bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROSTATE CELL HETEROGENEITY AND CXCL17 UPREGULATION IN MOUSE STEROID HORMONE IMBALANCE
Authors: Silver Samara V. , Tucker Kayah J. , Vickman Renee E , Lanman Nadia A. , Semmes O John , Alvarez Nehemiah S. , Popovics Petra 
Published: April 2024

AbstractBenign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrate and accumulate in the prostate lumen where they differentiate into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify the epithelia-derived signals that drive macrophage infiltration and luminal translocation.Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T+E2) and harvested the ventral prostates two weeks later for scRNA-seq analysis, or performed sham surgery. We identifiedEar2+ andCd72+ macrophages that were elevated in response to steroid hormone imbalance, whereas aMrc1+ resident macrophage population did not change. In addition, an Spp1+ foam cell cluster was almost exclusively found in T+E2 mice. Further markers of foam cells were also identified, includingGpnmbandTrem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factorsVegf, Tgfb1, Ccl6, Cxcl16andMmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelial-derivedCxcl17, a known monocyte attractant, in T+E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen.Our study identified macrophage subsets that respond to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.
SECRET-GWAS: Confidential Computing for Population-Scale GWAS
Authors: Rosenblum Jonah , Dong Juechu , Narayanasamy Satish 
Published: April 2024

AbstractGenomic data from a single institution lacks global diversity representation, especially for rare variants and diseases. Confidential computing can enable collaborative GWAS without compromising privacy or accuracy, however, due to limited secure memory space and performance overheads previous solutions fail to support widely used regression methods. We present SECRET-GWAS: a rapid, privacy-preserving, population-scale, collaborative GWAS tool. We discuss several system optimizations, including streaming, batching, data parallelization, and reducing trusted hardware overheads to efficiently scale linear and logistic regression to over a thousand processor cores on an Intel SGX-based cloud platform. In addition, we protect SECRET-GWAS against several hardware side-channel attacks, including Spectre, using data-oblivious code transformations and optimized speculative load hardening. SECRET-GWAS is an open-source tool and works with the widely used Hail genomic analysis framework. Our experiments on Azure’s Confidential Computing platform demonstrate that SECRET-GWAS enables multivariate linear and logistic regression GWAS queries on population-scale datasets (one million patients, four million SNPs, 12 covariates) from ten independent sources in just 4.5 and 29 minutes, respectively.
HSD2 neurons are evolutionarily conserved and required for aldosterone-induced salt appetite
Authors: Gasparini Silvia , Peltekian Lila , McDonough Miriam C. , Mitchell Chidera J.A. , Hefti Marco , Resch Jon M. , Geerling Joel C. 
Published: April 2024

AbstractExcessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption predicts end-organ damage in patients with aldosteronism. Preventing this increase may improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). Here, we identify HSD2 neurons in the human brain and use a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirm that dietary sodium deprivation increases aldosterone production, HSD2 neuron activity, and salt intake. Next, we show that activating HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that aldosterone-induced salt intake requires these neurons. Identifying HSD2 neurons in the human brain and their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.
Integrative Data Analysis to Uncover Transcription Factors Involved in Gene Dysregulation of Nine Autoimmune and Inflammatory Diseases
Authors: Naghavi Nader Hosseini , Kerfoot Steven M. , Shooshtari Parisa 
Published: April 2024

ABSTRACTAutoimmune and inflammatory diseases are a group of > 80 complex diseases caused by loss of immune tolerance for self-antigens. The biological mechanisms of autoimmune diseases are largely unknown, preventing the development of effective treatment options. Integrative analysis of genome-wide association studies and chromatin accessibility data has shown that the risk variants of autoimmune diseases are enriched in open chromatin regions of immune cells, supporting their role in gene regulation. However, we still lack a systematic and unbiased identification of transcription factors involved in disease gene regulation. We hypothesized that for some of the disease-relevant transcription factors, their binding to DNA is affected at multiple genomic sites rather than a single site, and these effects are cell-type specific. We developed a statistical approach to assess enrichment of transcription factors in being affected by disease risk variants at multiple genomic sites. We used genetic association data of nine autoimmune diseases and identified 99% credible set SNPs for each trait. We then integrated the credible SNPs and chromatin accessibility data of 376 samples comprising 35 unique cell types, and employed a probabilistic model to identify the SNPs that are likely to change binding probability of certain transcription factors at specific cell types. Finally, for each transcription factor, we used a statistical test to assess whether the credible SNPs show enrichments in terms of changing the binding probability of that transcription factor at multiple sites. Our analysis resulted in identification of significantly enriched transcription factors and their relevant cell types for each trait. The prioritized immune cell types varied across the diseases. Our analysis proved that our predicted regulatory sites are active enhancers or promoters in the relevant cell types. Additionally, our pathway analysis showed that the majority of the significant biological pathways are immune-related. In summary, our study has identified disease-relevant transcription factors and their relevant cell types, and will facilitate discovering specific gene regulatory mechanisms of autoimmune diseases.
Iris Morphological and Biomechanical Factors Influencing Angle Closure During Pupil Dilation
Authors: Tan Royston K.Y. , Ng Gim Yew , Tun Tin A. , Braeu Fabian A. , Nongpiur Monisha E. , Aung Tin , Girard Michael J.A. 
Published: April 2024

