bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic signature and key transcriptional regulators of human antigen-specific type 1 regulatory T cells
Authors: Cepika Alma-Martina , Amaya Laura , Waichler Colin , Narula Mansi , Mantilla Michelle M. , Thomas Benjamin C. , Chen Pauline P. , Freeborn Robert Arthur , Pavel-Dinu Mara , Nideffer Jason , Porteus Matthew , Bacchetta Rosa , Müller Fabian , Greenleaf William J. , Chang Howard Y. , Roncarolo Maria Grazia 
Published: March 2024

AbstractHuman adaptive immunity is orchestrated by effector and regulatory T (Treg) cells. Natural Tregs arise in the thymus where they are shaped to recognize self-antigens, while type 1 Tregs or Tr1 cells are induced from conventional peripheral CD4+T cells in response to peripheral antigens, such as alloantigens and allergens. Tr1 cells have been developed as a potential therapy for inducing antigen-specific tolerance, because they can be rapidly differentiatedin vitroin response to a target antigen. However, the epigenetic landscape and the identity of transcription factors (TFs) that regulate differentiation, phenotype, and functions of human antigen-specific Tr1 cells is largely unknown, hindering Tr1 research and broader clinical development. Here, we reveal the unique epigenetic signature of antigen-specific Tr1 cells, and TFs that regulate their differentiation, phenotype and function. We showed thatin vitroinduced antigen-specific Tr1 cells are distinct both clonally and transcriptionally from natural Tregs and other conventional CD4+T cells on a single-cell level. An integrative analysis of Tr1 cell epigenome and transcriptome identified a TF signature unique to antigen-specific Tr1 cells, and predicted that IRF4, BATF, and MAF act as their transcriptional regulators. Using functional genomics, we showed that each of these TFs play a non-redundant role in regulating Tr1 cell differentiation, suppressive function, and expression of co-inhibitory and cytotoxic proteins. By using the Tr1-specific TF signature as a molecular fingerprint, we tracked Tr1 cells in peripheral blood of recipients of allogeneic hematopoietic stem cell transplantation treated with adoptive Tr1 cell therapy. Furthermore, the same signature identified Tr1 cells in resident CD4+T cells in solid tumors. Altogether, these results reveal the epigenetic signature and the key transcriptional regulators of human Tr1 cells. These data will guide mechanistic studies of human Tr1 cell biology and the development and optimization of adoptive Tr1 cell therapies.
A cryopreservation strategy for myoblast storage in paper-based scaffolds for inter-laboratory studies of skeletal muscle health
Authors: Rjaibi Saifedine T. , Jacques Erik , Ni Jiaru , Xu Bin , Kouthouridis Sonya , Sitolle Julie , Lad Heta , Gulati Nitya , Li Nancy T. , Ahn Henry , Ginsberg Howard J. , Zhang Boyang , Grand Fabien Le , Gilbert Penney M. , McGuigan Alison P. 
Published: March 2024

AbstractThree-dimensional tissue-engineered models are poised to facilitate understanding of skeletal muscle pathophysiology and identify novel therapeutic agents to improve muscle health. Adopting these culture models within the broader biology community is a challenge as many models involve complex methodologies and significant investments of time and resources to optimize manufacturing protocols. To alleviate this barrier, we developed a protocol with commercially available reagents to cryopreserve myoblasts in a 96-well compatible format that allows tissues to be transferred to users without expertise in 2D or 3D skeletal muscle cell culture. We validate that myoblasts encapsulated in a hydrogel and cryopreserved in paper-based scaffolds maintain cell viability, differentiation, and function via acetylcholine-induced transient calcium responses. Furthermore, we demonstrate successful shipping of myoblasts cryopreserved in paper-based scaffolds to intra-provincial and international collaborators who successfully thawed, cultured, and used the 3D muscle tissues. Finally, we confirm the application of our method to study muscle endogenous repair by seeding freshly isolated skeletal muscle stem cells to cryopreserved then differentiated and injured tissues, demonstrating expected responses to a known stimulator of muscle stem cell self-renewal, p38α/β MAPKi. Altogether, our 3D myoblast cryopreservation protocol offers broadened access of a complex skeletal muscle tissue model to the research community.
Road density simplifies regional food webs
Authors: Mestre Frederico , Bastazini Vinicius A. G. , Ascensao Fernando 
Published: March 2024

