bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential prediction performance between Caribbean- and Mainland-subgroups using state-of-the-art polygenic risk scores for coronary heart disease: Findings from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Authors: Hutten Christina G. , Boehm Frederick J. , Smith Jennifer A. , Spitzer Brian W. , Wassertheil-Smoller Sylvia , Isasi Carmen R , Cai Jianwen , Unkart Jonathan T , Sun Jiehuan , Persky Victoria , Daviglus Martha L , Sofer Tamar , Argos Maria 
Published: September 2024

AbstractBackgroundCoronary heart disease (CHD) is a leading cause of death for Hispanic/Latino populations in the United States. We evaluated polygenic risk scores (PRS) with incident myocardial infarction (MI) in a Hispanic/Latino study sample.MethodsWe leveraged data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) to assess four CHD-PRS from the PGS catalog, derived using multiple methods (LDpred, AnnoPred, stacked clumping and thresholding, and LDPred2). We evaluated associations between each standardized PRS and time to adjudicated incident MI, adjusted for age, sex, first 5 principal components, and weighted for survey design. Concordance statistics (c-index) compared predictive accuracy of each PRS with, and in addition to, traditional risk factors (TRF) for CHD (obesity, hypercholesterolemia, hypertension, diabetes, and smoking). Analyses were stratified by self-reported Caribbean- (Puerto Rican, Dominican or Cuban) and Mainland- (those of Mexican, Central American, or South American) heritage subgroups.ResultsAfter 11 years follow-up, for 9055 participants (mean age (SD) 47.6(13.1), 62.2% female), the incidence of MI was 1.0% (n = 95). Each PRS was more strongly associated with MI among Mainland participants. LDPred2 + TRF performed best among the Mainland subgroup; HR=2.69, 95% CI [1.71, 4.20], c-index = 0.897, 95% CI [0.848, 0.946]; a modest increase over TRF alone, c-index = 0.880, 95% CI [0.827, 0.933]. AnnoPred + TRF performed best among the Caribbean sample; c-index = 0.721, 95% CI [0.647, 0.795]; however, was not significantly associated with rate of MI (HR=1.14, 95% CI [0.82, 1.60]).ConclusionPRS performance for CHD is lacking for Hispanics/Latinos of Caribbean origin who have substantial proportions of African genetic ancestry, risking increased health disparities. AnnoPred, using functional annotations, outperformed other PRS in the Caribbean subgroup, suggesting a potential strategy for PRS construction in diverse populations. These results underscore the need to optimize cumulative genetic risk prediction of CHD in diverse Hispanic/Latino populations.
NXPE1alters the sialoglycome by acetylating sialic acids in the human colon
Authors: Lee Bum Seok , Cook Ashley , Sur Surojit , Dobbyn Laura , Popoli Maria , Khalili Sana , Zhou Shibin , Bettegowda Chetan , Papadopoulos Nickolas , Gabrielson Kathy , Buckhaults Phillip , Vogelstein Bert , Kinzler Kenneth W , Wyhs Nicolas 
Published: September 2024

AbstractMild periodic acid Schiff staining (mPAS) of human colonic tissue has been used to answer a variety of fundamental questions in germline and somatic genetics. mPAS staining is known to reflect sialic acid O-acetylation, but a full accounting of the genes contributing to sialoglycome diversity is incomplete. Using haplotypes derived from whole genome sequencing, we identified a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, onlyNXPE1haplotypes correlated perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis suggested that one common allele ofNXPE1, with a single base pair substitution in its promoter region, greatly reduces expression of the gene. Genetic manipulation ofNXPE1expression confirmed this conclusion and caused changes to modified sialic acid levels. Finally, high-performance liquid chromatography (HPLC) confirms that enzymatically active NXPE1 is capable of transferring an acetyl group from acetyl coenzyme A to sialic acidin vitro. These findings suggest thatNXPE1is the long-sought gene responsible for differences in colon mPAS staining and may be the prototype of a new family of sialic acid O-acetylation-modifying genes.
Effect of chronic upregulation of endocannabinoid signalingin vivowith JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice
Authors: Sepers Marja D. , Woodard Cameron L. , Ramandi Daniel , Vecchiarelli Haley A. , Hill Matthew N. , Raymond Lynn A. 
Published: September 2024

ABSTRACTSynaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Here, we tested the effects of JZL184 administeredin vivoto YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.
Trem2 deficiency attenuates breast cancer tumor growth in lean, but not obese or weight loss, mice and is associated with alterations of clonal T cell populations
Authors: Pierro Elysa W. , Cottam Matthew A. , An Hanbing , Lehmann Brian D. , Pietenpol Jennifer A. , Wellen Kathryn E. , Makowski Liza , Rathmell Jeffrey C. , Fingleton Barbara , Hasty Alyssa H. 
Published: September 2024

AbstractObesity is an established risk factor for breast cancer development and worsened prognosis; however, the mechanisms for this association − and the potential benefits of weight loss − have not been fully explored. The adipose environment surrounding breast tumors, which is inflamed in obesity, has been implicated in tumor progression. An emerging therapeutic target for cancer is TREM2, a transmembrane receptor of the immunoglobulin superfamily that is expressed on macrophages in adipose tissue and tumors. We utilized genetic loss of function (Trem2+/+andTrem2-/-) models and dietary (lean, obese, and weight loss) intervention approaches to examine impacts on postmenopausal breast cancer. Remarkably,Trem2deficiency ameliorated tumor growth in lean, but not obese or weight loss mice. Single-cell RNA sequencing, in conjunction with VDJ sequencing of tumor and tumor-adjacent mammary adipose tissue (mATTum-adj) immune cells, revealed that tumors of leanTrem2-/-mice exhibited a shift in clonal CD8+T cells from an exhausted to an effector memory state, accompanied with increased clonality of CD4+Th1 cells, that was not observed in any other diet-genotype group. Notably, identical T cell clonotypes were identified in the tumor and mATTum-adjof the same mouse. Finally, an immune checkpoint study demonstrated that αPD-1 therapy restricted tumor growth in lean and weight loss, but not obese mice. We conclude that weight history is relevant when considering potential efficacy of TREM2 inhibition in postmenopausal breast cancer. This work reveals immunological interactions between tumors and surrounding adipose tissue, highlighting significant differences under obese and weight loss conditions.
Particular sequence characteristics induce bias in the detection of polymorphic transposable element insertions
Authors: Verneret Marie , Le Van Anthony , Faraut Thomas , Turpin Jocelyn , Lerat Emmanuelle 
Published: September 2024

AbstractTransposable elements (TEs) have an important role in genome evolution but are challenging for bioinformatics detection due to their repetitive nature and ability to move and replicate within genomes. New sequencing technologies now enable the characterization of nucleotide and structural variations within species. Among them, TE polymorphism is critical to identify as it may influence species adaptation or trigger diseases. Despite the development of numerous bioinformatic programs, identifying the most effective tool is challenging due to non-overlapping results and varying efficiency across studies. Benchmarking efforts have highlighted the limitations of these tools, often evaluated on either real or simulated data. However, real data may be incomplete or contain unannotated TEs, while simulated data may not accurately reflect real genomes. This study introduces a simulation method generating data based on real genomes to control all genomic parameters. Evaluating several TE polymorphic detection tools using data fromDrosophila melanogasterandArabidopsis thaliana, our study investigates factors like copy size, sequence divergence, and GC content that influence detection efficiency. Our results indicate that only a few programs perform satisfactorily and that all are sensitive to TE and genomic characteristics, that may differ according to the species considered. UsingBos tauruspopulation data as a case study to identify polymorphic LTR-retrotransposon insertions, we found low-frequency insertions particularly challenging to detect due to a high number of false positives. Increased sequencing coverage improved sensitivity but reduced precision. Our work underscores the importance of selecting appropriate tools and thresholds according to the specific research questions.
Single molecule spectrum dynamics imaging with 3D target-locking tracking
Authors: Sha Hao , Wu Yu , Zhang Yongbing , Feng Xiaochen , Li Haoyang , Wang Zhong , Zhang Xiufeng , Hou Shangguo 
Published: September 2024

