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Thanks to COVID-19, comedians are trapped at home like the rest of us, so we decided we would do something a little different from our usual “Follow Friday” column while we’re all isolating
Instead of interviewing up-and-coming comedians we love on Twitter
we’re going live on Instagram every week to check in with some of our favorite people in comedy to get a firsthand look at how they’re handling the pandemic
So welcome to our new version of the column
now titled “Follow (From a Safe Distance) Friday.”
This week I got all done up to catch my light with Nika Lomazzo (the podcast Best Mistakes
cyberflirting with the disgraced former mayor of Fall River
Massachusetts) for a chat about how she’s doing at the start of yet another pandemic winter
She told us the tale of her run for Rhode Island state representative at the tender age of 22
waxed poetic on the topic of platonic soul mates who also kiss on the mouth
and encouraged us all to make mistakes (and then share them with her so she can discuss them on Best Mistakes
which she co-hosts with comedian Anya Volz)
She also gave some excellent advice about how to maintain as healthy a balance of chaos in life as she does: “Be as real with yourself as possible; do constant
Being chaotic in a controlled setting is a lot of fun
but it takes a lot of work to be this chaotic
Find that friend who you feel absolutely no judgment from
You can find Lomazzo on Twitter and Instagram at @NikaLomazzo.
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was running for City Council in the 12th Ward
It was this time last year that Kat and I had our first official girls night
We talked about our love for the city of Providence
and both chose to make our home after spending time in other places
I was captivated and drawn in by the young womxn sitting across from me as she spoke with effervescence about her past as a former intern with the city of Providence
her work as a student organizer at the University of Madison Wisconsin
and her future political aspirations to serve her Providence community and fight with fierce passion for a city she loved
From that night on I have not stopped sharing with anyone who will listen how much I admire this womxn
but like many young people in my generation
I didn’t access my full passion for advocacy until the 2016 presidential election
While Kat was organizing at the University of Wisconsin for gun safety and student rights
I was at the New School in Manhattan organizing for the Bernie Sanders campaign and serving as a student senator
during which time I advocated for accessibility and students rights for trans and nonbinary students
Shortly after I returned to Providence from New York
Donald Trump won the presidential election
I couldn’t bring myself to leave my apartment; I called out of work
Here was a womxn so much like myself who was turning her rage into a call to action
During that first summer of our friendship
Kat and I bonded in the deepest way I have ever experienced
Both of us are passionate young womxn who have felt silenced in one way or another throughout our lives
and we spent that summer fanning the flames of our shared vision for Providence and the country
unimpeachably dedicated to fighting a system that doesn’t take young people
Other than the spoken-word poetry I was performing around Providence
I couldn’t find tangible ways to put my pain into action
Nika?” I’d thought about it for a few years
a 22-year-old trans womxn would ever find a path to running for office without being the butt of countless jokes
“I’m an activist — running for office isn’t for me.” But Kat persisted
inviting me to fundraisers and womxn's caucus meetings
essentially taking on the role of being my professional hype girl
This is what Kat does best — she advocates for people to live up to their fullest potential and doesn’t give up until you see that potential for yourself
On a whirlwind evening in November 2017, as my phone buzzed with notifications that Danica Roem had won her election in Virginia and would go on to serve as the first openly trans state legislator in the country
I decided to run for state representative in Providence
As I stood in the kitchen at my waitressing job
I sent Kat a quick text that I was planning to run for office: “I’m going to do it
I’m going to be the next Danica Roem.” Within 24 hours
They had all heard of me because of Kat Kerwin
who — even after she’d returned to school in Wisconsin — was still advocating for me
When I dropped out of the race for state representative in Providence’s 8th District
the natural next step was to work on Kat’s campaign
being the smartest person I knew when it came to politics
even more because of her commitment to ethical government and inclusivity for all
Months passed as Kat and I worked side by side to get her elected
no matter what we had been doing the night before
Many afternoons were spent stuffing envelopes and talking strategy in Kat’s apartment
On weekends we went out to decompress after a week of campaigning
but politics were never far from our minds
During those months we would end our days together and talk about how surreal our reality had become
stories we will one day pass down to our daughters (who will absolutely be best friends)
We grew together and became even closer than I thought possible
like every victory she had along that campaign trail was my own
I watched Kat succeed through sheer force and willpower
and it sent a fire through me even in the searing summer heat
I vowed I would knock on as many doors as I could
Working on your best friend’s campaign for city council in your early 20s isn’t something everyone gets to do
I hope this becomes a reality for millennial and Gen Z youth across the country
This effectively secured Kat’s position as the next City Council representative in Ward 12
That night Kat found out that she would be the next councilperson and the first womxn to represent her ward
I take radical pride in having helped her surpass the odds and smash a glass ceiling for young womxn across the city and state
I cried from sheer happiness and excitement because I finally had faith that an elected official would fearlessly battle any and all mechanisms of the machine that keep the most marginalized people down
I saw a new future for millennial and Gen Z youth
a future that will serve to inspire and empower us
I have a totally different lived experience than my best friend
With her layers of cis heterosexual privilege
she could have easily turned a blind eye to the injustices I face every day
she has the uncomfortable conversations with her peers
she listens to the voices that go unheard all too often
Working on Kat’s campaign was the privilege of a lifetime
a movement in our state of Rhode Island has been created
one dedicated to passing the mic to youth organizers
and to live in a city that will go on to elect such a fearless leader as one of our next city councilors
Here is to more and more young womxn running for office across the country
Here is to more best friends working together in perfect duality to bring a shared vision to life
And here is to a continuation of smashing the patriarchal boys club that says it impossible for bubbly
and the millennial womxn and femmes are stepping onto the shore
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Related: Why Young People Should Vote
Volume 10 - 2016 | https://doi.org/10.3389/fnbeh.2016.00208
Exposure to inadequate nutritional conditions in critical windows of development has been associated to disturbances on metabolism and behavior in the offspring later in life
a known regulator of energy expenditure and adaptive behaviors
in the modulation of these processes is unknown
we investigated the impact of exposing rat dams to diet restriction (20% less calories than standard diet) during pre-gestational and gestational periods on: (a) neonatal outcomes; (b) endocannabinoid content in hypothalamus
hippocampus and olfactory bulb at birth; (c) metabolism-related parameters; and (d) behavior in adult male offspring
We found that calorie-restricted dams tended to have a reduced litter size
although the offspring showed normal weight at birth
Pups from calorie-restricted dams also exhibited a strong decrease in the levels of anandamide (AEA)
arachidonic acid (AA) and palmitoylethanolamide (PEA) in the hypothalamus at birth
pups from diet-restricted dams displayed reduced levels of AEA in the hippocampus without significant differences in the olfactory bulb
body weight and adiposity in adulthood as well as increased anxiety-related responses
We propose that endocannabinoid signaling is altered by a maternal caloric restriction implemented during the preconceptional and pregnancy periods
which might lead to modifications of the hypothalamic and hippocampal circuits
potentially contributing to the long-term effects found in the adult offspring
an optimal weight gain during pregnancy seems critical to avoid adverse neonatal outcomes
monitoring the maternal nutritional status in the early stages of the pregnancy
and determining whether the offspring are at risk of developing metabolic disorders later in life represent a crucial point to investigate
These events may occur independently of the pre-pregnancy maternal body weight or whether an adequate maternal nutrition is provided in the later phases of pregnancy
further investigation is necessary to clarify the role of the endocannabinoid system in these processes
we investigated the impact of a moderate maternal caloric restriction
implemented during the preconceptional and pregnancy period
on the levels of endocannabinoids and N-acylethanolamides (NAEs) in brain structures involved in metabolism and emotional responses
The neonatal outcomes were also assessed and the offspring were followed until adulthood to determine the impact of maternal diet on metabolism-related parameters and behavior
We propose that endocannabinoid signaling can be altered by a moderate calorie-restricted diet implemented before pregnancy and during pregnancy
and this alteration might be associated to metabolic and behavior abnormalities in the offspring later in life
This study was approved by the Animal Ethics Committee of the Complutense University of Madrid
experiments were performed in compliance with Spanish regulations (RD 53/2013 178/2004) and with the European Directive 2010/63/EU on the protection of animals used for scientific purposes
The study was carried out initially in adolescent female Wistar rats (Harlan
Animals were allowed to acclimate for at least 4 weeks before the diet assignation
Rats were handled and individually housed at a 12 h light-dark cycle with temperature of 22 ± 1°C
food intake and body weight gain were monitored weekly
animals were randomly assigned to control (n = 9) or caloric restriction diet (n = 15)
no statistical significant difference in body weight among groups was found (average weight 240.7 ± 3.4 g)
Water was provided ad libitum in both animal groups
the males were returned to their cage and restricted dams carried on with their assigned diets
vaginal smear was evaluated to detect the presence of vaginal plug or spermatozoa
The day these signs of successful mating were found
was designated as gestational day 0 (GD 0)
the overall procedure was repeated in the following proestrus period
During the gestational period, food intake and weight were measured daily and female rats were maintained on the calorie-restricted diet until the GD 20, 2 days previous to birth (GD 20), when restricted diet ended (Figure 1)
The birth day was defined as postnatal day 0 (PN0)
The remaining pups were quickly sacrificed by decapitation and brains were collected for further endocannabinoid analysis
Calorie-restricted rat dams received 80% of calories provided to the control group daily according to body weight (food restriction of 20%)
they were allowed to mate with males of the same strain
Food restriction continued up to gestational day 20 (GD 20)
endocannabinoid and N-acylethanolamide (NAE) levels of male offspring were measured in hypothalamus
rat dams from both groups continued on standard chow diet ad libitum
offspring were weaned on standard chow diet and rat dams were sacrificed
open field and chocolate preference test) were performed at adolescence (8th PN weeks)
Chocolate preference was also reevaluated at adulthood (12–13th PN weeks)
Adiposity was measured at 5th postnatal month
Caloric intake and weight gain were evaluated in rat dams and offspring during the entire duration of the experimental procedure
three quarters of the male offspring were sacrificed
All experiments in offspring were performed in males
The term “perinatal” was used to refer to pregestational
Prolonged diestrus was considered when diestrus lasted for three consecutive days or more
Food intake was determined by subtracting the amount of each food type left in the cage from the total amount of food provided
the individual food intake was determined by dividing the total food intake from each cage by the number of pups per cage
Comparisons among groups were carried out by calculating cumulative caloric intake relative to body weight (Kcal/Kg) as well as weight gain in each period of the study
the percentage of increase in body weight and caloric intake in rat dams was calculated at the end of the caloric restriction diet and specifically
on GD 20 and 21 and during the lactation period
Adiposity was estimated by calculating the percentage of abdominal fat weight over total body weight at the time animals were sacrificed
Rats were weighed immediately before death and sacrificed by decapitation after administration of Equitesin® (3 mg/kg)
perirenal and perigonadal fat deposits were dissected and weighed
The sum of both types of fat was used to determine the percentage of abdominal fat
male offspring chosen to be sacrificed from the two experimental groups were decapitated during the 2nd/3rd h of the dark phase and brains were quickly removed and frozen at −80°C until brain region isolation
To avoid the possibility of variable outcomes among litters
brains from at least three litters per group were used to carry out endocannabinoid measurements (control pups n = 7–5–3 and pups from restricted dams n = 16–11–9
For the isolation of the brain regions selected
brains were thawed in cold Tris-HCl buffer (50 mM
right hippocampus and right olfactory bulb were quickly isolated and immediately frozen at −80°C until lipid extraction
The overall isolation procedure was carried out in less than 7 min for all animals to avoid ex vivo production/degradation of endocannabinoids
the BCA method (bicinchoninic acid assay) was used and the measurements performed by using a FLUOstar Galaxy (BMG Lab technologies)
Anxiety-related behaviors were evaluated in handled animals with the elevated plus maze
at the 7–8th PN weeks (adolescence period)
Spain) consisted of a cross-shaped platform made of black and gray plastic
The platform was elevated 65 cm from the floor and had two opposing open arms (50 cm × 10 cm) and two closed arms of the same size
A central area of 10 cm connected all arms
The closed arms were fenced by 50-cm high opaque walls
The light intensity was adjusted at 150 lux in the open arms and 80 lux in the closed arms
The test was performed after 5 h from the beginning of the dark phase
each rat was placed in the central area facing one of the open arms and opposite to the experimenter position
the animal was allowed to explore the maze freely for 5 min
the rat was moved back to the home cage and the maze was cleaned
The number of open-arm and closed-arm entries and the percentage of time spent on open and closed arms were determined by a computer-controlled system recording the interruptions of infrared photo beams located along each arm
Data were analyzed by using the MAZE soft software (Panlab
Animals that fell off the maze during the test were excluded from the analysis
Locomotor activity and anxiety-related behavior were evaluated with the open field test in the 2 days following the elevated plus maze test
The open field consisted of a square arena (80 cm × 80 cm and 40 cm high) virtually divided into a peripheral zone and a central zone (40 cm × 40 cm)
It was made of plywood and was located in an experimental room illuminated with low light intensity (30 lux)
The test was performed 5 h after the beginning of the dark phase
Each rat was positioned in the center of the open field and was allowed to explore freely for 5 min
the rat was moved back to the home cage and the arena was cleaned
A video camera installed above the arena was connected to a monitor and a video tracking motion analysis system (Smart
which measured the total distance traveled (cm) and mean speed (cm/s)
The program calculated the percentage of time spent in the central area as well as the number of entries to the center zone
The chocolate preference test was performed at adolescence (8–9th PN weeks) and adulthood (12–13th PN weeks)
animals were single-housed in new cages provided with both types of food (standard chow and the mixture of chocolates) and water ad libitum
Food intake for both types of food and animal weight was determined 24 h after the beginning of the test
Chocolate preference was calculated as the percentage of chocolate eaten over total food provided
a measure that was independent of the body weight of the animal and that only reflects food preference
All data are expressed as mean ± SEM
Statistical analysis of results was performed by using the GraphPad Prism version 5.0 program (GraphPad Software Inc.