AbstractRoads stands as major threats to biodiversity, affecting the functioning of ecosystems and their provision of ecosystem services. Understanding how road-related impacts affect the dynamics of ecological interactions is essential to help manage human impacts on biodiversity, but such studies remain largely unexplored. We investigated the intricate relationship between roads, species vulnerability to road density, and the ensuing effects on food webs across Europe. Utilizing species-specific road density thresholds and trophic interaction data, we constructed regional food webs to assess the potential loss of trophic interactions due to roadkill. Our analysis, encompassing 551 species across three trophic levels, revealed spatially varied impacts, with areas surrounding major cities facing drastic losses of trophic interaction exceeding 90%. Notably, 191 species may be affected by trophic interaction losses (loss of prey or predator). Apex predators exhibited lower direct impacts from road density, while basal-level species seem to be more exposed to direct road-related effects, potentially triggering a cascade of interaction disruptions. Our findings emphasize the need for informed road infrastructure development and targeted conservation strategies to mitigate the negative impacts of roads and traffic, thereby preserving the integrity of ecological networks. This research offers valuable insights for policymakers and conservation practitioners globally by identifying critical areas where road-induced cascade effects may be most pronounced and highlighting trophic groups of species that may be at higher risk.
A simple regulatory network coordinates a bacterial stress response in space and time
Authors: Choudhary Divya , Foster Kevin R. , Uphoff Stephan 
Published: March 2024

AbstractBacteria employ diverse gene regulatory networks to protect themselves from stressful environments. While transcriptomics and proteomics show that the expression of different genes can shift strongly in response to stress, the underlying logic of large regulatory networks is difficult to understand from bulk measurements performed at discrete time points. As a result, it remains challenging to predict how these regulatory networks function at a system level. Here we use time-resolved single-cell imaging to explore the functioning of a key bacterial stress response: TheEscherichia coliresponse to oxidative stress. Our work reveals a striking diversity in the expression dynamics of genes in the regulatory network, with differences in the timing, magnitude, and direction of expression changes. Nevertheless, we find that these patterns have a simple underlying logic. Firstly, all genes exhibit a transient increase in their protein levels simply due to the slowing down of cell growth under stress. Controlling for this effect reveals three classes of gene regulation driven by the transcription factor OxyR. Downregulated genes drop in expression level, while upregulated genes either show pulsatile expression that decays rapidly or gradual induction, dependent upon transcription factor binding dynamics. These classes appear to serve distinct functional roles in cell populations. Pulsatile genes are stress-sensitive and activate rapidly and transiently in a few cells, which provides an initial protection for cell groups. Gradually upregulated genes are less sensitive and induce more evenly generating a lasting protection that involves a larger number of cells. Our study shows how bacterial populations use simple regulatory principles to coordinate a stress response in space and time.
Identification of Neural Crest and Neural Crest-Derived Cancer Cell Invasion and Migration Genes Using High-throughput Screening and Deep Attention Networks
Authors: Kasemeier-Kulesa JC , Martina Perez S , Baker RE , Kulesa PM 
Published: March 2024

