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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
Insights into pancreatic β cell energy metabolism using rodent β cell models
Background:Mitochondrial diabetes is primarily caused by β-cell failure, but there are gaps in our understanding of pathogenesis.Methods:By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function.Results:Culturing rat insulin-secreting INS-1 cells in low glucose conditions caused a rapid reduction in whole cell respiration, associated with elevated mitochondrial reactive oxygen species production, and an altered glucose-stimulated insulin secretion profile. Prolonged exposure to reduced glucose directly impaired mitochondrial function and reduced autophagy.Conclusions:Insulinoma cell lines provide a useful model of mechanisms affecting β-cell mitochondrial function or studying mitochondrial associated drug toxicity.
Insights into pancreatic β cell energy metabolism using rodent β cell models.
Background: Mitochondrial diabetes is primarily caused by β-cell failure, a cell type whose unique properties are important in pathogenesis. Methods: By reducing glucose, we induced energetic stress in two rodent β-cell models to assess effects on cellular function. Results: Culturing rat insulin-secreting INS-1 cells in low glucose conditions caused a rapid reduction in whole cell respiration, associated with elevated mitochondrial reactive oxygen species production, and an altered glucose-stimulated insulin secretion profile. Prolonged exposure to reduced glucose directly impaired mitochondrial function and reduced autophagy. Conclusions: Insulinoma cell lines have a very different bioenergetic profile to many other cell lines and provide a useful model of mechanisms affecting β-cell mitochondrial function.
A Feasibility Study of the Usefulness of the TEMPS-A Scale in Assessing Affective Temperament in Athletes.
Background and objectives: Current studies show an important role of affective temperament in sport performance. The aim of this study was to assess the feasibility of the use of the TEMPS-A scale, by using it to examine five dimensions of affective temperament in three groups of athletes. We hypothesized that temperament may be a predisposing factor to the level of commitment and type of training. Materials and methods: The study group (N:71, 33 female) consisted of professional canoeists (N:25, aged 18-30), sports pilots (N:21, aged 19-57) and non-professionals regularly performing aerobic exercises (N:25, aged 23-33). The Affective Temperament of Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) was used to evaluate affective temperament dimensions. Statistical analysis was performed using non-parametric tests. Results: The TEMPS_A scale shows good internal consistency; a hyperthymic temperament was associated with different factors compared to other temperament traits. The most prevalent trait in the study group was hyperthymic temperament. The study group scored higher on hyperthymic and lower on depressive and anxious temperaments when compared with the general population. Canoeists scored higher on cyclothymic temperament compared with non-professional athletes and on cyclothymic and irritable dimensions in comparison with pilots. Pilots obtained significantly lower scores on irritable and anxious temperaments than non-professional athletes. Females scored higher on both hyperthymic and irritable dimensions. No significant differences were found in respect of depressive, cyclothymic and anxious traits. Age was negatively correlated with cyclothymic and irritable temperament scores. Conclusions: TEMPS-A scale is a useful tool for assessing affective temperament in athletes. The results suggest that affective temperament may be a factor influencing physical activity engagement. Different types of activities may be connected with different temperament dimensions. Younger athletes present a higher tendency to mood lability and sensitivity to environmental factors. However, further research is needed, involving larger numbers of subjects.
Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic disease characterized by long-lasting persistent debilitating widespread fatigue and post-exertional malaise, remains diagnosed by clinical criteria. Our group and others have identified differentially expressed miRNA profiles in the blood of patients. However, their diagnostic power individually or in combinations seems limited. A Partial Least Squares-Discriminant Analysis (PLS-DA) model initially based on 817 variables: two demographic, 34 blood analytic, 136 PBMC miRNAs, 639 Extracellular Vesicle (EV) miRNAs, and six EV features, selected an optimal number of five components, and a subset of 32 regressors showing statistically significant discriminant power. The presence of four EV-features (size and z-values of EVs prepared with or without proteinase K treatment) among the 32 regressors, suggested that blood vesicles carry relevant disease information. To further explore the features of ME/CFS EVs, we subjected them to Raman micro-spectroscopic analysis, identifying carotenoid peaks as ME/CFS fingerprints, possibly due to erythrocyte deficiencies. Although PLS-DA analysis showed limited capacity of Raman fingerprints for diagnosis (AUC = 0.7067), Raman data served to refine the number of PBMC miRNAs from our previous model still ensuring a perfect classification of subjects (AUC=1). Further investigations to evaluate model performance in extended cohorts of patients, to identify the precise ME/CFS EV components detected by Raman and to reveal their functional significance in the disease are warranted.
