bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex biased human thymic architecture guides T cell development through spatially defined niches
Authors: Stankiewicz Laura N , Salim Kevin , Flaschner Emily A , Wang Yu Xin , Edgar John M , Lin Bruce ZB , Bingham Grace C , Major Matthew C , Jones Ross D , Blau Helen M , Rideout Elizabeth J , Levings Megan K , Zandstra Peter W , Rossi Fabio MV 
Published: April 2023

SummaryWithin the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a holistic, spatially defined map of tissue niches guiding postnatal T cell development we employed the multidimensional imaging platform CO-detection by indEXing (CODEX), as well as CITE-seq and ATAC-seq. We generated age-matched 4–5-month-old postnatal thymus datasets for male and female donors, and identify significant sex differences in both T cell and thymus biology. We demonstrate a crucial role for JAG ligands in directing thymic-like dendritic cell development, reveal important functions of a novel population of ECM-fibroblasts, and characterize the medullary niches surrounding Hassall’s corpuscles. Together, these data represent a unique age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, and provide an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.
Evidence for the role of selection for reproductively advantageous alleles in human aging
Authors: Long Erping , Zhang Jianzhi 
Published: April 2023

ABSTRACTThe antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), andPGSRincreased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined.PGSRandSV76remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless ofPGSR, having two children maximizesSV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans.
Plasma cells are formed in waning germinal centers via an affinity-independent process
Authors: Sutton Henry J. , Parker Brian J. , Lofgren Mariah , Dacon Cherrelle , Chatterjee Deepyan , Gao Xin , Kelly Hannah G. , Seder Robert A. , Tan Joshua , Idris Azza H. , Neeman Teresa , Cockburn Ian A. 
Published: April 2023

SummaryLong-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. It has been proposed that high affinity cells are preferentially selected into this compartment, potentiating the immune response. Here we used single cell RNA-seq to track the development of Ighg2A10cells, specific for thePlasmodium falciparumcircumsporozoite protein (PfCSP) within the germinal center (GC). We identified cells differentiating into memory B cells (MBC) or PCs and estimated their affinity by V(D)J sequencing. While pre-memory cells were of lower affinity than GC B cells generally, the affinity of pre-PC cells was indistinguishable. Rather, a larger proportion of cells differentiated into PCs in waning GCs. These later emigrants replaced early arrivals in the bone marrow allowing the development of a high affinity PC compartment.
A Randomised Controlled Trial of Nasal Immunisation with Live Virulence AttenuatedStreptococcus pneumoniaeStrains using Human Infection Challenge
Authors: Hill H , Mitsi E , Nikolaou E , Blizard A , Pojar S , Howard A , Hyder-Wright A , Devin Jack , Reiné J , Robinson R , Solórzano C , Jochems S , Kenny-Nyazika T , Ramos-Sevillano E , Weight CM , Myerscough C , McLennan D , Morton B , Gibbons E , Farrar M , Randles V , Burhan H , Chen T , Shandling AD , Campo JJ , Heyderman R , Gordon SB , Brown J , Collins AM , Ferreira DM 
Published: April 2023

AbstractRationalePneumococcal pneumonia remains a global health problem. Pneumococcal colonisation increases local and systemic protective immunity, suggesting nasal administration of live attenuatedS. pneumoniaestrains could help prevent infections.ObjectivesWe used a controlled human infection model to investigate whether nasopharyngeal colonisation with attenuatedS. pneumoniaestrains protected against re-colonisation with wild-type (WT)S. pneumoniae(Spn).MethodsHealthy adults aged 18-50 years were randomised (1:1:1:1) for nasal administration twice (two weeks interval) with saline, WT Spn6B (BHN418) or one of two genetically modified Spn6B strains - SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against re-colonisation (Stage II).Measurements and Main Results125 participants completed both study stages as per intention to treat. No Serious Adverse Events were reported. In Stage I, colonisation rates were similar amongst groups: SpnWT 58.1% (18/31), SpnA1 60% (18/30) and SpnA3 59.4% (19/32). Anti-Spn nasal IgG levels post-colonisation were similar in all groups whilst serum IgG responses were higher in the SpnWT and SpnA1 groups than the SpnA3 group. In colonised individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 but not SpnA3 in phase 1 were partially protected against re-colonisation with SpnWT (recolonisation rates of 29% versus 30% respectively).ConclusionNasal colonisation with genetically modified live attenuated Spn was safe and induced protection against recolonisation, suggesting nasal adminstration of live attenuated Spn could be an effective stategy for preventing pneumococcal infections.
Participant characteristics and exclusion from trials: a meta-analysis of individual participant-level data from phase 3/4 industry-funded trials in chronic medical conditions
Authors: Lees Jennifer S , Crowther Jamie , Hanlon Peter , Butterly Elaine , Wild Sarah H , Mair Frances S , Guthrie Bruce , Gillies Katie , Dias Sofia , Welton Nicky J , Katikireddi Srinivasa Vittal , McAllister David A 
Published: April 2023

