Metrics details which we experimentally demonstrated reproduces this cell state SCimilarity serves as a foundation model for single-cell profiles that enables researchers to query for similar cellular states across the human body providing a powerful tool for generating biological insights from the Human Cell Atlas a query cell profile is compared to a searchable reference foundation model of 23.4 million profiles from 412 studies samples with similar cells are identified and returned with information about the original sample conditions a SCimilarity score is computed between the query cell and each cell within a tissue sample 56 training and 15 test datasets with Cell Ontology annotations from across the body are used as input each consisting of an anchor cell (A) a positive cell (P, anchor-similar) and a negative cell (N, anchor-dissimilar) Only non-ambiguous relationships are allowed triplets are used to train a neural network that embeds similar cells closer than dissimilar ones regulatory T cells. The loss function is computed using a cell triplet a reconstructed anchor cell profile (Â), and a weighting parameter (β) to balance the triplet loss (Ltriplet) and the mean squared error loss (LMSE) showing how SCimilarity provides a powerful framework for scalable cell search across organs systems and conditions to generate biological insights and experimentally testable hypotheses from the Human Cell Atlas We focused on a single (β = 0.001) model that best combined query sensitivity and integration performance (below) A large-scale reference database of public gene expression datasets across tissues and diseases The number of cells (circle size) across tissues (outermost light blue circles) and disease states (middle green circles) across individual studies (innermost circles) in the training (gold) test (pink) or unannotated (purple) datasets is shown SLE, systemic lupus erythematosus; RA multiple sclerosis; LCH, Langerhans cell histiocytosis; LAM Benchmarking SCimilarity against established data integration models bottom left) and graph connectivity (y axis bottom right) for different integration methods and SCimilarity (coloured bars) each applied to integrate two kidney datasets two PBMC datasets and all 15 held out (test) datasets (x axis) are shown SCimilarity generalizes new datasets and flags outlier cells across different tissues and conditions The fraction (x axis) of cells with low similarity to training data (SCimilarity score of <50) in each study (points) from different diseases (y axis cell lines or induced pluripotent stem cell-derived cells from the training and test sets because their cell identity may be ambiguous We reasoned that a good similarity metric should both allow searching for similar cells and group together similar cells from different studies SCimilarity’s loss function decouples faithful cell representation (query) from sample mixing (integration) and learns features that capture meaningful biology reduce technical noise and generalizes to data held out of the training set while SCimilarity was trained exclusively on 10x Genomics Chromium data it effectively generalized to other single-cell profiling platforms coloured by FM query SCimilarity scores (colour bar) SCimilarity’s explainability framework scores FM-associated genes by importance The distribution of Integrated Gradients attribution scores (y axis top; horizontal bars show the mean) for genes (x axis bottom) with the top 50 scores for FMs versus lung macrophages and their membership (red absence) in published macrophage signatures (bottom The left colour bar represents the AUC for the attribute score match to published signatures The signature publication source and P value (two-sided Mann–Whitney U-tests; in signature > not in signature) across the top 3,000 genes by mean attribution score are shown on the right AUC values and P values were calculated using the n = 500 cells most similar to FMs against n = 500 randomly sampled cells from the full n = 2,578,221 cell monocyte and macrophage query set is well represented in SCimilarity’s query score and embedding clusters or a group of highly similar cells defined by a gene signature SCimilarity assesses a query’s coherence and the model’s confidence in the cell’s representation Using a cell’s full expression profile captures its full complexity bypassing the need for curated (and biased) gene signatures SCimilarity can generate a robust signature for a cell state using an explainability technique As public data are diverse and different biological questions may have different assumptions SCimilarity enables users to make case-by-case decisions on proper study or cell filtering and SCimilarity score cut-offs appropriate to their investigation we have removed any sample duplication across training and test sets; however there are duplicated samples within our full reference dataset as a consequence of including published datasets in toto We made SCimilarity available as an open-sourced Python API with tutorials for querying The API facilitates tailored queries by k-nearest neighbours (k-NN) score-based filtering and visualization tools and each query result is traceable to the original dataset for further analysis suggesting a broader role for these cells in the damage response and tissue remodelling processes previous foundation models did not perform well on identifying cells similar to FM or myofibroblasts As SCimilarity can generalize to cells and datasets not seen in the training cell profiles can be filtered or added without recomputing the existing embeddings cell queries and gene signature derivation all are simplified using SCimilarity’s generalized representation and can be applied to cells not seen during training without informing the model about the importance or variability of specific genes We trained SCimilarity on both scRNA-seq and snRNA-seq data collected by 10x Genomics Chromium data (of varying tissue coverage) and it was able to handle test data from profiles collected by other scRNA-seq platforms that were not included in training users should always interpret cross-technology integrations with care The strong performance of SCimilarity’s learned representation for both the integration and querying tasks may suggest that it can perform well for other tasks but these need to be assessed in future studies By training on Cell Ontology annotations from many published studies SCimilarity learns a consensus of how experts define a given cell type the set of labels that SCimilarity can predict is by necessarily limited by available Cell Ontology terms and experimental observation of cell states across studies irrespective of whether the cell state is in the Cell Ontology or observed in training Note that we deliberately withheld cancer cells and cell lines from training due to lack of clear cell type identity and these may not be well represented in the current model probably because most training data were sourced from adult tissues and due to ambiguity in lineage commitment of non-differentiated populations While SCimilarity’s API provides guidance to assess the coherence of a query cell profile the quality of query results ultimately depends on the assumptions and quality of the input profile An input cell profile can be derived from a single cell or an aggregation of cells scored and filtered by a user-defined gene signature—all of which require some subjective selections that can influence downstream analyses As larger SCimilarity representations are trained on the growing Human Cell Atlas the model will allow querying and searches on expanded swaths of human biology The SCimilarity model consists of one fully connected encoder and one decoder stage and reuses the same encoding network three times per training triplet such that updates to the model after each batch are shared equally for each subsequent batch of training triplets The decoder stage is not part of the conventional triplet loss architecture but is included to compute a MSE reconstruction loss the objective is to place cells of different types sufficiently far apart The minimum desired distance between cells of different types is called the margin By fixing the volume of the embedding space to the surface of a unit length 128-dimensional hypersphere the margin is interpreted consistently between model runs cells can be placed up to an infinite distance apart To learn features that place datapoints considered similar near each other, the loss function depends on distances between data points embedded in a learned low dimensional latent space, described with equation (1): where x and y are two high-dimensional vectors (here passed through a neural network encoder f() The triplet-loss model learns from three vectors at a time: the anchor (\({{\bf{x}}}_{i}^{a}\)) positive (\({{\bf{x}}}_{i}^{p}\)) and negative (\({{\bf{x}}}_{i}^{n}\)) The anchor and positive vectors are considered to be similar whereas the anchor and negative are dissimilar The model parameters are iteratively updated to decrease the number of triplets where the distance between the anchor and negative data vectors is insufficiently large relative to the distance between the anchor and the positive points, therefore minimizing the triplet-loss function defined in equation (2): which denotes how much further the negatives should be from the anchor than the positives The reconstruction loss is computed on the anchor cell only, because each anchor cell is used only once as an anchor within a batch. The reconstruction loss is defined in equation (3): where N is the number of anchor cells in a batch and g() is the function learned by the neural network decoder stage Authors may annotate cell types at different granularities which confounds triplet sampling by introducing cell type annotations with hierarchical relationships that cannot be unambiguously defined as either similar or dissimilar cell type annotations used for training are defined using standardized Cell Ontology terms and valid triplets are restricted to cells without vertical Cell Ontology relationships between the members of the triplet A vertical relationship is defined as any directed path of one or more ancestor–descendant relationships in the Cell Ontology network there are three binary relationships defined for annotation: (1) similar pairs with identical annotations (for example T cell and T cell); (2) dissimilar pairs with non-vertical ontology relationships (for example αβ T cell’); and (3) ambiguous pairs with vertical relationships (for example Positives are drawn from cells similar to the anchor negatives are drawn from cells dissimilar to the anchor and cells that are ambiguous to the anchor are excluded from sampling Cell type annotations were manually converted into terms contained within the Cell Ontology Cells with annotations that did not clearly map to the Cell Ontology were not included in training Cell profiles previously annotated as doublets, scored as doublets by infer_doublets from Pegasus73 had >20% total UMI counts aligned to mitochondrial genes or had <500 total genes detected were removed Training and test sets were chosen such that entire studies were held out of training (rather than holding out a subset of cells from each