school in the city &#8211; much like Duncanville is among the largest in Texas
When he began playing every sport imaginable
he said it opened new opportunities for him
the path we chose was the competitive world,&#8221; he said
I was able to channel that frustration into sports.&#8221;
And now he&#8217;s helping his players at Duncanville do the same thing
&#8220;Every day we come in here and we try to teach these kids everything you&#8217;re learning in soccer
Do you think it through?&#8221; Passos said
&#8220;We&#8217;re fighting the battle of teaching these kids not only the rules about soccer
the consequences they need to be able to navigate the real game &#8211; and that&#8217;s the game of life.&#8221;
The only state championship in Panthers soccer history was in 1986 under Green
and it has taken some of the best teams in the state to eliminate them
the Panthers were eliminated in the third round by Garland Sachse 1-0
regional finalist Irving MacArthur 2-0 ousted them in the fourth round
Three years ago it was a 1-0 third-round loss to state finalist Rockwall Heath
&#8220;We fly under the radar here because of the success of our football and basketball programs,&#8221; Passos said
&#8220;It is such a fine line between winning and losing in soccer because soccer is almost the most unfair sport you can play
&#8220;Something happens where they get one chance
You&#8217;ve had 10 chances and dominated the game
Passos said it&#8217;s tough seeing opponents he knows they could have defeated go on in the playoffs
You sit there the last four or five years and think that could have been us,&#8221; he said
We&#8217;ve been so close; we just haven&#8217;t gotten the bounce we need
&#8220;We&#8217;re still waiting for that one player to make that special play for us to get us where we want to be.&#8221;
Duncanville is known as the &#8220;home of champions,&#8221; and Passos believes his program will join the success of others
such as girls&#8217; basketball with a dozen titles (including this season)
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Sabrina Passos was a 2015 Professional Fellow from Latin America with ICFJ.&nbsp;
Passos is a project coordinator and innovation editor of Zero Hora
She is in charge of the digital production
where she worked as digital editor and executive editor of the newspaper in Santa Catarina
The agency create content for portals like IG
She graduated in journalism at Bom Jesus University
She completed her post-graduate studies in Digital Strategies
she finished a Master’s in Journalism and Brand Strategic Management
Both post-grad courses had international extensions
she participated in an executive program at the University of Florida
she was at the University of Miami and other Florida institutions
She is 32 years old and happily engaged to her beloved fiancé
She also loves her little puppy enjoys traveling the world
We exposed corruption and human rights abuses working in a cross-border network supported by ICFJ
P&nbsp; <a href="tel:2027373700">(202) 737-3700</a>F&nbsp; (202)&nbsp;737-0530E&nbsp; <a href="mailto:communications@icfj.org" title="communications@icfj.org">communications@icfj.org</a>
<a href="https://www.guidestar.org/profile/11-2724905" target="_blank"></a>
©2025 International Center for Journalists
The HydroHazards project explores locations
and vital societal functions exposed to multiple hydrometeorological events
The project devises methods and tools to assess the cascading effects that multiple events may have upon critical infrastructures and social groups
This brief provides an overview of these methods and tools and a summary of their application in a Swedish case study
Assessing Cascading Effects from Multiple Hazards: An Example from Sweden
<a href="https://doi.org/10.51414/sei2022.042" target="_blank">https://doi.org/10.51414/sei2022.042</a>
Much of the existing assessments of climate change impacts are large-scale simulations
Small- and local-scale assessments are necessary for nuanced understanding of possible impacts of multiple hazards on society
This view is needed for supporting local adaptation strategy and planning
societies’ dependency on critical infrastructure and vital societal services is increasing
due to growing system complexity and interconnectedness
these shifts are likely to increase societal vulnerability and impact adaptive capacity
HydroHazards zooms into the municipality of Halmstad to explore the likelihood of multiple hydrometeorological (i.e.
water and weather) events occurring sequentially or in the same location
we investigate the effects that climate change may have on the intensity and frequency of multiple hazards by focusing on extreme – low likelihood but high impact – events
we look at the cascading or so-called domino effects on critical infrastructures and vital societal services and how these effects may cause new social vulnerabilities
11 November 2022: This publication has been corrected to reflect a co-author&#8217;s name is Faisal Bin Ashraf
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A 53-year-old man has been charged with first-degree murder for bludgeoning an unhoused transgender woman to death as she slept on the front steps of the Miami City Ballet in Miami Beach
Miami-Dade Circuit Court Judge Mindy Glazer ordered Gregory Fitzgerald Gilbert to be held in prison without bail as he awaits trial for the murder of 37-year-old Andrea Doria Dos Passos
According to the <a href="https://www.miamiherald.com/news/local/crime/article288007530.html#storylink=cpy" target="_blank" rel="noopener">Miami Herald</a>
Glazer upped the charge against Gilbert from second-degree murder to first-degree murder based on actions that appeared to show intent
&#8220;It looks like he defiled the body by doing other things to the victim,&#8221; Glazer said
Glazer said a judge would likely also address a current probation violation against Gilbert
who has a history of convictions for various violent and non-violent crimes
Dos Passos arrived at the Miami City Ballet around midnight on April 21 and lay down on the steps to sleep
Surveillance video near the ballet hall reportedly captured Gilbert arriving and surveying the area
and repeatedly beat her head and face with the pipe while she slept
Gilbert was seen on surveillance video disposing of the pipe allegedly used to kill Dos Passos in a trash bin
A ballet employee discovered Dos Passos&#8217;s body at 6:45 a.m
Her body was partially covered by a sweater
and two wooden sticks had been placed into her nostrils
with one stick exiting her face just over her right eye
while the other appeared lodged in a nose cavity
She also suffered a puncture wound to her chest
Police issued a &#8220;be on the lookout&#8221; alert for a Black male in a black shirt
Detectives linked Gilbert to the crime based on a physical description of the man in the video and a prior arrest record
They located him at one of his known addresses
reportedly wearing clothing that matched the surveillance video
TV news outlet <a href="https://wsvn.com/news/local/miami-dade/man-arrested-in-connection-to-brutal-murder-of-transgender-woman-outside-miami-city-ballet/" target="_blank" rel="noopener">WSVN</a> reported that Gilbert was out on probation on the morning of the murder
There appears to be no connection between Dos Passos and Gilbert
and the motivation for the murder is unclear
Gilbert has not been charged with a hate crime
which could lead to enhanced penalties if he is convicted of the killing
there is no evidence to suggest that Andrea was targeted because of her sexuality or gender,&#8221; Miami Beach Police Chief Wayne Jones said in a statement
we understand the concerns within the LGBTQIA+ community
And I want to emphasize that MBPD is committed to ensuring the safety and well-being of all our community members.&#8221;
Dos Passos reportedly had been struggling with mental health issues since age 25
Victor Van Gilst told the <a href="https://www.miamiherald.com/news/local/community/miami-dade/miami-beach/article288118045.html#storylink=cpy" target="_blank" rel="noopener">Herald</a> that Dos Passos spent eight months at Agape
a Miami nonprofit that offers a residential treatment program for women struggling with substance abuse
She then moved to a halfway house in Miami Gardens
she was discharged from the psychiatric unit of Mount Sinai Hospital in Miami Beach
Ana Van Gilst told the Herald that she had asked her daughter if she wanted to return home
but Dos Passos told her she &#8220;wanted to be free.&#8221;
A  spokesperson for the city of Miami Beach said the city&#8217;s homeless outreach team and a contracted provider
had sought to connect Dos Passos with shelter options
but she &#8220;declined services&#8221; two separate times
Edward Summers, the executive director of the Miami Beach-based LGBTQ organization Pridelines, said he and other staffers had tried to connect Dos Passos with shelter beds, but she repeatedly declined, saying she didn&#8217;t want to be bound by curfews and other restrictions that <a href="https://www.metroweekly.com/2021/04/hud-withdraws-trump-era-revisions-restricting-shelter-access-to-transgender-people/" target="_blank" rel="noopener">shelters</a> typically impose on residents
She also said staying in a shelter wouldn&#8217;t allow her to be fully herself
Summers noted that many of Pridelines&#8217; LGBTQ clients have left shelters because of concerns over safety or due to harassment by other residents
noting that there are no LGBTQ-affirming homeless shelters in Miami-Dade County
&#8220;[Dos Passos] was really a free spirit and wanted to just live her life on her terms,&#8221; Summers said
more widely known by her drag persona Jiggly Caliente
has passed away following a "serious health setback."