Weight gain over the time and caloric intake were analyzed by one-way repeated measures analysis of variance (ANOVA)
Multiple comparisons were assessed by Bonferroni post hoc test
To assess the differences among groups on fertility-related parameters the chi-squared test was adopted
Results from the chocolate preference test were analyzed by two-way ANOVA with group (control vs
free-choice animals) and age period used as variables
Further analyses were performed by using the Student t-test
when data passed normality requirements (D’Agostino-Pearson test) or U Mann Whitney test
A p-value below 0.05 was considered statistically significant
The evaluation of estrous cycle was performed daily during the 2 weeks before mating in order to detect alterations in regularity and duration of the different stages of the estrous cycle
6 over 15 calorie-restricted dams suffered from prolonged diestrus or irregular cycle
whereas only 1 over 9 control rat dams did
chi-squared test did not show significant differences between groups (xdf12 = 2.272
Regarding the number of days required to become pregnant
dams assigned to restricted diet had higher tendency to spend 2 days or more with a male in proestrus (chi-squared test: xdf12 = 3.646
successful mating was finally achieved in both experimental groups
These results indicate that a moderate preconceptional caloric restriction do not affect fertility
despite the subtle changes observed during the estrous cycle and mating phase
Repeated measures ANOVA revealed that dams from caloric restriction group gained less weight than controls before pregnancy (F(1,23) = 19.538, p < 0.001). The differences started to be significant after the first week from the beginning of the restriction diet (F(1,23) = 65.361, p < 0.001; Figure 2A)
calorie-restricted dams tended to weigh less as compared to control dams (mean weight control vs
235.4 ± 2.882; Student’s t-test control vs
Cumulative weight gain (g) of control (open triangles) and restricted dams (solid squares) during pregestation (A) gestation (B) and lactation (C)
Values are expressed as means ± SEM
the percentage of increase in body weight between GD 20 and 21 was higher for restricted dams as compared to controls (U Mann Whitney test
Despite the change in body weight at the end of diet restriction
at PN0 calorie-restricted dams still tended to be leaner than controls (mean weight and SEMs control vs
restriction: 291 ± 12.06 (n = 9) vs
273 ± 2.95 (n = 15); Student’s t-test: t = 1.820
the percentage of increase in body weight between PN day 1 and 22 was higher for restricted dams than controls (5.578% ± 1.83% vs
11.24 ± 1.076%; Student’s t-test
Repeated measures ANOVA demonstrated that cumulative caloric intake in rat dams from diet restriction group was significantly lower than controls before pregnancy (F(1,23) = 8.798, p < 0.01; Figure 3A). These differences were particularly evident after 2 weeks from the beginning of the restricted diet (F(1,23) = 20.228, p < 0.001; Figure 3A)
as revealed by Bonferroni multiple comparisons
Maternal caloric intake during pregestation
Cumulative caloric intake (g) of control (open triangles) and restricted dams (solid squares) during pregestation (A) gestation (B) and lactation (C)
The arrow in (B) with statistical points ***denotes the interval of time with significant differences between groups (p < 0.001)
During the overall gestational period, calorie-restricted dams continued consuming less calories per kg (repeated measures ANOVA F(1,20) = 62.491, p < 0.001; Figure 3B)
As restricted mothers were allowed to eat ad libitum at day 20
they presented increased caloric intake compared to controls between GD 20 and 21 (Student’s t-test: t = 4.550
Control pups were born between GD 21 or 22
whereas all pups from calorie-restricted dams were born at GD 22 (data not shown)
Student’s t-test analysis revealed that offspring from preconceptional/pregnancy calorie-restricted dams did not differ in weight from control pups
either when analysis was done in both sexes together or in male and female separately (data not shown)
litter size tended to be lower in the diet restriction group (11.67 ± 0.81 vs
8.73 ± 1.01; Student’s t-test
a significant decreased little size was found in female (6.111 ± 0.67 vs
Hypothalamic endocannabinoid and NAE levels in male offspring at birth
and (E) palmitoylethanolamide (PEA) in the hypothalamus of male offspring from control dams (open bars) and calorie-restricted dams (solid bars) at birth.*p < 0.05
These results indicate that a prolonged caloric restriction during the preconceptional/pregnancy period induces a strong decrease in the levels of the predominant endocannabinoids (AEA and 2-AG)
their precursor (AA) as well as in PEA levels in the hypothalamus of offspring at PN0
Hippocampal endocannabinoid and NAE levels in male offspring at birth
and (E) palmitoylethanolamide (PEA) in the hippocampus of male offspring from control dams (open bars) and calorie-restricted dams (solid bars) at birth
a prolonged caloric restriction during the preconceptional/pregnancy period predominantly induces decreased levels of AEA in the hippocampus of the offspring at birth
U Mann Whitney test showed a slight tendency to decreased levels of AEA in the olfactory bulb of offspring from calorie-restricted dams (Figure 6A). No significant differences between groups were found in 2-AG, AA and PEA levels (Figures 6B–D)
The OEA values in olfactory bulb could not be reliably quantified due to interference of a peak corresponding to an isobaric structure of OEA (data not shown)
Endocannabinoid and NAE levels in the olfactory bulb of male offspring at birth
(C) Arachidonic acid (AA) and (D) palmitoylethanolamide (PEA) in the olfactory bulb of male offspring from control dams (open bars) and calorie-restricted dams (solid bars) at birth
Values are expressed as mean ± SEM
Repeated measures ANOVA indicated no differences between groups in weight gain during the lactation period (F(1,81) = 0.021, p > 0.05). However, at PN day 1 pups from calorie-restricted dams gained more weight than controls (F(1,81) = 4.024 p < 0.05; Figure 7A)
Effect of preconceptional/pregnancy restricted diet on metabolic-related parameters in male rat offspring after birth
Cumulative weight gain (g) of control group offspring (open triangles) and caloric restricted group offspring (solid squares) during lactation (A) and postweaning (B) period
Cumulative caloric intake (Kcal/kg) of control offspring (open triangles) and calorie-restricted offspring (solid squares) during postweaning period (C)
calculated as the percentage of the abdominal fat (the sum of perirenal and perigonadal fat) at 5th PN month
is shown in (D): control offspring (open bars) vs
Regarding the variable absolute body weight
repeated measures ANOVA did not show a significant main effect of the perinatal diet on male offspring body weight (F(1,36) = 1.185
when considering the entire period as statistical variable
the interaction between time and body weight was statistically significant (F(1,36) = 2.684
Bonferroni multiple comparisons revealed that the absolute body weight of offspring from calorie-restricted mothers started to be significantly higher at the 15th PN week (F(1,36) = 5.024
p < 0.05; F(1,36) = 2.539,p = 0.120; F(1,36) = 4.451
Concerning caloric intake, repeated measures ANOVA indicated no statistical differences between groups in this variable, despite the fact that offspring from calorie-restricted dams started to gain more weight in adulthood (F(1,36) = 1.865, p > 0.05; Figure 7C)
Regarding adiposity, male offspring from preconceptional-gestational calorie-restricted dams presented a statistically significant increase in abdominal fat as compared to control offspring at the 5th PN month (Student’s t-test, t = 2.069, p < 0.05; Figure 7D)
These data are consistent with the increased body weight exhibited by these animals
these results show that male offspring from preconceptional-gestational calorie-restricted dams presented higher body weight and weight gain and increased adiposity than controls in adulthood
despite the fact that caloric intake was not changed in these animals
Student’s t-test and U Mann Whitney test analysis revealed that offspring from calorie-restricted dams showed higher propensity to display anxiety-like behaviors as compared to controls. Indeed, offspring from preconceptional calorie-restricted dams spent significantly less time in the open arms (t = 2.213, p < 0.05; Figure 8A) and longer time in the closed arms of elevated plus maze (t = 3.727, p < 0.001; Figure 8B)
no differences were found either in the percentage of number of entries in the open arms or in the percentage of entries in the closed arms of the elevated plus maze (data not shown)
U Mann Whitney and Student’s t-test analysis showed that offspring from restricted dams tended to spend less time in the central area of the arena (U = 63.00
no significant differences between groups were found in the number of entries in the central zone of the arena (t = 0.06
Anxiety-related behaviors in male rat offspring
Anxiety-related responses were evaluated through the elevated plus maze test
The percentage of time spent in open and closed arms of the elevated plus maze test is indicated in (A,B) respectively
and was calculated over the total test time (300 s)
*p < 0.05 and ***p < 0.001
Student’s t-test analysis showed no significant differences between groups in the total distance traveled in the open field test
the mean speed was not statistically different between groups (data not shown)
These results suggest that alterations in the perinatal diet do not affect locomotor activity in the offspring
Two way ANOVA test performed with the chocolate preference test carried out in adolescence and adulthood
showed a statistically significant effect for the factor age period (adolescence vs
the preference for chocolate was increased over time in all groups
no significant differences in the main effect of perinatal diet and no significant interaction between factors (perinatal diet × age time) were found
the increment for chocolate preference by age period was slightly different between groups as revealed by Bonferroni multiple comparisons
although offspring from control dams showed increased chocolate preference in adulthood (F(1,68) = 11.613
offspring from calorie-restricted dams displayed a more pronounced increase for chocolate preference by age period (F(1.68) = 23.353
we have demonstrated that a maternal caloric restriction implemented during the preconceptional/pregnancy period until 2 days prior birth
alters the weight gain during pregnancy and affects the litter size without changing offspring weight at birth
this is the first study to demonstrate that this moderate caloric restriction decreases endocannabinoid and/or NAE levels in hypothalamus and hippocampus in male offspring at birth
and that these alterations are associated to overweight
increased adiposity and anxiety-related responses in adulthood
These findings suggest the need for considering the endogenous cannabinoid system as a relevant signaling system involved in metabolic/behavioral programming
This hypothesis is supported by the fact that offspring were born 2 days after switching the calorie-restricted dams to ad libitum feeding
suggesting that birth occurred only when fetuses reached the appropriate birth weight
The endocannabinoid system is a relevant homeostatic network of signals controlling energy expenditure and metabolism (Matias and Di Marzo, 2007; Bermudez-Silva et al., 2010)
its role in developmental programming has not been studied in depth
this is the first study investigating the levels of endocannabinoids and NAEs at birth after maternal exposure to restricted feeding during the preconceptional/pregnancy period
we found that offspring from calorie-restricted mothers presented in general reduced levels of endocannabinoids and their precursor
in hypothalamus and hippocampus and a similar tendency in the olfactory bulb
Reduced AA levels may be explained in part because AA (20:4n-6) derives from linoleic acid (18:2n-6)
which is an essential fatty acid obtained from dietetic sources
decreased availability of nutrients after a prolonged calorie-restricted maternal diet might have affected the levels of the precursor (AA) of the two predominant endocannabinoids (AEA and 2-AG)
may also have determined in part the reduced levels of AA
Future research will address these possibilities
we have recently analyzed the expression of cannabinoid CB1 and CB2 receptors mRNA in the hypothalamus of adult offspring born from mothers exposed to pre- and gestational moderate caloric restriction and we have found a clear upregulation in the expression of both receptors
indicating long-term alterations in the offspring as result of maternal undernutrition (Ramírez-López submitted)
Further research should be pursued to corroborate these possibilities
Future studies are necessary to confirm these speculations
the role of the endocannabinoid system in perinatal programming has not been elucidated yet and
we have not addressed the potential impact of maternal diet restriction on endocannabinoid signaling alterations in the periphery
recent preliminary data obtained using this model indicates changes in the expression of the enzymes controlling production and degradation of endocannabinoids in these peripheral tissues in adult offspring
suggesting that the observed alteration at birth might extend to the adulthood (Ramírez-López submitted)
Although we did not monitor the evolution of these changes
one may speculate that endocannabinoid level alterations at birth and/or alterations in peripheral tissues involved in energy expenditure could have contributed to the increased adiposity found in adulthood
Further investigation are required to address these possibilities
these data suggest that impairment in endocannabinoid signaling in the developing brain could lead to neurobehavioral alterations in the offspring
further investigations must be pursued to establish whether decreased endocannabinoid levels at birth are correlated to the development of anxiety later in life
This is the first study to demonstrate that a moderate maternal calorie-restricted diet applied during the preconceptional and pregnancy period leads to altered endocannabinoid and NAE levels