dataset) (Supplementary Table 1); there were 56 and 15 datasets in the training and test sets This presents a harder generalization challenge and reflects how users are likely to use SCimilarity Test datasets were selected to reflect the tissue diversity within the training sets As the size or annotation quality of training data grows the number of Cell Ontology terms meeting the inclusion criteria are expected to increase batches of 1,000 cells are sampled from the training datasets This sampling is weighted by study and cell type to have a similar number of observations per cell type from each study per batch Owing to the maximum operation within the loss function not all viable triplets contribute to the gradient based on their contribution to the gradient Easy negatives are defined by equation (5): Hard negatives are defined by equation (6): Hard negatives may be enriched for incorrectly annotated cells Semi-hard negatives are defined by equation (7): we chose to train SCimilarity using only semi-hard negative triplets An explainability framework was used to identify genes of which the variation leads to the most significant variations of the learned features and affects the relative distance between different cells This approach differs in several key ways from the standard integrated gradient approach because: (1) gradients are computed with respect to a learned distance instead of output features; (2) attributions where xi < yi are ignored; and (3) the sign of the integral is ignored due to the complex interactions between features As the pairwise comparisons are averaging relative comparisons the sampling of \(\{{b}_{1},\ldots ,{b}_{N}\}\) impacts the signature scoring a background of cells in other states of the same type are sampled Confidence intervals for each gene i are computed as the standard error of the mean This results in an attribution score for each gene Gene attributions were calculated using a set of foreground cells and a set of background cells Foreground cells were the 500 cells most similar to the query (FM) among the searched cells (for example high confidence in vivo monocytes and macrophages) Background cells were selected by randomly sampling 500 cells outside of the top 10,000 cells (within in vivo monocytes and macrophages) by SCimilarity score to the query cell (FM) The AUC enrichment statistic was calculated based on the 3,000 genes with the highest attributions For each published signature, the AUC and one-sided P value were calculated using Mann–Whitney U-tests according to equation (10): n1 is the number of genes in the published signature among the 3,000 genes and n2 is the number of genes not in the published signature among the 3,000 genes The SCimilarity score is defined as the inverse of the cosine distance of two embedded cell profiles as in equation (11): where ci and cj are the embeddings of the ith and jth cell profiles with unit length The threshold for similarity varies in practice by question and cell types CI is the set of cells of author-annotated type t and CJ are the cells of all other cell types the ASW as typically formulated does not account for differences in granularity of cell type annotations across studies a modified formulation is used where CI contains cell type label t and all of its ontological descendants and CJ is the set of all other cell types except cells of type t and any of its ontological descendants or ancestors the distances between all types of T cell terms (CD4-positive αβ regulatory T cell and so on) are members of the T cell term are not members of the T cell class (nor a T cell subset) but are excluded from the summation indices in the calculations of a(i) and b(i) To test how the SCimilarity distance represents distance between predefined cell states a signature-based definition of cell state was correlated with the SCimilarity score (above) and the Pearson’s correlation coefficient is calculated between the vectors ARI and NMI were calculated as integration benchmark metrics As ‘ground truth’ cell type annotations are required to assess preservation of biological signal methods were benchmarked on the 15 test studies with author-provided cell type annotations held out during SCimilarity training As the scArches workflow requires a reference dataset 101,133 cell profiles were sampled across all training datasets with uniform probability across studies for use as the reference or with weights by distance in SCimilarity’s reduced dimensionality latent space according to equation (15): To allow users to annotate new datasets from a restricted list of cell types of interest specific cell types can be excluded (blocklisting) or annotations may be limited to specific cell types (safelisting) blocklisting or safelisting is recommended to improve interpretability and reduce spurious annotations extensive blocklisting or safelisting can slow the annotation process substantially because the pre-built k-NN indices are not optimized for a modified target cell type list Searching this k-NN found the 50 nearest neighbours (default behaviour) for cell type annotation (k = 50) and ef = 100 Cell query relied on a separate 23.4-million-cell k-NN index also built using hnswlib This index was constructed with the following parameters: ef_construction = 400 and M = 50 The search parameters are set by the user’s request for how many similar cells to return The default behaviour is set to k = 1,000 and ef = k but k can vary widely depending on the use case SCimilarity cell type annotation was constrained to 7 Cell Ontology terms that were most similar the three author-provided annotations (B cell Pairwise distance distributions were calculated for up to 1,000 randomly sampled cell pairs (limited by cell numbers) for the most abundant SCimilarity annotated cell types Distributions were generated for pairs of selected populations within annotation and protocol (cell to cell or nucleus to nucleus) within annotation and across protocols (cell to nucleus) and across annotation (one cell type to another cell type) and within protocol Profiling platforms were compared using the data for the human PBMC sample from SCP42431 The distribution of nearest-neighbour SCimilarity scores was retrieved from the k-NN graph both irrespective of platform and constrained to within-platform and within-replicate neighbours Cell type annotations were constrained to nine Cell Ontology terms most similar to the author-provided annotations Annotation precision was calculated as the percent of cells with SCimilarity-predicted annotations identical to the Cell Ontology mapped author-provided annotations within each platform and replicate separately For benchmarking across all 15 test datasets (Fig. 3e) 143,638 cell profiles were sampled with uniform probability across the 15 studies These were then filtered to cell types found within the test set annotations TOSICA and scANVI models were learned with the remaining 103,116 training cell profiles sampled across all training datasets weighted so that each study was equally represented in the complete training set To filter outlier cells before visualization and downstream analysis SCimilarity’s score is used to flag cells that are out of distribution Cells with a SCimilarity score < 33 from the nearest cell in the training set were removed before further analysis Many of these cells were from immortalized cell lines and reflect their difference from primary cells (and absence in the training) Note that if out-of-distribution cells are not removed these cells will not be accurately annotated and can confound visualization Spearman rank correlation coefficient values (ρ) were calculated between the gene signature score and distances to the query cell state across all cells in each model Cell type annotations predicted by SCimilarity were constrained to 28 Cell Ontology terms present in lung tissue The results of cell queries depend on the centroids used for the query To help users generate effective cell state queries a statistic is calculated from the query cells (that is a cell state should be a centroid of a coherent its underlying cells are subclustered (k = 10 clusters) 10 centroids are computed from the subclustering and a SCimilarity search is conducted for the most similar cells to each of the 10 centroids (default n = 100 nearest neighbours) The mean overlap in cell query results between the parent centroid profile and each k-means subcluster centroid is reported as a measure of query stability Only in vivo tissue samples with at least 50 macrophages and 50 fibroblasts were considered 500 cells were randomly sampled from the full 2.5-million-cell monocyte and macrophage query set with multiple-hypothesis correction using the Benjamini–Hochberg method and the background gene universe restricted to the approximately 28,000 genes included in SCimilarity Pathways were considered to be significant if they met the criteria of adjusted P value (Q) ≤ 0.05 and gene count ≥ 4 Wells of the 3D hydrogel culture were washed with PBS followed by recovery of the hydrogel and cells by gentle pipetting in PBS buffer This solution was centrifuged for 5 min at 750g and the hydrogel/PBMC pellet was resuspended in TrypLE solution (Thermo Fisher Scientific) and incubated at 37 °C for 10 min RPMI medium with 10% FBS was added and the solution was centrifuged for 5 min at 750g The resultant pellet was washed twice with PBS to remove hydrogel matrix debris PBMCs were resuspended in PBS and passed through a 40 µM filter pelleted by centrifugation at 300g for 5 min and resuspended in RPMI medium with 10% FBS The cell solution was subjected to FACS to isolate cells from any remaining hydrogel debris and recovered cells were concentrated to 1,000 cells per µl in RPMI medium with 10% FBS for downstream profiling by scRNA-seq scRNA-seq was performed using the Chromium Single Cell 3′ Library and Gel bead kit v3 (10x Genomics) according to the manufacturer’s user guide the cell density and viability of the single-cell suspension were determined using the Vi-CELL XR cell counter (Beckman Coulter) The cell density was used to impute the volume of single-cell suspension needed in the reverse transcription master mix aiming to achieve around 10,000 cells per sample cDNAs and libraries were prepared according to the manufacturer’s user guide (10x Genomics) Libraries were profiled using the Bioanalyzer High Sensitivity DNA kit (Agilent Technologies) and quantified using the Kapa Library Quantification Kit (Kapa Biosystems) Libraries were sequenced on the NovaSeq 6000 (Illumina) system according to the manufacturer’s specifications with 28 + 90 bp paired-end reads at a depth of 101 million mate-pair reads Sequencing reads were aligned to the GENCODE 27 Basic gene model on the human genome assembly GRCh38 using Cell Ranger v.6.0 (10x Genomics) SCimilarity cell type classification was applied to both public and validation cells using SCimilarity with the following safelist: B cell Benchmarks were run on servers with 8 Intel Xeon E5-2650 v4 CPUs with 2.20 GHz cores and a total of 128 GB of RAM where the query was directly compared against 2.58 million 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Zenodo https://doi.org/10.5281/zenodo.14087552 (2024) Download references