Castro-Abejo recently battled a "severe infection," requiring hospitalization
according to an Instagram post from her family
She underwent surgery and had to have much of her right leg amputated
A post shared by Jiggly Caliente (@jigglycalienteofficial)
A transgender protester from Illinois was arrested for washing her hands in the women's bathroom at the Florida State Capitol
But it wasn't because she was outed or reported to the police by another person
20-year-old college student Marcy Rheintgen alerted Florida lawmakers of her intention to use the women's restroom in protest of the state's 2023 transgender bathroom ban
which prohibits transgender individuals from using bathrooms matching their gender identity in public buildings
A Tucson Walmart called the police on a Black "stud"-identified lesbian last month
claiming a man had entered the women's room
The two male Pima County sheriff's deputies accosted 19-year-old Kalaya Morton just after she had used a tampon and while she was in the stall still trying to pee
They demanded that she come out immediately
Even after she finished her business and exited the stall
lifting her shirt to show the two men that she was a cisgender woman
one of the male deputies still complained that Kalaya "looked like a man."
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Dos Passos&#39;s body was found outside the Miami City Ballet building
<a href="https://www.facebook.com/photo.php?fbid=104970824567806&set=pb.100051646660635.-2207520000&type=3" target="_blank">Andrea Doria Dos Passos</a>, 37, a <a href="https://www.advocate.com/transgender?utm_campaign=SmartLinks">transgender</a> woman who was experiencing homelessness
was found beaten to death Tuesday outside the Miami City Ballet building in Miami Beach
The attack on Dos Passos was caught on surveillance video and led to the arrest of Gregory Fitzgerald Gibert, 53, who is charged with second-degree murder, the <a href="https://www.miamiherald.com/news/local/crime/article287969500.html" target="_blank">Miami Herald</a> reports
An employee of the ballet company found Dos Passos lying on the ground about 7 a.m
The worker initially thought she was sleeping
then saw that she was surrounded by blood and called police
Surveillance video showed a man beating her with a pipe
and police matched the description to Gibert
who was on probation on charges including aggravated assault with no intent to kill and attempted robbery with a weapon
He had been sentenced to four years of probation on the charges just six days before the attack on Dos Passos
Police said they do not consider Dos Passos’s death a hate crime
but some are calling for prosecutors to add a hate-crime enhancement to the charges against Gibert
“We have no evidence indicating that she was targeted solely based on her sexuality and/or gender,” Officer Christopher Bess
the Miami-Dade County state attorney’s office’s hate crimes unit is reviewing the case “to see if Florida’s hate-crime enhancement is applicable to the specific situation,” as it does with every case
a spokesperson said in a statement to the paper
Flamingo Democrats, the Miami-Dade chapter of the Florida <a href="https://www.pride.com/lgbtq/?utm_campaign=SmartLinks" target="_blank">LGBTQ</a>+ Democratic Caucus
urged prosecutors to add the hate-crime enhancement
“The safety of all residents of Miami Beach and Miami-Dade County should be of the utmost importance
especially those in marginalized communities such as our transgender community,” said a statement from the group
Dos Passos’s stepfather, Victor Van Gilst, mourned her in an interview with <a href="https://www.cbsnews.com/miami/news/arrest-made-after-woman-was-beaten-to-death-in-front-of-miami-city-ballet-on-miami-beach/" target="_blank">Miami’s CBS affiliate.</a> “She had no chance to defend herself whatsoever,” he said
“I don’t know if this was a hate crime since she was transgender or if she had some sort of interaction with this person because he might have been homeless as well
The detective could not say if she was attacked because she was transgender
She has been struggling with mental health issues for a long time
going back to when she was in her early 20s
this is like a nightmare that turned in to reality
Andrea moved around a lot and even lived in California for a while
Rosa Passos with Kenny Barron and Ron Carter brings the iconic Brazilian vocalist and guitarist to the Appel Room for the first time since her sold-out 2016 appearance with NEA Jazz Master pianist Kenny Barron
Their spellbinding simpatico will be enhanced by Passos’ reunion with Ron Carter—also an NEA Jazz Master who bass virtuoso Stanley Clarke once described “as the most important bass player of the last fifty years.”—after their lauded 2003 “Entre Amigos” album
While Passos has been called the &#8220;female João Gilberto&#8221; she is a prolific and distinct vocalist and guitarist with a playful yet sophisticated style
marked by perfect pitch and spacious elegance
Enhancing this first-ever meeting of these three masters is first-call Brazilian drummer
You can purchase the 9:30 performances on March 24 and 25 as part of the 9:30 in The Appel Room series &#8211; three 9:30 Appel Room shows for $99 (includes all fees) for any seat in the house while seats are available
Your Appel Room ticket stub can be used for a free cover to that evening’s Dizzy’s Late Night Session
For more information, visit: <a href="https://2023.jazz.org/rosa-passos-with-kenny-barron-and-ron-carter">https://2023.jazz.org/rosa-passos-with-kenny-barron-and-ron-carter</a>
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This article appeared in the Culture section of the print edition under the headline “The winds of war”
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Georgia’s ruling party <a href="https://civil.ge/archives/589747">plans</a> to reintroduce <a href="https://www.hrw.org/news/2023/03/08/dark-day-georgias-democracy">highly controversial Russia-style “foreign agent”</a> legislation aimed at incapacitating civil society and independent media
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we need an EU that in words and actions protects civic space and sets the right standards
This text has been edited to reflect the correct contents of the draft law that the Georgian ruling party introduced to parliament
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International Biodeterioration and BiodegradationCitation Excerpt :Notably
these microorganisms play an essential role as biogeochemical reactors in nitrogen cycling (Dahibhate et al.
are a vital nitrogen sink that has the potential to eliminate approximately 6% of artificial nitrogen inputs to the environment (Mamidala et al.