AbstractPurposeTo use finite element (FE) analysis to assess what morphological and biomechanical factors of the iris and of the anterior chamber are more likely to influence angle narrowing during pupil dilation.MethodsThe study consisted of 1,344 FE models comprising of the cornea, sclera, lens and iris (stroma, sphincter and dilator tissues) to simulate pupil dilation and to assess changes in angle. For each model, we varied the following parameters: anterior chamber depth (ACD = 2 –4 mm) and width (ACW = 10–12 mm), iris convexity (IC = 0–0.3 mm), thickness (IT = 0.3–0.5 mm), stiffness (E= 4–24 kPa) and Poisson’s ratio (v= 0–0.3), and simulated pupil dilation. We evaluated for the change in anterior chamber angle (△∠) and the final dilated anterior chamber angles (∠f) from baseline to dilation for each parameter.ResultsThe final dilated AC angles decreased with a smaller ACD (∠f= 53.4°±12.3° to 21.3°±14.9°), smaller ACW (∠f= 48.2°±13.5° to 26.2°±18.2°), larger IT (∠f= 52.6°±12.3° to 24.4°±15.1°), larger IC (∠f= 45.0°±19.2° to 33.9°±16.5°), largerE(∠f= 40.3°±17.3° to 37.4°±19.2°) and largerv(∠f= 42.7°±17.7° to 34.2°±18.1°).The change in AC angle increased with larger ACD (△∠ = 9.37°±11.1° to 15.4°±9.3°), smaller ACW (△∠ = 7.4°±6.8° to 16.4°±11.5°), larger IT (△∠ = 5.3°±7.1° to 19.3°±10.2°), smaller IC (△∠ = 5.4°±8.2° to 19.5°±10.2°), largerE(△∠ = 10.9°±12.2° to 13.1°±8.8°) and largerv(△∠ = 8.1°±9.4° to 16.6°±10.4°).ConclusionsThis parametric study offered valuable insights into the factors that could influence angle closure. The morphology of the iris (IT and IC) and its innate biomechanical behavior (Eandv) were crucial in influencing the way the iris deformed during dilation, and angle closure was further exacerbated by decreased AC biometry (ACD and ACW).
Ecosystem engineers cause biodiversity spill-over: beavers affect breeding bird assemblages on both wetlands and adjacent terrestrial habitats
Authors: Fedyń Izabela , Sobociński Wojciech , Czyżowicz Sławomir , Wyka Jakub , Ciach Michał 
Published: April 2024

AbstractThe influence of ecosystem engineers on habitats and communities is commonly acknowledged in a site-bounded context, i.e. in places directly affected by the presence of the focal species. However, the spatial extent of the effects of such engineering is poorly understood, raising the question as to what impact they have on ecosystems situated beyond the species’ direct influence. BeaversCastorspp., iconic ecosystem engineers, are capable of significantly transforming aquatic ecosystems. Their presence boosts biodiversity in near-water habitats, but as a result of cascading processes, beavers may affect terrestrial habitats situated beyond the range of their immediate activity. Our study investigates the breeding bird assemblage along a spatial gradient from the water to the forest interior on central European watercourses modified and unmodified by beavers. The results show that beaver sites are characterized by a higher species richness and abundance of breeding birds than unmodified watercourses. Such sites also host a different species pool, as 27% of the recorded bird species occurred exclusively on the beaver sites. The effect of the beaver’s presence on the bird assemblage caused this to spill over from the wetlands to adjacent terrestrial habitats located up to 100 m from the water’s edge, where the species richness and abundance was higher and the species composition was substantially modified. We also found a positive correlation between the total area of beaver wetland and the numbers of bird species and individuals recorded. Our study indicates that beaver activity has major consequences for ecosystem functioning that extend beyond the wetland, spilling over on to adjacent terrestrial ecosystems. These findings add to the general understanding of the spatial context of the ecosystem engineering concept, as the changes brought about by engineers have an influence beyond the area of their immediate occurrence. Our work also has implications for landscape planning and management, where existing beaver sites with terrestrial buffer zones may constitute a network of biodiversity hot-spots.Highlights:• Beavers create hot-spots of bird richness and abundance in temperate forests• The beaver’s impact spills over beyond wetlands on to terrestrial ecosystems• Bird richness, number and composition is changed up to 100 m from beaver sites• The area of a beaver wetland positively correlates with bird richness and numbers• The beaver is an umbrella species for the riparian forest bird community
Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines
Authors: Wang Ruiying , Oliveira Lorena V. N. , Hester Maureen M. , Carlson Diana , Christensen Dennis , Specht Charles A. , Levitz Stuart M. 
Published: April 2024