Tripathi for coming up with the name ‘SCimilarity’ and J Freimer for their suggestions on the manuscript These authors contributed equally: Graham Heimberg These authors jointly supervised this work: Josh Kaminker performed data ingest and model implementation with input from J.A.V.H. conceived the biological application of the method with input from G.H. performed experimental validation with guidance from J.R.R wrote the manuscript with input from J.A.V.H. All of the authors reviewed the manuscript All of the authors are employees of Genentech or Roche is a co-founder and equity holder of Celsius Therapeutics was an scientific advisory board member of Thermo Fisher Scientific Nature thanks the anonymous reviewers for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Cumulative number of (a) cells (y axis) and (b) samples (y axis) profiled by sc/snRNA-seq (and matching our filters; Methods) over time (x axis) Doubling time is calculated based on the publication date from the most recent 150 data points (dashed red line) Author-annotated cell types used in training Number of author-annotated cells (colour bar) from each Cell Ontology type (rows) and study (columns) used for SCimilarity model training y or x axis) used for model training from each tissue (rows Top left: Spearman’s ρ between signature score rankings and distances to the query cell and scFoundation (fourth) scores as in (d) for n = 28 SCimilarity predicted cell types across n = 58,530 cells (outliers removed) coloured by cell type after integration with each of five methods coloured by cell annotations obtained without constraining to the scope of author-provided annotations in the study Annotation is robust to the number of nearest neighbours Cell type classification score (y axis) at different number of nearest-neighbours Benchmarking of annotation by established methods UMAP embedding of cell profiles as in (a) coloured by annotations predicted by CellTypist (c) Percentage (colour bar) and number of author-annotated cells (columns) matching annotations predicted by CellTypist (d) Author annotated cDCs express a mixture of DC markers and markers of other cell types Mean expression (dot colour) and percent of expressing cells (dot size) for canonical marker genes of monocytes (Mono) and conventional dendritic cells (cDCs) (i) or epithelial (Epi) or other non-myeloid lineages (Other) (j) in author-annotated cDCs (row 1) and the subset of those same cells predicted as different myeloid subsets (rows Right bar plots and counts: number of cells per annotation SCimilarity’s annotation accuracy is on par or better than three other methods Left: UMAP embedding (as in a) of cell profiles coloured by annotations predicted by SCimilarity (b) Right: Percentage (colour bar) and number of author-annotated cells (columns) matching annotations predicted by SCimilarity (c) Surface marker protein levels of selected cell populations Distribution (y axis) and median level within population (colour bar) of author-normalized protein levels for selected markers (rows) across cell types (x axis) for author (left) and SCimilarity (left) annotated cells Distribution of myofibroblast signature (first) and scFoundation (fourth) scores as in (c) for n = 28 SCimilarity predicted cell types across n = 58,530 total cells (outliers removed) FMΦ important genes are enriched for relevant pathways x axis) for enrichment of Reactome pathways (y axis Q ≤ 0.05 and gene count ≥ 4) with the 100 genes with the top integrated gradients attribution scores for the FMΦ query (ranked by score) Colour: ratio of important genes within a Reactome pathway to the total size of the pathway Expression of known and novel genes associated with FMΦs Distribution of the fraction of cells (y axis) in ILD tissue samples (dots) among n = 500 randomly sampled FMΦ-like (top 10,000 cells by SCimilarity score) cells (orange n = 23 tissue samples) and n = 500 randomly sampled non-FMΦ-like (remaining cells) macrophages and monocytes (blue n = 13 tissue sample) that express (>0 UMI counts) the known FMΦ marker TREM2 (e) and two FMΦs-enriched genes not previously described for FMΦs (f,g) Crossbar: upper/lower quartiles (vertical line) and median (horizontal line) Supplementary Note 1: analysis task parameters Training and testing datasets and cell type labels SCimilarity gene importance scores by annotation Download citation DOI: https://doi.org/10.1038/s41586-024-08411-y Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science SIDE-LINE Q: Can you share some background about yourselves and the journey that led to the formation of Heimberg what’s the significance behind the name Heimberg Alex: Quentin and I became roommates in 2021 We started playing music together and were part of a local band Anthony moved to Strasbourg sometime later and was looking for a band to join we decided to start our own band and be serious about it We started as beginners and are now growing and learning together musically The name Heimberg comes from the Alsatian words ‘heim’ ‘household’ and ‘berg’ It represents the concept of a warm home in a very cold environment “Isolation” and “Blind Eye” which were combined and released as a full-length album through Icy Cold Records Can you tell us more about these EPs and how the transition from “Isolation” (2022) to “Blind Eye” (2024) shaped your music Anthony: “Isolation” was the first ‘state’ of the band We wrote some songs before it but never released them “Isolation” is leaning more toward the Cold-Wave genre and the production and writing process are different from what we do now It was the first release for all of us and with it we landed our first concerts and started building an audience It sounds more ‘young’ and ‘homemade’ than “Blind Eye” for which we worked harder “Blind Eye” is a complete shift from “Isolation” We think that “Blind Eye” represents us more and made us realize the direction we want to take we learned a lot and pushed ourselves in creating a real ambiance for our songs while trying to distance ourselves from simpler structures It is something that we are still working on for our next project which you’ve reimagined into a contemporary Post-Punk style any artists or producers you draw inspiration from and how you’ve developed your own distinctive sound whether it’s from English-speaking countries/western or eastern Europe But we also draw inspiration from Black-Metal We are also vastly influenced by Electronic music Some bands that has influenced the project are: Ritual Howls and we are still discovering new bands and styles that give us new ideas Various genres of Post-Punk are our main influence in Heimberg but we also draw influence from Electronic music I think our ‘distinctive’ sound comes from a merge of different inspirations Q: What does your composition and production process typically look like How do you divide responsibilities within the band and how do you determine when a song is truly finished or we jam together until something comes out of it a universe and the emotions that we want to convey We are not attached to our instrument and often collaborate the guitarist to the synth… We are now aiming for a two-guitar arrangement The work is divided between us according to what each one of us wants to do and Quentin the hunt for concerts and the conception of our set’s light show All decisions are discussed and approved by each member It’s hard to determine when a song is finished There’s always something to change or to improve which makes it a never-ending process it helps us set goals and once they’re reached Q: Are there recurring themes or concepts that inspire your lyrics How personal are the stories or messages behind the words Anthony I think there are recurring themes in our lyrics sometimes we imagine a scene like a movie and start writing lyrics around it Sometimes there is no message behind the words Q: I can easily imagine you must be busy working on new material and have you noticed a significant evolution in your songwriting What does this new year hold for Heimberg in terms of new releases Heimberg: We are indeed working on some new material We started in the second part of 2024 and our creative work is progressing well now the whole project is starting to look like what we envisioned The song writing is more mature than before we know more about what we want to make and where we are going We operate more and more with ideas and song concepts that will suit our path It makes the whole process more artistically coherent especially with the addition of a second guitar on some of our songs and supporting vocals More people are reading Side-Line Magazine than ever but advertising revenues across the media are falling fast we haven’t put up a paywall – we want to keep our journalism as open as we can - and we refuse to add annoying advertising So you can see why we need to ask for your help Side-Line’s independent journalism takes a lot of time But we do it because we want to push the artists we like and who are equally fighting to survive you can support Side-Line Magazine – and it only takes a minute The donations are safely powered by Paypal Electronic Bodies - Nightside Sessions by Shane Aungst Electronic Bodies - Session 1 by Various Artists Electronic Resistance - Reconstruction by Various Artists Electronic Resistance - A Darkwave / Post-Punk Compilation From The Ukrainian Underground by Various Artists Swiss water diver Michelle Heimberg has had to cancel her participation in this week's World Cup final in Beijing the 24-year-old from Aargau has been "banned from flying due to illness" which is why she will not be traveling to China She will focus on making a full recovery so that she can prepare optimally for the next highlight of the season the European Championships in Antalya from 22 to 28 May About Akin Leadership Client Value Awards & Accolades All Locations Boston Dallas Fort Worth Houston Irvine Los Angeles New York Philadelphia San Antonio San Francisco Washington, D.C. Hong Kong Singapore Geneva London Abu Dhabi Dubai Government Contracts Bid Protests Claims, Disputes & Litigation Construction Litigation Disputes & Investigations Transportation Policy & Regulation False Claims Act/Qui Tam Defense Government Contracts Bid Protests Claims, Disputes & Litigation Construction Litigation Disputes & Investigations Scott frequently represents technology and start-up companies seeking to identify potential government markets and evaluate the benefits and liabilities associated with selling to the government. In addition, he counsels clients on issues of fraud, waste and abuse, including suspension and debarment matters. He has successfully defended Fortune 500 technology and health care companies, as well as construction companies, against civil False Claims Act actions. 