Most studies have only focused on the genes and microbes of the partial nitrogen cycle
iScienceCitation Excerpt :Eutrophication not only changes the dynamics of organic C by affecting plant biomass and microbial processes
but also drives the marsh loss due to the reduction of geomorphic stability.19 Other human disturbances
can also alter the salinity and supply of sediment.20,21 In summary
the interactions between multiple anthropogenic activities are very complex; thus
understanding the changes in organic C accumulation rate (OCAR) and sources is fundamental to predicting the C sequestration potential in mangrove wetlands
Environment InternationalCitation Excerpt :For various periods
the peak OC level of XJ (1905–1991) matched the growth of the UL
Increased urbanization means the growing urban consumption of food and coal
which will push the frequency of soil excavation and the lateral migration of SOC (Passos et al.
LS grew with a slight pendulum to 1996; however
the second peak in the 1960s was likely the result of soil erosion induced by tree felling during the Great Leap Forward
which was mainly influenced by nature (meteorology and topography) (Bing et al.
Science of the Total EnvironmentCitation Excerpt :Mangroves grow in the coastal intertidal zones of tropical and subtropical regions and are mainly distributed along the southern coastal regions of China
acting as barriers to provide numerous coastal ecological protection services
Volume 6 - 2015 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fphys.2015.00257">https://doi.org/10.3389/fphys.2015.00257</a>
The need for simulation models to thoroughly test the inflammatory effects of dental materials and dentinogenic effects of specific signaling molecules has been well recognized in current dental research
The development of a model that simulates the transdentinal flow and the mass transfer mechanisms is of prime importance in terms of achieving the objectives of developing more effective treatment modalities in restorative dentistry
The present protocol study is part of an ongoing investigation on the development of a methodology that can calculate the transport rate of selected molecules inside a typical dentinal tubule
The transport rate of biological molecules has been investigated using a validated CFD code
In that framework we propose a simple algorithm that
given the type of molecules of the therapeutic agent and the maximum acceptable time for the drug concentration to attain a required value at the pulpal side of the tubules
can estimate the initial concentration to be imposed
Pre-clinical testing of dental materials to evaluate biologically their application includes studies in animals and humans. Human studies are most appropriate when investigating dentine-pulp reactions to various newly introduced substances and commercially available formulas. However, protection of patients from possible hazards presented by dental materials and the biological effects that they might have is needed (<a href="#B10">Murray et al., 2007</a>)
animals&#x00027; studies have raised concerns of their capability to predict human dental pulp reactions because of the fact that there are possible species variations
Thus the numbers of both clinical and animal screening tests must be minimized to make this form of testing legally and ethically acceptable
Development of several in vitro approaches simulating clinical conditions that are helpful to control parameters concerning experimental conditions is in progress during the last two decades
They concluded that an RDT greater or equal to 0.5 mm is necessary to protect the underlying odontoblasts form the operative trauma
an up to date literature review has revealed that there is no significant progress interpretation of flow phenomena inside the dentinal tubules
desirable to be able to suggest a new integrated computational approach that could adequately simulate both the fluid flow and diffusion characteristics inside the tubules
The present work is part of an ongoing investigation on phenomena related to the dental therapeutic practice and is expected to provide insights on the key issues of transdentinal regulation of the dentin-pulp complex functions
This article comprises the study of the diffusion of substances similar to dental materials components and bioactive agents used in today clinical practice and promising regenerative approaches respectively
we describe the basic principles for the development of a model that would simulate the flow and mass transfer in the dentinal tubules and propose a numerical methodology for investigating the mass transfer characteristics in a microtube (&#x003BC;-tube) that closely resembles a typical dentinal tubule geometry
The CFD code is validated using the outcome of an analytical solution as well as with experimental data acquired using the non-intrusive experimental technique &#x003BC;-LIF
The CFD simulations concerning mass transfer of chemical compounds confirm that:
&#x02022; the diffusion is a very slow process
&#x02022; large molecules penetrate at a lower rate inside the dentinal tubules compared to smaller ones
&#x02022; the mass flux inside a tubule increases by increasing the initial concentration of the substance and
&#x02022; the time required for the concentration of the signaling molecules to attain a predefined value at the pulp can be controlled by their initial concentration
in the framework of developing more effective treatment modalities in restorative dentistry we are able to provide an algorithm that
the size of the molecules of the therapeutic agent
&#x02022; the required drug concentration at the pulpal side of the tubules and
&#x02022; the maximum acceptable time to attain the aforementioned concentration
can estimate the initial concentration that must be imposed
The commercial CFD code ANSYS CFX&#x000AE; 15.0 is employed for the simulations, i.e., for solving the incompressible Navier-Stokes and mass transfer equations (<a href="#B8">McCabe et al., 2005</a>)
This paper tackles the problem of the diffusion of substances through a conical &#x003BC;-tube that simulates a typical dentinal tubule
before proceeding to the computational simulations
is common practice the CFD code to be validated
the theoretical and experimental study of the diffusion process inside the dentinal tubules is practically impossible
at an initial stage the flow through a cylindrical &#x003BC;-channel studied using the CFD code and the numerical results are compared with the analytical solution of Fick&#x00027;s Second Law
Experiments concerning the diffusion of a fluorescent dye in water are also performed in a glass capillary