AA levels in the hypothalamus and reduced AEA levels in the hippocampus
although offspring were weaned on standard chow diet
the alterations in endocannabinoid levels may be correlated to overweight
abdominal adiposity and increased anxiety-related responses in adulthood
these data suggest that the contribution of the endocannabinoid system in the early life programming after maternal exposure to undernutrition is relevant
especially considering that an inadequate endocannabinoid signaling could disrupt the circuitries involved in metabolism and emotional control
Further investigations aimed at understanding how and why these alterations occur might be a useful strategy in the search of efficient therapies to address impaired programming
RGH and FRF conceptualized and designed the experimental approaches
EL and CH did the endocannabinoid measurements
FA and FRF did statistical analysis and graphs
BL and MTR-L wrote the draft of the manuscript that was revised by all authors
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
This work was supported by the Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (PI13/0226 to FRF
CP12/03109 to JS and PSI-2012-35388 to RGH)
Red de Trastornos Adictivos (RD12/0028/0001 to FRF)
Junta de Andalucía (SAS111224 to JS and FRF)
and the German Research Foundation DFG (FOR926
MTR-L has been funded by a FPU predoctoral fellowship of the Spanish Ministerio de Educación
Cultura y Deporte (AP-2009-0225); JS holds “Miguel Servet” research contract from the National System of Health
The authors also thank Claudia Schwitter for her help and support during lipid extraction and BCA analysis
Moderate maternal food restriction in mice impairs physical growth
behavior and neurodevelopment of offspring
Cannabinoid receptors and cholecystokinin in feeding inhibition
Prenatal exposure to the CB1 receptor agonist WIN 55,212–2 causes learning disruption associated with impaired cortical NMDA receptor function and emotional reactivity changes in rat offspring
An intrauterine catch-up growth regimen increases food intake and post-natal growth in rats
The origins of the developmental origins theory
Type 2 (non-insulin-dependent) diabetes mellitus
hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth
Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets
eating behavior and energy homeostasis: the end or a new beginning
Altering cannabinoid signaling during development disrupts neuronal activity
Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period
doi: 10.1002/(sici)1098-2396(19990901)33:3<181::aid-syn3>3.0.co;2-r
Extraction and simultaneous quantification of endocannabinoids and endocannabinoid-like lipids in biological tissues
Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice
Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring
Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy
Perinatal undernutrition modifies cell proliferation and brain-derived neurotrophic factor levels during critical time-windows for hypothalamic and hippocampal development in the male rat
de Salas-Quiroga
Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons
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Leptin-regulated endocannabinoids are involved in maintaining food intake
Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep
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Catch-up growth in childhood and death from coronary heart disease: longitudinal study
Fernández-Gonzalez
Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes
Moderate caloric restriction during gestation in rats alters adipose tissue sympathetic innervation and later adiposity in offspring
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Adipose tissue gene expression profiling reveals distinct molecular pathways that define visceral adiposity in offspring of maternal protein-restricted rats
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but not sexual performance and food intake
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obstetric and perinatal health outcomes in eating disorders
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Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile
Endocannabinoid signals in the control of emotion
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Determination of the estrous cycle phases of rats: some helpful considerations
Endocannabinoids and the control of energy balance
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Palmitoylethanolamide prevents metabolic alterations and restores leptin sensitivity in ovariectomized rats
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Eating disorders symptoms in pregnancy: a longitudinal study of women with recent and past eating disorders and obesity
Long-term behavioural and neuroendocrine effects of perinatal activation or blockade of CB1 cannabinoid receptors
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Ramírez-López
Exposure to a highly caloric palatable diet during pregestational and gestational periods affects hypothalamic and hippocampal endocannabinoid levels at birth and induces adiposity and anxiety-like behaviors in male rat offspring
Cardiovascular metabolic syndrome–an interplay of
Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring
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Rodríguez de Fonseca
Effects of pre- and perinatal exposure to hashish extracts on the ontogeny of brain dopaminergic neurons
The Dutch famine and its long-term consequences for adult health
Maternal nutrient restriction between early and midgestation and its impact upon appetite regulation after juvenile obesity
The early programming of metabolic health: is epigenetic setting the missing link
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The endocannabinoid system controls food intake via olfactory processes
Effect of severe maternal dietary restriction on growth and intra-abdominal adipose tissue weights in offspring rats
Effects of feed restriction on fertility in female rats
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obesity and hypertension and postnatal amplification by hypercaloric nutrition
Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction
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Citation: Ramírez-López MT
Gómez de Heras R and Rodríguez de Fonseca F (2016) Maternal Caloric Restriction Implemented during the Preconceptional and Pregnancy Period Alters Hypothalamic and Hippocampal Endocannabinoid Levels at Birth and Induces Overweight and Increased Adiposity at Adulthood in Male Rat Offspring
Received: 12 August 2016; Accepted: 17 October 2016; Published: 01 November 2016
Copyright © 2016 Ramírez-López, Vázquez, Bindila, Lomazzo, Hofmann, Blanco, Alén, Antón, Decara, Arco, Ouro, Orio, Suárez, Lutz, Gómez de Heras and Rodríguez de Fonseca. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)
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ShareSaveThis article is more than 5 years old.Blockchain product leader Mehran Hydary
UNICEF office of innovation co-founder Chris Fabian
and Unicef France web marketing Hubert Chaminade prepare to announced the Unicef Crypto Fund at Devcon 5 in Kyoto
she used to hop back and forth across the U.S
and when things were slow in her hometown she and her friends would pile into a black SUV
cross the Detroit River to the United States and watch all-star Rasheed Wallace and the Detroit Pistons
Instead of buying each other presents when she was a kid
Lomazzo’s family took trips around the world
Now the 28-year-old former project coordinator for the Bank of Canada and cofounder of Deloitte’s government blockchain practice is leveraging her international background at the United Nations
where in September 2018 she was hired as the United Nations Children’s Fund’s first head of blockchain
the technology behind bitcoin that makes transactions across borders as easy as if borders didn’t exist at all
After 14 months’ work at the imposing United Nations Plaza in New York
Lomazzo and her international team today announced the Unicef Crypto Fund
a prototype that lets the agency accept bitcoin and ether donations and invest them directly into blockchain startups
In addition to investing cryptocurrency into early-stage
open-source companies working with children
the fund represents the first time any UN agency
much less one that generated $6.7 billion revenue last year
will be able to accept bitcoin and ethereum donations
launched today with a donation of 1 bitcoin and 10,000 ether from the Switzerland-based Ethereum Foundation
and Unicef New Zealand to start accepting cryptocurrency donations immediately
which received $15 billion in donations last year
kicks off a new phase of development in which it sees itself as not only dispenser of aid but as a financial innovator
the ability to accept cryptocurrency donations and track exactly how they were spent could pave the way for a new
Lomazzo was born in April 1991 in Windsor, Ontario, just a short drive from where she grew up in the town of Amherstburg, and an even shorter drive to the Pistons’ former home stadium. The child of a computer engineer father and a worker advocate mother, Lomazzo was raised by her Italian grandmother, who never learned English.
at around the same time Unicef was starting to explore blockchain
where she worked in an office across the street from the Parliament building in Ottawa
the office’s blockchain work was still a part of the emerging tech division
but she and innovation lead Kevin Armstrong spun off the blockchain project
provincial and state agencies around the world use the technology
at around the time her future colleagues at the United Nations finished their first blockchain prototype
Lomazzo entered a “super-seedy,” now-closed
bar in Toronto called the Clocktower Brew Pub and began documenting how bitcoin was evolving
She photographed a bitcoin ATM that was “behind a black curtain
so you felt like you were doing something wrong,” she says
and took what ended up being the first of four photos of the ATM
It shows a price of $551 CAD; the price today is $10,920
Photos of the bitcoin ATM taken by Lomazzo
“The cool part is that bitcoin ATM has moved since then
“That exact one has moved to a convenience store closer to where I lived
‘Where’s your Bitcoin ATM?’ It was in the middle
As bitcoin struggled to change its reputation from a currency for criminals to something businesses might use
Lomazzo stumbled across the job post for the lead blockchain position at Unicef “two hours before it closed.” Following the prodding of her younger sister
and a month and a half later she had crossed another border
The birth of the Crypto Fund actually preceded Lomazzo
going all the back to 2007 when Unicef launched its Office of Innovation
which prototypes a wide range of experimental technology
quickly established a reputation for identifying projects that could be integrated into the larger organization
evolved into Unicef’s current information technology and data division
long before most people had even heard about bitcoin
the United Nations General Assembly adopted resolution 65/146
titled “Innovative mechanisms for financing of development.” Dubbed “innovative finance” for short
the resolution requested that agencies identify new
steady sources of financing to supplement existing donations
In spite of some less than successful work at the Office of Innovation involving virtual reality
Fabian and London School of Economics grad Sunita Grote
took a cue from the resolution and launched the Unicef Venture Fund in February 2016 as a way to fund startups working with open source technology in developing nations
including Unicef’s first blockchain investment
using blockchain to help schoolchildren prove their identity
the same time Lomazzo was promoted to senior consultant at Deloitte
the Office of Innovation had its first internal discussion about the Crypto Fund with Unicef’s Department of Finance and Asset Management
the team formulated an official product description and created an accounting structure for holding cryptocurrencies in cooperation with the United Nations Office for Project Services (UNOPS)
they were still without a dedicated leader
with Fabian and Grote helping run a number of other efforts
as the first round of feedback from senior leadership on the Crypto Fund was being processed
Lomazzo was finally brought on board full-time to not only build out the blockchain team and manage the entirety of Unicef’s blockchain work but help bring the Crypto Fund over the finish line
“And cryptocurrency’s a complicated application of it
Christina has the ability to make that really understandable because she’s done it with bankers and governments before”
UN secretary-general António Guterres published a lengthy strategic plan for how the United Nations could increasingly use a wide range of technologies to take a new kind of leadership role in solving the world’s problems
He formed a high-level panel co-chaired by Melinda Gates and Jack Ma to explore how cooperative efforts could reduce redundancies and expand the United Nation’s impact
the panel issued its “declaration of digital interdependence,” with five recommendations for building an infrastructure capable of solving global problems across borders
giving fuel and further guidance to Unicef’s Crypto Fund and its other blockchain projects
the 47-page report called for the creation of an inclusive digital economy and society
1.7 billion people were excluded from the global banking economy
Using terms very familiar to blockchain developers
the report called for the creation of affordable access to “digital networks” and financial services for every adult on earth by 2030
multi-stakeholder alliance involving the UN to create a platform for sharing digital public goods and data
all things touted by blockchain advocates as potential benefits of using a shared
“The Unicef Crypto Fund provides an amazing opportunity for us to work collaboratively with Unicef teams around the world,” says Aya Miyaguchi
executive director of the Ethereum Foundation
which will be providing technical support to Unicef and its blockchain portfolio as part of the investment
“Unicef has a network of 190 offices across the world that brings to the Ethereum ecosystem the ability to work with leading minds in regions that could benefit the most from Ethereum technology.”