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J.D., The George Washington University Law School, with honors, 1984 B.A., Franklin & Marshall College, 1981 ‘No TikTok on Government Devices Act’—Implementation for Federal Contractors and Subcontractors Read More The Legal 500 US 2023 Recommends Numerous Akin Practices, Lawyers Read More Akin Advises Paine Schwartz Partners in its Investment in Elemental Enzymes Read More Trump Administration Seeks to Streamline Federal Procurement Read More DEI Implementation: GSA Announces Class Deviation to the Federal Acquisition Regulation to Implement DEI Related Executive Orders Read More Executive Order: Ending DEI and Affirmative Action for Federal Contractors/Grant Recipients Read More 11 Akin Lawyers Featured as Washingtonian “Top Lawyers” Read More The Legal 500 US 2024 Recommends Numerous Akin Practices, Lawyers Read More IRS Issues Proposed Rules on New Tech-Neutral Clean Energy PTC and ITC Read More IRS Updates PTC and ITC Domestic Content Bonus Guidance Read More OMB Issues Final Buy America Rule and Guidance for Infrastructure Projects Read More Federally Funded Research & Development: New Executive Order Pushes Federal Agencies to Take Title to Subject Inventions and Require Domestic Manufacturing Read More View All Insights Meet Our People Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application Enter your phone number above to have directions sent via text This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors The National Institutes of Health grant supports a collaboration between Temple University's dentistry and psychology researchers The dread many feel about going to the dentist can result in serious health consequences you see avoidance," said Marisol Tellez Merchán associate professor at Temple University’s Kornberg School of Dentistry and residency director of Dental Public Health "Avoiding dental care leads to delayed treatments Our aim is to reduce anxiety so patients can get the care they need." A collaboration between Temple University's dentistry and psychology researchers is showing promising results in the battle against dental anxiety as evidenced by a $2.59 million award from the National Institute of Dental and Craniofacial Research a branch of the National Institutes of Health (NIH) This is the largest NIH grant ever received by the Kornberg School of Dentistry and the latest in a series of multimillion-dollar grants awarded to the Psychology Department of Temple’s College of Liberal Arts It will fund a five-year clinical trial for 450 patients at Temple’s Faculty Dental Practice in North Philadelphia Tellez Merchán’s dentistry expertise is coupled with the clinical psychology expertise of research collaborator Bolton Professor of Psychology in Temple University’s College of Liberal Arts He runs the Adult Anxiety Clinic of Temple which most frequently focuses on the treatment of social anxiety and general anxiety seemed like a subject better managed in the dental environment than a psychologist's office psychology and dentistry didn't have much of a history together," said Heimberg Carnell Professor in the Kornberg School of Dentistry—with introducing him and Tellez Merchán and supporting their work together "We wanted to pursue whether it's possible to put a psychologist's tool in the hands of dental assistants," Heimberg said The tool he and Tellez Merchán have developed is an online intervention to help dental patients become more comfortable with treatment the patient learns about dental anxiety and chooses the three subjects most relevant to them the patient is shown three videos per topic easing them into the procedure the first video is shown at a distance with animations of the inside of the mouth and voiceover detailing the experience The second video shows a closer view of the patient's face and the dentist at work as the two talk about coping with anxiety featuring the patient's point of view of the procedure and the patient’s voice describing coping thoughts "The goal isn't to make people love going to the dentist," Heimberg said "But we do want to change anxious thoughts into coping thoughts." Ismail began seriously thinking about dental anxiety 12 years ago when he observed that some patients refused to seek care even when it was provided for free That led him to assemble the researchers necessary to plan studies and advance potential solutions he’s thrilled to see this clinical trial come to life "It is exciting to see that after 12 years of working on an idea we are successfully moving forward with a major clinical trial to test the hypothesis that we can reduce dental anxiety and improve access to dental care," Ismail said With their funding secured for the next five years Heimberg and Tellez Merchán are currently building up their staff and will soon enter the recruiting phase of their clinical trial the impact of their approach could be significant because of its potential to be used by dental practitioners and patients anywhere might include translations into additional languages for even greater reach Research reported in this publication was supported by the National Institute Of Dental & Craniofacial Research of the National Institutes of Health under Award Number U01DE027328 The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health Temple Now: The official source for Temple news.Copyright 2015 This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page and a little short to mid-term look at the title’s future The vast majority of the interview saw Heimberg discuss the iteration of the game some of his personal challenges with processing feedback correctly and finding reasons to “care” about art (he’s a programmer and how other games’ hits and misses in terms of design compel him to make better systems in Gorgon He also jokes that he likes working on an MMORPG because it’s a game type that best manifests his ADHD Heimberg mentions how the financial boost from the playerbase helps the game forward for the next several months (a refrain echoed by Powers before him) then talks about general plans for new monetization such as providing a “starter version” of Gorgon for between $10 to $15 that can be expanded on with additional purchases that open more character slots or help newer players get up to speed and “grind down the sharp points.” Heimberg also brings up work on the Statehelm area the game’s “massive” final capital city and the place where instanced player housing will reside; it’s at a design document phase right now but will be fleshed out if funding rolls forth Project Gorgon took MassivelyOP’s indie MMO of the year award at the end of 2023 The Daily Grind: Do you think MMO subscriptions are greedy WoW Factor: Down with raid nonsense addons We’re finally getting our first glimpse of 12-year-old Camelot Unchained since last year in today’s dev stream The Daily Grind: Do you feel bad about skipping new MMORPG launches The Soapbox: Could an official WildStar revival succeed in 2025 The Daily Grind: How much does voice acting impact an MMORPG Nilsson moved up for silver with Heimberg having to settle for bronze 🥇","event":null,"destination_url":"","entry_point_tag":"base","entry_point_type":"instory_campaign"}" data-tracking="click" href="https://www.olympics.com/en/sign-in?entry_point_type=instory_campaign&entry_point_tag=base&template=base&origin=https%3A%2F%2Folympics.com%2Fen%2Folympic-channel" target="_blank" rel="noopener noreferrer">Olympic Membership - Free Live Stream Sports & Original Series - join now Share on FacebookShare on X (formerly Twitter)Share on PinterestShare on LinkedInST (WIBW) - A Topeka man is behind bars in Pottawatomie Co Marys were made aware of a stolen vehicle headed into the city The St. Marys Police Department says that around 3:45 p.m law enforcement officials were contacted by those in Shawnee Co about a stolen vehicle reported out of Topeka SMPD noted that the driver had allegedly checked door handles in the Rossville area and made their way to St officers saw the suspect vehicle headed into the city and confirmed it had been reported stolen SMPD said a high-risk traffic stop was initiated was arrested and booked into the Pottawatomie Co Heimberg remains behind bars as his bond amount remains pending Neenma Ebeledike on October 19 was at the hearing aid center for a scheduled appointment.  “I got to my appointment on time but had to wait about 40 minutes for the driver to pick me up when I was done,” Heimberg said This wait was longer than expected but not unusual for Heimberg and others who rely on Richmond’s Paratransit service, R-Transit which provides low-cost transportation to West Contra Costa County residents unable to use regular transit because of a disability or health-related condition Last month, the Richmond City Council approved a $250,000 contract with TransMETRO to expand the R-Transit service.  TransMETRO CEO Fred Khan said supplemental services should be available this week “What we will be seeing between 12 to 24 months is about a 40% increase in ridership because the users have a more reliable service,” he said a paratransit driver who coordinates driver scheduling That number is down nearly 70% from early 2020 said the additional funding will allow them to increase the number of drivers as demand grows “We only have two drivers currently serving all of west county “We can increase the participation and enrollment into our program with more drivers TransMETRO will be offering.”  who has been riding with the service since 2018 regardless of the occasional long wait times The supplemental service will help older people take classes and engage more with the community Transportation Richmond Confidential welcomes comments from our readers but we ask users to keep all discussion civil and on-topic Comments post automatically without review from our staff but we reserve the right to delete material that is libelous We request that commenters consistently use the same login name Comments from the same user posted under multiple aliases may be deleted Richmond Confidential assumes no liability for comments posted to the site and no endorsement is implied; commenters are solely responsible for their own content Richmond Confidential is an online news service produced by the UC Berkeley Graduate School of Journalism for, and about, the people of Richmond, California. Our goal is to produce professional and engaging journalism that is useful for the citizens of the city.Please send news tips to richconstaff@gmail.com Riley Ramirez on May 5 Jennifer Ugwa on April 30 Haydee Barahona on April 29 Subscribe to Richmond Confidential to get the latest news sent straight to your inbox richconstaff@gmail.com University of CaliforniaNorth Gate HallBerkeley Richmond Confidential is an online news service produced by the UC Berkeley Graduate School of Journalism for Our goal is to produce professional and engaging journalism that is useful for the citizens of the city LBV Magazine English Edition On the eve of a construction project in Heimberg the Archaeological Service of the Canton of Bern (Switzerland) conducted a salvage excavation in the autumn of 2023 While the investigation barely yielded new findings about a planned Roman site it did reveal the remains of a previously unknown Bronze Age settlement During the three-month investigation in Schulgässli in Heimberg various settlement remains were documented over an area of almost 1,000 m²: in addition to a horizon of use with a very high proportion of hearth stones and a (relatively) large quantity of Bronze Age pottery several post positions and pits were also found Two of these pits were filled to the brim with hearth stones meaning stones that had been