Search

Problem To identify plasma immuno-regulatory molecules up or down regulated between the follicular phase and ovulation of the human menstrual cycle. Method of study RayBio® cytokine arrays were used to screen 174 immuno-regulatory molecules in plasma collected during the follicular phase at menstrual cycle day 5 and at ovulation from five healthy, non-smoking, fertile women of reproductive age not using hormonal contraception. Results A total of 23 differentially expressed molecules were found: 10 molecules were differentially up-regulated and 13 down-regulated at ovulation compared with that at the follicular phase (α = 0.05, false discovery rate of 0.45). Conclusion Circulating immuno-regulatory molecules fluctuate over the menstrual cycle in healthy women. The combination of differentially expressed molecules suggests roles in cyclical regulation of angiogenesis and immune cell trafficking. [ABSTRACT FROM AUTHOR]

Pathogens have played a substantial role in human evolution, with past infections shaping genetic variation at loci influencing immune function. We selected 168 genes known to be involved in the immune response, genotyped common single nucleotide polymorphisms across each gene in three population samples (CEPH Europeans from Utah, Han Chinese from Guangxi, and Yoruba Nigerians from Southwest Nigeria) and searched for evidence of selection based on four tests for non-neutral evolution: minor allele frequency (MAF), derived allele frequency (DAF), Fst versus heterozygosity and extended haplotype homozygosity (EHH). Six of the 168 genes show some evidence for non-neutral evolution in this initial screen, with two showing similar signals in independent data from the International HapMap Project. These analyses identify two loci involved in immune function that are candidates for having been subject to evolutionary selection, and highlight a number of analytical challenges in searching for selection in genome-wide polymorphism data. [ABSTRACT FROM AUTHOR]

The C-C chemokine receptor 5, 32 base-pair deletion (CCR5-Δ32) allele confers strong resistance to infection by the AIDS virus HIV. Previous studies have suggested that CCR5-Δ32 arose within the past 1,000 y and rose to its present high frequency (5%-14%) in Europe as a result of strong positive selection, perhaps by such selective agents as the bubonic plague or smallpox during the Middle Ages. This hypothesis was based on several lines of evidence, including the absence of the allele outside of Europe and long-range linkage disequilibrium at the locus. We reevaluated this evidence with the benefit of much denser genetic maps and extensive control data. We find that the pattern of genetic variation at CCR5-Δ32 does not stand out as exceptional relative to other loci across the genome. Moreover using newer genetic maps, we estimated that the CCR5-Δ32 allele is likely to have arisen more than 5,000 y ago. While such results can not rule out the possibility that some selection may have occurred at C-C chemokine receptor 5 (CCR5), they imply that the pattern of genetic variation seen atCCR5-Δ32 is consistent with neutral evolution. More broadly, the results have general implications for the design of future studies to detect the signs of positive selection in the human genome. [ABSTRACT FROM AUTHOR]

Haplotype-based methods offer a powerful approach to disease gene mapping based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease. [ABSTRACT FROM AUTHOR]

The hippocampus is heterogeneous in its architecture. It contributes to cognitive processes such as memory and spatial navigation and is susceptible to neurodegenerative disease. Cytoarchitectural features such as neuron size and neuronal collinearity have been used to parcellate the hippocampal subregions. Moreover, pyramidal neuron orientation (orientation of one individual neuron) and collinearity (how neurons align) have been investigated as a measure of disease in schizophrenia. However, a comprehensive quantitative study of pyramidal neuron orientation and collinearity within the hippocampal subregions has not yet been conducted. In this study, we present a high-throughput deep learning approach for the automated extraction of pyramidal neuron orientation in the hippocampal subregions. Based on the pretrained Cellpose algorithm for cellular segmentation, we measured 479 873 pyramidal neurons in 168 hippocampal partitions. We corrected the neuron orientation estimates to account for the curvature of the hippocampus and generated collinearity measures suitable for inter- and intra-individual comparisons. Our deep learning results were validated with manual orientation assessment. This study presents a quantitative metric of pyramidal neuron collinearity within the hippocampus. It reveals significant differences among the individual hippocampal subregions ( P   < 0.001), with cornu ammonis 3 being the most collinear, followed by cornu ammonis 2, cornu ammonis 1, the medial/uncal subregions and subiculum. Our data establishes pyramidal neuron collinearity as a quantitative parameter for hippocampal subregion segmentation, including the differentiation of cornu ammonis 2 and cornu ammonis 3. This novel deep learning approach could facilitate large-scale multicentric analyses in subregion parcellation and lays groundwork for the investigation of mental illnesses at the cellular level., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Interventions related to the perpetration of Domestic Violence and Abuse (DVA) have gained traction over the past several years, in response to dissatisfaction by victims, an inadequate response from the criminal justice system, increased demand on police time and a lack of rehabilitative responses to the perpetration of domestic abuse. The CARA model is a conditional diversionary caution, offered by police for first time offenders of 'standard' or 'medium risk' domestic abuse, that engages perpetrators in awareness raising workshops and signposts them onto further services. Although quasi-experimental studies have indicated that CARA showed promise at reducing reoffending, the CARA model has yet to be evaluated nationally and there is no qualitative evidence related to understanding or learning about the lived experience of perpetrators and victims as they engage with the intervention., Methods: Using a concurrent pragmatic mixed methods design model we will undertake a national evaluation of CARA by triangulating quantitative data from up to nine police forces, and routine data from service providers, with qualitative data from workshop participants, victims and professional stakeholders to: (1) understand the long-term impact of CARA implementation on DVA reoffending and engagement with services and (2) explore perceptions and experiences of both delivery and receipt of CARA. We will use qualitative methodologies that draw on interpretivist and phenomenological perspectives, as well as quantitative methodologies using interrupted time series models, Poisson regression models, Geo mapping and a cost benefits analysis., Ethics and Dissemination: Where currently the CARA model is being introduced as a national option for standard risk first-time offending, we will engage with policymakers and academics nationally in the live debate on its effectiveness and suitability during its roll-out. Ethical approval was approved by the University of Southampton on the 1 st June 2022 (Ref: ERGO ID: 71818.A1)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Morgan SA et al.)