The local dye concentration is measured by the non-intrusive &#x003BC;-LIF measuring technique and the acquired experimental data are compared with the CFD results
It is therefore quite reasonable to assume that the validated computational code can be applied for studying the diffusion of substances similar to potential therapeutic agents through a typical dentinal tubule
In this stage and in accordance with the dental clinic practice
no fluid outflow from the &#x003BC;-tube is assumed
The experiments were performed in a glass capillary (ID = 580&#x003BC;m
The measuring section was illuminated by a double cavity Nd:YAG Laser emitting at 532 nm
The fluid flux was measured by a high sensitivity CCD camera (Hisense MkII)
connected to a Nikon (Eclipse LV150) microscope
which moves along the vertical axis with an accuracy of one micron
A 10X air immersion objective with NA = 0.20 was used
For each measurement at least 20 images were acquired at a sampling rate of 5 Hz
Image processing and concentration calculations were performed using appropriate software (Flow Manager by Dantec Dynamics)
A typical procedure for &#x003BC;-LIF measurements consists of the following steps:
&#x02022; Determination of the relationship between the measured fluorescence intensity field I(x
&#x02022; Calibration experiments prior to the actual measurements using a series of aqueous Rhodamine B solutions with known concentrations
&#x02022; Image masking of the acquired images is also necessary in order to reduce noise and then an appropriate Region of Interest (ROI) is defined
at which the fluorescence intensity is measured
For our experiments the optical system was set to have a ROI of 300x580 &#x003BC;m
while the lens was focused on the middle plane of the capillary
Care was taken to ensure that the experiments are conducted at identical conditions with the calibration procedure
so as to minimize the uncertainty of the experimental procedure
After the calibration of the measuring system, the two liquids, namely water and the colored aqueous solution at C = 0.05 mg/L, were successively inserted into the capillary. A syringe pump (ALLADIN 2000) was employed for the suction of the two liquids inside the capillary (Figure <a href="#F2">2</a>)
Test-section connected with a syringe pump
It is very important that the fluids enter the capillary at a very low velocity so as to avoid mixing due to convection
although a small initial concentration distribution of Rhodamine B inside the capillary is unavoidable
After the two liquids have entered the &#x003BC;-channel
the syringe pump is turned off and the capillary is placed carefully under the microscope at a horizontal position for conducting the LIF measurements
The test-section remains connected to the syringe pump during the measurements to ensure constant pressure condition inside the &#x003BC;-channel
concentration measurements were performed at 10&#x02013;15 locations on the middle plane
at 1 mm from each other along the axis of symmetry of the &#x003BC;-tube
we can assume that the concentration is constant along the diameter of the &#x003BC;-tube
Thus the LIF measurement corresponds to the concentration at a cross-section of the conduit
The axial length x is normalized with respect to the tube length
L; thus x/L = 0 denotes the entrance of the capillary
The image processing of the LIF images comprises the definition of the mean image out of the set of 20 images acquired and their processing according to the LIF calibration record that has been created
appropriate numerical simulations that fully represent the initial experimental conditions are performed
In Figure <a href="#F3">3A</a> a typical comparison of CFD data with the corresponding results from the &#x003BC;-LIF technique is presented concerning the concentration inside the channel after t = 4 h. The dashed line represents the calculated final concentration value Ct inside the capillary for t = 8. In Figure <a href="#F3">3B</a> the two methods are compared with respect to the temporal concentration variation at two locations inside the capillary (x/L = 0.067 and 0.330)
Comparison of CFD data with the corresponding results from the LIF technique: (A) mass concentration distribution inside the capillary after t = 4 h and (B) mass concentration values for x/L = 0.067 and 0.330; error bars: &#x000B1;10%
The experimental results are in fairly good agreement (&#x0003C; 10%) with the CFD data
The discrepancy between the two methods may be attributed to the fact that the experimental data concern the mean concentration values that were measured at the applied ROI
while the corresponding values from the CFD results give the concentration at the center of a grid cell with an axial dimension of 5 &#x003BC;m
After comparing the data of the numerical simulations with the available experimental results from the &#x003BC;-LIF technique we can come to the conclusion that the CFD code is able to predict diffusion of substances through liquids in such small diameter conduits
The ability of the computational code to effectively simulate diffusional mass transfer in &#x003BC;-conduits is confirmed by comparing the CFD results with analytical solutions of the governing equations for molecular mass transport
Diffusion is the net movement of a substance from a region of high concentration to a region of low concentration
it is the movement of a substance down a concentration gradient
In steady state conditions the diffusive flux j of a substance driven by the concentration gradient in one dimension is given by the Fick&#x00027;s First Law (Equation 1):
&#x02202;C&#x02215;&#x02202;x is the concentration gradient and x is the distance in the direction of transfer
This equation follows the general rule that matter diffuses from a region of higher concentration to a region of lower concentration
The diffusion coefficient D is a function of temperature
and its units are in length squared per unit time
Fick&#x00027;s Second law is used to predict how diffusion causes the concentration to change with time
and in one dimension is given by Equation (2):
C the concentration which is a function of both location x and time t
To comply with the actual case of transdentinal diffusion of substances
there is need to apply a rigorous analytical equation
originated from the Fick&#x00027;s Second Law
that incorporates a zero flux boundary condition at x/L = 1
The new formulated analytical solution which is a sum of a cosine series is given by Equation (3):
M is the total amount per area of the diffusing species
L the channel length and Mt the final estimated concentration value inside the &#x003BC;-channel
Figure <a href="#F4">4</a> presents the comparison between the results of Equation (3) and the data obtained from the CFD simulations for two time periods (i.e.