shattered by intense heat They could have served as heat accumulators for cooking or heating and are a typical find from the Bronze Age Other pits could have been used for extracting clay Clay was an important raw material at the time and was used in house construction for plastering wattle walls or making pottery A package of clay layers up to 35 meters thick in the excavation area fits into this context As evidenced by some much younger extraction pits this clay deposit was also later exploited by the well-known potters of Heimberg from the modern era A brick factory excavated in Heimberg in 1964 provides similar evidence for the Roman period The Heimberg site is part of a series of new Bronze Age discoveries between Thun and Bern in recent years it has been known that remains of pile-dwelling houses are also preserved in the lower basin of Lake Thun and Kehrsatz/Chlywabere have also revealed extensive Bronze Age settlement remains The new Bronze Age sites demonstrate the importance of the Aare Valley as a habitat and transportation route between the Alps (passes) and the Swiss plateau Kanton Bern Subscribe to get the latest posts sent to your email Archaeologists from universities in the United States and Denmark found deep within the Actun Uayazba Kab cave in Belize two small stone tools dated between 250 and 900 AD that… men and women gathered to play a game called Cuju A team of researchers has succeeded in recreating for the first time in a laboratory experiment a phenomenon that until now only existed as a theory in the realm of… the Cantonal Archaeology of Aargau carried out a rescue excavation between early May 2024 and the end of March 2025 The Egyptian archaeological mission affiliated with the Supreme Council of Antiquities announced the discovery of a group of defensive structures and a system of moats that could indicate… In the southeastern area of the city of Rome archaeologists excavating inside the Triton Baths within the monumental complex of the Villa di Sette… Why did some animals from ancient eras become fossils while others simply disappeared without a trace A recent study on the cave paintings of the Altamira Cave in Santillana del Mar Cantabria (Spain) has concluded that some of the artworks it contains could be much older… A team of paleontologists from the University of Leicester has managed to decipher one of the many enigmas of the dinosaur era—the exact moment when pterosaurs Rome achieved numerous military victories that allowed it to grow and dominate nearly the entire known world in Antiquity Receive our news and articles in your email for free You can also support us with a monthly subscription and receive exclusive content About  .  Contact  .  Donation the excavation in Schulgässli revealed various settlement remains across an area of approximately 1,000 square meters Among the findings was evidence of a high proportion of hearth stones and a significant quantity of Bronze Age pottery two pits were discovered filled with hearth stones suggesting their use as heat accumulators for cooking or heating—a characteristic feature of the Bronze Age Clay extraction also played a vital role in the settlement with pits likely utilized for this purpose an essential raw material during the Bronze Age such as plastering wattle walls and crafting pottery vessels The excavation unearthed a package of clay layers up to 35 meters thick indicative of the significance of clay in the area’s historical activities the investigation revealed that the clay deposit was later exploited by potters from Heimberg during the modern era as evidenced by subsequent extraction pits Similar activities were observed in a brick factory excavated in Heimberg in 1964 suggesting a continuity of ceramic production in the region since Roman times The discovery in Heimberg adds to a series of Bronze Age findings between Thun and Bern in recent years underscoring the importance of the Aare Valley as both a habitat and a transportation route connecting the Alps with the Swiss plateau Remains of pile-dwelling houses in the lower basin of Lake Thun and extensive settlement remnants in areas like Thun-Schoren and Kehrsatz/Chlywabere further emphasize the region’s historical significance and website in this browser for the next time I comment Δdocument.getElementById("ak_js_1").setAttribute("value",(new Date()).getTime()) Learn how to describe the purpose of the image (opens in a new tab) Leave empty if the image is purely decorative Aristos is a Newsweek science and health reporter with the London He is particularly focused on archaeology and paleontology although he has covered a wide variety of topics ranging from astronomy and mental health Aristos joined Newsweek in 2018 from IBTimes UK and had previously worked at The World Weekly He is a graduate of the University of Nottingham and City University You can get in touch with Aristos by emailing a.georgiou@newsweek.com. Languages: English either observed and verified firsthand by the reporter or reported and verified from knowledgeable sources Translations may contain inaccuracies—please refer to the original content Mystery surrounds the remains of a previously unknown prehistoric settlement next to a road that has been discovered by archaeologists thought to date to around 3,200-3,500 years ago was uncovered by the Schulgässli road in the municipality of Heimberg the Archaeological Service of the Canton of Bern (ASCB) announced in a press release the archaeological service carried out a rescue excavation at the site in the fall of 2023 in the expectation that the investigations would reveal an ancient brick workshop from the Roman era But no remains of such a workshop were found—instead archaeologists unexpectedly identified traces of a Bronze Age settlement "What is exciting about the Heimberg site is that no settlement from the Middle Bronze Age was previously known at this location," Regine Stapfer which took place over the course of three months revealed various traces of the prehistoric settlement but several aspects of the site remain a mystery Among the structures that the researchers uncovered were ditches and several pits some of which were filled to the brim with stones These stones appear to have been shattered by significant heat although researchers are not exactly sure what their original purpose was "It is not clear what these pits with the fragmented stones were used for," Stapfer said It is conceivable that the stones were heated in a fire and then placed in the pits to provide warmth for the Bronze Age community Another possible explanation is that they were used for cooking purposes Similar pits have previously been found at other settlements dated to the Middle Bronze Age The archaeological service also identified other pits at the site that may be evidence of clay extraction clay was an important raw material used for various purposes such as to plaster the wicker walls of houses or to produce ceramics The excavations at the site revealed a relatively large quantity of prehistoric pottery The style and decoration of the pottery indicates that the ceramic artifacts date to around 1500-1200 B.C.—providing an age for the settlement Only part of the Bronze Age settlement has been excavated so far The true identity of the Bronze Age people who once inhabited the site also remains unknown although it is likely that they came from the region "We know of no burial ground for the settlement and therefore have no evidence of the people who inhabited the settlement," Stapfer said The discovery of the Heimberg settlement is one of a series of newly discovered settlements on dry ground—i.e. not on lakeshores—from the Bronze Age that have been found at various locations in the Canton of Bern in recent years Heimberg is situated beside the Aare River in the Swiss Plateau which lies between the Jura and Alps mountains The recently discovered Bronze Age sites demonstrate the importance of the Aare Valley as a place to live during this time period and as a transport route between the Alps and the Swiss Plateau Do you have a tip on a science story that Newsweek should be covering Newsweek is committed to challenging conventional wisdom and finding connections in the search for common ground Newsletters in your inbox See all Metrics details Rodent acinar cells exhibit a remarkable plasticity as they can transdifferentiate to duct- We evaluated whether exocrine cells from adult human pancreas can similarly respond to proendocrine stimuli Exocrine cells from adult human pancreas were transduced directly with lentiviruses expressing activated MAPK (mitogen-activated protein kinase) and STAT3 (signal transducer and activator of transcription 3) and cultured as monolayers or as 3D structures Expression of STAT3 and MAPK in human exocrine cells activated expression of the proendocrine factor neurogenin 3 in 50% to 80% of transduced exocrine cells the number of insulin-positive cells increased only in the exocrine cells grown initially in suspension before 3D culture Lineage tracing identified human acinar cells as the source of Ngn3- and insulin-expressing cells Long-term engraftment into immunocompromised mice increased the efficiency of reprogramming to insulin-positive cells Our data demonstrate that exocrine cells from human pancreas can be reprogrammed to transplantable insulin-producing cells that acquire functionality Given the large number of exocrine cells in a donor pancreas this approach presents a novel strategy to expand cell therapy in type 1 diabetes To overcome the scarcity of endocrine β cells for cell replacement therapy in patients with type 1 diabetes additional sources of transplantable β cells are needed Reprogramming of non-endocrine pancreatic cells into β cells offers one attractive approach Exocrine cells comprise the vast majority of cells obtained from cadaveric donor pancreases but are discarded following isolation of the endocrine islets and thus could provide a large pool of cells for conversion to β cells we hypothesized that ectopic signaling through MAPK and STAT3 might convert human acinar cells to β-like cells as well The current study shows that ectopic expression of activated MAPK and STAT3 in human pancreatic acinar cells activates the proendocrine transcription factor neurogenin 3 (Neurog3) and reprograms human acinar cells to insulin-positive β-like cells able to ameliorate chemical diabetes Overexpression of MAPKCA and STAT3CA promotes endocrine differentiation in vitro (a and c) Gene expression profile of endocrine markers (a) LeMS conditions are normalized to control conditions (LeGFP) set at 1 (red line) Protocol 1: Original protocol with 7-day combined STAT3CA/MAPKCA (LeMSCA) (n=6; *P<0.05; **P<0.01) Protocol 2: Sequential treatment with 3-day MAPKCA followed by 7-day combined STAT3CA/MAPKCA (LeMCA3dMSCA7d) (n=9; *P<0.05; **P<0.01) PDX1 and NKX6.1 are significantly upregulated in protocol 2 whereas exocrine genes MIST1 and FOXA2 were downregulated compared with protocol 1 The trend on endocrine genes combined with the increase in ONECUT1 transcripts suggests an accelerated endocrine differentiation in protocol 2 (d) Immunocytochemical analysis of Neurog3 and insulin expression after the original 7-day protocol (LeMSCA) and