An integrated single-cell reference atlas of the human endometrium
Abstract The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal–epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.
Genome-wide analyses identify 25 infertility loci and relationships with reproductive traits across the allele frequency spectrum.
Genome-wide association studies (GWASs) may help inform the etiology of infertility. Here, we perform GWAS meta-analyses across seven cohorts in up to 42,629 cases and 740,619 controls and identify 25 genetic risk loci for male and female infertility. We additionally identify up to 269 genetic loci associated with follicle-stimulating hormone, luteinizing hormone, estradiol and testosterone through sex-specific GWAS meta-analyses (n = 6,095-246,862). Exome sequencing analyses reveal that women carrying testosterone-lowering rare variants in some genes are at risk of infertility. However, we find no local or genome-wide genetic correlation between female infertility and reproductive hormones. While infertility is genetically correlated with endometriosis and polycystic ovary syndrome, we find limited genetic overlap between infertility and obesity. Finally, we show that the evolutionary persistence of infertility-risk alleles may be explained by directional selection. Taken together, we provide a comprehensive view of the genetic determinants of infertility across multiple diagnostic criteria.
What do women and rhinos have in common?
The concept that human reproductive physiology is unique, and little can be learned or benefits gained by studies in other model system or exotic species is woefully out of date. The cross-fertilization that can be gleaned by furthering our knowledge about the basic biology and molecular mechanisms that regulate everyday physiological processes in other species is vast. In this review, I share how studying rhinoceros ovarian physiology, exploring novel culture techniques, and overcoming unexpected challenges that are presented by working with such unique samples has benefitted my program of research that focuses on developing fertility preservation technologies for women — and rhinoceros.
The changing molecular epidemiology of HIV-1 in Liangshan prefecture, China, in 2021-2023.
INTRODUCTION: Liangshan Prefecture is one of the areas in China most severely affected by human immunodeficiency virus (HIV), but little is known about the molecular epidemiology of HIV-1 in this area. We aimed to analyze the distribution of HIV-1 genetic variants in Liangshan Prefecture in recent years. METHODS: 8,523 blood samples were collected from people living with HIV with treatment failure and newly diagnosed individuals in all 17 counties and cities in Liangshan Prefecture between 2021 and 2023. RESULTS: The majority of study participants were male (66%), farmers (78%) and illiterate (53%). The main HIV-1 transmission routes were heterosexual contact (57%) and injecting drug use (27%). Among the 6,298 successfully obtained pol sequences the following HIV-1 variants were identified: CRF07_BC (93.9%), CRF08_BC (3.3%), CRF01_AE (1.4%), URFs (0.9%), CRF105_0108 (0.1%), CRF55_01B (0.1%), subtype B (0.1%), subtype C (0.1%), CRF88_BC (0.1%), CRF83_cpx (0.1%), CRF85_BC (0.03%), CRF67_01B (0.02%), CRF77_cpx (0.02%), and subtype A (0.02%). During the study period, the proportion of CRF07_BC gradually decreased, while other HIV-1 variants increased, a shift seen across all counties in Liangshan Prefecture. Newly diagnosed patients mainly acquired HIV through heterosexual transmission (86.7%), had a lower proportion of CRF07_BC (90.9%) and higher proportion of other HIV-1 variants, compared to treatment failure patients. CONCLUSION: Future prevention and control policies need to take these changes into account.