AbstractThe fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01). CAF01 promotes humoral and T helper (Th) 1 and Th17 immune responses and has been safely used in human vaccine trials. Four subcutaneous vaccines, each containing single recombinantCryptococcus neoformansprotein antigens, partially protected mice from experimental cryptococcosis. Protection increased, up to 100%, in mice that received bivalent and quadrivalent vaccine formulations. Vaccinated mice that received a pulmonary challenge withC. neoformanshad an influx of leukocytes into the lung including robust numbers of polyfunctional CD4+T cells which produced Interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8+T cells were also found, albeit in lesser numbers. A significant, durable IFNγ response was observed in the lungs, spleen, and blood. Moreover, IFNγ secretion following ex vivo stimulation directly correlated with fungal clearance in the lungs. Thus, we have developed multivalent cryptococcal vaccines which protect mice from experimental cryptococcosis using an adjuvant which has been safely tested in humans. These preclinical studies suggest a path towards human cryptococcal vaccine trials.Author summaryCryptococcosis is a fungal infection that poses great challenges to public health, especially in resource-limited regions with high HIV prevalence. Despite the urgent need, no licensed vaccines are currently available. In this study, we used a lethal mouse model of cryptococcosis to explore protection and immune responses elicited by vaccines consisting of recombinant cryptococcal proteins formulated with CAF01, an adjuvant that has an established safety and immunogenicity profile in human clinical vaccine trials. We discovered that while vaccines containing a single protein partially protected mouse strains, the protection was greatly augmented when the mice received vaccines formulated with multiple antigens. The lungs of vaccinated and infected mice had a robust influx of CD4+T cells, many of which made the cytokines IFNγ and IL-17 when stimulated ex vivo. Moreover, we found the production of IFNγ directly correlated with clearance of fungi from the lungs. Cytotoxic CD8+T cell responses were also observed, albeit in lesser numbers. Our promising findings from this preclinical research paves the way for future human cryptococcal vaccine trials.
The role of mitochondrial DNA copy number in neuropsychiatric disorders: A bidirectional two-sample Mendelian randomization study
Authors: Niu Mengqi , Chen Chen , Maes Michael 
Published: April 2024

AbstractBackgroundInconsistent findings characterize studies on mitochondrial DNA copy number (mtDNA-CN) and its relation to neuropsychiatric disorders. This bidirectional two-sample Mendelian Randomization (MR) study explores potential causal links between mtDNA-CN and neuropsychiatric disorders, including Alzheimer’s disease, Attention-deficit/hyperactivity disorder, Anorexia nervosa, Autism spectrum disorder (ASD), Bipolar disorder, Major depressive disorder, Obsessive-compulsive disorder, Schizophrenia, Anxiety disorders, and Post-traumatic stress disorder.MethodsGenetic associations with mtDNA-CN were drawn from the UK Biobank’s GWAS data (n = 395,718), while neuropsychiatric disorder data came from the Psychiatric Genomics Consortium and FinnGen Consortium. Three MR methods—Inverse Variance Weighting (IVW), MR-Egger, and Weighted Median—were used to establish relationships. Cochran’s Q test, MR-PRESSO, and MR-Egger’s intercept test assessed heterogeneity and pleiotropy. A leave-one-out analysis evaluated the impact of individual SNPs on MR results, and a bidirectional analysis examined the relationship between mtDNA-CN and neuropsychiatric disorders.ResultsThe MR analysis indicated a causal relationship between mtDNA-CN and ASD using the IVW method (OR = 0.735, 95%CI: 0.597 to 0.905; P = 0.004). Conversely, a causal relationship was identified between Anxiety disorders and mtDNA-CN (β= 0.029, 95%CI: 0.010 to 0.048; P = 0.003). No causal associations were found for other disorders. Sensitivity tests corroborated the robustness of these findings.ConclusionIn this study, potential causal relationships between mtDNA-CN and both ASD and Anxiety disorders were established. These findings provide insights into the biological mechanisms of mtDNA-CN on ASD and underscore the significance of mtDNA copy number as a potential biomarker for Anxiety disorders.
Maternity care professionals’ preparedness for and experiences of screening and responding to disclosures of domestic violence in the peripartum period: a protocol for a qualitative evidence synthesis
Authors: O’Shea Laura , Corbally Melissa , Daly Déirdre 
Published: April 2024