Auditing & Finance showed that charities displaying a seal of transparency from the nonprofit GuideStar experienced a 53% increase in donations over the following year
Lomazzo and Hydary test the Crypto Fund workflow using a test version of ethereum and their United ..
“We're working on a way to actually have a visual that's reading from each chain that shows money going in and flowing,” says Lomazzo
you no longer have to trust in the organization that the money has gone there
You can actually go ahead and verify yourself.”
Since Unicef isn’t currently able to pay salaries
the fund received a special waiver from the director of finance at Unicef’s private fundraising and partnerships division saying that it would forgo a fee it normally charges to recover its own costs
“We’re going into an era where our top leadership recognizes that Unicef needs to be a financing and financial institution,” says Fabian
“And what that means is we need to be able to take our multibillion budget a year and deploy it in much more sophisticated ways.”
The United Nations International Children’s Emergency Fund (it has since dropped the “International” and “Emergency”) was founded in 1946 to bring food
shelter and other support to children and young people in the aftermath of World War II
a part of the United Nations General Assembly
consisting of 193 member states working together to solve a wide range of international problems
form national committees to raise funds and provide support in their own nations and around the world
It is in these national committees where one of the most interesting aspects of the Crypto Fund comes into play
The United Nations is on what’s called international territory
meaning government laws and regulations don’t apply in United Nations Plaza on the east side of Midtown Manhattan in quite the same way they do elsewhere
As a result of the UN’s extraterritoriality
each of the 190 national agencies that could potentially benefit from the crypto muscles built by the Unicef Office of Innovation needs to sort through its own regulatory requirements
So while the fund is notable in what it says about Unicef’s back-office capabilities
each country has to see to its own regulatory compliance before joining
Of the four countries already signed up for the Crytpo Fund
Unicef France executive director Sebastien Lyon started exploring ethereum as a new way to accept donations and says he has lined up a “significant amount” of individual donors who are only interested in giving if the national committee doesn’t convert the donations to fiat
One of the biggest reasons France has taken the lead in accepting crypto donations
is that the existing regulations in France clearly show how to categorize cryptocurrency for accounting purposes
accepting crypto still required “extensive discussion with the regulators
So in the build-up to today’s announcement Lyon says he spoke to several other national committees
that were looking to learn from his experience
“I'm in touch with many of my colleagues in different countries in the world,” says Lyon
Lomazzo’s work with blockchain extends far beyond the Crypto Fund
She heads a small but growing team of five people in the Office of Innovation
the office’s cofounder and head of the Innovation Fund
who is fund manager on a number of blockchain initiatives
Unicef is exploring how blockchain can be used to track internet connectivity in schools as part of its Project Connect
The Atrium is a platform being build by Unicef to encourage UN agencies to share what they’ve learned about blockchain and to collaborate on projects
The Boost Token is being explored as a way to reward mentors for contributing open-source code and students for studying it
back-office side is a prototype now under construction using the ethereum smart contract language Solidity to automate certain back-office procedures
in addition to Fabian’s work with Lomazzo and others in Unicef
a group of 1,200 people from all United Nations agencies
Following an Innovation Network report last year on all the blockchain work being done across the United Nations
the network is now in the process of assembling its first working group specifically on cryptocurrency
“That means we can get people who are my counterparts from other agencies to take what we have done today
“If one agency gets its legal people to sign off on something
it can basically be used by any other agency
“This obviously starts with the Crypto Fund,” Lomazzo added
“But the hope is that this can be expanded
and so that donations have more visibility into where they're coming from
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Questa estate Delta Powerboats varerà il suo nuovo Delta 72
Originariamente commissionato da un cliente abituale
entrerà ufficialmente nella gamma del cantiere svedese
Ancora una volta sviluppato in collaborazione con Mannerfelt Design
vanta anch’esso una costruzione in fibra di carbonio
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When a young woman who is Rhode Island’s first openly transgender candidate announces a bid for the General Assembly
Some readers disagreed — and not all for the reasons you might suspect
The story was Jackie Tempera’s interview with Nika Lomazzo, a 22-year-old Providence resident who said she was planning to take on state Rep. John Lombardi, the city’s onetime acting mayor, in next year’s election.
In a box on the front page of the Dec. 6 Journal that told readers we had the story, we explained the reason we thought this was newsworthy: “If she wins, Lomazzo would be the first openly transgender person to serve in Rhode Island government.” On the story itself, inside the paper, the headline took a different approach: “Woman, 22, plans to challenge Rep. Lombardi.”
It was a variation of that headline — “Woman, 22, plans to challenge Rep. Lombardi in Providence District 8” — that appeared on our website. But there, it had no introduction that told the bigger story.
All of which prompted discussion in the newsroom: Was that the strongest online headline we could use?
A newspaper headline is forever, but online we can keep perfecting (or, depending on your view, tinkering) until we’re satisfied. So we took a step back to think about this one.
Normally, we wouldn’t have written a story about a 22-year-old who said she planned to run for one of 113 legislative seats in a race that legally doesn’t even open up for another half-year. But a transgender woman had just been elected to Virginia’s legislature — a national first that made headlines around the country. And now here came Lomazzo, who would be Rhode Island’s first openly transgender candidate.
But Maria Caporizzo, our top digital editor, pointed out that we’ve heard in the past from advocates for people who are transgender that they wish we wouldn’t be so hung up on the physical details of their being transgender.
And then social-media editor Whitman Littlefield, who sits in our producer-editor hub with me, Maria, managing editor Mike McDermott, and several others, got into the conversation.
He’d just been having a Facebook discussion with readers who objected to the “Woman, 22” headline on the grounds that we should simply have used the candidate’s name.
In this view, writing the headline using her gender and age — both of them from “marginalized” groups — only pointed out the uphill battle she would face, and made that battle harder.
Well, one of the maxims of any newsroom is that “names make news.” But that doesn’t apply to just any name — what it means is that a story about someone famous is more newsworthy than the same story about someone you’ve never heard of.
Along the same lines, we want to make sure that every word in a headline does useful work in helping the reader understand why they should want to read it. When a person’s name isn’t well known, it does less of this work than other words that would tell something a reader might relate to — age, hometown, occupation, gender.
So there was little chance we’d be using this first-time candidate’s name in a headline, at least until she earned some renown of her own.
Whitman answered on Facebook again, which sparked some more conversation. One reader wrote later that using the representative’s name, but not his challenger’s, in the headline unfairly maximized the advantages of incumbency. More food for thought.
We talked about it some more, and weighed all the points of view. It became clear that this wasn’t a case where we could satisfy all of them.
So we went back to the basics of the story. What was most important about it?
Nika Lomazzo had made her transgender status a key part of her announcement and her platform — she wanted to work, in part, for rights for people who are transgender.
And John Lombardi’s well-known name would help people understand that they wanted to read the story.
So we changed the headline to this: “Transgender woman to challenge Providence Rep. Lombardi.” And felt we had written the best head we could.
Now, all this took us about 15 minutes. The fate of the republic didn’t lie in the balance. And it wasn’t the in-depth discussion we expect to have in coming months to make sure we have the right policies in place on writing about people who are transgender. That’s a subject that deserves extended thought.
But I tell you the story because it shows the care we try to give to treating people fairly and consistently, within the strictures of our news judgment.
We listen to, and care about, what our readers have to say. We try to hear all sides. We work to get it right.
And then we make the decision we think is best for our readers.
Alan Rosenberg is The Journal’s executive editor.
The junior couldn’t wait to don the Dundee blue for the first time in a varsity wrestling match.
He made his Viking debut memorable by going 2-0 to help his new team fly past Erie Mason 84-0 and Ida 75-6 Wednesday night.
“He’s been excited to go,” Dundee coach Tim Roberts said. “He had to sit out a year after changing schools. He was up late last night. He’s just excited to be able to wrestle again.”
Lamazzo placed third in Division 1 at 125 pounds as a freshman at Detroit Catholic Central, then had to sit out last season after transferring back to Dundee.
He accepted a void against Mason, then scored a 13-4 major decision over state-placer Joe Barton of Ida at 171 pounds.
The addition of Lamazzo helps flesh out an already impressive lineup for Dundee, which won the Monroe County Sheriff’s Tournament last weekend.
“He’s a good wrestler,” Roberts said. “It’s nice to have a guy that of that caliber in the lineup.”
Especially in the upper weights where Dundee was a little thin.
“We’re still working on the upper weights,” Roberts said of his 6-0 team. “Guys are bumping up. Hopefully soon, we’ll get another big guy (Kaiden Hubbell) back who is recovering from a broken hand in football.”
Also going 2-0 for Dundee were Braeden Davis (103), Kaden Chinavare (112), Gabe Massingill (125), Aiden Davis (130), Austin Fietz (135), Kyle Yuhas (140), Christian Killian (145), Tyler Swiderski (152), Stoney Buell (160), Jackson Guinn (215), Caleb Fairchild (189) and Dennis Root (285).
It was a tough night for Mason and Ida, who had to face potential state champions Dundee and Ida.
“It’s been that way for as long as I can remember,” Ida coach Alex Phillips said. “We always get both of them on the same night.”
The Blue Streaks also fell 70-6 to Hudson.
Hunter Assenmacher went 2-0 for Ida with a pin against Dundee and an 8-4 victory against a state runner-up from Hudson.
“We definitely showed some good fight in some of those matches,” Phillips said. “Against tough opponents, it’s tough to get great results.”
Mason (5-7) had seven nine wrestlers out of the lineup, leaving the Eagles with eight freshmen and a sophomore on the mat. Coach Justin Gessner was pleased with the effort despite getting shut out in both matches.
“They knew they were going against better teams but all of them went out there and wrestled,” Mason coach Justin Gessner said. “Honestly all of them looked good.”
TECUMSEH – Bedford rebounded from what coach Kevin Vogel though was one of their poorest performances of the season Saturday to beat Ann Arbor Huron 83-0 and Chelsea 65-12 Wednesday.
“We went back in the room Monday and had a great practice,” Vogel said. “We got right back on track. We kept up our intensity up.”
Brock Jandasek (103), Nathan Gerber (112), Jack Nigh (119) Chase Grzegorczyk (125), Grant Burton (130), Tyler Borst (135), Rollie Deneker (145), Nathan Rimmer (152), Logan Frantz (160), Colin Jagielski (189), Cage Dye (215) and Cole Bettencourt (285) all won both their matches for the 14-1 Mules.
JACKSON – Tim Murphy (119) and Anthony Payne (125) each had two pins each as Monroe beat Ann Arbor Pioneer 65-6 and lost to Jackson 38-24 Wednesday.
Nathan Puccetti (135) and Connor Martin (160) also went 2-0 and Damien Jones won his only match for his second career varsity victory.
LINCOLN PARK – Gibraltar Carlson got its Downriver League season started by topping Southgate Anderson 51-22 and Lincoln Park 68-12.
John Wallace Jr., Deisel Gessner, Dawson Gessner, Ryan Goulet, Owen Sugarbaker, Eddie Light, Nathan Hammac and Davison Sopo all went 2-0 for the 4-0 Marauders.
“It was a nice start to our league meet season,” Carlson coach Lance Hassell said. “We have been pretty close with Southgate for the past few years but they always seemed to find a way to squeak by us. I think this is Carlson's first win over Southgate in 15 years.”
CARLETON – Jefferson did not lose a match from 103 to 140 in rolling to wins over Airport (57-22) and Grosse Ile (81-0) Wednesday night.
“Our little guys get a lot of things done,” Jefferson coach Mike Humphrey said.
Humphrey praised the work of Ethan Brabant at 125 pounds.
“We were super pleased with Ethan Brabant,” the coach said. “He was physical and went after people.”
Joining Brabant at 2-0 were Cody Richards (103), Dylan Garcia (112), Hunter Major (119), anner Kirkpatrick (130), Ron Allen (135), Josh McGree (140), Brendan Bashaw (171), Broc Peer (215) and Drayden Ray (285).
The Bears are 5-3 with all of the losses coming against teams ranked in the top five in the state.