AbstractObjectivesTrials often do not represent their target populations, threatening external validity. The aim was to assess whether age, sex, comorbidity count and/or race/ethnicity are associated with likelihood of screen failure (i.e., failure to be randomised to the trial for any reason) among potential trial participants.DesignBayesian meta-analysis of individual participant-level data (IPD).SettingIndustry-funded phase 3/4 trials in chronic medical conditions. Participants were identified as “randomised” or “screen failure” using trial IPD.ParticipantsData were available for 52 trials involving 72,178 screened individuals of whom 24,733 (34%) failed screening.Main outcome measuresFor each trial, logistic regression models were constructed to assess likelihood of screen failure, regressed on age (per 10-year increment), sex (male versus female), comorbidity count (per one additional comorbidity) and race/ethnicity. Trial-level analyses were combined in Bayesian hierarchical models with pooling across condition.ResultsIn age- and sex-adjusted models, neither age nor sex was associated with increased odds of screen failure, though weak associations were detected after additionally adjusting for comorbidity (age, per 10-year increment: odds ratio [OR] 1.02; 95% credibility interval [CI] 1.01 to 1.04 and male sex: OR 0.95; 95% CI 0.91 to 1.00). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (OR 0.97 per additional comorbidity, 95% CI 0.94 to 1.00, adjusted for age and sex). Those who self-reported as Black were slightly more likely to fail screening (OR 1.04; 95% CI 0.99 to 1.09); an effect which persisted after adjustment for age, sex and comorbidity count (OR 1.05; 95% CI 0.98 to 1.12).ConclusionsAge, sex, comorbidity count and Black race/ethnicity were not strongly associated with increased likelihood of screen failure. Proportionate increases in screening these underserved populations may improve representation in trials.Trial registrationRelevant trials in chronic medical conditions were identified according to pre-specified criteria (PROSPERO CRD42018048202).
Longitudinal sequencing and variant detection of SARS-CoV-2 across Southern California wastewater from April 2020 – August 2021
Authors: Rothman Jason A. , Saghir Andrew , Zimmer-Faust Amity G. , Langlois Kylie , Steele Joshua A. , Griffith John F. , Whiteson Katrine L. 
Published: April 2023

AbstractWastewater based epidemiology (WBE) is a useful method to detect pathogen prevalence and may serve to effectively monitor diseases at a broad scale. WBE has been used throughout the COVID-19 pandemic to track localized and population-level disease burden through the quantification of SARS-CoV-2 RNA present in wastewater. Aside from case load estimation, WBE is being used to assay viral genomic diversity and the emergence of potential SARS-CoV-2 variants.Here, we present a study in which we sequenced RNA extracted from sewage influent samples obtained from eight wastewater treatment plants representing 16 million people in Southern California over April 2020 – August 2021. We sequenced SARS-CoV-2 with two methods: Illumina Respiratory Virus Enrichment and metatranscriptomic sequencing (N = 269), and QIAseq SARS-CoV-2 tiled amplicon sequencing (N = 95). We were able to classify SARS-CoV-2 reads into lineages and sublineages that approximated several named variants across a full year, and we identified a diversity of single nucleotide variants (SNVs) of which many are putatively novel SNVs, and SNVs of unknown potential function and prevalence. Through our retrospective study, we also show that several sublineages of SARS-CoV-2 were detected in wastewater up to several months before clinical detection, which may assist in the prediction of future Variants of Concern. Lastly, we show that sublineage diversity was similar between wastewater treatment plants across Southern California, and that diversity changed by sampling month indicating that WBE is effective across megaregions.As the COVID-19 pandemic moves to new phases, and additional SARS-CoV-2 variants emerge, the ongoing monitoring of wastewater is important to understand local and population-level dynamics of the virus. Our study shows the potential of WBE to detect SARS-CoV-2 variants throughout Southern California’s wastewater and track the diversity of viral SNVs and strains in urban and suburban locations. These results will aid in our ability to monitor the evolutionary potential of SARS-CoV-2 and help understand circulating SNVs to further combat COVID-19.
Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution
Authors: Casanova-Salas Irene , Cordoba-Terreros Sarai , Aguilar Daniel , Agundez Laura , Brandariz Julian , Herranz Nicolas , Gonzalez Macarena , Morales-Barrera Rafael , Sierra Alexandre , Soriano-Navarro Mario , Cresta Pablo , Simonetti Sara , Rodrigues Gonçalo , Arce-Gallego Sara , Delgado-Soriano Luisa , Agustí Irene , Castellano-Sanz Elena , Mast Richard , Albert Matias de , Celma Ana , Santamaria Anna , Gonzalez Lucila , Castro Natalia , Suanes Maria del Mar , Hernández-Losa Javier , Nonell Lara , Peinado Hector , Carles Joan , Mateo Joaquin 
Published: April 2023

AbstractExtracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from a range ofin-vitroandin-vivomodels of metastatic prostate cancer (mPC) revealed a high contribution of tumor material to EV-loaded DNA/RNA. Findings were validated in a cohort of longitudinal plasma samples collected from mPC patients during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA genomic features recapitulated matched-patient biopsies and associated with clinical progression. We developed a novel approach to enable the transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptomic profile in mPC EV-RNA is enriched for tumor-associated transcripts when compared to same patient blood RNA and healthy individuals EV-RNA, and reflect early on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.
No general effects of advancing male age on ejaculates: a meta-analysis across the animal kingdom
Authors: Sanghvi Krish , Vega-Trejo Regina , Nakagawa Shinichi , Gascoigne Samuel J.L. , Johnson Sheri , Salguero-Gómez Roberto , Pizzari Tommaso , Sepil Irem 
Published: April 2023

AbstractSenescence, the deterioration of organismal function with advancing age, is a puzzling biological phenomenon. While actuarial senescence (i.e., age-dependent increases in mortality rates) is well described across some taxa, reproductive senescence (i.e.age- dependent declines in reproduction) is less understood, especially in males, with mixed patterns reported across studies. To examine the evidence for male reproductive senescence, we investigated how advancing male age affects ejaculate traits across non-human animals via a meta-analysis yielding 1814 effect sizes from 379 studies. We found no evidence for a general pattern of reproductive senescence. Instead, we found high heterogeneity for how reproduction changes with male age across animals. Some of this heterogeneity (>10%) was associated with biological factors. For example, there were taxonomical differences for some ejaculate traits — sperm motility declined with male age in lab rodents and fish, whereas ejaculate size improved with male age in bulls, fish, and insects. Some methodological factors were also important in explaining this heterogeneity: studies sampling a larger proportion of a species’ lifespan were more likely to detect senescence in ejaculate traits, emphasising the need to examine the full life cycle of species to document senescence. Contrary to predictions, we reveal that the evidence for senescence in ejaculate traits is sporadic. Our findings will help generate novel hypotheses and identify more effective methodological approaches for studying male reproductive senescence.
Deep flanking sequence engineering for efficient promoter design
Authors: Zhang Pengcheng , Wang Haochen , Xu Hanwen , Wei Lei , Hu Zhirui , Wang Xiaowo 
Published: April 2023

AbstractHuman experts are good at summarizing explicit strong patterns from small samples, while deep learning models can learn implicit weak patterns from big data. Biologists have traditionally described the sequence patterns of promoters via transcription factor binding sites (TFBSs), while the flanking sequences among TFBSs, which can also significantly influence promoter activity and function, remain largely uncharacterized. Thus, current synthetic promoters are mainly designed by the manipulation of TFBSs, while the flanking sequence is often chosen arbitrarily or by previous experience due to a lack of well-summarized optimization criteria. Here, we introduced an AI-aided promoter design framework, DeepSEED, that employs expert knowledge and deep learning methods to efficiently design synthetic promoters that have various desirable functions. DeepSEED incorporates the user-defined cis-regulatory sequences as ‘seeds’ and generates flanking sequences that match the ‘seeds’. We showed that DeepSEED can automatically capture k-mer frequencies and DNA shape features from active promoters in the training set and efficiently optimize the flanking sequences to better match desired properties in synthetic promoters. We validated the effectiveness of this framework for diverse synthetic promoter design tasks in both prokaryotic and eukaryotic cells. DeepSEED successfully designedE. coliconstitutive, isopropyl-beta-D-1-thiogalactopyranoside (IPTG)-inducible, and mammalian cell doxycycline (Dox)-inducible promoters with significant performance improvements, suggesting that DeepSEED has potential as an efficient AI-aided flanking sequence optimization approach for promoter design that may be of great benefit in synthetic biology applications.Availabilityhttps://github.com/WangLabTHU/deepseed
Investigating the role of lipid genes in liver disease using fatty liver models of alcohol and high fat in zebrafish (Danio rerio)
Authors: Shihana Fathima , Cholan Pradeep Manuneedhi , Fraser Stuart , Oehlers Stefan H , Seth Devanshi 
Published: April 2023