The initial mass of the diffusate is located at x/L = 0
A very good agreement (&#x000B1;10%) exists between the experiments and the analytical solution with the corresponding numerical ones
we can conclude that the CFD code is capable of handling diffusion and mass transport phenomena in the microscale
Concentration distribution of a diffusate in a cylindrical &#x003BC;-tube
Comparison between CFD data and the corresponding results from Equation (3) for: (A) t = 0.5 h and (B) t = 3.5 h after the diffusate release
For studying the transdentinal diffusion, we use substances whose molecular sizes are the same as those of potential therapeutic agents that are used in dental clinic practice. The radius Rmin and the diffusion coefficient D of a protein can be determined by Equations (4, 5) (<a href="#B4">Erickson, 2009</a>)
where Rmin is given in nanometers and the molecular weight Mw in Daltons (Da) and
where k = 1.38 &#x000D7; 10&#x02212;16 g cm2 s&#x02212;2 K&#x02212;1 is the Boltzman&#x00027;s constant and T the absolute temperature
k is given here in centimeter&#x02013;gram&#x02013;second units because D is expressed in centimeter&#x02013;gram&#x02013;second
while &#x003BC; that stands for the solute viscosity is in g/(cm&#x000B7;s)
represents the radius of a smooth sphere that would have the same frictional coefficient f with a protein and is expressed in centimeters in this equation
the minimal frictional coefficient that a protein of a given mass would obtain if the protein was a smooth sphere of radius Rmin
then Rmin could replace Rs in Equation (5)
In Table <a href="#T1">1</a> some representative examples of substances or ions released from dental materials in use or experimentally designed bioactive agents are presented. Released monomers from resins (TEGDMA) or dental adhesives (HEMA) disturb cell functions including responses of the immune system, mineralization, and differentiation of dental pulp cells, or induce cell death via apoptosis (<a href="#B19">Schweikl et al., 2014</a>)
The role of bases and liners (zinc oxide-eugenol or calcium hydroxide or calcium silicate-based materials) indicated for pulp protection is still controversial in terms of molecules or ions diffusion through the exposed dentinal tubules
Furthermore biologically active molecules applied as possible therapeutic drugs with an appropriate delivery system (BMP-7) or endogenous growth factors released after dentin treatment with EDTA (TGFbeta) have shown important tissue specific activity for dentin-pulp complex regeneration
Representative traditional or experimental applications in the situation of exposed dentinal surfaces with the characteristics of released molecules or ions
In this computational study three different substances were used
The radius Rs of their molecules is in the range of 2.2&#x02013;22.0 nm and consequently the corresponding diffusion coefficient
in water at 37 C is in the range of 1.36&#x02013;0.14&#x000B7;10&#x02212;10 m2/s
The range of molecular sizes employed in this study corresponds to the size of actual bioactive molecules
BMP-7 is such a bioactive protein used in the dental clinic practice with approximately 50 kDa molecular weight and Rs of 2.2 nm
three initial concentration values for each diffusing substance are also employed
&#x02022; the initial diffusate concentration and
on the transdentinal diffusion characteristics
A grid dependence study has been also performed for the case involving the diffusate with the highest diffusion coefficient value
As the study comprises the time-dependent solution of diffusion
all simulations were run in transient mode
A time-step dependence study was also performed
to ensure that a suitable time step is selected for each simulation
the minimum number of calculation steps performed without jeopardizing the accuracy of the solution
The total simulation time for each run was set at 10 h as the diffusion process is expected to be extremely slow
The diffusion of a substance similar to the therapeutic agent BMP-7, through a dentinal tubule under different values of initial concentration has been studied. Figure <a href="#F5">5A</a>, which presents the therapeutic agent concentration at the bottom of the dentinal tubule, i.e., at the dentin-pulp junction, as a function of time, demonstrates the effect of initial substance concentration on the concentration change. Figure <a href="#F5">5B</a> shows the effect of the type of substance
on the concentration change at the pulpal area
(A) Effect of the initial substance concentration on the diffusion characteristics [t(1
2) time needed to reach a specified concentration value at the pulp] and (B) Effect of the molecular size on the diffusion characteristics
It is obvious that the diffusion rate is particularly low
since it takes more than 10 h for the concentration at the pulpal side to reach its final value
the first molecules of the substances do reach the bottom end
as the diffusion coefficient is a function of the size of the molecules
substances/proteins with larger molecules penetrate at a lower rate inside the dentinal tubules
It is worth noting that the time required for the concentration of signaling molecules to attain a specific value at the pulp can be controlled by their initial concentration
By increasing the initial concentration of a potential therapeutic agent
the mass flux inside the dentinal tubule increases and as a result the signaling time of the molecules may also decrease
since it gives the possibility to predict the behavior of each therapeutic agent prior to its application on the dental clinic practice
Obviously it is important to be able to predict the final concentration of an applied therapeutic agent. In this case one must run the relevant CFD simulation to produce an appropriate curve like the one presented in Figure <a href="#F5">5</a>
this is not a trivial procedure to be used in every day practice
an effort was made to propose a simple correlation that could predict with reasonable accuracy the temporal concentration value at the pulp through the dentinal tubules
as a function of the diffusion coefficient of the substance
The proposed correlation can be then used to estimate the maximum required time for the diffusion process to reach steady state condition
when the concentration of the substance has the same value along the tubule
has been formulated by data fitting on the computational results and incorporates the dimensionless time t*:
In Figure <a href="#F6">6</a> the computational results concerning the dimensionless concentration at the pulpal area vs
the dimensionless time t* are compared with the values predicted by Equation (6)
Comparison of CFD results on the transdentinal diffusion of a protein (Rs = 2.2 nm
C0 = 0.10 mg/mL) with the prediction of Equation (6)
The data are in excellent agreement with the prediction of the proposed correlation and consequently one can draw the conclusion that Equation (6) is suitable for estimating the concentration at the pulp during the diffusion process
the proposed correlation can be applied for substances with various molecular sizes Rs and hence different diffusion coefficients
since diffusion in dentinal tubules can be safely considered one-dimensional
In the present protocol study a stepwise procedure for estimating the diffusate concentration to be imposed at the dentin-enamel junction so as the drug concentration to attain a required value at the pulpal side of the tubules is proposed given the geometrical characteristics of the dentinal tubules:
&#x02022; Estimate the diffusion coefficient of the agent through Equations (4
&#x02022; Choose the required value of the drug concentration
&#x02022; Choose the maximum acceptable time
for the drug concentration to attain the required value Cr
&#x02022; Calculate the initial concentration C0 of the substance by solving Equation (6) either numerically or graphically (Figure <a href="#F7">7</a>)
A detailed example concerning the application of this stepwise procedure, based on Figure <a href="#F7">7</a>
for the estimation of the initial concentration of the therapeutic agent (Co)
in order to achieve the required final concentration (Cr) after an acceptable time (t) is given hereafter
&#x02022; A typical protein with diameter Rs = 2.2 nm is considered
&#x02022; The diffusion coefficient D of the protein calculated by Equation (5) is 1.36&#x000B7;10&#x02212;10 m2/s
&#x02022; A typical length (L) of a dentinal tubule can be considered to be 2.5 mm
&#x02022; Using the aforementioned values and Equation (6) one can plot the corresponding curve (Figure <a href="#F7">7</a>)