AbstractBackgroundMaternity care professionals, such as midwives, public health nurses, doctors, and social workers, are in the unique position of having regular contact with women in the peripartum period. They are well-placed to recognise and respond to disclosures of domestic violence, however many lack confidence and feel unprepared for this in practice. While there are screening tools used for enquiry about domestic violence in pregnancy, there are variations in the tools used, the frequency and timing of enquiry, and the response/referral pathways across professions. Research exists on the role of health care professionals such as midwives, doctors, and nurses with regards to domestic violence, however little is understood about the collective and shared experience of maternity care professionals who screen for and respond to domestic violence in the peripartum period.MethodsA qualitative evidence synthesis of maternity care professionals’ preparedness for and experiences of screening and responding to disclosures of domestic violence in the peripartum period will be conducted. Qualitative studies of any design, and mixed method and other design studies where qualitative data can be extracted will be considered for inclusion. A systematic search of the following electronic bibliographic databases will be conducted: ASSIA, CINAHL, EMBASE, Maternity and Infant Care, MEDLINE, PsycINFO and SocINDEX. The Critical Skills Appraisal Programme (CASP) qualitative studies tool will be used to assess methodological quality of included studies. Data synthesis will involve three sequential stages, coding, development of descriptive themes and generation of analytical themes. Confidence in findings will be assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) tool.DiscussionThis QES will provide a deeper understanding of maternity care professionals’ preparedness for and experiences of screening and responding to domestic violence disclosures in the peripartum period. The findings will, potentially, identify what aspects of education and preparedness work well and what might be improved.
Prevalence of Dural Puncture headache after caesarean section at a Tertiary Hospital in the Gambia
Authors: Anyanwu Matthew , Coker Admire , Simon Donkor 
Published: April 2024

AbstractBackgroundFollowing a caesarean section performed under spinal anaesthesia, a common complication is post-dural puncture headache (PDPH). Spinal anaesthesia has become the most common anaesthetic procedure during caesarean section in our practice. Therefore, knowing the prevalence and risk factors of PDPH will inform practice and add value in our obstetrics practice.MethodologyA cross-sectional study was conducted at Edward Francis Small Teaching Hospital from July to. September 2023. A structured data collection tool was used to collect data. The data was entered into a computer database and analyzed using the SPSS version 26. Pain was graded using a 10-cm visual analogue scale. Results were expressed in simple descriptive statistics and test of significance was set at p-value 0.05.ResultsA total of 89 participants with mean age of 28 years (SD±6.1) and majority 45(50.6%), between 21 to 30 years. Majority had low parity (0 to 3), 64(71.9%), emergency CS of 71(79.8%), while only 20.2% (n=18) were elective CS. Overall prevalence of Post Dural Puncture Headache (PDPH) was 42.7% with majority of cases presenting with Occipital headache (29.2%), lasting for 3hrs (18%). A statistically significant association between PDPH and Gestational age withp-value (p=0.02); number of attempts withp-value (p=0.01);larger needle gauge and number of CSF drops (p=0.01), respectively were observed.ConclusionPrevalence of PDPH was high and associated with the use of large needle gauges, multiple attempts and increased CSF drops. Patients that underwent emergency CS, have a higher risk of developing Post-Dural Puncture Headache.
Infant spatial relationships with adult males in a wild primate: males as mitigators or magnifiers of intergenerational effects of early adversity?
Authors: Zipple Matthew N , Southworth Chelsea A , Zipple Stefanie P , Archie Elizabeth A , Tung Jenny , Alberts Susan C 
Published: April 2024

AbstractAdult male mammals can provide infants with protection and enhance their access to resources. They can also pose a risk to infants, either directly through infanticide or other aggression, or indirectly by placing infants at increased risk of conspecific or heterospecific conflict. Both benefits and costs may be especially important for offspring born to mothers in poor condition. Here we present the most detailed analysis to date of the influence of adult non-human primate males on a wide range of infant behaviors, and a description of the predictors of individual infants’ proximity to adult males. We show that the number of adult males near an infant predicts many infant behavioral traits, including aspects of the mother-infant relationship, infant activity budgets, and the frequency of social interactions with non-mothers. Infant exposure to adult males is statistically significantly repeatable over time (R = 0.16). This repeatability is partially explained by whether the infant’s mother experienced early life adversity: offspring of high-adversity mothers spent time in close proximity to more males during the first months of life. Our results are consistent with the possibility that the effects of maternal early life adversity can be mitigated or magnified by relationships with adult males.