AbstractFluorescence spectrum can provide rich physicochemical insights into molecular environments and interactions. However, imaging the dynamic fluorescence spectrum of rapidly moving biomolecules, along with their positional dynamics, remains a significant challenge. Here, we report a three-dimensional (3D) target-locking tracking-based single molecule fluorescence Spectrum Dynamics Imaging Microscopy (3D-SpecDIM), which is capable of simultaneously capturing both the rapid 3D positional dynamics and the physicochemical parameters changing dynamics of the biomolecules with enhanced spectral accuracy, high spectral acquisition speed, single-molecule sensitivity, and high 3D spatiotemporal localization precision. As a demonstration, 3D-SpecDIM is applied to real-time spectral imaging of the mitophagy process, showing its enhanced ratiometric fluorescence imaging capability. Additionally, 3D-SpecDIM is used to perform multi-resolution imaging, which provides valuable contextual information on the mitophagy process. Furthermore, we demonstrated the quantitative imaging capability of 3D-SpecDIM by imaging the cellular blebbing process. By continuously monitoring the physicochemical parameter dynamics of biomolecular environments through spectral information, coupled with 3D positional dynamics imaging, 3D-SpecDIM offers a versatile platform for concurrently acquiring multiparameter dynamics, providing comprehensive insights unattainable through conventional imaging techniques. 3D-SpecDIM represents a substantial advancement in single-molecule spectral dynamics imaging techniques.
Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy
Authors: Shorer Ofir , Pinhasi Asaf , Yizhak Keren 
Published: September 2024

SummaryDespite the crucial role of T cell clones in the anti-tumor activity, their characterization and association with clinical outcome following immune checkpoint inhibitors (ICI) is lacking. Here we analyzed paired single-cell RNA-sequencing/T-cell receptor sequencing of 767,606 T cells from 460 samples spanning 6 cancer types. We found a robust signature of response based on expanded CD8+clones that differentiates between responders and non-responders. Analysis of persistent clones showed transcriptional changes that are differentially induced by therapy in the different response groups, suggesting an improved reinvigoration capacity in responding patients. Moreover, a gene trajectory analysis revealed changes in the pseudo-temporal state of de-novo clones that are associated with response to therapy. Lastly, we found that clones shared between tumor and blood are more abundant in non-responders and execute distinct transcriptional programs. Overall, our results highlight differences in clonal transcriptional states that are linked to patient response, offering valuable insights into the mechanisms driving effective anti-tumor immunity.Graphical abstract
Transcription-dependent swelling of a transplanted chromosome in an artificial cell
Authors: Greiss Ferdinand , Daube Shirley S. , Noireaux Vincent , Bar-Ziv Roy 
Published: September 2024

AbstractTransplanting chromosomes from living to artificial cells would impact our understanding of chromosome organization and DNA transactions, with implications for autonomous biological systems. Here, we transplantedEscherichia colichromosomes into artificial cells, enabling real-time labeling, manipulation, and steady-state gene expression down to the single-molecule limit. Chromosomes stripped of native proteins transitioned from a swollen to compacted state induced by transcription inhibition, in contrast to protein-bound chromosomes retaining an organization with blobs. In a cell-free expression reaction, RNA polymerases were uniformly distributed along the entire chromosome and rapidly detached, consistent with a global transcriptional activity. We used tailored surfaces to capture and count 20 nascent proteins per hour from a single gene on the chromosome. We mapped stably bound condensins to the blobs, supporting a model where swelling by transcription is counterbalanced by condensin-mediated compaction. Our data suggest transplanted chromosomes as active gels organized by molecular machines.
CCR5 antagonists as cerebroprotective and stroke recovery enhancing agents: a preclinical systematic review and meta-analysis
Authors: Sharif Ayni , Jeffers Matthew S. , Fergusson Dean A. , Bapuji Raj , Nicholls Stuart G. , Humphrey John , Johnston Warren , Mitchell Ed , Speirs Mary-Ann , Stronghill Laura , Vuckovic Michele , Wulf Susan , Shorr Risa , Dowlatshahi Dar , Corbett Dale , Lalu Manoj M. 
Published: September 2024