&#x02022; If it is desirable for the required drug concentration value to reach the pulp within 2 h
&#x02022; From Figure <a href="#F7">7</a> the ratio Cr/Ct = 0.25 is determined
&#x02022; As the required effective drug concentration (Cr) is dictated by the dental clinic practice
the final concentration (Ct) can be calculated as Ct = Cr/0.25
for a given Ct and the corresponding mass balance (drug quantity and tubule&#x00027;s dimensions one can easily estimate
where Vt is the total volume of the tubulus and the drug)
the initial concentration of the drug C0 to be imposed at the DEJ
Following the stepwise procedure and assuming that Ct = Cr/0.25 for the required effective concentration at the pulp for all the therapeutic substances of Table <a href="#T1">1</a>, the corresponding critical time are calculated through Equations (6, 7) and are presented in Table <a href="#T2">2</a>
Critical time for Ct = Cr/0.25 for various therapeutic agents
In the present study we propose a simple algorithm which
An example on the application of the proposed methodology is given in the stepwise procedure
We must point out here that our study deals with a sole microtube that represents a typical dentin tubule that bears no obstructions of any type
&#x02022; The geometry comprises a typical dentinal tubule 2.5 mm long and 1 and 3 &#x003BC;m in diameter at the dentin-enamel and the dentin-pulp junction respectively
&#x02022; The diffusion can be safely presumed one-dimensional
&#x02022; Molecules/ions that enter a dentinal tubule do not react with each other
&#x02022; The presence of large plasma proteins underlying the pulp
such as fibrinogen (Mw &#x0003E;300 kDa) or immunoglobulins (150 kDa) are not expected to impede the diffusion of therapeutic agents from the DE junction to the pulp
However, the overall dentin permeability may be reduced due to occlusions of one or more dentin tubules and for this reason one must be able to apply a typical value (i.e., coefficient) of potential permeability, but this is beyond the scope of the present study. In the literature several factors that may lower the dentin permeability are introduced. <a href="#B16">Pashley and Tay (2012)</a> mention that tubules in the dentin of mature teeth can be totally occluded
partially occluded and patent due to the presence of organic fibers and inorganic crystals or that smear layer and smear plugs that are produced during operative dental treatment may cover the exposed dentinal surface and seal the dentinal tubules
Understanding the central role that fluid dynamics plays in the maintenance of vitality and function of the dentin-pulp complex
scientists can address the problems of delivery and control of potent toxic effects of molecules released from dental materials and of biologically active molecules used in tissue engineering approaches
Both advantages offer opportunities for development of new therapies in dental clinical practice
The authors would like to thank the Lab technician Mr
Lekkas for the construction and installation of the experimental setup
Stogiannis are also kindly acknowledged for their valuable comments and suggestions
This research has been co-financed by the EU (ESF) and Hellenic National Funds Program &#x0201C;Education and Lifelong Learning&#x0201D; (NSRF)-Research Funding Program: &#x0201C;ARISTEIA&#x0201D;/&#x0201C;EXCELLENCE&#x0201D; (grant no 1904)
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Received: 29 July 2015; Accepted: 02 September 2015; Published: 15 September 2015
Copyright &#x000A9; 2015 Passos, Mouza, Paras, Gogos and Tziafas. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
provided the original author(s) or licensor are credited and that the original publication in this journal is cited
*Correspondence: Spiros V. Paras, Department of Chemical Engineering, Aristotle University of Thessaloniki, University Box 455, GR 54124 Thessaloniki, Greece,<a id="encmail">cGFyYXNAYXV0aC5ncg==</a>
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United Nations Member States adopt <a href="http://www.pops.int/TheConvention/ConferenceoftheParties/OverviewandMandate/tabid/578/Default.aspx">the Stockholm Convention.</a> The Convention
aims to protect human health and the environment from chemicals that persist for long periods in the environment
103 countries sign the Cartagena Protocol on Biosafety
a supplement to the Convention on Biological Diversity
The international agreement aims to ensure the safe handling
transport and use of organisms that have been modified using modern biotechnology
The Protocol aims to guard against adverse effects on biological diversity and risks to human health
<a href="https://www.un.org/en/development/devagenda/millennium.shtml">The Millennium Declaration</a> outlines the Millennium Development Goals
Millennium Development Goal 7 sets specific environmental targets
forest cover and access to safe drinking water
United Nations Member States adopt <a href="https://www.unglobalcompact.org/what-is-gc">The United Nations Global Compact</a>
With more than 8,500 signatories from 135 countries
the initiative aims to encourage businesses worldwide to adopt sustainable and socially responsible policies and to report on their implementation
The United Nations launches the <a href="http://www.pic.int/TheConvention/Overview/TextoftheConvention/tabid/1048/language/en-US/Default.aspx">Rotterdam Convention</a> to promote shared responsibilities in relation to the import of hazardous chemicals and pesticides
The General Assembly convenes a Special Session focused on the environment. Known as <a href="https://www.un.org/en/ga/search/view_doc.asp?symbol=A/RES/S-19/2">Earth Summit +5</a>
its aim is to accelerate the implementation of Agenda 21 and launch a new global partnership for sustainable development
<a href="https://www.unccd.int/convention/about-convention">The United Nations Convention to Combat Desertification</a> enters into force
is the only legally binding international agreement that links environment and development to sustainable land management
In a victory for ecosystem research, parties agree to the Convention on the Protection and Use of Transboundary Watercourses and International Lakes, also known as the <a href="https://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&amp;mtdsg_no=XXVII-5&amp;chapter=27&amp;clang=_en">Water Convention</a> on 17 March
<a href="https://wedocs.unep.org/bitstream/handle/20.500.11822/28288/WMO_UNEPCC.pdf?sequence=1&amp;isAllowed=y">UNEP and the World Meteorological Organization</a> launch the <a href="https://www.ipcc.ch/">Intergovernmental Panel on Climate Change</a> with the objective of providing governments at all levels with scientific information that they can use to develop climate policies
<a>The World Commission on Environment and Development delivers the </a><a href="https://sustainabledevelopment.un.org/content/documents/5987our-common-future.pdf">Brundtland Report</a> to the General Assembly
ushering in a new approach to environmental action focused on the concepts of sustainable development
The Governments of Botswana, Mozambique, Tanzania, Zambia, and Zimbabwe adopt <a href="http://www.fao.org/3/w7414b/w7414b0j.htm">the Zambezi River Action Plan.</a> Covering eight countries across southern Africa
the plan sets a new standard for transboundary water resources management
All 197 United Nations Member States adopt the <a href="https://ozone.unep.org/treaties/montreal-protocol">Montreal Protocol on Substances that Deplete the Ozone Layer</a>
The landmark multilateral environmental agreement regulates the production and consumption of nearly 100 human-made chemicals referred to as ozone-depleting substances
The Protocol is to date the only United Nations treaty to be ratified by every country on Earth
UN General Assembly designates the 1980’s as the <a href="https://apps.who.int/iris/handle/10665/61592">International Drinking Water Supply and Sanitation Decade</a>
once considered to be an abundant resource
is becoming scare in several geographical areas
Only 2.8 per cent of earth’s water is fresh water
The world is in unanimous agreement on the need to save and conserve water
In partnership with the International Union for the Conservation of Nature and the World Wildlife Fund, UNEP publishes the <a href="https://digitallibrary.un.org/record/91329?ln=en">World Conservation Strategy</a>
This landmark document defines the concept of sustainable development and shapes the global sustainable development agenda