the sequential 3-day MAPKCA followed by 7-day combined STAT3CA/MAPKCA (LeMCA3dMSCA7d) Neurog3+ cells were readily detected in LeMSCA and the fraction of Ngn3-expressing cells slightly increased in LeMCA3dMSCA7d No insulin+ cells could be detected in LeMSCA or LeMCA3dMSCA7d (e) Immunocytochemical analysis of Pdx1 and Neurog3 after LeMSCA and LeMCA3dMSCA7d The number of Pdx1-expressing cells is markedly increased in LeMCA3dMSCA7d compared with the LeMSCA condition The majority of the Pdx1+ cells coexpress Neurog3 (f) Quantification of the proportion of transduced cells (EGFP+) expressing Neurog3 or Pdx1 The increase in the percentage of Neurog3+ is comparable in both protocols (40±2% in LeMCA3dMSCA7d versus 38±1% in LeMSCA; n=4; P>0.05); however an increase can be detected in the percentage of PDX1+ cells with LeMCA3dMSCA7d compared with LeMSCA (28±3% in LeMCA3dMSCA7d versus 8±1% in LeMSCA; n=4; *P<0.05; **P<0.01) Engraftment of LeMCA3dMSCA7d monolayer-cultured human exocrine cells allows for in vivo maturation (a–c) Immunohistochemical analysis of the graft-bearing kidney of immunodeficient mice transplanted with the human cells transduced with LeMCA3dMSCA7d a near total loss of Ngn3 expression is observed after transplantation of the LeMCA3dMSCA7d cells whereas Pdx1 remains detectable in the majority of the epithelial cells (b and c) All transplanted human cells remain Krt19+ (b) Gcg+ cells were detected dispersed within the transplanted epithelial cells we observed only few insulin+ cells coexpressing MafA (d) Quantification of the protein expression after the transduction protocol LeMCA3dMSCA7d before transplantation (in vitro) and after 42 days under the kidney capsule (in vivo) The most striking observation is the appearance of insulin+ cells after in vivo transplantation combined with the disappearance of Neurog3+ cells Overexpression of MAPKCA and STAT3CA promotes re-expression of Ngn3 and Pdx1 and endocrine differentiation in 3D matrix cultures in vitro (a and b) Gene expression profile of endocrine (a) and exocrine markers (b) we observed a significant increase in NEUROD and NEUROG3 transcripts compared with controls These observations were mirrored in the LeMSCAFF/3D condition with additional increase in INS Both the LeMSCA3D and LeMSCAFF/3D condition showed a modest but significant increase in PTF1A transcripts (n=5) (*P<0.05; **P<0.01) (c–e) Immunocytochemical analysis after 3D culture (LeMSCA3D) and the free-floating culture followed by 3D culture (LeMSCAFF/3D) (c) Both in the LeMSCA3D and LeMSCAFF/3D condition Neurog3+ cells can be detected in transduced (EGFP+) cells The majority of these Ngn3+ cells coexpress the ductal marker Krt19 Cells expressing Neurog3 protein were never observed in the corresponding control conditions (LeGFP3D and LeGFPFF/3D) (d) In the LeMSCA3D and LeMSCAFF/3D condition cells expressing high levels of Pdx1 protein can be detected A fraction of these cells displayed coexpression with Neurog3 Cells expressing high Pdx1 protein were only rarely observed in the corresponding control conditions (LeGFP3D and LeGFPFF/3D) (e) LeMSCA3D and LeMSCAFF/3D conditions show for the first time the presence of INS+ cells in vitro These insulin+ cells do not express the ductal marker Krt19 (f) Quantification of the proportion of cells expressing the different phenotypical markers A significant increase in the number of insulin+ cells can be observed in the LeMSCAFF/3D condition (7.3±2.6% in LeMSCAFF/3D (n=7) versus 0.83±0.40% in LeMSCA3D (n=8) and 0.06±0.06% in LeGFPFF/3D (n=10); *P<0.05; **P<0.01) The percentage of Neurog3+ and Pdx1+ cells is significantly increased in both LeMSCA3D and LeMSCAFF/3D conditions compared with controls (*P<0.05; ***P<0.001) Unlike the exocrine cell cultures, transduction of human islets with LeMSCA did not activate the expression of Neurog3 (Supplementary Figure S4) both transduced (GFP+) and non-transduced (GFP−) β cells expressed MafA showing that viral transduction does not prevent their expression Short-term transplantation of LeMSCAFF cells yields a limited number of insulin+ cells (a and c) Immunohistochemical analysis of LeMSCAFF human exocrine cells following 42-day engraftment under the kidney capsule of immunodeficient mice (a) In contrast to the cell preparation before transplantation insulin+ cells can be observed in LeMSCAFF condition after engraftment in vivo LeGFPFF controls never showed an increase in the fraction of insulin+ cells (b) Pdx1 expression is prominent in the majority of the Krt19+ epithelial cells both in LeGFPFF and LeMSCAFF conditions (the latter contains more cells with high Pdx1 expression) compared with the cell preparation before transplantation we observed a near total loss of Neurog3+ cells after engraftment in the LeMSCAFF condition LeGFPFF conditions never show Neurog3+ cells (c) Hormone+ cells (INS+ or Gcg+) do not express the ductal marker Krt19 (d) Quantification of the fraction of cells expressing insulin Neurog3 or high levels of Pdx1 protein in LeGFPFF and LeMSCAFF conditions A significant increase in the number of insulin- and Pdx1-expressing cells could be observed in the transplanted LeMSCAFF condition (5.6±1.1% insulin+ cells (n=10); 4.2±0.7% Pdx1+ cells (n=5); ***P<0.001) Genetic lineage tracing of human acinar cells reveals acinar to β-cell transdifferentiation To trace the fate of adult human acinar cells in our culture system the cells were transduced with Cre recombinase under the control of the acinar-specific elastase 2 A promoter and the reporter construct CMV-LSL-nls-DsRed (a) Original acinar cells identified by the presence of the DsRed fluorescent protein were readily detected in both LeGFPFF/3D and LeMSCAFF/3D conditions insulin+/DsRed+ cells were only detected in LeMSCAFF/3D condition but never in the LeGFPFF/3D control Every insulin+/DsRed+ cell in the latter condition also contained the GFP label indicative of transduction with MAPKCA-STAT3CA (b) Neurog3+ cells containing the acinar lineage tracer DsRed were observed in the LeMSCAFF/3D condition only as Neurog3+ cells were never detected in the control condition Long-term engraftment generates acinar-derived islet-like clusters in vivo (a) Circulating human c-peptide levels in mice engrafted with either LeGFPFF or LeMSCAFF cells Significantly increased levels of c-peptide are detected in LeMSCAFF mice from day 90 postengraftment C-peptide levels become stable around day 148 (0.30±0.02 ng/ml in LeMSCAFF versus 0.08±0.02 ng/ml in LeGFPFF; P<0.01 c-peptide levels in LeMSCAFF mice further increased to 0.38±0.02 ng/ml No human c-peptide could be detected after nephrectomy of the graft-bearing kidney at day 210 (b) Blood glucose levels in mice engrafted with either LeGFPFF or LeMSCAFF cells both groups are indistinguishable (on day 190 6.3±0.2 mmol/l in LeMSCAFF versus 5.8±0.2 mmol/l in LeGFPFF; P>0.05 blood glucose levels of LeMSCAFF mice remain significantly lower compared with LeGFP mice (on day 206 16.6±0.5 mmol/l in LeMSCAFF versus 32.7±0.3 mmol/l in LeGFPFF; P<0.01 Removal of the graft-bearing kidney provoked an acute reversal to hyperglycemia in LeMSCAFF mice (on day 212 31.9±0.6 mmol/l versus 33.0±0.2 mmol/l in LeGFPFF; P<0.01 (c) Intraperitoneal glucose tolerance test (IPGTT) Two micrograms of glucose per kg body weight was injected and clearance in blood was measured at indicated time points to indirectly measure the glucose responsiveness of insulin secretion by β cells (*P<0.05; n=6 each) (d) Two hundred and ten days after engraftment of LeMSCAFF cells results in stable grafts visualized by GFP expression (e) Immunohistochemical analyses showed an increased fraction of insulin+ cells in LeMSCAFF conditions to almost 10% Whereas GFP was detected in only 30% of the Krt19+ cells at the time of analysis GFP was found in over 60% of the insulin+ cells indicating a preferential differentiation of LeMSCAFF-transduced cells to a β-like phenotype Genetic lineage tracing using the acinar-specific elastase 2A promoter and the reporter construct CMV-LSL-LacZ revealed that 61% of the insulin+ cells originated from acinar cells whereas the same holds true for 30% of the Krt19+ cells (f) LeGFPFF control grafts lacked expression of insulin+ cells but many cells expressed both GFP and β-galactosidase (βgal) demonstrating acinoductal metaplasia contained clusters of cells devoid of Krt19 expression while clearly positive for GFP and the acinar-specific βgal label Closer examination demonstrated the expression of insulin and Pdx1 in these LeMSCAFF β-like cells (scale bars=100 μm When adult islet β cells were subjected to LeMSCAFF/3D treatment MafA and Pdx1 in adult islet β cells was not influenced by LeMSCA These observations confirm the hypothesis that activated MAPK and STAT3 can convert human exocrine cells into β-like cells and pre-existing β cells are unlikely to be the source of the Neurog3+ or newly formed insulin+ cells Engraftment of LeMSCAFF cells during an extended period of 210 days allowed the cells to acquire functionality these mice displayed an increase in circulating human c-peptide starting around day 90 postengraftment Upon chemical destruction of the endogenous rodent β cell population c-peptide levels further spiked and the sharp increase in blood glucose levels in controls was attenuated in LeMSCAFF mice In addition these animals showed an improved glucose tolerance suggesting that these LeMSCAFF cells formed stable grafts able to respond to change in glycemia Removal of the graft unequivocally identified the human cells as source of c-peptide and control over blood glucose levels serial transplantation revealed that these stable acinar-derived grafts could partially correct blood glucose levels when transplanted into a new diabetic recipient mouse is the first to show that human acinar cells can initiate proendocrine differentiation by activated signaling without the introduction of transcription factors and thus opening the possibility of inducing endocrine differentiation with a combination of growth factors The number of Neurog3+ cells in MSCA cells was substantial but the absolute amount of insulin+ cells remained low in vitro even under the most optimal culture conditions tested Short-term engraftment of these cells only modestly improved endocrine differentiation We did observe increased expression of MafA in some of the β-like cells after short-term engraftment suggesting improved in vivo maturation of the insulin+ cells rather than ongoing differentiation of exo- to endocrine cells long-term engraftment of MSCA cells appeared to provoke a significant increase in human insulin+ cells which are now organized in structures resembling islets GFP expression seems to be enriched in β-like cells This observation is suggestive of a preferential endocrine differentiation of MSCA cells following more than 200 days in vivo not only did we observe an increase in β-like cell numbers genetic lineage tracing also showed that more than 60% of these insulin+ cells originated from human acinar cells compared with 30% of the duct-like population of the grafts The current report demonstrates for the first time that human acinar cells can adopt a β-like phenotype without the need to introduce a combination of pancreatic transcription factors This