Prevalence and transmission of HIV-1 drug resistance mutations among patients with treatment failure and newly diagnosed people in Liangshan Prefecture, China, in 2021-2023.
INTRODUCTION: Despite expanded antiretroviral therapy (ART) in China, HIV transmission persists. Liangshan Prefecture is one of the areas in China most severely affected by HIV, with high levels of drug resistance. A deeper understanding of HIV-1 drug resistance can lead to improvements in current treatment policies. METHODS: We conducted an analysis of HIV drug resistance mutations (DRMs) among patients with treatment failure and people newly diagnosed with HIV in Liangshan Prefecture. 8,523 blood samples were collected from people living with HIV with treatment failure and newly diagnosed individuals in all 15 counties and two cities in Liangshan Prefecture between 2021 and 2023. RESULTS: 43.0% of patients with treatment failure acquired HIV through the heterosexual route, followed by injecting drug use (38.7%), while newly diagnosed individuals mainly acquired HIV through the heterosexual route (86.7%). 95.6% of patients with treatment failure were infected with HIV-1 variant CRF07_BC and 2.7% with CRF08_BC, and newly diagnosed individuals were also main infected with HIV-1 variant CRF07_BC (90.9), followed by CRF08_BC (4.0%) and CRF01_AE (2.5%). The overall prevalence of acquired drug resistance (ADR) among patients with treatment failure was 57.4%. The overall prevalence of pre-treatment drug resistance (PDR) among newly diagnosed individuals was 23.9%. A high prevalence of ADR and PDR (especially high-level resistance) to efavirenz (48.0% vs. 11.1%) and nevirapine (49.6% vs. 11.4%) was found. The main non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated ADR and PDR mutations were K103, V106, and V179. Our findings highlight age <18 years, injecting drug use, and initiation on NNRTI-based regimen as independent risk factors for HIV ADR development. We found minor variants as a risk factor for PDR, and CRF01_AE was associated with a higher risk than CRF07_BC for nucleoside reverse transcriptase inhibitor (NRTI) PDR. DISCUSSION: Given the high levels of NNRTI ADR and PDR, future clinical treatment plans should minimize the use of NNRTI-based regimens and should instead adopt alternative ART regimens more frequently.
HIV Nef-mediated CD4 down-regulation is adaptor protein complex 2 dependent.
Nef is a crucial viral protein for HIV to replicate at high titers and in the development of AIDS. One Nef function is down-regulating CD4 from the cell surface, which correlates with Nef-enhanced viral pathogenicity. Nef down-regulates CD4 by linking CD4 to clathrin-coated pits. However, the mechanistic connection between the C-terminal dileucine motif of Nef and the component(s) of the clathrin-coated pits has not been pinpointed. In this report we used two AP-2 complex-specific inhibitors: a dominant negative mutant of Eps15 (Eps15DIII) that binds to the alpha subunit of AP-2 complex and a small interference RNA that is specific for the mu2 subunit of AP-2 complex. We show that both HIV Nef- and SIV Nef-mediated CD4 down-regulations were profoundly blocked by the synergistic effect of Eps15DIII and RNA interference of AP-2 expression. The results demonstrate that HIV/SIV Nef-mediated CD4 down-regulation is AP-2 dependent. We also show that the PMA-induced CD4 down-regulation was blocked by these two inhibitors. Therefore, PMA-induced CD4 down-regulation is also AP-2 dependent. The results demonstrate that, like the tyrosine sorting motif-dependent endocytosis (for which the transferrin receptor and the epidermal growth factor receptor are the two prototypes), dileucine sorting motif-dependent endocytosis of Nef and CD4 are also AP-2 dependent.
An essential role for interleukin 1 and a dual function for interleukin 2 in the immune response of murine B lymphocytes to sheep erythrocytes.
