bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Specific CD8+T Cells from the Bone Marrow Resist Exhaustion and Exhibit Increased Persistence in Tumor-Bearing Hosts as Compared to Tumor Infiltrating Lymphocytes
Authors: Zawidzka Elizabeth M. , Biavati Luca , Thomas Amy , Zanettini Claudio , Marchionni Luigi , Leone Robert , Borrello Ivan 
Published: August 2023

AbstractImmunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor infiltrating lymphocytes (TILs) with significant clinical results. Despite these successes, the limitations of the current strategies are also emerging and novel approaches are needed. The bone marrow (BM) is an immunological niche that houses T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies. Herein, we demonstrate that T cells from the BM appear superior to TILs as a source of cells for cellular therapy. Specifically, they possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. Taken together, these data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.Key MessagesWhat is already known on this topicTIL therapy shows efficacy but significant limitations. T cell quality is an important determinant of responses to cellular immunotherapy.What this study addsT cells from the BM appear superior to TILs in phenotype, transcriptional profile, and function. These differences appear driven by tissue (e.g., bone marrow as compared to tumor).How this study might affect research, practice or policyThe BM could serve as an alternative source of cells for adoptive cellular therapy for solid tumors.
Ketogenic diet alters microglial morphology and changes the hippocampal lipidomic profile distinctively in stress susceptibleversusresistant male mice upon repeated social defeat
Authors: Ibáñez Fernando González , Halvorson Torin , Sharma Kaushik , McKee Chloe , Carrier Micaël , Picard Katherine , Vernoux Nathalie , Bisht Kanchan , Deslauriers Jessica , Lalowski Maciej , Tremblay Marie-Ève 
Published: August 2023

AbstractPsychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD)versusKD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress.HighlightsKetogenic diet tends to promote resistance to psychological stressHippocampal microglia show morphological adaptations to stress and dietMicroglia of stress-susceptible mice make less synaptic contactsMicroglia of ketogenic diet-fed mice show less signs of cellular stressLipids are differentially regulated in the hippocampi of susceptible mice
Environmental circadian disruption re-programs liver circadian gene expression
Authors: Duong Hao A. , Baba Kenkichi , DeBruyne Jason P. , Davidson Alec J. , Ehlen Christopher , Powell Michael , Tosini Gianluca 
Published: August 2023

AbstractCircadian gene expression is fundamental to the establishment and functions of the circadian clock, a cell-autonomous and evolutionary-conserved timing system. Yet, how it is affected by environmental-circadian disruption (ECD) such as shiftwork and jetlag, which impact millions of people worldwide, are ill-defined. Here, we provided the first comprehensive description of liver circadian gene expression under normal and after ECD conditions. We found that post-transcription and post-translation processes are dominant contributors to whole-cell or nuclear circadian proteome, respectively. Furthermore, rhythmicity of 64% transcriptome, 98% whole-cell proteome and 95% nuclear proteome is re-written by ECD. The re-writing, which is associated with changes of circadian cis-regulatory elements, RNA-processing and protein trafficking, diminishes circadian regulation of fat and carbohydrate metabolism and persists after one week of ECD-recovery.One-Sentence SummaryEnvironmental-circadian disruption re-writes the circadian gene expression process which persists after one week of recovery.
A Novel Computational Approach for the Mining of Signature Pathways Using Species Co-occurrence Networks in Gut Microbiomes
Authors: Kim Suyeon , Thapa Ishwor , Ali Hesham 
Published: August 2023