acinoinsular reprogramming depends on 3D growth activation of MAPK/STAT3 signaling and an intermediate Neurog3+ step Given the volume of human acinar cells discarded upon clinical islet isolation this approach may present an interesting strategy to increase the amount of transplantable β cells provided the efficiency of cell-type conversion can be improved and the involvement of viruses avoided All animal experimentations were performed in agreement with the regulations approved by the ethical committee of the Free University of Brussels Eight-week-old NOD.CB17-Prkdcscid/NCrCrl or C.B-17/IcrHsd-PrkdcscidLystbg-J mice and BALB/cAnNCrl-nuBR nude mice (Charles River Laboratories France) weighing 22–28 g were used as recipients for transplantation Acinar lineage tracing was achieved by the combination of an adenovirus expressing Cre recombinase under the control of a 550 kb human pancreatic elastase 2A promoter fragment (Ad-Cela-2ACre) and a lentivirus expressing either DsRed or LacZ preceded by a stop sequence flanked by loxP sites under the control of the constitutive active CMV promoter (Le-CMV-LSL-DsRed/LacZ) This allows for indefinite labeling of acinar cells β-Cell neogenesis was induced in exocrine cell cultures after a differentiation period of 7 days monolayer culture 7 days 3D matrix culture or a sequential period of 10 days suspension followed by 7 days 3D matrix The matrix constitutes undiluted Matrigel Matrix Growth Factor Reduced (Matrigel GFR; BD Biosciences Human exocrine cells were transduced directly after isolation with lentiviruses expressing activated MAPK and STAT3 The cells were cultured in RPMI-1640 medium supplemented with 1% FBS (Life Technologies Total RNA was isolated using the RNeasy Mini Kit (Qiagen USA; 74106) and was transcribed and amplified as described by the manufacturer using blanks in each assay a lentivirus production was started following the described protocol generating a pTrip-CMV-MAPKCA-ires-eGFP vector Combining both single vectors to a single pTrip-CMV-MAPKCA-ires-eGFP-NheIpoly-invPGK- STAT3CA vector generated a bicistronic vector expressing both MAPKCA and STAT3CA All images were acquired with a Zeiss LSM710 NLO TiSa multiphoton confocal microscope using Zeiss Zen2011 software (Carl Zeiss NV-SA All pictures were analyzed with VolocityLE software (Improvision Cells were detached using 0.25% Collagenase-V (Sigma (St a small incision was made in the kidney capsule The cells were collected in a catheter and delivered under the kidney capsule using a microdispenser pipet (Mitutoyo An average of 3 00 000 human exocrine cells was engrafted under the kidney capsule three mice were engrafted and six independent donors were used for transplantation Blood glucose levels were monitored in tail vein samples (Glucocard Memory Strips; A Menarini Diagnostics Benelux Mice were fasted during 6 h and injected intraperitoneally with glucose (2 g per kg body weight) for glucose tolerance tests and blood glucose concentration was measured from tail vein blood with a portable glucometer Plasma c-peptide concentration was determined with the Human C-peptide ELISA Kit (Millipore pancreatic islets were isolated by collagenase digestion Secreted insulin levels were determined at low (2 h at 2.5 mM glucose) and high (2 h at 20 mM glucose) concentrations The level was determined with the Human Insulin ELISA Kit (Millipore) GraphPad Prism version 5.0b was used to create the graphs and perform the statistics (GraphPad Prism Results compared with their control set at 1 were analyzed using a one-sample Student's t-test Mean values are presented as the mean±S.E.M The number of independent experiments is indicated in the text N-values represent independent human donors signal transducer and activator of transcription 3 Proliferation and differentiation in the human fetal endocrine pancreas Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans In vitro cultivation of human islets from expanded ductal tissue Proc Natl Acad Sci USA 2000; 97: 7999–8004 Characterization of endocrine progenitor cells and critical factors for their differentiation in human adult pancreatic cell culture In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro Cytokeratins and cell differentiation in the pancreas In vitro generation of insulin-producing beta cells from adult exocrine pancreatic cells Plasticity in the adult rat pancreas: transdifferentiation of exocrine to hepatocyte-like cells in primary culture Notch signaling as gatekeeper of rat acinar-to-beta-cell conversion in vitro Gastroenterology 2009; 136: 1750–1760 e1713 Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells Proc Natl Acad Sci USA 2005; 102: 15116–15121 Generation of insulin-secreting cells from pancreatic acinar cells of animal models of type 1 diabetes Am J Physiol Endocrinol Metab 2007; 292: E158–E165 Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas Gastroenterology 2011; 141: 731–741 and 731-734 Ngn3 expression during postnatal in vitro beta cell neogenesis induced by the JAK/STAT pathway Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3 Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo MafA and MafB regulate genes critical to beta-cells in a unique temporal manner Islet beta-cell-specific MafA transcription requires the 5'-flanking conserved region 3 control domain Effect of extracellular matrix and 3D morphogenesis on islet hormone gene expression by Ngn3-infected mouse pancreatic ductal epithelial cells Extracellular matrix remodelling and cellular differentiation Expression of the Notch signaling pathway and effect on exocrine cell proliferation in adult rat pancreas Investigation and characterization of the duct cell-enriching process during serum-free suspension and monolayer culture using the human exocrine pancreas fraction Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas Proc Natl Acad Sci USA 2000; 97: 1607–1611 Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors Expression of neurogenin3 reveals an islet cell precursor population in the pancreas Adult pancreatic acinar cells dedifferentiate to an embryonic progenitor phenotype with concomitant activation of a senescence programme that is present in chronic pancreatitis EGF-induced proliferation of adult human pancreatic duct cells is mediated by the MEK/ERK cascade Culture of adult human islet preparations with hepatocyte growth factor and 804 G matrix is mitogenic for duct cells but not for beta-cells Suppression of Epithelial to mesenchymal transitioning (EMT) enhances ex vivo reprogramming of human exocrine pancreatic tissue towards functional insulin producing beta-like cells In vivo reprogramming of adult pancreatic exocrine cells to beta-cells Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3 Cytokeratins as markers of ductal cell differentiation and islet neogenesis in the neonatal rat pancreas Peptidylprolyl isomerase A (PPIA) as a preferred internal control over GAPDH and beta-actin in quantitative RNA analyses A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation Download references Erik Quartier and Jan De Jonge for technical advice and assistance Daniel Pipeleers for logistic support and Matthias Hebrok for helpful discussions LBa is a postdoctoral fellow of the Research Foundation – Flanders (FWO) This work was financially supported by the Research Foundation – Flanders (FWO) (HH the European Foundation for the Study of Diabetes (EFSD) (LBo and LBa) Seventh (HEALTH-F5-2009-241883) Framework Program (HH and LBo) NIH P30 DK063720 and Leona M and Harry B Helmsley Charitable Trust (2012PG-T1D017) (MSG) and the Iaccoca Family Foundation (MSG Design: ML and LBa; execution of experiments: ML GL and YH; analyses: ML and LBa; interpretation of results: ML Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research The authors declare no conflict of interest Supplementary Information accompanies this paper on Cell Death and Differentiation website Download citation An estimated 5 percent of the population is not able to redirect or put their worries aside when more pressing matters call suffering from uncontrollable and excessive worry known as Generalized Anxiety Disorder (GAD) With funding awarded by the National Institute of Mental Health Temple’s Adult Anxiety Clinic is currently evaluating the effectiveness of a new treatment for GAD Heimberg and his collaborators at Yale University and Kent State University contend that worry in those with GAD may be an often unintentional strategy to avoid intense emotional experience medication-free treatment helps patients increase their emotional regulation skills by taking stock of personal values and goals Patients are given weekly homework assignments self-observation and developing coping responses the idea is for the clients to identify what is important to them and try to guide their actions based on their values and goals which refers to one’s ability to be involved in the present moment in a nonjudgemental way is a big component of the therapy,” he said “We guide clients to change what they do to live a more fulfilling life Rather than making choices based on worries we want them to make choices based on life goals and values.” Those with GAD may worry about any number of life areas from day-to-day responsibilities and finances to work or school to relationships and the well-being of loved ones worrying becomes confused with problem solving; for others an unhappy possibility that is unlikely to come true report that they spend as much as 90 percent of their time worrying about matters large and small it is often hard for them to organize themselves and they find themselves late for important appointments GAD can also negatively affect the quality of one’s personal relationships and work life The symptoms of GAD can even interfere with attempts to seek treatment the cancellation rate for initial diagnostic interviews to begin treatment for GAD is twice that of other disorders “People with GAD are often too busy worrying to receive the treatment they would most benefit from,” he said Treating GAD presents some additional challenges GAD has been the anxiety disorder that has been hardest to treat have not addressed the broader emotional experience of the person,” said Heimberg.  