MILAN – New Boston Huron got some good contributions from its lower weights in beating Riverview 55-12 and Flat Rock 70-12 Wednesday.
“Our little guys, our younger guys wrestled really well,” Huron coach Jake Shulaw said. “They wrestled hard.”
Eric Radulescu (112), Codi Clark (119), Nathan Farkas (135), Michael Ramsey (140), Dylan Carr (145), Griffin Cholette (152), Nelson Poet (160), Braden Damiani (189), Brendan Damiani (215), Tyler Short (285) were all 2-0 for the 9-2 (2-0 Huron League) Chiefs.
Volume 11 - 2018 | https://doi.org/10.3389/fnmol.2018.00067
This article is part of the Research TopicBiology of Lipids in the Control of the Motor Function, in Health and DiseasesView all 13 articles
Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability
an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use
Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA])
Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy
modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA
and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties
Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases
and antiepileptic effects in pentylenetetrazol (PTZ)
maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures
numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential
dose limiting side effects and psychoactive effects
rendering PEA an appealing candidate as antiepileptic compound or adjuvant
we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA)
KA-induced epilepsy in rodents is assumed to resemble to different extents human temporal lobe epilepsy (TLE) depending on the route of KA administration; intracerebral (i.c.) injection was recently shown to most closely mimic human TLE
while systemic KA administration causes more widespread pathological damage
To explore the potential of PEA to exert therapeutic effects both in brain and periphery
acute and subchronic administration of PEA by intraperitoneal (i.p.) injection was assessed on mice with systemically administered KA
we investigated: (i) neuroprotective and anticonvulsant properties of acute and subchronic PEA treatment in KA-induced seizure models
and (ii) temporal dynamics of eCB and eicosanoid (eiC) levels in hippocampus and plasma over 180 min post seizure induction in PEA-treated and non-treated KA-injected mice vs
we compared the systemic PEA treatment with
pharmacological blockade of fatty acid amide hydrolase (FAAH) in brain and periphery
in terms of anticonvulsant properties and modulation of eCBs and eiCs
we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity
promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice
identification of molecular causes of and/or correlates with epilepsy in various animal models is essential to discover new drug targets and markers for follow-up monitoring
Exogenous administration of AEA has similar biphasic effects
We previously evidenced that systemic administration of KA in mice leads to widespread damage in brain and peripheral organs and increased peripheral inflammation at acute seizure state (Lerner et al., 2016)
the latter resembling thus a pathological feature of TLE
We specifically aimed at investigating the PEA treatment effectiveness in acute injury phase of the KA-induced excitotoxicity
and therefore we chose a time course of 180 min to reflect this epileptogenesis phase
whereby at 1 h post injection a maximum of seizure activity typically occurs
a mouse model of KA-systemic induced epileptic seizure was chosen as suitable to assess the neuroprotective and anti-inflammatory role of PEA
its potential to affect both periphery and brain by inhibiting inflammatory signals
We determined anticonvulsant effects of acute and subchronic administration of PEA by behavioral examination for 180 min post KA injection
Neuroprotective effects of subchronic PEA administration (double injection) were demonstrated in brain sections of PEA-treated vs
we evaluated by targeted mass spectrometry-based quantitative profiling the temporal dynamics of eCB- and eiC-levels with epileptic seizures
Anticonvulsive effects of PEA were associated with a modulation of both peripheral and hippocampal levels of eCBs and eiCs
antiepileptic properties of PEA were compared to those exhibited by systemic pharmacological blockade of FAAH (URB597) and peripheral FAAH blockade by URB937
as well as in combinatorial therapeutic administration
Calibration standards: arachidonoyl ethanolamide (AEA)
5(S)-hydroxyeicosatetraenoic acid (5(S)-HETE)
8(S)-hydroxyeicosatetraenoic acid (8(S)-HETE)
12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE)
15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE)
19(S)-hydroxyeicosatetraenoic acid (19(S)-HETE)
were obtained from BIOMOL Research Laboratories Incorporation (Plymouth Meeting
Internal standards (ISTD): arachidonoyl ethanolamide-d4 (AEA-d4)
5(S)-hydroxyeicosatetraenoic acid-d8 (5(S)-HETE-d8)
12(S)-hydroxyeicosatetraenoic acid-d8 (12(S)-HETE-d8)
20-hydroxyeicosatetraenoic acid-d6 (20-HETE-d6) were obtained from BIOMOL Research Laboratories Incorporation (Plymouth Meeting
For multiple reaction monitoring (MRM) analysis and lipid extraction
and formic acid of LC-MS grade were invariably used (Sigma-Aldrich
HPLC grade methyl tert-butyl ether (MTBE) was purchased from Sigma-Aldrich (St
and methanol were obtained from Honeywell International Incorporation (Morristown
Palmitoylethanolamide (PEA) was obtained from Cayman Chemical (Ann Arbor
URB597 (3′-(aminocarbonyl)[1,1′-biphenyl]-3-yl)-cyclohexylcarbamate and URB937 (N-cyclohexyl-carbamic acid
3′-(aminocarbonyl)-6-hydroxy[1,1′-biphenyl]-3-yl ester) was purchased from Cayman Chemical (Ann Arbor
Cremophore and indomethacin were obtained from BIOMOL Research Laboratories Incorporation (Plymouth Meeting
C57BL/6N male mice (8–10 weeks of age) were ordered from Janvier Labs (Saint-Berthevin
Experimental procedures were carried out in accordance with the European Community’s Council Directive of 22 September 2010 (2010/63EU) and approved by the local animal care committee of the German Rhineland-Palatinate (file reference: 23 177-07/G16-1-075)
Overview of the time scale for treatment and seizure induction
and plasma and hipppocampal sampling: t1–t4; animal sacrificing
blood and brain tissue sampling; tp1–1st palmitoylethanolamide (PEA) administration for subchronic treatment; tp2–2nd time point for PEA administration for subchronic treatment
and time point for the acute treatment of PEA
URB597 and URB937; t0–time point of kainic acid (KA) injection
For time course analysis of acute KA-induced epilepsy
At 60 min (t2) post KA injection seizures are assumed to reach maximal intensities
therefore this timepoint is referred throughout the study as acute epileptic state
which is preceded by pre- or early acute and followed by late- or after-acute phase
Animals were monitored and scored at 10/20/40/60/90/120/ 150/180 min post KA injection according to the following scale: 0—no response; 1—immobility and staring; 2—forelimb and/or tail extension, rigid posture; 3—repetitive movements, head bobbing; 4—rearing and falling; 5—continuous rearing and falling; 6—severe clonic-tonic seizures; 7—death (Monory et al., 2006)
Behavior was assessed as a score of 5 in case of continuously rearing and falling for at least three consecutive episodes and without break as a score 6 for generalized convulsive tonic-clonic seizures
as well as for the so-called “popcorn” bouncing activity
characterized by intermediate hyperactive periods of running
Occurrence of the latter type of seizure activity was restricted to short durations (2–4 min) and subsequently caused death
Status epilepticus (SE) was defined as a period of seizure activity
characterized by tonic clonic convulsions without intermediate recovery for >30 min
mice were referred to as being acute epileptic with an onset of epileptic motor activity corresponding to seizure score 3 or higher
The results were analyzed using SPSS Statistics Software for Windows (version 23
Repeated-measures analysis of variances (ANOVAs) with experimental group and time as independent variables were used to analyze seizure severity after KA injection
The Greenhouse–Geisser correction was used if the condition of sphericity was not met
Significant group effects were further analyzed using Bonferroni’s post hoc analysis for multiple comparisons
whereas significant interactions were further analyzed using simple effects analysis for the effect of group for each time point
also adjusted for multiple testing using Bonferroni correction
The error bars are presented as standard error of the mean (SEM)
subchronic palmitoylethanolamide (PEA)-treatment of kainic acid (KA)-induced epileptic mice
Behavioral scores were obtained over a time course of 180 min post KA-seizure induction to discriminate effects of acute (PEA/KA) vs
subchronic (PEA2/KA) treatment compared to non-treated epileptic mice (KA)
(A) Repeated measures analysis of variance (ANOVA) revealed significant interaction
thus Tukey’s post hoc analysis was performed to determine time-point specific alterations on behavioral level of the different groups
Significant changes of the acute and subchronic PEA treatment vs
non-treated epileptic mice were calculated and assigned as follows: *P < 0.05
Error bars indicate standard error of the mean (SEM)
At 40 min the significance is indicated for: KA-group vs
(B) Behavioral scores given in percentage of the total scores obtained per time point for each experimental groups
presented in a heatmap illustrating comparison of seizure severity and mortality rates between the groups
Group sizes were the following: non pre-treated KA-induced epileptic mice: n = 48 at 10 and 20 min; n = 36 at 40 and 60 min; n = 24 at 90 and 120 min; and n = 12 at 150 and 180 min
Acute PEA-treated and subchronically PEA-treated epileptic mice: n = 24 at 10
KA-seizure induction led to death in 4% of the untreated epileptic mice 90 min post KA injection
seizure score 7 (death) from the time point they occur is rescored for all the remaining time course
At 120 min mortality rate remained unchanged compared to 90 min
From 150 min another 4% of untreated epileptic mice were depicted with score 7 resulting thus in 8% mortality at 150 min which remained unchanged at 180 min
Upon acute PEA treatment no seizure score higher than 5 was obtained
Subchronic PEA treatment has even more suppressive impact on seizure intensities
with a maximal score of 4 and 50% of the mice with a score of 0 at 180 min
To better illustrate distribution of individual scores, i.e., scores higher than 5 and mortality rates, we included a heat map displaying behavior score distribution given in percentage of animals exhibiting a given score from the total number of scored animals (e.g., total number of animals alive at that time point) per experimental group per time point (Figure 1B)
4% of the untreated epileptic mice exhibited SE that eventually led to death for 2%
were housed for 5 more days for the purpose of neurodegenerative and immuno-histochemical staining of brain sections that are representative for most severe seizure state
see “Brain and Plasma Sampling” and “Neurodegenerative and Immunohistochemical Staining” sections
At 20/60/120/180 (t1–t4) minutes after KA injection, mice were shortly anesthetized with isoflurane (Forene R, AbbVie Deutschland GmbH and Co. KG, Wiesbaden, Germany) and sacrificed by decapitation (Nomura et al., 2011; Scheme 1). Brains were isolated and directly frozen on dry ice. Dissection of the brains was carried out according to the protocol described previously (Lerner et al., 2016)
All tissue samples were then stored at −80°C until further processing
500 μL EDTA plasma extraction tubes (KABE Labortechnik
containing previously added 10 μM indomethacin to prevent ex-vivo COX-2 activity
This collection procedure took 30 s per mouse
Plasma tubes were directly centrifuged at 4°C
and the resulting upper plasma phase was removed and stored at −80°C without delay
eCBs and eiCs were co-extracted using a method recently developed by our group. The same sampling, extraction and quantification protocol as previously reported was applied in this study for both plasma and hippocampal eCBs and eiCs investigation (Lerner et al., 2017). The eCB and eiC values were normalized to protein amount and plasma volume for tissue (Bindila and Lutz, 2016) and plasma samples
In this study we focused on the analysis of AEA
AEA and 2-AG are eCBs that bind to cannabinoid receptor CB1; PEA is an eCB-like molecule
AA is a precursor for the synthesis of prostaglandins (PGs)
We focused our analysis on the PGE2 and PGD2 due to their prominent involvement in inflammatory processes in general
and arising from KA-induced excitotoxicity
Lipid levels were analyzed at each time-point separately by means of univariate ANOVA for experimental group
Statistical significance was defined as P < 0.05
Eight mice (four mice were subchronically PEA-treated epileptic mice
and four mice were non pre-treated epileptic mice) were kept single housed post KA injection for 5 days
Health conditions of mice were frequently checked
all mice showed normal behavior after acute seizure state (3 h post KA injection) and remained like that even though ongoing neurodegenerative processes are expected
In order to determine effect of subchronic treatment of PEA
silverstaining and immunhistochemical staining were performed
perfusion of the brain is required prior to staining
mice were deeply anesthetized using pentobarbital (100 mg/kg) and Buprenorphin (0.1 mg/kg) as narcotic
trans-cardially perfused with phosphate buffered-saline (PBS)
followed by perfusion with 4% paraformaldehyde (PFA; ROTH
The isolated brains were fixed for 24 h in 4% PFA in PBS solution
treated with 30% sucrose in PBS solution for 48 h and stored at −80°C
Forty micrometer thick free floating coronal brain sections were prepared on a Microm HM560 cryostat (Microm) and stored at 4°C in cryoprotection solution (25% glycerol
25% ethylene glycol and 50% PBS) until use