ABSTRACTAdvances in metagenome sequencing data continue to enable new methods for analyzing biological systems. When handling microbial profile data, metagenome sequencing has proven to be far more comprehensive than traditional methods such as 16s rRNA data, which rely on partial sequences. Microbial community profiling can be used to obtain key biological signals that pave the way for better and accurate understanding of complex systems that are critical for advancing biomedical research and healthcare. There have been few attempts to uncover microbial community associations with certain health conditions. However, such attempts have mostly used partial or incomplete data to accurately capture those associations. This study introduces a novel computational approach for the identification of co-occurring microbial communities using the abundance and functional roles of species-level microbiome data. The proposed approach is then used to identify signature pathways associated with inflammatory bowel disease (IBD). Furthermore, we developed a computational pipeline to identify microbial species co-occurrences from metagenome data. When comparing IBD to a control group, we show that co-occurring communities of species are enriched for potential pathways. We also show that the identified co-occurring microbial species operate as a community to facilitate pathway enrichment. The obtained findings suggest that the proposed network model, along with the computational pipeline, provide a valuable analytical tool to analyze complex biological systems and extract pathway signatures that classify or diagnose certain health conditions.CCS CONCEPTS• Applied computing→Biological networks;Bioinformatics;Systems biology.ACM Reference FormatSuyeon Kim, Ishwor Thapa, and Hesham Ali. 2023. A Novel Computational Approach for the Mining of Signature Pathways Using Species Co-occurrence Networks in Gut Microbiomes. InProceedings of ACM Conference (Conference’17). ACM, New York, NY, USA, 10 pages.https://doi.org/10.1145/nnnnnnn.nnnnnnn
Effective mechanical potential of cell–cell interaction in tissues harboring cavity and in cell sheet toward morphogenesis
Authors: Koyama Hiroshi , Okumura Hisashi , Otani Tetsuhisa , Ito Atsushi M. , Nakamura Kazuyuki , Kato Kagayaki , Fujimori Toshihiko 
Published: August 2023

AbstractMeasuring mechanical forces of cell–cell interactions is important for studying morphogenesis in multicellular organisms. We previously reported an image-based statistical method for inferring effective mechanical potentials of pairwise cell–cell interactions by fitting cell tracking data with a theoretical model. However, whether this method is applicable to tissues with non-cellular components such as cavities remains elusive. Here we evaluated the applicability of the method to cavity-harboring tissues. Using synthetic data generated by simulations, we found that the effect of expanding cavities was added to the pregiven potentials used in the simulations, resulting in the inferred effective potentials having an additional repulsive component derived from the expanding cavities. Interestingly, simulations by using the effective potentials reproduced the cavity-harboring structures. Then, we applied our method to the mouse blastocysts, and found that the inferred effective potentials can reproduce the cavity-harboring structures. Pairwise potentials with additional repulsive components were also detected in two-dimensional cell sheets, by which curved sheets including tubes and cups were simulated. We conclude that our inference method is applicable to tissues harboring cavities and cell sheets, and the resultant effective potentials are useful to simulate the morphologies.
A novelf-divergence based generative adversarial imputation method for scRNA-seq data analysis
Authors: Si Tong , Hopkins Zackary , Yanev John , Hou Jie , Gong Haijun 
Published: August 2023

AbstractComprehensive analysis of single-cell RNA sequencing (scRNA-seq) data can enhance our understanding of cellular diversity and aid in the development of personalized therapies for individuals. The abundance of missing values, known as dropouts, makes the analysis of scRNA-seq data a challenging task. Most traditional methods made assumptions about specific distributions for missing values, which limit their capability to capture the intricacy of high-dimensional scRNA-seq data. Moreover, the imputation performance of traditional methods decreases with higher missing rates. We propose a novelf-divergence based generative adversarial imputation method, called sc-fGAIN, for the scRNA-seq data imputation. Our studies identify fourf-divergence functions, namely cross-entropy, Kullback-Leibler (KL), reverse KL, and Jensen-Shannon, that can be effectively integrated with the generative adversarial imputation network to generate imputed values without any assumptions, and mathematically prove that the distribution of imputed data using sc-fGAIN algorithm is same as the distribution of original data. Real scRNA-seq data analysis has shown that, compared to many traditional methods, the imputed values generated by sc-fGAIN algorithm have a smaller root-mean-square error, and it is robust to varying missing rates, moreover, it can reduce imputation bias. The flexibility offered by thef-divergence allows the sc-fGAIN method to accommodate various types of data, making it a more universal approach for imputing missing values of scRNA-seq data.
The citrate transporter SLC13A5 as a therapeutic target for kidney disease: evidence from Mendelian randomization to inform drug development
Authors: Gill Dipender , Zagkos Loukas , Gill Rubinder , Benzing Thomas , Jordan Jens , Birkenfeld Andreas L. , Burgess Stephen , Zahn Grit 
Published: August 2023