ABSTRACTBackgroundCell migration and invasion are well-coordinated processes in development and disease but remain poorly understood. We previously showed that highly migratory neural crest (NC) cells share a 45-gene panel with other cell invasion phenomena, including cancer. To identify critical genes of the 45-gene panel, we performed a high-throughput siRNA screen and used statistical and deep learning methods to compare NC- versus non-NC-derived human cell lines.ResultsWe find 14 out of 45 genes significantly reduces c8161 melanoma cell migration; only 4 are shared with HT1080 fibrosarcoma cells (BMP4, ITGB1, KCNE3, RASGRP1). Deep learning attention network analysis identified distinct cell-cell interaction patterns and significant alterations after BMP4 or RASGRP1 knockdown in c8161 cells. Addition of recombinant proteins to the culture media identified 5 out of the 10 known secreted molecules stimulate c8161 cell migration, including BMP4. BMP4 siRNA knockdown inhibited c8161 cell invasionin vivoandin vitro; however, its addition to the culture media rescued c8161 cell invasion.ConclusionA high-throughput screen and deep learning rapidly distilled a 45-gene panel to a small subset of genes that appear critical to melanoma cell invasion and warrant deeperin vivofunctional analysis for their role in driving the neural crest.
The human reward system encodes the subjective value of ideas during creative thinking
Authors: Moreno-Rodriguez Sarah , Béranger Benoît , Volle Emmanuelle , Lopez-Persem Alizée 
Published: March 2024

AbstractCreative thinking is composed of a generation phase, where individuals form candidate ideas, and an evaluation phase, where individuals monitor the quality of their ideas, in terms of both their originality and adequacy, to select the best one. Here, we conceptualize creative evaluation as a specific type of decision-making, where participants attribute subjective values to ideas to guide their choice. Yet, while subjective values and preferences have been the focus of many studies in classical decision-making, their involvement in creative decision-making remains largely unexplored. Combining creative generation tasks and rating tasks, the present study demonstrates that individuals assign subjective values to ideas and that these values depend on a relative balance of the ideas’ originality and adequacy, which is determined by individual preferences and predicts their creative abilities. Using functional Magnetic Resonance Imaging, we found that the human reward system encodes the subjective value of ideas, and that the Default Mode and the Executive Control Networks, rather than being split into idea generation and evaluation, respectively reflect the originality and adequacy of ideas. Interestingly, the relative functional connectivity of the Default Mode and Executive Control Networks with the human reward system correlates with the relative balance of adequacy and originality in individuals’ preferences. These results bridge a gap in the current literature by providing new evidence regarding the neural bases for originality and adequacy monitoring and add valuation to the incomplete behavioral and neural accounts of creativity, offering perspectives on the influence of individual preferences on creative abilities.
Loss of Bbs8 leads to cystic kidney disease in mice and affects tubulin acetylation through HDAC2
Authors: Kieckhöfer Emilia , Matthiessen Peter A. , Ebert Lena K. , Klausen Christina , Wachten Dagmar , Benzing Thomas , May-Simera Helen , Schermer Bernhard 
Published: March 2024

AbstractBardet-Biedl Syndrome (BBS) is a genetic disorder marked by considerable genetic and phenotypic diversity. BBS often presents as a combination of retinitis pigmentosa, obesity, polydactyly, and cystic kidney disease and is considered a model ciliopathy. The syndrome is caused by pathogenic variants in BBS genes, some of which encode components of a ciliary multi-protein complex, known as the BBSome, as well as a chaperonin-like complex, which is required for BBSome assembly. In this study, we describe the occurrence of kidney cysts in a BBS mouse model. Specifically, loss of BBS8 led to the development of cystic kidney disease by the end of the first year of life. In addition to transcriptional changes of key genes involved in regulated cell death and inflammation, proteomic approaches revealed increased expression and altered phosphorylation of histone deacetylase HDAC2 in knockout kidneys. Consistently, loss ofBbs8resulted in a reduction of acetylated alpha-tubulin in primary cilia. This leads to diminished stability and altered dynamics of primary cilia, potentially contributing to the formation of cystic kidneys and other BBS manifestations previously described inBbs8deficient mice.
Integrating spatial transcriptomics count data with Crescendo improves visualization and detection of spatial gene patterns
Authors: Millard Nghia , Chen Jonathan H. , Palshikar Mukta G. , Pelka Karin , Spurrell Maxwell , Price Colles , He Jiang , Hacohen Nir , Raychaudhuri Soumya , Korsunsky Ilya 
Published: March 2024