The macrophage-derived lymphokine interleukin 1 (IL-1) and the T cell-derived lymphokine interleukin 2 (IL-2) help B lymphocytes to generate antibodies against sheep erythrocytes in vitro. It has been difficult to determine whether these factors act on antigen-reactive B cells directly or via accessory cells, since it is not technically feasible to prepare completely homogenous cell populations. Therefore we examined the question of lymphokine action on B cells using an indirect approach. First we determined effects of the two factors in the phenotypic differentiation assay, a short-term culture of cloned B cells certainly free of accessory cells. Next, we investigated whether the effects seen in this assay could be related to results obtained in the long-term (four-day) assay of antibody production. Interleukin 1 induced cloned 70Z/3 B lymphocytes to express new cell surface markers in the phenotypic B cell differentiation assay. IL-2 rendered these B cells refractory to differentiation caused by IL-1. In the antibody production assay, IL-1 controlled, as was shown previously, an early phase of the response in which B cells become responsive to T cell-derived helper factors. In order to demonstrate the requirement for IL-1, it was necessary to rigorously prevent endogenous IL-1 production. Synergy between IL-1 and IL-2 was observed when IL-2 was given as late as day 2 of a four-day culture period. This synergy was seen over a broad dose range of IL-2 (10-1,000 U/ml). However, IL-2, when added in high concentrations (200-1,000 U/ml) during the early (IL-1-dependent) phase of the B cell response inhibited antibody production.(ABSTRACT TRUNCATED AT 250 WORDS)
Conditional requirement for accessory cells in the response of T cells to Con A.
The response to Concanavalin A (Con A) of unseparated lymph node cells and of T cells isolated from them has been studied over a mitogen dose range of 0.2 microgram to 16 micrograms/ml. Accessory cell depleted T cells respond only to high doses of Con A and then only weakly. The magnitude (proliferative activity) of the response as well as the sensitivity to the mitogen can be modified by accessory cells (AC), lymphokines and by chemical modification of cell surface glycoproteins. Accessory cell function can be inhibited by antibodies directed against cell surface molecules on accessory cells (Ia) or on T cells (L3T4). Changes in the mitogen sensitivity of the response are not necessarily associated with changes in the magnitude of the response. The mitogen sensitivity can be decreased with anti-Ia antibody and can be increased by treatment with IL-l and/or interferon gamma (IFN-). We postulate that the increase in sensitivity to Con A is a function of the density of cell surface molecules with which T and AC cells interact. The magnitude of the response is primarily determined by the frequency of AC in culture; it decreases as the number of AC is reduced and increases as AC are added to the cultures. Mitogen sensitivity is a new tool for the analysis of nonspecific T cell activation. Our data bring the accessory cell requirement for mitogen activation of T cells into a new perspective: AC--or factors produced by them--are essential when low (1-2 micrograms/ml Con A) doses are used and are less or not at all necessary when high doses (6-10 micrograms/ml) of mitogen are applied.
Enhancement of cytotoxic activity of natural killer cells by interleukin 2, and antagonism between interleukin 2 and adenosine cyclic monophosphate.
Two cytokines, interferon (IFN) and interleukin 2 (IL-2), activate murine natural killer (NK) cells in vitro. Together both factors synergize considerably. Antibody against IFN eliminates the response of NK cells to IFN as well as to IL-2, whereas antibody against IL-2 blocks the effect of IL-2 but not of IFN. These findings as well as previous observations imply that both factors act on the same cell but have different roles. We suggest that IFN induces NK cell activation and IL-2 enhances this effect. Further studies revealed that besides inducing cytotoxicity in NK cells IFN induces the production of prostaglandin E (PGE) which inhibits NK cell activation. We propose therefore that IFN has a dual effect on NK cells: it induces NK cells to become cytotoxic and initiates a negative feedback by increasing the production of PGE. IL-2, which synergizes with IFN in the activation of NK cells, ceases to do so when the negative feedback (PGE-mediated) is blocked with indomethacin. We infer that IL-2 enhances NK cell activity by interfering with the negative feedback rather than by aiding NK cell activation.