AbstractBackgroundSolute carrier family 13 member 5 (SLC13A5) is a Na -coupled citrate co-transporter that mediates the entry of extracellular citrate into the cytosol. SLC13A5 inhibition has been proposed as a therapeutic target for reducing progression of kidney disease via its effects on citrate metabolism. However, evidence of its efficacy in humans is limited. The aim of this study was to leverage the Mendelian randomization paradigm to gain insight into the effects of SLC13A5 inhibition in humans, towards prioritizing and informing clinical development efforts.MethodsThe primary Mendelian randomization analyses investigated the effect of SLC13A5 inhibition on measures of kidney function, including creatinine and cystatin C based measures of estimated glomerular filtration rate (creatinine-eGFR and cystatin C-eGFR), blood urea nitrogen (BUN), urine albumin-creatinine ratio (uACR), and risk of chronic kidney disease and microalbuminuria. Secondary analyses included a paired plasma and urine metabolome-wide association study, investigation of secondary traits related to SLC13A5 biology, a phenome-wide association study (PheWAS), and a proteome-wide association study. All analyses were compared to the effect of genetically predicted plasma citrate levels using variants selected from across the genome, and statistical sensitivity analyses robust to the inclusion of pleiotropic variants were also performed. Data were obtained from large scale genetic consortia and biobanks, with sample sizes ranging from 5,023 to 1,320,016 individuals.ResultsWe found evidence of associations between genetically proxied SLC13A5 inhibition and higher creatinine-eGFR (p=0.002), cystatin C-eGFR (p=0.005), and lower BUN (p=3×10-3). Statistical sensitivity analyses robust to the inclusion of pleiotropic variants suggested that these effects may be a consequence of higher plasma citrate levels. There was no strong evidence of associations of genetically proxied SLC13A5 inhibition with uACR or risk of CKD or microalbuminuria. Secondary analyses also identified evidence of associations with higher plasma calcium levels (p=6×10-13) and lower fasting glucose (p=0.02). PheWAS did not identify any safety concerns.ConclusionThis Mendelian randomization analysis provides human-centric insight to guide clinical development of an SLC13A5 inhibitor. We identify plasma calcium and citrate as biologically plausible biomarkers of target engagement, and plasma citrate as a potential biomarker of mechanism of action. Our human genetic evidence corroborates evidence from various animal models to support effects of SLC13A5 inhibition on improving kidney function. Further study in the form of early-stage clinical trials may now be warranted to help translate these findings towards improving patient care.
Streptococcus pneumoniaeserotype 3 population structure in the era of conjugate vaccines, 2001-2018
Authors: Cella Eleonora , Sutcliffe Catherine G , Grant Lindsay R , Tso Carol , Weatherholtz Robert C , Littlepage Shea , Becenti Ladonna , Jubair Mohammad , Simons Brenna C , Harker-Jones Marcella , Reid Raymond , Yazzie Del , Santosham Mathuram , O’Brien Katherine L , Hammitt Laura L , Azarian Taj 
Published: August 2023

AbstractBackgroundDespite use of highly effective conjugate vaccines, invasive pneumococcal disease (IPD) remains a leading cause of morbidity and mortality and disproportionately affects Indigenous populations. Although included in the 13-valent pneumococcal conjugate vaccine (PCV13), which was introduced in 2010, serotype 3 (ST3) continues to cause disease among Indigenous communities in the Southwest US. In the Navajo Nation, ST3 IPD incidence increased among adults (3.8/100,000 in 2001-2009 and 6.2/100,000 in 2011-2019); in children the disease persisted although the rates dropped from 5.8/100,000 to 2.3/100,000.MethodsWe analyzed the genomic epidemiology of ST3 isolates collected from 129 adults and 63 children with pneumococcal carriage (n=61) or IPD (n=131) from 2001–2018 of the Navajo Nation. Using whole-genome sequencing data, we determined clade membership and assessed changes in ST3 population structure over time.ResultsThe ST3 population structure was characterized by three dominant subpopulations:clade II(n=90, 46.9%) andclade Iα(n=59, 30.7%), which fall into Clonal Complex (CC) 180, and a non-CC180 clade (n=43, 22.4%). The proportion ofclade II-associated IPD cases increased significantly from 2001-2010 to 2011-2018 among adults (23.1% to 71.8%; p<0.001) but not in children (27.3% to 33.3%; p=0.84). Over the same period, the proportion ofclade II-associated carriage increased; this was statistically significant among children (23.3% to 52.6%; p=0.04) but not adults (0% to 50.0%, p=0.08).ConclusionsIn this setting with persistent ST3 IPD and carriage,clade IIhas increased since 2010. Genomic changes may be contributing to the observed trends in ST3 carriage and disease over time.
Novel autoantibodies help diagnose anti-SSA antibody negative Sjögren’s disease and predict abnormal labial salivary gland pathology
Authors: Parker Maxwell , Zheng Zihao , Lasarev Michael , Alexandridis Roxana A. , Newton Michael A. , Shelef Miriam A. , McCoy Sara S. 
Published: August 2023