ABSTRACTBackgroundC-C chemokine receptor type 5 (CCR5) antagonists may improve both acute stroke outcome and long-term recovery. Despite their evaluation in ongoing clinical trials, gaps remain in the evidence supporting their use.MethodsWith a panel of patients with lived experiences of stroke, we performed a systematic review of animal models of stroke that administered a CCR5 antagonist and assessed infarct size or behavioural outcomes. MEDLINE, Web of Science, and Embase were searched. Article screening and data extraction were completed in duplicate. We pooled outcomes using random effects meta-analyses. We assessed risk of bias using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool and alignment with the Stroke Treatment Academic Industry Roundtable (STAIR) and Stroke Recovery and Rehabilitation Roundtable (SRRR) recommendations.ResultsFive studies representing 10 experiments were included. CCR5 antagonists reduced infarct volume (standard mean difference −1.02; 95% confidence interval −1.58 to −0.46) when compared to stroke-only controls. Varied timing of CCR5 administration (pre- or post-stroke induction) produced similar benefit. CCR5 antagonists significantly improved 11 of 16 behavioural outcomes reported. High risk of bias was present in all studies and critical knowledge gaps in the preclinical evidence were identified using STAIR/SRRR.ConclusionsCCR5 antagonists demonstrate promise; however, rigorously designed preclinical studies that better align with STAIR/SRRR recommendations and downstream clinical trials are warranted.RegistrationProspective Register of Systematic Reviews (PROSPERO CRD42023393438)
Antimicrobial Resistance and Virulence-Associated Genes ofPasteurella multocidaandMannheimia haemolyticaIsolated from Polish Dairy Calves with Symptoms of Bovine Respiratory Disease
Authors: Lachowicz-Wolak Agnieszka , Chmielina Aleksandra , Przychodniak Iwona , Karwańska Magdalena , Siedlecka Magdalena , Klimowicz-Bodys Małgorzata , Dyba Kamil , Rypuła Krzysztof 
Published: September 2024

AbstractBackgroundBovine respiratory disease causes significant economic losses in cattle farming due to mortality, treatment costs, and reduced productivity. It involves viral and bacterial infections, withPasteurella multocida(P. multocida) andMannheimia haemolytica(M. haemolytica) as key bacterial pathogens. These bacteria contribute to severe pneumonia and are often found together. A total of 70 bacterial strains were analysed: 48P. multocidaand 22M. haemolytica, collected from deep nasal swabs or lung and bronchial swabs from affected calves. The bacterial species were confirmed molecularly using PCR, which was also employed to detect antimicrobial resistance and virulence-associated genes. Antimicrobial susceptibility was determined using the broth microdilution method.ResultsAntimicrobial resistance varied between the two bacterial species studied. The highest resistance inP. multocidawas observed to chlortetracycline 79.2% and oxytetracycline 81.3%, whileM. haemolyticashowed 63.6% resistance to penicillin and tilmicosin. Multidrug resistance amongP. multocidawas 27.1%, while amongM. haemolyticait reached 40.9%. The most commonly observed phenotypic resistance patterns were ‘chlortetracycline, oxytetracycline’ in 37.5% ofP. multocidaand ‘ceftiofur, chlortetracycline, oxytetracycline, penicillin, tilmicosin, tulathromycin’ in 18.2% ofM. haemolytica. The highest susceptibility was found for fluoroquinolones:P. multocidademonstrated 91.7% susceptibility to enrofloxacin, while 77.3% ofM. haemolyticawere susceptible to both enrofloxacin and danofloxacin. Multidrug resistance was detected in 31.4% of all tested strains. MIC50and MIC90determinations were performed for all tested antimicrobials. AllM. haemolyticacontained thelkt, gs60, andgcpgenes.P. multocidacarried thesodAgene, while thehgbBandompHgenes were present in 37.5% and 20.8% of strains, respectively. ThetetHandtetRgenes were observed only inP. multocida, at frequencies of 20.8% and 16.7%, respectively. Both species carried themphEandmsrEgenes, though at lower frequencies between 6.3% and 14.6%.ConclusionsThis study expands the knowledge of the pathogenicity and antimicrobial resistance ofP. multocidaandM. haemolyticain dairy calves.P. multocidaexhibited the highest resistance to tetracyclines,M. haemolyticademonstrated the greatest nonsusceptibility to penicillin. Both bacterial species were found to be susceptible to fluoroquinolones. One third of strains showed multidrug resistance.
AnalyzAIRR: A user-friendly guided workflow for AIRR data analysis
Authors: Mhanna Vanessa , Pires Gabriel , Bohl-Viallefond Grégoire , El Soufi Karim , Tchitchek Nicolas , Klatzmann David , Six Adrien , Pham Hang P. , Mariotti-Ferrandiz Encarnita 
Published: September 2024