AbstractSpatial transcriptomics allows for the analysis of a cell’s gene expression in the context of its physical location. With spatial transcriptomics data, investigators often want to find genes of interest whose spatial patterns are biologically relevant in multiple samples. However, due to confounding factors in spatial data that produce noise across samples, datasets, and technologies, it is challenging to visualize genes and their spatial patterns across samples. We present Crescendo, an integration algorithm that performs correction directly on gene expression counts to reduce variation from technical confounders. We first apply Crescendo to a 3-sample spatial transcriptomics mouse brain dataset to show how Crescendo enables accurate visualization of gene expression across these spatial transcriptomic samples. We then demonstrate Crescendo’s scalability by integrating a 16-sample immuno-oncology dataset of 7 million cells. Finally, we show that Crescendo can perform cross-technology integration by merging a colorectal cancer (CRC) scRNA-seq dataset with two CRC spatial transcriptomics samples. By transferring information between technologies, Crescendo can impute poorly expressed genes to improve detection of gene-gene colocalization, such as ligand-receptor interactions.
Bridging geometric morphometrics to medical anatomy: An example from an experimental study of the human smile
Authors: Bookstein Fred L. , Kent John T. , Khambay Balvinder , Mardia Kanti V. 
Published: March 2024

AbstractThe method of Cartesian transformations introduced by D’Arcy Thompson a century ago in his celebrated bookOn Growth and Formprecipitated an important development in 20th-century biometrics: a fusion of the geometrical and biological approaches to morphology. Some decades later this fusion, in turn, spun off another multidisciplinary focus,statistical shape analysis,that bridges between biostatistics and biomedical imaging. Our article is intended to seed a complementary focus: a bridge between biostatistics and medical anatomy, a field that has to this day remained mainly verbal rather than quantitative. Specifically, we are proposing a novel methodology for arriving at anatomical interpretations of statistical findings about large-scale contrasts of organismal morphology or its dynamics by combining two toolkits hitherto separate in their notation and their disciplinary housing: morphometrics and psychometrics. A contemporary morphometric analysis deals with patterns of shape coordinate covariation in terms of their geometric adjacency; psychometric factor analysis, the same patterns of covariation in terms of simplicity of interpretation. By combining these tools we account for the dynamics of a facial expression in terms of the actions of the underlying muscles, thereby realizing Thompson’s original metaphor, the “origins of form in force,” for systems that “vary in a more or less uniform manner.”This paper reviews the history of Thompson’s metaphor and then the current literature quantifying smiles, in order to set the stage for the combination of scaling analysis and factor analysis that we are putting forward. We demonstrate the new approach by reanalyzing a data set of ten landmarks around the vermilion borders of the human lip contrasting the dynamics of two socially stereotyped physiological cycles, the open-lip smile and the closed-lip smile, over a sample of 14 normal faces. Our analysis centers on just two dimensions of statistical shape space, those of largest geometrical scale, which can be identified with the action of two different muscles, orbicularis oris and zygomaticus major. The two smiles differ radically in their achieved deformations. Furthermore, while the closed-lip smiles arrived at their final forms along similar shape trajectories, the open-lip smiles did not. Our closing discussion explores some aspects of morphodynamics that are illuminated by the example here.
Spatially conserved pathoprotein profiling in the human suprachiasmatic nucleus in progressive Alzheimer disease stages
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Li Song Hua , Tu Chia-Ling , Judge Grace , Yang Yumi , Suemoto Claudia Kimie , Paraízo Leite Renata Elaine , Paes Vitor , Pasqualucci Carlos A. , Jacob-Filho Wilson , Spina Salvatore , Seeley William W. , Chang Wenhan , Neylan Thomas , Grinberg Lea T. 
Published: March 2024