ABSTRACTObjectivesSj□gren’s disease (SjD) diagnosis requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of SjD patients lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose ‘seronegative’ SjD.MethodsIgG binding to a high density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca controls without autoimmunity (n=75), and autoimmune controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for peptide abundance and controlled false discovery rate in group comparisons. For predictive modeling, we used logistic regression, model selection methods, and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity.ResultsIgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) was bound more in SSA- SjD than sicca controls (p=.004) and more than combined controls (sicca and autoimmune controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 (RESF1) and DTD2, were bound more in FS-positive than FS-negative participants (p=.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (AUC 74%) and between FS-positive versus FS-negative (AUC 72%).ConclusionWe present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS-positivity.KEY MESSAGESWhat is already known on this topic- Seronegative (anti-SSA antibody negative [SSA-]) Sjögren’s disease (SjD) requires a labial salivary gland biopsy for diagnosis, which is challenging to obtain and interpret.What this study adds- We identified novel autoantibodies in SSA- SjD that, when combined with readily available clinical variables, provide good predictive ability to discriminate 1) SSA- SjD from control participants and 2) abnormal salivary gland biopsies from normal salivary gland biopsies.How this study might affect research, practice or policy- This study provides novel diagnostic antibodies addressing the critical need for improvement of SSA- SjD diagnostic tools.
Infection Risk Perception, Reporting and Post-Exposure Management of Occupational Injuries Among Healthcare Workers in District Hospitals (Yaoundé, Cameroon)
Authors: Takougang Innocent , Lekeumo Cheuyem Fabrice Zobel , Ndungo Jonathan Hangi , Lyonga Emilia Enjema , Mbopi-Keou François-Xavier 
Published: August 2023

AbstractBackgroundThe risk of infection among healthcare workers (HCW) is a looming public health problem worldwide. Developing countries are most affected. The present study aimed to identify knowledge gaps, risk perceptions, reporting patterns, and post-exposure management, following needle stick and sharp injuries and contact with other body fluids HCW.MethodsA cross sectional descriptive study was carried out from January to April 2022 in six District Hospitals in Yaoundé. An auto-administered questionnaire was addressed to consenting HCW. Data were analyzed using R statistic version 4.2.3 andp-value<5% was considered significant.ResultsOut of the 217 HCWs that were enrolled, some 10% were unaware of sources of exposure to blood and other body fluids (BBF). Respondents displayed insufficient awareness (74-94%) of the main infectious agents that are likely to be transmitted during an accidental exposure to body fluids (AEB). Some HCWs (6,9%) reported a lack of knowledge of the vaccine against Viral Hepatitis B (VHB). Almost half of participants did not know the appropriate recommended action for post-exposure case management (42.9%). Most HCW who had experienced exposure (53.7 %) reported that they did not receive any post-exposure care. Such exposure was often (56.4%) not reported. There was a horizontal variation in underreporting for the same level of healthcare facilities, as it was higher in the Efoulan (OR=3.33) and Nkolndongo (OR=5) District Hospitals. Reasons explaining AEB underreporting were underestimation of vulnerability (51 %) and lack of unawareness of existing post-exposure prophylaxis procedures (42%).ConclusionWhile most HCW are aware of the risk of infection associated with exposure to blood and body fluids, reporting was low. Continued educational activities on the risk of infections associated to AEB is warranted. There is a need to implement and scale up structural facilities to enforce measures to prevent exposure, report cases of accidental exposure, ensure post-exposure prophylaxis and counselling.
Step-wise activation of a Family C GPCR
Authors: Kumar Kaavya Krishna , Wang Haoqing , Habrian Chris , Latorraca Naomi R. , Xu Jun , O’Brien Evan S. , Zhang Chensong , Montabana Elizabeth , Koehl Antoine , Marqusee Susan , Isacoff Ehud Y. , Kobilka Brian K. 
Published: August 2023

AbstractMetabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain (ECD) that is linked via a cysteine-rich domain (CRDs) to their 7-transmembrane (TM) domain. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the ECD to the G protein-coupling TM. In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging we reveal distinct receptor conformations upon allosteric modulator and G protein binding.