Hippocampal subregions differ in specialization and vulnerability to cell death. Neuron death and hippocampal atrophy have been a marker for the progression of Alzheimer's disease. Relatively few studies have examined neuronal loss in the human brain using stereology. We characterize an automated high-throughput deep learning pipeline to segment hippocampal pyramidal neurons, generate pyramidal neuron estimates within the human hippocampal subfields, and relate our results to stereology neuron counts. Based on seven cases and 168 partitions, we vet deep learning parameters to segment hippocampal pyramidal neurons from the background using the open-source CellPose algorithm, and show the automated removal of false-positive segmentations. There was no difference in Dice scores between neurons segmented by the deep learning pipeline and manual segmentations (Independent Samples t-Test: t(28) = 0.33, p = 0.742). Deep-learning neuron estimates strongly correlate with manual stereological counts per subregion (Spearman's correlation (n = 9): r(7) = 0.97, p < 0.001), and for each partition individually (Spearman's correlation (n = 168): r(166) = 0.90, p <0 .001). The high-throughput deep-learning pipeline provides validation to existing standards. This deep learning approach may benefit future studies in tracking baseline and resilient healthy aging to the earliest disease progression., (© 2023. The Author(s).)

One in five children in the UK are affected by domestic violence and abuse. However, primary care clinicians (GPs and nurses) struggle to effectively identify and support children and young people living in homes where it is present. The IRIS+ (Enhanced Identification and Referral to Improve Safety) training and advocacy support intervention aimed to improve how clinicians respond to children and young people affected by domestic violence and abuse. IRIS+ training was delivered as part of a feasibility study to four general practices in an urban area in England (UK). Our mixed method design included interviews and questionnaires about the IRIS+ intervention with general practice patients, including children and young people as well as with clinicians and advocacy service providers. We collected the number of identifications and referrals by clinicians of children experiencing domestic violence and abuse through a retrospective search of medical and agency records 10 months after the intervention. Forty-nine children exposed to domestic violence and abuse were recorded in medical records. Thirty-five children were referred to a specialist domestic violence and abuse support service over a period of 10 months. Of these, 22 received direct or indirect support. The qualitative findings indicated that children benefitted from being referred by clinicians to the service. However, several barriers at the patient and professional level prevented children and young people from being identified and supported. Some of these barriers can be addressed through modifications to professional training and guidance, but others require systematic and structural changes to the way health and social care services work with children affected by domestic violence and abuse., (© 2021 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

The lateralized ERP N2pc component has been shown to be an effective marker of attentional object selection when elicited in a visual search task, specifically reflecting the selection of a target item among distractors. Moreover, when targets are known in advance, the visual search process is guided by representations of target features held in working memory at the time of search, thus guiding attention to objects with target-matching features. Previous studies have shown that manipulating working memory availability via concurrent tasks or within task manipulations influences visual search performance and the N2pc. Other studies have indicated that visual (non-spatial) vs. spatial working memory manipulations have differential contributions to visual search. To investigate this the current study assesses participants' visual and spatial working memory ability independent of the visual search task to determine whether such individual differences in working memory affect task performance and the N2pc. Participants ( n = 205) completed a visual search task to elicit the N2pc and separate visual working memory (VWM) and spatial working memory (SPWM) assessments. Greater SPWM, but not VWM, ability is correlated with and predicts higher visual search accuracy and greater N2pc amplitudes. Neither VWM nor SPWM was related to N2pc latency. These results provide additional support to prior behavioral and neural visual search findings that spatial WM availability, whether as an ability of the participant's processing system or based on task demands, plays an important role in efficient visual search., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Couperus, Lydic, Hollis, Roy, Lowe, Bukach and Reed.)