AbstractIndividuals with Alzheimer’s Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12 controls without AD neuropathological changes (Braak stage 0) and 36 subjects at progressive Braak stages (I, II, and VI). To investigate potential AD-specific changes, we measured the neuronal counts of arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) positive neurons, along with the Braak stages in the SCN. We investigated in adjacent hypothalamic nuclei which are also composed of AVP+ neurons but show more resilience to AD: paraventricular nucleus (PVN) and supraoptic nucleus (SON). To understand the dysregulated proteins associated to AD progression, we performed in-situ proteomics, investigating 57 proteins, including commonly dysregulated in AD, using GeoMx Digital Spatial Profiling (DSP) in the three nuclei (total of 703 area of interests). Neurofibrillary tangles (NFTs) and tau fibrils were found selectively in SCN. We failed to detect NFTs in SON, only a mild dysregulation of p-tau at Braak VI in PVN and SON. Amyloid plaque was absent in the SCN and SON. Additionally, the SCN showed increased glial proteins already at Braak stage I, whereas the level of these proteins sustained in the other nuclei. The SCN is exclusively vulnerable to AD-tau pathology and show immune dysregulation even at Braak I but is protected against amyloid plaque. This finding revealed selectively in amnestic AD, showing more resilience in AD variant. This tau-related molecular dysregulation in the SCN contributes to circadian rhythm disturbances in AD, a phenomenon observed before the onset of cognitive disorder.
Nucleobindin-1(Nucb1)disruption affects feeding, metabolism, and glucose homeostasis in mice in an age-, sex-, diet- and light cycle-dependent manner
Authors: Nasri Atefeh , Vélez Emilio J , Rajeswari Jithine Jayakumar , Hatef Azadeh , Unniappan Suraj 
Published: March 2024

AbstractBackgroundNesfatin-1 (NESF-1), encoded in the calcium and DNA binding protein (Nucleobindin 2, NUCB2) is an orphan ligand with metabolic effects. Recently, our lab provided evidence for a NESF-1-like peptide (NLP) in a NUCB2-related precursor, NUCB1, in zebrafish and rodents. This research aims to determine whether endogenous NUCB1 is critical for energy homeostasis.Methods and Main FindingsGlobal genetic disruption ofNucb1(Nucb1knockout/KO mice) led to increased food intake in chow-fed male and female mice across different points of light and dark phases. A similar increase in water intake was seen in femaleNucb1KO mice but not in males. White adipose tissue weight was significantly increased in male and femaleNucb1KO mice. Dark phase total activity was increased in maleNucb1KO mice, while it was decreased in femaleNucb1KO mice compared to wildtype littermates. Energy derived from carbohydrates was raised during the dark phase; while energy derived from fat was significantly decreased in both male and femaleNucb1KO mice. MaleNucb1KO mice were lighter in the early stages, but these differences disappeared as they aged. Meanwhile, no differences in bodyweight were observed in femaleNucb1KO mice. MaleNucb1KO mice handled glucose better during an oral glucose tolerance test, while the opposite effect was found in an intraperitoneal (IP) glucose tolerance test. The above results from chow-fed mice were largely true in 10% and 60% fat diet-fed mice. A significant two-way interaction between mice group and time was observed on weekly food intake of male and femaleNucb1KO mice fed control fat diet, but not in 60% fat-fed group. Handling of blood glucose during IPGTT was better in maleNucb1KO mice fed both diets, while such an effect was not observed in female KO mice. A significant two-way interaction of mice group and time on food and water intake value in 24 h was observed for maleNucb1KO mice fed 10% fat diet. The total physical activity during the dark phase and energy expenditure during the light phase showed a sex-specific pattern in male and femaleNucb1KO mice fed 10% fat diet. Energy expenditure showed a sex-specific pattern inNucb1KO mice during the dark phase. Moreover, adiposity increased in maleNucb1KO mice fed a high fat diet.ConclusionsOur results indicate that the disruption ofNucb1leads to metabolic changesin vivo. The phenotype appears to depend on sex, age, diet, and the light-dark cycle. In conclusion, these outcomes furnish important evidence supporting critical roles for endogenous NUCB1 in energy homeostasis.