To enable detection of KA-provoked neurodegeneration and evaluation of PEA’s assumed neuroprotective properties we performed neurodegenerative FJC and silver staining, and additionally, immunohistochemical double staining of neuronal nuclei (NeuN) and caspase-3 (CASP3) activation in brain sections of previously perfused brains. FJC staining was conducted following previously reported protocol (Schmued et al., 2005)
40 μm coronal brain sections were collected and mounted
Slides were then rinsed twice in ddH2O and counterstained with DAPI
The staining was then visualized with a Leica DM5500 fluorescence microscope
then incubated in impregnation solution (saturated LiCO3 in ddH2O with 10% AgNO3 and 25% NH4OH) and washed six times in ddH2O
Sections were transferred in developer solution (ddH2O with 19% formaldehyde (v/v)
and 1% Tri-Na-Acetate (w/v)) and washed twice in ddH2O
The staining was then visualized with a Leica DM5500 bright field microscope
30 μm coronal brain sections of perfused brains were blocked for 90 min in PBS containing 5% normal donkey serum (NDS)
and 0.3% Triton X-10 (TX) and then incubated over night with primary antibodies: mouse anti-NeuN (1:1000
Abcam) and rabbit anti-cleaved Casp3 (1:200
Alexa Fluor 488 (Invitrogen 1:1000) and Goat-anti Rabbit IgG
Alexa Fluor 546 (1:1000 Invitrogen) were applied for 2 h for immunofluorescent staining
visualized with a Leica DM5500 fluorescent microscope and evaluated with a Leica Application Suite Advanced Fluorescence (LAS AF) Software
In order to comparatively assess the extent of neurodegenerative processes in hippocampal areas from untreated vs
image comparison was performed using identical channel settings in terms of exposure time
FJC-positive signals were semi-quantitatively analyzed in the hilus region of the hippocampus from PEA-treated vs
green fluorescent signals were manually counted using ImageJ software in the region of interest (ROI)
on three consecutive sections from the same animal
The three coronal brain sections were sampled at 200 μm distance across the brain
Brightness and contrast settings were set fixed prior to import of the picture and FJC signals were split from DAPI signals using split channel function
Positive FJC signals were counted using multipoint tool and statistically analyzed via Graphpad prism 7 software
It is of note that normal behavior (score 0) was observed only for mice with subchronic PEA treatment at 10 min post KA administration and more prominent
but not with acute PEA treatment (Supplementary Figure S1)
Impact of PEA treatment on temporal dynamics of hippocampal and plasma lipid levels in KA-induced epilepsy mouse model
Anandamide (also known as arachidonoylethanolamide [AEA])
prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) were comparatively analyzed at 20
vehicle injected (Ctrl) and subchronically PEA-treated KA injected animals (PEA2/KA)
Error bars indicate SEM and asterisks in the figures indicate significant differences
acute and subchronic treatment with PEA of KA-mice modulated the eCB and eiC hippocampal levels
the acute PEA treatment alleviated to a lower extent the KA-induced eCB and eiC changes compared to subchronic treatment (Supplementary Figure S1)
in plasma a temporal shift in the increase of the inflammatory markers PGE2 and PGD2 in KA-injected mice occur: PGE2 increased significantly at the acute state and was maintained highly elevated up to 180 min post-injection
whereas PGD2 increased in the late-acute seizure phase at 120 min and remained elevated at 180 min after KA injection
Plasma PEA levels remained unaffected by epileptic seizures throughout the 180 min-lasting time course analysis
Subchronic PEA treatment did not restore AEA and AA alterations in the immediate (20 min) and acute phase (60 min) of seizure, but it exerted significant effects in the late-phase of seizure progression occurring at 180 min post KA injection. The increase of 2-AG levels observed in the acute seizure phase (Figure 2) was normalized to basal upon subchronic PEA treatment
subchronic PEA administration decreased the 2-AG level compared to controls
Subchronic PEA treatment reversed to basal level the increase of PGE2 in the acute phase of epilepsy (60 min)
while it induced a substantial alleviation but not complete recovery of the increased PGE2 levels at 120 min and 180 min post-seizure induction
The late-phase (120 min and 180 min) increase of PGD2 with seizures was also attenuated but not to basal level by subchronic PEA treatment
Subchronic PEA dose more effectively alleviated the modulation of plasma eiCs with seizure compared to acute PEA treatment (Supplementary Figure S2)
Subchronic PEA treatment in KA-injected mice led to a significant increase of PEA levels in plasma over the entire time course (180 min) due to accumulation of exogenous PEA
plasma PEA levels were significantly higher than in controls and non-treated KA-injected mice up to 120 min
and were then restored to basal at 180 min post KA injection (Supplementary Figure S2)
Intraperitoneal subchronic administration of PEA in controls and vehicle injection in controls was performed to understand whether and how PEA modulates the hippocampal and plasma eCB and eiC levels under healthy physiological conditions
subchronic PEA treatment significantly increased the AEA levels and decreased 2-AG over the entire time course (Supplementary Figure S3)
AA levels in plasma were significantly decreased compared to vehicle-injected mice up to 1 h
were also significantly decreased upon subchronic PEA administration in controls (Supplementary Figure S3)
plasma PEA levels were significantly increased upon exogenous PEA administration in controls over the entire time-course
Subchronic administration of PEA in controls significantly augmented in hippocampus only the levels of PEA and AA (Supplementary Figure S4)
which suggests an up-take of exogenous PEA in the brain
Immunohistochemical double staining of NeuN and CASP3 (Figure 3A), as well as neurodegenerative FJC- (Figure 3B) and silver (Figure 3C) staining on brain sections sampled 5 days post KA-seizure induction revealed neurodegenerative processes in mice without subchronic PEA treatment compared to saline injected control mice
Neurodegenerative and immunohistological staining 5 days post KA-seizure induction
To unravel PEA’s neuroprotective potential neurodegenerative and immunostainings were performed on brain sections sampled 5 days post KA-induced epileptic seizures in mice without subchronic PEA treatment (red labeled middle column)
with subchronic PEA treatment (purple labeled right column) and of saline injected control mice (green labeled left column)
behavioral scores were obtained over a time course of 180 min (post KA/Saline-injection) analog to the procedure described for the other experimental groups of this study (see “Materials and Methods” section)
No behavioral changes were observed for control animals (Panels A–C; left image
Untreated epileptic mice exhibited maximal seizure scores from 5 (continuously rearing and falling) for 15 min 1 h post KA injection (Panel B upper middle image) to 6 (Status epilepticus (SE)) for 70 min 1 h post KA injection (Panel A; middle image
Panel B; lower middle image and Panel C; middle image)
Subchronic PEA-treated epileptic mice exhibited a maximal seizure score of 4 (rearing and falling) for 15 min post KA injection (Panels A–C; right image
Brain sections were compared regarding neurodegeneration by (A)
Neuronal nuclei protein (NeuN) staining (green signal) and caspase-3 (CASP3) activation (red signal)
(B) Fluoro-Jade C (FJC) staining (green signal)
KA- induced SE causes massive loss of NeuN signal
accompanied by apoptotic events indicated by CASP3 signal (Panel A; middle image) compared to control (Panel A; left image)
Subchronic PEA-treatment (Panel A; right image) notably preserves NeuN signal
FJC staining indicates neurodegeneration predominantly in cortical layer adjacent to CA3 region of the hippocampus in untreated epileptic mice with a maximal score of 4 (Panel B; upper middle image)
In untreated epileptic mice with SE (Panel B
lower middle image) a widely spread FJC-signal throughout DG and hilus region is observed
Brain sections from subchronically PEA-treated mice display comparatively weak occurrence of neurodegenerative events (Panel B; upper and lower right image)
while sections from control mice do not show FJC-signal (Panel B; upper and lower left image)
Silver stained brain sections of untreated epileptic mice (Panel C; middle image) indicate widespread neurodegenerative effect of KA-induced SE and comparatively only moderate effect on brain sections from PEA-treated mice (Panel C; right image) in relation to brain section from healthy control mice (Panel C; left side)
Semiquantitative comparison of positive FJC signals in the hilus region 5 days post KA injection revealed significantly reduced (**P < 0.0016 KA vs
PEA2/KA) levels of FJC-sensitive neurodegeneration upon subchronic PEA treatment (the treated mouse had a max
behavioral score of 4 within the 180 min time-course) compared to FJC-signals in the hilus regions obtained 5 days post KA-induced SE (Supplementary Figure S5)
Silver staining indicates widespread neurodegenerative effects provoked by KA-induced SE (Figure 3C, middle image), while a moderate extent of neurodegeneration was observed on brain section from mice with subchronic PEA treatment (Figure 3C; right image) in relation to brain section from healthy control mice (Figure 3C; left side)
performed a time course study of the effects of URB597
URB937 and each in combination with exogenous PEA administration on the modulation of AEA and PEA
as well as related eCB and eiCs in brain and plasma
and of the anticonvulsant properties in epileptic mice in comparison with PEA-treated epileptic mice
Behavioral analysis of seizure intensity over 180 min post-KA injection in mice treated with PEA, URB597, and combination of PEA and URB597 showed no significant differences between the three groups (Figure 4A). This indicates that PEA-induced anticonvulsion is similarly effective as for URB597 and that co-administration with URB597 does not induce any cumulative therapeutic effect due to drug interaction (Figure 4A)
PEA treatment of KA-induced epileptic mice
Behavioral scores were obtained over a time course of 180 min post KA-seizure induction in (A) URB597-treated (URB597/KA)
PEA- and URB597-treated (PEA/URB597/KA) vs
as well as in (B) URB937-treated (URB937/KA)
PEA- and URB937-treated (PEA+URB937/KA) vs
Pharmacological blockade of peripheral FAAH was less effective than PEA treatment in maintaining anticonvulsive effects over the entire time course. This is evident in the pre- and late-acute seizure phase, where URB937-treated mice showed significantly higher convulsion intensity compared to those animals treated with PEA only (Figure 4B)
the combination of PEA/URB937 fails to be effective in the acute (60 min) and late-acute seizure phase (60–120 min)
suggesting some mutually exclusive effects of these combined treatments in the acute seizure state
the pharmacological increase of AEA and PEA must occur also in the brain in order to exert an effective therapeutic action for seizure prevention
Impact of URB597 treatment on temporal dynamics of hippocampal and plasma lipid levels in KA induced epilepsy mouse model
PGE2 and PGD2 were comparatively analyzed in URB597-treated mice (URB597/KA) vs
URB597 administration maintains in hippocampus at late-acute seizure phase (120–180 min) a higher level of inflammation markers, PGE2 and PGD2 compared to PEA administration only. This molecular feature occurs also when PEA and URB597 are co-administered, but is less significant compared to URB597 treatment alone (Figure 5)
Similar effects are observed for AA at and after acute seizure state (60–180 min) upon URB597 and URB597/PEA treatment compared to PEA treatment only
Impact of URB937 treatment on temporal dynamics of hippocampal and plasma lipid levels in KA induced epilepsy mouse model
PGE2 and PGD2 were comparatively analyzed in URB937-treated mice (URB937/KA) vs
Plasma levels of 2-AG were significantly decreased upon URB937 administration and in co-administration with PEA, which indicates a similar 2-AG modulation as by URB597 and URB597/PEA treatments. PGE2 is maintained in the late-seizure phase (120–180 min) at higher levels upon URB937 and URB937/PEA treatment compared to PEA treatment (Figure 6)
Conclusively, the peripheral effects of URB937 on the AEA levels are less effective compared to PEA treatment to achieve a sustained anticonvulsive effect, and this concurs with significantly stronger epileptic seizure episodes compared to PEA treatment at acute and late-acute seizure phase (Figure 6)
This also indicates that pharmacological modulation of peripheral FAAH tone only is not sufficient to sustain anticonvulsive effects
Further elucidation and validation of these findings to draw reliable conclusions for TLE patients is certainly necessary
our data indicate that the therapeutic effect of PEA relies in part on a modulation of eCB and eiC levels across the periphery-brain axis
2-AG and inflammation markers in the hippocampus only in the presence of KA-excitotoxic stimuli (Supplementary Figures S2
This clearly indicates a PEA- mediated regulation of the peripheral and hippocampal AEA level that takes place specifically with an underlying pathological condition
Future mechanistic studies of the PEA antiepileptic role will be designed considering the intriguing role of PEA in modulation of peripheral and hippocampal AEA
and of periphery-brain cross-talk involved in antiepileptic effects
FAAH blockade must necessarily occur in the brain in order to exert efficient anticonvulsive properties
these findings are limited and valid for this particular model of epilepsy and its restricted level of resemblance to human TLE
Future studies focused on rodent models better resembling TLE such as intra-hippocampal injected KA
and suitable models for seizure re-occurrence and/or chronic seizures
should be carried out to derive the long-term potential of PEA treatment and its clinical relevance for patients