another of six recognized anxiety disorders dominates the media and captures our imagination in popular television series like “Monk” and “Obsessed,” GAD seems to fly under our radar This despite the fact that it is characterized by symptoms in addition to worry — restlessness muscle tension — that most of us can relate to on some level GAD was not officially recognized as a disorder until 1980 and knowledge of the condition has accumulated slowly But it is one of two primary areas of research and treatment undertaken by Temple’s Adult Anxiety Clinic — the other is Social Anxiety Disorder the fear of being negatively judged by others psychologists and advanced doctoral student therapists who work under the supervision of Heimberg serve a geographically and ethnically diverse clientele “The advantages of receiving treatment at a research site are many,” said Heimberg if you qualify for participation in a current research study we perform a very detailed diagnostic work up We watch you more closely than a private practitioner who may have another patient in their waiting room The experience has been transformational for Liaqat Ali who was referred to Temple from the University of Pennsylvania where he had gone seeking treatment for what he thought was another anxiety disorder “Now I feel like I have a whole new life.” “I was looking for treatment for my anxiety that did not involve medication,” said Davis “The therapy gave me tools that I continue to use and the difference in my life is amazing.” For more information about GAD treatment at Temple, call 215-204-1575 or visit the <Adult Anxiety Clinic website> By Mary JacobsSpecial Contributor 2020 was a challenging year for Eileen Gregory The risk of COVID-19 kept her isolated much of the time Then she developed vertigo and headaches at the start of 2021 I was desperate to be out and about and connecting with people,” says Gregory She signed up for a drawing class and a pottery course connected with a group of artists through a cultural center and reconnected with old friends many older adults started getting back out again this spring and summer after a year of isolation With news of a second surge because of the COVID-19 delta variant some are growing cautious about venturing out or are returning to online options Breaking NewsGet the latest breaking news from North Texas and beyond GoogleFacebookBy signing up you agree to our Terms of Service and Privacy Policy “We’ve known for some time that loneliness has negative health effects a medical doctor and assistant professor of psychiatry at UT Southwestern Medical Center specializing in geriatric mental health One analysis of multiple studies found that stroke and heart attack risks increased as much as 30% for people who report loneliness Another showed increased mortality from all causes there are studies that show that people who retire and then become engaged in social groups live longer and have a better quality of life,” Camp says “There’s not just the detriment of loneliness but also the positive effect of social engagement.” Social connections also may help preserve brain health and delay or reduce the risk for Alzheimer’s disease or dementia you’re more likely to get out of the house and feel happier and less stressed,” says Bryan James associate professor at Rush Alzheimer’s Disease Center in Chicago “Having friends who rely on you for friendship and support also creates a sense of purpose a key factor linked to mental and physical health.” James cautions that socializing doesn’t prevent dementia researchers believe that an active social life boosts one’s cognitive reserves — a kind of mental resilience that allows seniors to tolerate the disease better and function independently longer with it Isolation represents such a significant health risk that the Department of Veterans Affairs is piloting an intervention to help veterans Originally designed for suicide prevention the Connection program encourages participants to commit to simple steps such as: “Go the local park three times a week and say hello to people,” or “Call four friends from church on Sunday afternoon and ask how they’re doing.” Socializing gets harder if you can’t get around anymore or if you no longer drive you’re not interacting regularly with co-workers the more likely you are to lose a spouse or close friends to death About a quarter of people in their 60s and 70s report feeling lonely and loneliness affects about half of all people in their 80s usually with a few neighbors and their dogs she takes Phoebe to a nearby hardware store and walks her around the aisles She says it helps people recognize and remember her “‘Lonely’ is not on my calendar,” she jokes Now’s a good time to reset and restart your social life Signing up for classes and activities adds structure to your days even on days when you’re tempted to stay home “Scheduled activities give you a kind of scaffolding that makes you feel a little less unmoored,” says Eileen Gregory also a retired college professor in Dallas out for daily walks at a favorite trail near her home Pets are great conversation starters.” Dog walking offers the added advantage of being outdoors A class or a course that interests you is more likely to connect you with people on your wavelength and that leads more easily to friendships outside of class Heimberg takes classes at Richland College’s Emeritus Program for seniors and participates in a long list of groups including an acting group and the neighborhood association for the Junius Heights Historic District But virtual options can still expand and supplement your social life Luke “Community” United Methodist Church in Dallas is proud of the way that seniors in the congregation stepped up to learn technologies during the pandemic Even though in-person worship has resumed at the church many meetings are still offered via Zoom or in person with the option to join by Zoom “Now that I’m comfortable enough with Zoom grief counseling and funeral planning on Zoom,” she said “It’s just easier to do some things virtually And if someone is sick or can’t drive to the church but casual connections can enrich your social life Greet and thank the clerk at the grocery store or the barista who makes your coffee “The gratitude that we normally don’t take time to express can open up conversations with strangers,” Heimberg says you don’t just help yourself but may be helping someone who’s lonely caseworkers point this out to encourage veterans who are shy or hesitant ‘Others are feeling lonely as well,’” says Prasad Padala a medical doctor who is associate director for clinical innovations with Central Arkansas Veterans Healthcare System While many seniors are eager to reconnect in person now that they are vaccinated says some of her clients are a little more hesitant either feeling out of practice or nervous about the risk of COVID-19 delta variant Both Althea Hills and Heimberg said they limit most indoor gatherings to groups of friends and family they know are vaccinated against COVID-19 Heimberg moves meetings to her well-ventilated Don’t be afraid to ask about protocols to stay safe write a letter or look up an old friend on Facebook Camp says many of her patients reached out by telephone to old friends — friends from high school or someone they knew when their children were young — during the height of the pandemic That rekindled old friendships and reduced feelings of isolation but the emergence of COVID-19 variants means the situation is changing “I keep up with what’s happening with COVID and how to stay safe,” she said the Hamilton Park United Methodist Church member volunteers for the church’s Helping Hands ministry which provides groceries and other items to those in need Volunteering can provide a sense of purpose and create new social connections You don’t need to be the life of the party to make friends “I think people underestimate how important listening is for friendships,” Camp says “People who are good at making friends are good at getting other people to share themselves.” Larkin agrees “People are having a tough time these days,” she says RSVP: The Senior Source’s RSVP program matches volunteers 55 and older with needs in more than 50 community organizations in the Dallas area Dallas College: Most campuses offer continuing education classes for older adults through the Emeritus program. Students over 65 can apply for tuition waiver for credit courses, too. Visit dallascollege.edu/cd/senior-adults Collin College: The Seniors Active in Learning (SAIL) program offers low-cost continuing education courses in a variety of subjects for those 55 and up. Courses for the fall 2021 semester courses are online. You don’t need to live in Collin County. Visit collin.edu/sail Libraries and senior centers in your community are also a good place to find classes, volunteer opportunities and social gatherings. In Dallas, visit dallaslibrary2.org, dallasparks.org/453/Senior-Programs. Offshore wind developer Vattenfall and Preem have entered into the feasibility phase of a project to assess accelerating the development of an offshore wind to green hydrogen value chain they plan to assess how to link offshore wind and the production of green hydrogen using electricity from offshore wind with the refining industry on Sweden’s west coast to swiftly transition from fossil-free fuels Vattenfall and Preem signed a three-year agreement for increased collaboration around fossil-free hydrogen for the production of biofuels The feasibility study is the next stage of collaboration Vattenfall said it sees “huge potential” to decarbonise industries such as refining using fossil-free electricity and hydrogen Preem and Vattenfall believe that to strengthen Sweden’s position as a frontrunner in the emerging market for fossil-free fuels new partnerships between fossil-free energy suppliers and decarbonising industries are required “Fossil-free hydrogen enables both decarbonisation of refineries and increased production of renewable fuels such as HVO renewable gasoline and sustainable aviation fuels,” said Preem “Increased supply of green hydrogen will also enable Preem to explore the development of e-fuels for hard-to-decarbonise segments such as aviation and the shipping industry.” “Electrification of society and industry is at the core of our business strategy Our strong and growing Swedish offshore wind development portfolio “Vattenfall has taken the initiative on the west coast where offshore wind and hydrogen production can play a key role in the transformation to a fossil-free industry Cross sector co-operation and partnerships are the way forward,” she said Preem chief executive Magnus Heimberg said “Society’s need for renewable fuels is increasing rapidly New infrastructure for hydrogen from offshore wind could swiftly increase supply and speed up the transition.” Mr Heimberg said it was possible to produce 5M m3 renewable fuels and e-fuels by 2035 Two thirds of Swedish CO2 emissions come from industry and transport Sweden’s environmental targets mean that CO2 emissions from the transport sector must fall by 70% between 2010 and 2030 Get Pollstar News and more delivered right to your inbox with Pollstar Daily Pulse By signing up, you agree to Pollstar’s Privacy Policy and Terms of Use Semmel Concerts promotes Leipzig’s Highfield Festival in cooperation with FKP Scorpio and is promoting Germany’s inaugural version of C2C: Country to Country The Bernische Pensionskasse and Frutiger AG want to realize a mixed use with residential commercial and generally accessible open spaces on the former Rigips AG site The 30,600 sqm site is located in the northern district of Untere Au in a central well-developed location in the immediate vicinity of Heimberg train station As can be seen from the guideline concept for "Louelipark" manageable residential units are to be built as point houses or short row buildings Public uses are planned on some first floors A low commercial building is planned facing Stockhornstrasse the building height varies from two to seven stories and a ten-story building volume 60 of which in the condominiums and around 240 as rental apartments The public consultation process is currently underway and the large-scale project is to be put to the vote in the summer of 2024