AbstractThe analysis of bulk adaptive immune receptor repertoires (AIRR) enables the understanding of immune responses in both normal and pathological conditions. However, the complexity of AIRR calls for advanced, specialized methods to extract meaningful biological insights. These sophisticated approaches often present challenges for researchers with limited bioinformatics expertise, hindering access to comprehensive immune system analysis. To address this challenge, we developed AnalyzAIRR, an AIRR-compliant R package enabling advanced bulk AIRR sequencing data. The tool integrates state-of-the-art statistical and visualization methods applicable at various levels of granularity. It offers a platform for general data exploration, filtering and manipulation, and in-depth cross-comparisons of AIRR datasets, aimed at answering specific biological questions. We illustrate AnalyzAIRR functionalities using of a published murine dataset of 18 T-cell receptor repertoires from three diferrent T cell subsets. We first detected and removed a major contaminant in a group of samples, before proceeding with to the comparative analysis. Subsequent cross-sample analysis revealed differences in repertoire diversity that aligned with the respective cell phenotypes, and in repertoire convergence among the studied subsets. AnalyzAIRR’s set of analytical metrics is integrated into a Shiny web application and complemented with a tutorial to help users in their analytical strategy, making it user-friendly for biologists with little or no background in bioinformatics.
Cisplatin exposure dysregulates pancreatic islet function in male mice
Authors: Basu Lahari , McKay Kelsea S. , Hoyeck Myriam P. , Grieco-St-Pierre Lili , Rick Kayleigh R.C. , Poleo-Giordani Emilia , Fadzeyeva Evgenia , Mulvihill Erin E. , Mennigen Jan A. , Bruin Jennifer E. 
Published: September 2024

AbstractCancer survivors have an increased risk of developing new-onset Type 2 diabetes compared to the general population. Moreover, patients treated with cisplatin, a commonly used chemotherapeutic agent, are more likely to develop metabolic syndrome and Type 2 diabetes compared to age- and sex-matched controls. Insulin-secreting beta cells—located within pancreatic islets—are critical for maintaining glucose homeostasis, and dysregulated insulin secretion is central to Type 2 diabetes pathophysiology. Surprisingly, the impact of cisplatin treatment on pancreatic islets has not been reported. In this study, we aimed to determine if murine islet function is adversely affected by direct or systemic exposure to cisplatin.In vitrocisplatin exposure to male mouse islets profoundly dysregulated insulin release, reduced oxygen consumption, and altered the expression of genes related to insulin production, oxidative stress, and the Bcl-2 family.In vivocisplatin exposure led to sustained hypoinsulinemia and hypoglycemia in male mice. Pancreas tissues from cisplatin-exposed male mice showed increased proinsulin accumulation and expression of DNA-damage markers in beta cells, but no change in average islet size or % insulin+area per islet. Our data suggest both direct and systemic cisplatin exposure cause acute defects in insulin secretion and may have lasting effects on islet health in mice.