Subchronic administration of PEA was more effective in reducing seizure intensity (Figure 1) and had more significant effects on regulating the eCBs and eiCs compared to single dose injection of PEA (Supplementary Figures S1, S2), and it reduces the KA-induced neurodegeneration to almost 50% (Figure 3)
these results highlight a promising potential of chronic PEA administration as an anticonvulsant therapy
PEA may represent a more beneficial therapeutic option than FAAH inhibitors
does not show dose-dependent or long-term side effects
and its extensively reported direct anti-inflammatory properties
Although PEA modulates brain AEA levels in seizure
this effect is independent from a direct action on the eCB system whose ubiquitous and broad activation may be less beneficial in complex pathological conditions as epilepsy
Subchronic PEA treatment is an effective anticonvulsant therapy in KA-induced acute mouse model of epilepsy by significantly decreasing the seizure intensity at and after-acute seizure state
exerting significant neuroprotective effects in brain and downregulating the peripheral and hippocampal inflammatory responses to the excitotoxicity
These results highlight PEA as a promising candidate for chronic antiepileptic treatment
Prospective application of PEA treatment on other models resembling TLE in humans will help elucidating its applicability and potential beyond the current epilepsy model
this is the first study that reveals time-point specific PEA-mediated antiepileptic effects
as well as eCB and eiC dynamics in KA-mouse model of epilepsy
plasma lipids are shown to serve as viable candidates for follow-up drug monitoring
hence facilitating the quest of AED-therapies
The positive effects of PEA pre-treatment revealed here highlight its potential applicability in translational human studies that aim at establishing novel antiepileptic pharmaco-therapeutic strategies
This work was partially supported by the funding provided by University of Mainz to LB (Stufe I
JMP was partly funded by the Focus Program Translational Neuroscience (FTN) in Mainz
We greatly acknowledge the technical support provided by Claudia Schwitter
Georgia Mitsa and Sima Celik throughout the study
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnmol.2018.00067/full#supplementary-material
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Lutz B and Bindila L (2018) Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy
Received: 06 November 2017; Accepted: 16 February 2018; Published: 14 March 2018
Copyright © 2018 Post, Loch, Lerner, Remmers, Lomazzo, Lutz and Bindila. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)
distribution or reproduction in other forums is permitted
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*Correspondence: Laura Bindila, YmluZGlsYUB1bmktbWFpbnouZGU=
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A local group dedicated to spreading awareness about Alzheimer’s disease celebrated its 10th year on Sunday
Precious Memories has raised approximately $90,000 for the Alzheimer Society of Windsor-Essex and other efforts to support those with Alzheimer’s
During its annual luncheon at Jose’s Bar and Grill
the group received a $10,000 donation from the Toldo Foundation to support Project Lifesaver
That initiative sees loved ones with dementia wear wristbands that emit a tracking signal
so emergency personnel can quickly locate them if they wander
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“I started (Precious Memories) because my mother had Alzheimer’s
it hits you like a storm,” said founder Gino Lomazzo
He and his family members scrambled to find her support until the local Alzheimer Society stepped in to help
“It’s about trying to help others,” he said
Windsor is a community that has the biggest hearts
“Alzheimer’s is only growing in the community
The numbers in our area happen to be exploding
“This is our way to try to make the world a little bit better place.”
tcampbell@postmedia.com
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When the Michigan High School Athletic Association announces its team wrestling tournament seedings on Selection Sunday
there's no doubt that Novi Detroit Catholic Central will be No
The Shamrocks improved to 26-1 overall on Wednesday night by repeating as Regional 106 champ by defeating host Dearborn Fordson in the finals
CC has outscored its opponents by a combined total of 295-15
The Shamrocks' only setback this season came against Ohio power Lakewood St
Related: Defending team champ CC qualifies 14 for individual regional
Related: John Glenn Rockets down Bedford to win D1 wrestling team regional.
The Shamrocks open defense of their state title beginning at 2:15 p.m
23 at the Wings Event Center in Kalamazoo. Rounding out the eight-team field will be Davison
last year's runner-up; Westland John Glenn
our focus is on wrestling to the best of our ability," said CC coach Mitch Hancock
who will be gunning for his sixth state title since 2010 and 14th in school history
Dom Lomazzo (125 pounds), Aidan Wagh (171), Brendin Yatooma (215) and Steven Kolcheff (285) each finished 2-0 on the night in the regional conquest at Fordson
Yatooma (8-2) and Kolcheff (1-0) each won by decisions
Also scoring pins against the Tractors for CC included Josh Edmond (135)
Kevon Davenport (145) and Derek Gilcher (140)
Fordson's only three points came at 189 when Mohamad Zahwi decisioned Rory Cox
The Tractors advanced to to the finals against CC with a 46-23 semifinal win over Livonia Franklin
Earning pins for the Shamrocks against Salem included Devon Johnsen (112)
John Browning (160) won by injury default and Caleb White (103) won by void
"We had some quality wins today and I was happy with our guys and their focus level," Hancock said
"We have a few adjustments to make prior to Saturday's individual regionals (at Saline) and the team state tournament next Friday."
Contact Brad Emons: bemons@hometownlife.com
Metrics details
Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders
The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH)
Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans
the mechanisms and impact of decreased AEA signaling remain to be delineated in detail
using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system
FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice
This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons
to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA)
but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged
Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP)
excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity
apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI)
These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior
and a deficit in object recognition memory and in extinction of aversive memory
This study indicates that AEA is not involved in hippocampal short-term plasticity
but modulates glutamatergic transmission most likely via presynaptic sites
and that disturbances in this process impair learning and emotional responses
the mechanisms by which altered FAAH activity and thereby changed endogenous AEA regulate these processes are not well understood
considering that endocannabinoid-mediated effects at the synaptic level are tightly dependent on the type of neurons and tissue where they are released and/or where their targets (e.g.
complete FAAH knockout mice or FAAH blockers do not provide the possibility to discriminate cell type-specific AEA signaling
Despite the well-documented FAAH-mediated modulation of hippocampal functions
cell type-specific FAAH functions have not yet been reported
we hypothesized that a selective depletion of AEA signaling at hippocampal glutamatergic neurons affects distinct forms of synaptic plasticity associated with behavioral alterations in stress-related emotional response
we generated a mouse model in which adeno-associated virus (AAV)-mediated overexpression of FAAH was selectively achieved in the CA1-CA3 pyramidal neurons of the hippocampus
leading to increased expression and enzymatic activity of FAAH
Efficient spreading of the virus was reached to ensure FAAH overexpression in all hippocampal CA1-CA3 glutamatergic pyramidal neurons
We then investigated whether impaired AEA signaling in FAAH-overexpressing mice leads to alterations of endocannabinoid-regulated synaptic plasticity (LTP
HEK293 cells were CaCl2 transfected with either CBA-zerotrans-HA-FAAH-WPRE-bGH plasmid together with the HA-NLS-Cre plasmid
Mice were anesthetized by intraperitoneal injection of fentanyl (0.05 mg/kg
AAV (1 µl; 1.3 × 1012 tu/ml) was injected bilaterally into the dorsal and ventral hippocampus at the following coordinates from bregma: AP: −2.0 mm
using a microprocessor-controlled minipump with 34 G beveled needles (World Precision Instruments) at a rate of 200 nl/min
Anesthesia was antagonized by intraperitoneal injection of flumazenil (0.5 mg/kg
Mice received a subcutaneous injection of buprenorphine (0.05 mg/kg)
and 0.9% saline to compensate fluid loss and were kept on a heating plate at 37 °C overnight and constantly monitored to ensure recovery
Mice were decapitated under deep isoflurane anesthesia (2.5% in O2, Abbott, Wiesbaden, Germany) and horizontal slices (300 μm) containing hippocampus and entorhinal cortex were prepared. Whole-cell patch-clamp recordings in voltage-clamp mode were obtained from CA1 pyramidal cells (details reported in Supplementary Information)
Drugs were purchased from Abcam plc (Cambridge
Postsynaptic currents (PSCs) were evoked by a bipolar tungsten stimulation electrode placed locally in stratum radiatum
2-(3-Carboxypropyl)-3-amino-6-(4 methoxyphenyl) pyridazinium bromide (Gabazine
DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5
or 6,7-Dinitroquinoxaline-2,3-dione disodium salt (DNQX
10 μM) were added to the extracellular solution to block GABAergic or glutamatergic postsynaptic currents
and to isolate postsynaptic excitatory (EPSCs) or inhibitory (IPSCs) currents
PSCs were evoked at a frequency of 0.033 Hz
Stable baseline responses were recorded for 10 min
In LTP experiments and for recording of spontaneous (s) EPSCs
cells were held at −70 mV using a K-gluconate-based intracellular solution
The stimulus intensity was set to evoke EPSC amplitudes of 30–50% of the maximum response during baseline recordings
and the stimulus intensity was set to evoke EPSC amplitudes of 50% of the maximum response during baseline recordings
In inhibitory LTD (iLTD) experiments and for recording of spontaneous (s) IPSCs
neurons were held at +10 mV using a Cs-methanesulfonate-based intracellular solution
The stimulus intensity was set to evoke IPSC amplitudes of 50–70% of the maximum response during baseline recordings
Changes in synaptic strength were measured for 30 min after induction
Long-term plasticity was calculated by averaging the responses collected during 36–40 min (LTP or iLTD) or 45–50min (eLTD) of each experiment
All individual cells recorded were included into analysis and no arbitrary threshold was set to define LTP
Detection and analysis of sEPSCs and sIPSCs was done offline using Mini Analysis program (Version 6.0.7
expression of FAAH led to a significant reduction of AEA (0.55 ± 0.02 ng/g protein; p = 0.0001) compared to Cre expression control (1.49 ± 0.07 ng/g protein) and to a significant reduction of PEA (0.10 ± 0.00 µg/g protein; p = 0.001) compared to control (0.17 ± 0.01 µg/g protein)
The AA level was also significantly (p = 0.017) reduced in FAAH-expressing cells (12.66 ± 1.82 µ/g protein) compared to Cre-expressing control (18.50 ± 0.91 µg/g protein; n = 6)
Long-term plasticity at hippocampal CA3-CA1 synapses
a Schematic drawing illustrates placement of stimulation and recording electrodes in the hippocampal slice
b Discharge pattern of CA1 neurons upon depolarizing (500 pA) and hyperpolarizing (−250 pA) current pulses
c Number of generated action potentials (APs) plotted against positive current injection (in pA) in CA1 pyramidal cells of AAV-WT and AAV-Glu-FAAH mice
e LTP in CA1 following high-frequency stimulation (HFS
100 Hz) is significantly enhanced in AAV-Glu-FAAH mice compared to AAV-WT mice (unpaired t test
d Inset shows sample EPSC traces at indicated time points before and after HFS
f PPI does not change after induction of LTP
g Analysis of the coefficient of variation (CV2) plotted against mean EPSC ratios indicates a presynaptic mechanism involved in LTP in AAV-Glu-FAAH mice and a postsynaptic one in AAV-WT mice
i Excitatory LTD (eLTD) at CA3-CA1 synapses following low-frequency stimulation (LFS
1 Hz) is unchanged in AAV-Glu-FAAH mice compared to AAV-WT mice
h Inset shows sample EPSC traces at indicated time points before and after LFS
j PPI does not change after induction of eLTD
k Analysis of CV2 plotted against mean EPSC ratios point to a postynaptic mechanism involved in eLTD in both genotypes
Both AAV-WT and AAV-Glu-FAAH mice showed intact inhibitory LTD (iLTD) at CA3-CA1 synapses
inset shows sample IPSC traces at indicated time points before and after HFS
n PPI does not change after induction of iLTD
o Analysis of CV2 plotted against mean IPSC ratios indicates a presynaptic mechanism involved in iLTD in mice of both genotypes
scatter plots and corresponding mean ± SEM represent amplitudes recorded after plasticity induction (LTP and iLTD: min 36–40; eLTD: min 46–50)
numbers indicate the number of recorded cells/animals
Endocannabinoids can induce long-term and short-term plasticity at both excitatory and inhibitory synapses. Therefore, we recorded evoked EPSCs and IPSCs from CA1 pyramidal cells upon local electrical stimulation in stratum radiatum (Fig. 3a) and tested the effects of FAAH overexpression on different forms of synaptic plasticity
Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) at hippocampal CA3-CA1 synapses
c Upon postsynaptic depolarization (−70 to 0 mV
both AAV-WT and AAV-Glu-FAAH mice showed comparable DSE and DSI
Numbers indicate the number of recorded cells/animals
d Scatter plot and corresponding mean ± SEM of amplitudes recorded immediately before (pre)