AbstractBackgroundAccumulation of lipid in the liver is the first hallmark of both alcohol-related liver disease (ALD) and non-alcohol-related fatty liver disease (NAFLD). Recent studies indicate that specific mutations in lipid genes confer risk and might influence disease progression to irreversible liver cirrhosis. This study aimed to understand the function/s of lipid risk genes driving disease development in zebrafish genetic models of alcohol- and non-alcohol related fatty liver.MethodsWe used zebrafish larvae to investigate the effect of alcohol and high fat to model fatty liver and tested the utility of this model to study lipid risk gene functions. CRISPR/Cas9 gene editing was used to create knockdowns in 5 days post-fertilization zebrafish larvae for the available orthologs of human cirrhosis risk genes (pnpla3, faf2, tm6sf2). To establish fatty liver models, larvae were exposed to ethanol and a high fat diet (HFD) consisting of chicken egg yolk. Changes in morphology (imaging), survival, liver injury (biochemical tests, histopathology), gene expression (qPCR) and lipid accumulation (dye specific live imaging) were analysed across treatment groups to test the functions of these genes.ResultsExposure of 5-day post-fertilization (dpf) WT larvae to 2% ethanol or HFD for 48 hours developed measurable hepatic steatosis. CRISPR-Cas9 genome editing depletedpnpla3, faf2andtm6sf2gene expression in these CRISPR knockdown larvae (crispants). Knockdown significantly increased effects of ethanol and HFD toxicity by increasing hepatic steatosis and hepatic neutrophil recruitment ≥2-fold in all three crispants. Furthermore, ethanol or HFD exposure significantly altered the expression of genes associated with ethanol metabolism (cyp2y3) and lipid metabolism-related gene expression, includingatgl(triglyceride hydrolysis),axox1, echs1(fatty acid β-oxidation),fabp10a(transport),hmgcra(metabolism),notch1(signaling) andsrebp1(lipid synthesis), in all threepnpla3, faf2andtm6sf2crispants. Nile Red staining in all three crispants revealed significantly increased lipid droplet size and triglyceride accumulation in the livers following exposure to ethanol or HFD.ConclusionsWe identified roles forpnpla3, faf2andtm6sf2genes in triglyceride accumulation and fatty acid oxidation pathways in a zebrafish larvae model of fatty liver.
The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase 4
Authors: Mesmar Fahmi , Muhsen Maram , Tourigny Jason P. , Tennessen Jason M. , Bondesson Maria 
Published: April 2023

AbstractObesity is increasing worldwide, particularly in rural communities, where people are likely exposed to high levels of pesticides. We here investigated whether six commonly used agricultural pesticides on corn and soy fields have adipogenic activity and act as obesogens. Exposure to two pesticides, the herbicides acetochlor and metolachlor, induced adipogenesisin vitroin mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure caused morphological malformations and lethality in zebrafish larvae with an EC50of 7.8 µM and an LC50of 12 µM. Acetochlor exposure also resulted in lipid accumulation is zebrafish larvae when simultaneously fed a high cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we preformed transcriptomic and targeted lipidomic analysis of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consequently, Gpx4 activity was efficiently repressed by acetochlor, and lipid peroxidation was increased in zebrafish. We propose that acetochlor disrupts lipid homeostasis by inhibiting Gpx4, resulting in accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species in the cells, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contain the chloroacetamide group, inhibition of Gpx4 activity may represent a novel, common molecular initiating event of obesogens.SynopsisRural populations have a high prevalence of metabolic disease and are highly exposed to pesticides. This study reports that the herbicide acetochlor, heavily used on soy and corn fields, inhibits an enzyme that protects from oxidation of lipids in the cell membrane, oxidative stress and a type of cell death called ferroptosis, features that are linked to metabolic disruption and obesity.
Evolution of chemosensory tissues and cells across ecologically diverseDrosophilids
Authors: Bontonou Gwénaëlle , Saint-Leandre Bastien , Kafle Tane , Baticle Tess , Hassan Afrah , Sánchez-Alcañiz Juan Antonio , Arguello Roman J. 
Published: April 2023

AbstractChemosensory systems display exceptional variation between species, but little is known about how the evolution of gene expression and cell types contribute to this diversity. We have generated transcriptomes for five chemosensory tissues across six ecologically diverseDrosophilaspecies and integrated their analyses with single-cell datasets to address these questions. The evolution of chemosensory transcriptomes has been predominantly shaped by stabilizing selection, but several thousand genes have nevertheless evolved expression changes in each tissue. Phylogenetic analyses of differentially expressed genes revealed strong evidence that their expression changes have been driven by a combination ofcis-regulatory and cell composition evolution. We have also found that chemosensory-related gene families have undergone pervasive expression level changes and numerous species-specific expression gains/losses. Follow-up experiments revealed several chemoreceptors that evolved novel patterns of tissue and cellular expression that likely contribute to sensory differences. Finally, analyses of the genes that are differentially expressed between sexes uncovered extensive species-specific differences. Among these rapid changes, we discovered aD. melanogaster-specific excess of male-biased gene expression in its forelegs and identified sensory and muscle cells as the primary source of this dimorphism. Together, our analyses provide new insights for understanding evolutionary changes in ecologically key tissues at both global and individual gene levels.