Background: Primary care needs to respond effectively to patients experiencing or perpetrating domestic violence and abuse (DVA) and their children, but there is uncertainty about the value of integrated programmes. The aim of the study was to develop and test the feasibility of an integrated primary care system-level training and support intervention, called IRIS+ (Enhanced Identification and Referral to Improve Safety), for all patients affected by DVA. IRIS+ was an adaptation of the original IRIS (Identification and Referral to Improve Safety) model designed to reach female survivors of DVA., Methods: Observation of training; pre/post intervention questionnaires with clinicians and patients; data extracted from medical records and DVA agency; semi-structured interviews with clinicians, service providers and referred adults and children. Data collection took place between May 2017 and April 2018. Mixed method analysis was undertaken to triangulate data from various sources to assess the feasibility and acceptability of the intervention., Results: Clinicians and service providers believed that the IRIS+ intervention had filled a service gap and was a valuable resource in identifying and referring women, men and children affected by DVA. Despite increased levels of preparedness reported by clinicians after training in managing the complexity of DVA in their practice, the intervention proved to be insufficient to catalyse identification and specialist referral of men and direct identification and referral (without their non-abusive parents) of children and young people. The study also revealed that reports provided to general practice by other agencies are important sources of information about adult and children patients affected by DVA. However, in the absence of guidance about how to use this information in patient care, there are uncertainties and variation in practice., Conclusions: The study demonstrates that the IRIS+ intervention is not feasible in the form and timeframe we evaluated. Further adaptation is required to achieve identification and referral of men and children in primary care: an enhanced focus on engagement with men, direct engagement with children, and improved guidance and training on responding to reports of DVA received from other agencies.

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid abundant in fish oil that exerts a wide spectrum of documented beneficial health effects in humans. Because dietary interventions are relatively inexpensive and are widely assumed to be safe, they have broad public appeal. Their endorsement can potentially have a major impact on human health, but hard mechanistic evidence that specifies how these derivatives work at the cellular level is limited. EPA (50 microM) caused a small elevation of cytoplasmic Ca(2+) concentration ([Ca(2+)]) in intact NCM460 human colonic epithelial cells as measured by fura 2 and a profound drop of [Ca(2+)] within the endoplasmic reticulum (ER) of permeabilized cells as monitored by compartmentalized mag-fura 2. Total internal reflection fluorescence microscopy showed that this loss of ER store [Ca(2+)] led to translocation of the ER-resident transmembrane Ca(2+) sensor STIM1. Using sensitive FRET-based sensors for cAMP in single cells, we further found that EPA caused a substantial increase in cellular cAMP concentration, a large fraction of which was dependent on the drop in ER [Ca(2+)], but independent of cytosolic Ca(2+). An additional component of the EPA-induced cAMP signal was sensitive to the phosphodiesterase inhibitor isobutyl methylxanthine. We conclude that EPA slowly releases ER Ca(2+) stores, resulting in the generation of cAMP. The elevated cAMP is apparently independent of classical G protein-coupled receptor activation and is likely the consequence of a newly described "store-operated" cAMP signaling pathway that is mediated by STIM1.

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

Purpose: To determine whether the waiting trade-off (WTO) is feasible for differentiating short-term biopsy preferences in an acute situation where anxiety is the symptomatic disease state., Methods: 75 women with past experience of either breast core-needle biopsy (CNB), more invasive excisional surgical biopsy (EXB), or both, had telephone WTO assessments. Patients' baseline and test-related anxiety were valued by time trade-off (TTO) used to scale the WTO. Rating scales (RS) were obtained for convergent validity assessment with WTO and TTO., Results: Data were obtained in 38 women who had both CNB and EXB ("paired") and 20 who had CNB only and 16 who had EXB only ("unpaired"). Patients rated only the procedure(s) they experienced. Median paired and mean unpaired WTO scores indicated patients were willing to wait significantly longer to avoid EXB (P = 0.0003, P = 0.0002, respectively). The waiting time difference between EXB and CNB was 2.1 weeks greater in unpaired data than paired data. RS scores comparing the procedures were significantly different only for paired data (P < 0.05). Median TTO preferences for baseline (1.00) and test anxiety (0.93) obtained in 74 patients were significantly different (P < 0.0001) and consistent with RS. Correlation was noted between WTO and RS (-0.307 to -0.453, P = 0.0205 to 0.0001). The median EXB quality-adjusted life years toll (1.5 quality-adjusted life days) calculated from pooled WTO data (paired and unpaired) from 54 patients is near a threshold in a published model., Conclusion: The WTO is feasible for discriminating preferences for short-term health states in an acute medical scenario where it might have been expected to be impracticable.