2 min (post II) and 4 min after depolarization (post III)
This discrepancy can be explained by considering that our approach aims at overexpressing FAAH exclusively in CA1-CA3 pyramidal neurons
whereas determination of FAAH levels and activity was carried out in the whole hippocampal tissue where other sites of FAAH expression exist
suggesting that stress coping in response to FST is dependent on CB1 receptors expressed specifically on glutamatergic neurons
we observed that decreased AEA and PEA levels by overexpressing FAAH in vivo did not affect endocannabinoid-mediated DSI/DSE at hippocampal CA1-CA3 synapses
2-AG seems to mediate the short-term retrograde control of presynaptic inputs at hippocampal CA3-CA1 synapses in adult mice
These notions highlight the necessity to investigate endocannabinoid signaling-mediated regulation of physiology
behavior and its therapeutic value in the female brain
will be part of our next future investigations
Differently from previous studies where PEA contribution to anxiety states is addressed by enhancing PEA pathways
our mouse model adopts an AEA/PEA signaling depletion approach
where investigating PEA-PPARγ and PEA-GPR55 pathways is very challenging
connecting the functional contributions of PEA and behavioral outcome is not straightforward
as PEA is not the unique endogenous ligand at PPARγ and/or GPR55 receptors
Further studies will have to address the differential functions of AEA and PEA signaling via their respective receptors regarding behavior and synaptic processes
our study shows that FAAH-mediated depletion of AEA and PEA levels and AEA-mediated synaptic signaling in hippocampal glutamatergic neurons modulates LTP and distinct behaviors in mice
Our experimental strategy using the AAV-stop-FAAH construct represents a useful tool to further elucidate AEA and/or PEA signaling and function in the brain
This work was supported in part by the German Research Foundation (CRC/TR 58 to BL (A04) and HCP (A03
The authors declare no competing interests
Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants
Metabolism of the endocannabinoid anandamide: open questions after 25 years
Elevation of endogenous anandamide impairs LTP
and memory through CB1 receptor signaling in mice
COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation
Mammalian enzymes responsible for the biosynthesis of N-acylethanolamines
Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus
Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): discovery of phosphorylcholine derivatives of N-acyl ethanolamines
Assignment of endogenous substrates to enzymes by global metabolite profiling
N-palmitoyl-ethanolamine: biochemistry and new therapeutic opportunities
Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase
Modulation of anxiety through blockade of anandamide hydrolysis
Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats
Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors
Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress
Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task
Genetic targeting of principal neurons in neocortex and hippocampus of NEX-Cre mice
AAV vector-mediated overexpression of CB1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicity
Development and optimization of adeno-associated virus vector transfer into the central nervous system
Impaired 2-AG signaling in hippocampal glutamatergic neurons: aggravation of anxiety-like behavior and unaltered seizure susceptibility
Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction
The stress-inducible actin-interacting protein DRR1 shapes social behavior
Changes in object recognition and anxiety-like behaviour in mice expressing a Cx47 mutation that causes Pelizaeus-Merzbacher-like disease
Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex
Modulation of synaptic transmission and long-term potentiation: effects on paired pulse facilitation and EPSC variance in the CA1 region of the hippocampus
Applicability of the coefficient of variation method for analyzing synaptic plasticity
NMDA receptor-dependent and -independent long-term depression in the CA1 region of the adult rat hippocampus in vitro
Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability
Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure
Peripheral gating of pain signals by endogenous lipid mediators
Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474
Removal of G(ialpha1) constraints on adenylyl cyclase in the hippocampus enhances LTP and impairs memory formation
The endogenous cannabinoid system controls extinction of aversive memories
GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response
Effects of chronic and acute stressors and CRF on depression-like behavior in mice
Forced swimming test in mice: a review of antidepressant activity
Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase: new targets for future antidepressants
Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses
The hippocampal-prefrontal pathway: the weak link in psychiatric disorders
The brain reward circuitry in mood disorders
Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training
Neurobiological interactions between stress and the endocannabinoid system
The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase a mediates retrograde suppression of synaptic transmission
Endocannabinoid-mediated control of synaptic transmission
Synaptic functions of endocannabinoid signaling in health and disease
Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo
Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors
A second endogenous cannabinoid that modulates long-term potentiation
and endocannabinoids are involved in a cascade leading to hippocampal long-term depression
Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons
Endocannabinoid signaling and synaptic function
Sex differences in molecular signaling at inhibitory synapses in the hippocampus
Occurrence and biosynthesis of endogenous cannabinoid precursor
Palmitoylethanolamide modulates GPR55 receptor signaling in the ventral hippocampus to regulate mesolimbic dopamine activity
Genetic deletion of neuronal PPARγ enhances the emotional response to acute stress and exacerbates anxiety: an effect reversed by rescue of amygdala PPARγ function
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and Marcus Keil for excellent technical assistance
The anti-FAAH antibody was a gift from Ken Mackie (Bloomington
These authors contributed equally: Tina Zimmermann
University Medical Center of the Johannes Gutenberg University Mainz
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DOI: https://doi.org/10.1038/s41386-018-0274-7
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Davide Marzullo was born and raised in a family linked to the restaurant business and
he decided to study to turn his passion into a career
he began to gain experience in some of the most prestigious kitchens in Europe
The Connaught in London and The Market Place in Como
His journey continued with his participation and victory in the 2019 Antonino Chef Academy television program
where he worked alongside chef Antonino Cannavacciuolo
He then decided to put his creativity and vision into a project of his own
opening the Trattoria Contemporanea in Lomazzo
the restaurant was awarded its first Michelin star in 2023
making Marzullo one of Italy's youngest starred chefs
His approach is characterized by the use of simple ingredients from the popular tradition
following a philosophy that aims to give value to products that are often forgotten or undervalued
as well as modern and inclusive: every detail is designed to offer his guests a different experience
Do you want to discover the latest news and recipes of the most renowned chefs and restaurants in the world
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overcoming challenges and striving to be great despite adversity has earned several local teens praises and an investment in their future
the Children’s Services Council of St
Lucie County held its annual Awards Dinner to recognize a group of outstanding youth and child advocates who are making a difference in the community
Five teens earned this year’s Outstanding Youth Award
which comes with a $1,000 college scholarship upon graduation from high school
Winners are nominated by the programs in which they participate for displaying exemplary leadership characteristics
This year’s winners included Kaylee Batten
Jeida Cotto and Naima Dore from PACE Center for Girls; Andrew Priest from Treasure Health and Frontline for Kids; and Yaluris Torres from Boys & Girls Club of St
The Children’s Services Council also recognized two local child advocates for their dedication to the mission of the council of improving the quality of life for children in the area
Debra Adamski has worked with Helping People Succeed for 17 years
enriching the lives of thousands of students in her role as the program manager of the Helping Youth Succeed program
Adamski truly goes above and beyond to ensure that her students have the tools they need to improve their grades
Also receiving a Champion for Children Award
posthumously named after the council’s longtime leader Kathryn Basile
was Healthy Families’ Leila Lomazzo. Lomazzo is often the first person families see from the Healthy Families program and her positive engaging personality is what attracts so many to the services
Lomazzo was one of three finalists for Family Assessment Worker of the Year for the state of Florida
She is a true team player and works hard to ensure families get off to a great start
Lucie County Sheriff’s Office and Post Insurance & Financial Inc
and was held at the Regal Event Hall in St
The Children’s Services Council of St
Lucie County improves the lives of more than 40,000 children and families in the community by funding and partnering with quality agencies that ensure that every baby is a healthy baby
For more information on the Children’s Services Council of St. Lucie County, call 772-408-1100 or visit the website at www.cscslc.org.
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Piazzetta Ho Fengshan (Ho Fengshan square)
was officially unveiled in Milan on March 15
to commemorate Ho's saving Jews during World War II
Ho risked his life and career to save more than 3,000 Jews by issuing them visas to Shanghai
saving them from the Nazis in his capacity as then-Chinese consul general in Vienna
Ho's actions in Vienna went unnoticed during his lifetime until "Jews in Shanghai"
a series of cultural activities jointly held in 1999 by the Chinese Cultural Centre of Vancouver and the Vancouver Holocaust Education Centre
Ho was posthumously awarded the title “Righteous Among the Nations” by Israeli organization Yad Vashem in 2001 and made an honorary citizen by the Israeli government in 2007
the United Nations praised Ho as the "Chinese Schindler"
in reference to German businessman Oskar Schindler
who harbored Jews in his factories during the war
in 1901 and died in San Francisco at the age of 96 in 1997
Ho was the Chinese consul general in Vienna from 1938 to 1940
Piazzetta Ho Fengshan is located at the intersection of Via Paolo Sarpi (Paul Sapilu Road) - Milan's China Town - and Via Lomazzo (Lomazzo Lou Road)
HAMPTON — A 1930s tourist cabin that used to be a part of Young's Cabins at Hampton Beach is the newest attraction at the Tuck Museum
Members of the Hampton Historical Society unveiled the exhibit to the general public for the first time on Sunday
"This has been as few years in the making," said Hampton Historical Society member Betty Moore
The 20th century cabin joins the 1700s barn and 1900s school house on the museum grounds
The cabin was officially opened after a ribbon-cutting ceremony
followed by a presentation by Historical Society member Bill Keating titled
Moore said officials first found out about the cabin in 2005 from Elizabeth Aykroyd
a member of the town's Heritage Commission
The cabin and other cabins that were part of the Sea Castle Motel and Cottages were slated to be demolished to make room for luxury condominiums
Aykroyd said the Heritage Commission signs off on all demolition permits and was able to convince the developer to allow the museum to take ownership of the cabin
"This is one of the last tourist cabins on the beach," Moore said
"It's a unique part of 20th century Hampton history that's worth preserving."
The cabin was built by Hamblet Young in 1930
A later owner from Manchester by the surname of Lomazzo operated the property as Young's Motel in the 1950s
in addition to running the Hollywood Motel and a restaurant
Aykroyd said the cabin is what you would have seen all over around beach in 1930s
"This was absolutely typical of what was at the beach from 1920 and into 1950s," she said
Moore said they were able to move the cabin to the museum grounds with the aid of former selectman and Budget Committee member Michael Plouffe
He donated his time and a flatbed to move the cabin from Ocean Boulevard to Park Avenue
What transpired next was a two-year effort to get the cabin ready for exhibit
Officials spent the first year working on the exterior and this summer
"We tried to make the cabin as it would have been like in the 1950s," Moore said
The cabin features original linoleum flooring and original pine kitchen seating area and combination sink/stove/refrigerator from the 1950s
Volunteers donated items such as a bathing suit and dress from the 1950s to give the cottage a nostalgic feel
An old bed that was in the attic of the museum was put inside the cottage and Ann Carnaby made curtains to go over the window
"We also have an old coke bottle opener that was used back then," Moore said
"As we go along we would like to keep adding things to the cabin."
Moore said one of the reasons it took so long to get the cabin open is because society members got caught up in the restoration of the 1700s barn
"I think it's going to be fun for people to see what it was like staying at Hampton Beach in the 50s," Moore said
"It does tell a story of Hampton Beach that is almost gone."