Seventeen countries agree to cooperate in research and support protections on 120 migratory species and establish the <a href="https://www.cms.int/">Bonn Convention on Migratory Species</a>
The United Nations <a href="https://treaties.un.org/Pages/ViewDetails.aspx?src=TREATY&amp;mtdsg_no=XXVII-1&amp;chapter=27&amp;clang=_en">Convention on Long-range Transboundary Air Pollution</a> establishes the world’s first legally binding instrument to address regional air quality
Sixteen countries across the Mediterranean agree to promote integrated coastal zone management and adopt <a href="http://web.unep.org/unepmap/">the Mediterranean Action Plan</a>
The world celebrates the first <a href="https://www.worldenvironmentday.global/about-world-environment-day">World Environment Day</a> on 5 June
Kenya’s first President Jomo Kenyatta inaugurates the headquarters of UNEP at Kenyatta International Convention Centre
The first meeting of the <a href="https://wedocs.unep.org/bitstream/handle/20.500.11822/17274/73_06_GC1_report_%20K7309025.pdf?sequence=1&amp;isAllowed=y">Governing Council of UNEP</a> takes place in the Palais des Nations
United Nations Member States adopt <a href="https://www.cites.org/eng">The Convention on the International Trade in Endangered Species of Wild Fauna and Flora</a>
The United Nations Environment Programme (UNEP) is established after the first <a href="https://undocs.org/en/a/res/2997(XXVII)">United Nations Conference on the Human Environment</a> held in Stockholm
In a first-of-its-kind survey of global environmental issues, the Secretary-General’s report on <a href="https://digitallibrary.un.org/record/729455?ln=en">Problems of the Human Environment</a> issues a stark warning: “If current trends continue
In one of the earliest organizing documents of multilateral environmental action, the United Nations Secretary-General delivers a report, <a href="https://digitallibrary.un.org/record/729430?ln=en">Activities of United Nations Organizations and Programmes Relevant to the Human Environment</a>
The report lays the groundwork for the establishment of the United Nations Environment Programme (UNEP) as the world’s leading environmental authority
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it presents music shows and movies (in its previous incarnation
it was a movie theater with quite a bit of history)
Most of the regulars are connected to the city&rsquo;s cultural industry
and the bar has a queer-friendly environment
Passos Manuel is a place both for quiet evenings of chatting with friends in the upper floor or in private rooms (those tiny rooms hidden behind the counter) and for going wild on the downstairs dance floor
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Many politicians try a change of style during the course of their careers
Few have done so more dramatically – or more successfully – than Pedro Passos Coelho
Nowadays Passos Coelho comes across as modest
His counterparts around the conference table of the European Council might be surprised to learn that he was once a university drop-out
Early political successes and failures – and a career in management consulting –changed him
Yet beneath the change of style it is still possible to discern some traits that have remained constant: implacable stubbornness
a liberal vision for Portugal and a proximity to the grass-roots of Portugal’s centre-right
Passos Coelho is only a few years older than modern Portuguese democracy
which overthrew dictatorship as late as 1974
That same year Passos Coelho and his parents had come back from Angola (which became independent in 1975)
Passos Coelho joined the youth wing of the Partido Social Democrata (PSD) as a 14-year-old and proved so precocious that in 1981
the youth movement – a powerful body within the national party – nominated him to the national board of the PSD
That gave rise to a thorny legal issue: could a minor (he was then 17) sit on the board of a public association
but Passos Coelho is still the only one to have done so
when he was elected president of the youth movement at the age of 26
Passos Coelho had accumulated nearly a decade in national politics
recalls that: “His appointment as president of the youth movement was seen as the arrival of the new generation.” He adds that Passos Coelho had a “very youthful image”
The new youth leader championed progressive issues such as anti-discrimination and sexual equality laws
he became known nationwide for criticising his party leader Aníbal Cavaco Silva
the 27-year-old entered the national parliament as an MP for Lisbon
Although António Guterres’s socialists won the 1995 elections
Passos Coelho’s advancement continued: he became deputy leader of the PSD members in parliament and the party’s spokesperson
Passos Coelho became increasingly “disenchanted” with the PSD’s leadership
When Anibal Cavaco Silva resigned as prime minister in 1995 to run for the presidency (which he won in 2006 and again in 2011)
Passos Coelho supported José Manuel Barroso’s failed bid to lead the centre-right party
when Barroso was elected party leader (becoming prime minister three years later)
Passos Coelho left national politics that year and largely disappeared from the public eye
Perhaps he was making up for that excessively political youth
When Passos Coelho and his family returned from Angola they lived in Vila Real in Portugal’s north
Passos Coelho has a reputation for being formidably stubborn and for keeping his “heart in his mouth”
But increasingly politics kept him out of the classroom and he eventually dropped out of university in his early twenties
She represented Portugal twice in the Eurovision song contest
and once auditioned for a baritone role in a musical.)
But when Passos Coelho left politics in 1999 it was not to indulge this artistic and bohemian side of his character
learning cost-cutting and restructuring techniques that would prove useful when he took up office as prime minister
He worked at the investment holding company Fomentinvest
Passos Coelho attempted a return to the political fray
One year later the centre-left government of José Socrates
with Portugal in the grip of an economic crisis
Passos Coelho made extensive use of social network campaigning
The PSD won 39% of the votes and formed a coalition government with the centre-right Centro Democrático e Social-Partido Popular
But the eurozone crisis that had brought him to power has also defined his premiership
His room for manoeuvre has been circumscribed by the €78 billion loan granted to Portugal by the European Union and the International Monetary Fund to save the country from economic collapse
Implementation of the stringent austerity conditions attached to the bail-out proved very unpopular
As the government has cut public-sector salaries and jobs
its support in the opinion polls has plummeted
Critics of Passos Coelho point out that the prime minister enforcing Portugal’s most radical programme of reforms since the dictatorship has never previously held public office
They have attacked his government for being too reliant on technocrats
director of research at the European Central Bank
who was his finance minister but stepped down last year
a professor and former advocate general at the European Court of Justice
One of Passos Coelho’s most trusted colleagues is Carlos Moedas
a 43-year-old former Goldman Sachs banker who is tasked with implementing the bail-out conditions
Despite the adverse opinion polls and the criticism
a stubborn Passos Coelho has persevered with the reforms and is not shy of defending them
often “in the greatest detail” and like a “professor”
The government has already committed itself to continue reforming the economy after the bail-out programme ends
Portugal’s “ownership” of the bail-out programme has been held up by EU leaders as a model for others to follow
Passos Coelho himself remains very popular within the PSD (and wildly popular among the youth movement)
This is largely because he shuns the glamour and luxuries of political life
A family man with three daughters (including one with his second wife
Passos Coelho lives in a relatively poor neighbourhood of Lisbon
drives his own car and continues to takes his holidays in the same small seaside town
Passos Coelho will lose the next election in 2015
He has demonstrated plenty of resilience and knows how to make a comeback
Russian aide says date has not yet been set
The formation of an agri-chemical giant affects everything from pesticides to data
The move is unlikely to assuage the wrath of European environmentalists and nongovernmental organizations
Group funded by search giant’s opponents examines Google&#8217;s efforts to shape policy debate
<a href="https://i0.wp.com/theimaginativeconservative.org/wp-content/uploads/2013/02/John-Willson-hat-150x1501.jpg?ssl=1"></a>
Just after the execution of Sacco and Vanzetti in 1927
“All right we are two nations.”  Dos Passos was still a socialist America hater at the time
and seemed to represent the future in a year that Calvin Coolidge
and it is no longer necessary to celebrate the silly notion that the United States is the land of the free and the home of the brave
a few years after his “two nations” statement
saw close up what the country could become under a “New Deal,” and became a libertarian patriot
a flip-side ideologue who thought that you could do anything you want under a practically-no-government regime better than under a total government regime
I know that my Confederate friends would say that two nationhood radically predated Dos Passos
but that is not the argument I wish to make here
Call it a coincidence, but on the day after our annual nationalistic pridefest I received a fund-raising letter from Tom Fleming, the brilliant editor of Chronicles: A Magazine of American Culture, and a review copy of the brilliant writer Richard Gamble’s new book, <a href="https://smile.amazon.com/dp/1441162321" target="_blank">In Search of the City on a Hill: The Making and Unmaking of an American Myth</a>
Fleming says that “the modern world is predicated on the elimination of all distinctions
religion&#8211;all have to be destroyed or at least ignored
grammar&#8211;these are the true enemies of the great god Equality.”  Mr
Gamble’s book is about the misuse of a metaphor
its separation from the Bible in which early Americans believed so fervently
and put to the use of a nanny state and world empire
 Equality is itself a metaphor when transferred (the original Greek meaning) from the spiritual to the political realm; and politics is what has happened to everything in the modern world&#8211;now even and especially the family
To base public policy on a notion so manifestly without particular meaning as Equality
and to insist that a nation that does so is somehow heaven-blessed
 To think of a nation which has murdered over fifty million of its unborn children in the name of “choice” as “the greatest nation on earth” is the very definition of hubris
In both respects the cultural cry is for diversity (to be enforced by the state
Fleming as “the uniqueness of every individual who is to be exactly like every other absolutely unique individual.”  And woe to the individual who takes issue with the series of wars undertaken in the name of peace and responsibility for a chaotic world
once the province of progressive Democrats but in recent years made thoroughly bipartisan
ultimately incompatible (can you have a basketball team that is both equal and diverse?) and impossible to attain
is that the progressive thrust for Equality isn’t about equality&#8211;nobody really believes in it&#8211;but about power
 How many people do you know who are pining away for every neighborhood to be made up of the perfect mixture of tall and short people
every sexual arrangement that ever existed
these are actually things that congresses debate
 They are also things about which some folks get angry with me for saying
the inhabitants of the other nation get angry
had something very specific in mind when he cut the other half off
both the Left and the Right throw thunderbolts that are only what Lionel Trilling once called “irritable mental gestures seeking to resemble ideas.”  Herewith I offer five observations from news stories that appeared today (Thursday
July 5) and pertain to the general ideas expressed above
The AP reports a juicy thing from Anne Romney: Mitt is considering a woman (gasp!) for Vice President
Serena Williams won her way into her seventh Wimbledon final with a career high 24 service aces
This is a story about one of the great athletes of our time
doing something that very few people in any walk of life achieve
Janet Napolitano tries hard to say that our tough summer temperatures are about “climate change” without saying it
The other nation has made “climate change&#8221; into a religion
The Tom/Katie divorce is showing that Scientology is weird
 How long before this becomes a major issue of religious freedom
unlike what Catholics have been talking about lately
Or about what we won’t talk about in the proliferation of Muslim schools
WikiLeaks is putting out a couple of thousand documents about Syrian “crisis.” Good
 Maybe it will help slow down the rush to more war in the middle east
which is the main source of quite a few of our present troubles
But maybe it will give the other nation more excuse for slaughter
Yesterday Chris Rock (who the heck is he to judge anybody?) said something about “white Americans” independence
I won’t apologize to anybody about being white
about having ancestors who go back to the 1600s; about owning guns
teaching in a college that has a clearly defined commitment to the liberal arts
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I wonder how such ideologies came to triumph over real life for so many
I also wonder if it began once we no longer needed to spend most of our time staying alive and had spare time to daydream and meddle &#8211; say
a friend of &quot;Dos&quot; as he called him
presumably in the laten 30s or 40s when both had tired of leftism
the Right is not &quot;conservative&quot; and the Left not &quot;liberal&quot;
I can more readily converse with an intelligent liberal than with a knotheaded Rightist.In the musical &quot;1776&quot;
while it deliberately skewers men of substance and property (&quot;cool
it also has a gentleman from Georgia quote Burke on the duty of a representative of the people to give them his best judgment rather than follow the popular opinion.Thank you for providing your best judgment.I do not like to hide behind the anonymity of the Internet
Lewis in his clever essay &quot;Screwtape Proposes a Toast&quot; offers prophetic insights that are closely aligned with what you are explaining in this article
  &quot;As a result you can use the word democracy to sanction in his thought the most degrading (and also the least enjoyable) of human feelings
not only without shame but with a positive glow of self-approval
The feeling I mean is of course that which prompts a man to say I&#39;m as good as you
 The first and most obvious advantage is that you thus induce him to enthrone at the centre of his life a good
I don&#39;t mean merely that his statement is false in fact
that he is no more equal to everyone he meets in kindness
and good sensethan in height or waist measurement
I mean that he does not believe it himself
No man who says I&#39;m as good as you believes it
Lewis but this quote from CJH is over the top
 This idea that democracy is somehow an idea of satan implanted into the minds of modern man is not rational
 This is not to say that our Democracy doesn&#39;t have problems but it is the best system we have today
Karl Popper&#39;s &quot;open society&quot; is closer to the truth
 This idea that men in ages past were somehow &quot;more moral&quot; doesn&#39;t understand the human predicament
We are sinners and each day is a never ending quest to figure out how to be &quot;good&quot;
 I find many things reprehensible about modern society but I can do the same for any generation or age
 I find it interesting that &quot; democracy&quot; is being attacked on all fronts; liberals
 I guess my whole point is that the problem is not a political problem but a human problem
a variety of conservative and libertarians now approach democracy from a position similar to lewis&#39;s; some think that a single royal family of leeches cost less than many political parties full
and some look to a constitutional democracy as the best system
increasingly i think that churchill&#39;s beaten-to-death saying of democracy as the least worst is flummery
i do agree with screwtape that democracy encourages the kind of barbarianism under which no man recognises any betters or reason for self-improvement
i used to think this was merely due to poisonous progressivism
but now i think that it is a natural outcome of democracy
we may well ask if the american experiment was ever doomed to fail by dint of being based on an ideology (at one level) painted over Kirk&#39;s Revolution as a conservative reaction
In this sense a drop of Enlightenment spoiled the otherwise sensible brew
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