ResearchPad - reproductive-system https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Pathological and genetic aspects of spontaneous mammary gland tumor in <i>Tupaia belangeri</i> (tree shrew)]]> https://www.researchpad.co/article/elastic_article_15738 Mammary gland cancer is the most common cancer occurring in women globally. Incidences of this cancer in Japan are on the increase. Annually, more than 70,000 new cases are recorded in Japan and about 1.7 million in the world. Many cases are still difficult to cure completely, and animal models are required for the characterization of the biology, therapeutic strategy, and preventive measures for spontaneous mammary tumor. The mouse model used currently has some limitations owing to structural differences between mouse and human mammary glands. Tupaia belangeri (tree shrew), which belongs to the Tupaiidae family, shows relatively high genetic homology and structural similarity to human mammary glands. Here, we characterized the spontaneous mammary tumors in 61 female tree shrews of different ages. The incidence rate was 24.6% (15/61), and the rate of simultaneous or metachronous multiplex tumors was 60% (9/15). From the incidence pattern, some cases seemed to be of familial mammary gland tumor, as the offspring of female tree shrews No. 3 and 9 and male tree shrew No. 11 showed a high incidence rate, of 73.3% (11/15). Average incidence age for tumor development was 2 years and 3 months, and the earliest was 10 months. Histochemical analysis indicated that spontaneous mammary gland tumors in the tree shrew show the features of intraductal papillary adenomas (22 cases), except 2 tubulopapillary carcinoma cases (No. 75 and 131). All the cases were positive for the progesterone receptor, whereas 91.3% were positive for the estrogen receptor, and 4.3% were HER-2 positive. We have also confirmed the expression of nectin-4 in some mammary tumor cells. Additionally, we subjected tree shrews to cytodiagnosis or X-ray CT. Thus, the findings of this study highlight the potential of the tree shrew as a valuable new animal model for mammary gland tumor study.

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<![CDATA[Sexual norms and the intention to use healthcare services related to female genital cutting: A qualitative study among Somali and Sudanese women in Norway]]> https://www.researchpad.co/article/elastic_article_15732 Female Genital Cutting (FGC) is a traditionally meaningful practice in Africa, the Middle East, and Asia. It is associated with a high risk of long-term physical and psychosexual health problems. Girls and women with FGC-related health problems need specialized healthcare services such as psychosexual counseling, deinfibulation, and clitoral reconstruction. Moreover, the need for psychosexual counseling increases in countries of immigration where FGC is not accepted and possibly stigmatized. In these countries, the practice loses its cultural meaning and girls and women with FGC are more likely to report psychosexual problems. In Norway, a country of immigration, psychosexual counseling is lacking. To decide whether to provide this and/or other services, it is important to explore the intention of the target population to use FGC-related healthcare services. That is as deinfibulation, an already available service, is underutilized. In this article, we explore whether girls and women with FGC intend to use FGC-related healthcare services, regardless of their availability in Norway.MethodsWe conducted 61 in-depth interviews with 26 Somali and Sudanese participants with FGC in Norway. We then validated our findings in three focus group discussions with additional 17 participants.FindingsWe found that most of our participants were positive towards psychosexual counseling and would use it if available. We also identified four cultural scenarios with different sets of sexual norms that centered on getting and/or staying married, and which largely influenced the participants’ intention to use FGC-related services. These cultural scenarios are the virgin, the passive-, the conditioned active-, and the equal- sexual partner scenarios. Participants with negative attitudes towards the use of almost all of the FGC-related healthcare services were influenced by a set of norms pertaining to virginity and passive sexual behavior. In contrast, participants with positive attitudes towards the use of all of these same services were influenced by another set of norms pertaining to sexual and gender equality. On the other hand, participants with positive attitudes towards the use of services that can help to improve their marital sexual lives, yet negative towards the use of premarital services were influenced by a third set of norms that combined norms from the two aforementioned sets of norms.ConclusionThe intention to use FGC-related healthcare services varies between and within the different ethnic groups. Moreover, the same girl or woman can have different attitudes towards the use of the different FGC-related healthcare services or even towards the same services at the different stages of her life. These insights could prove valuable for Norwegian and other policy-makers and healthcare professionals during the planning and/or delivery of FGC-related healthcare services. ]]> <![CDATA[Deletion of inositol polyphosphate 4-phosphatase type-II B affects spermatogenesis in mice]]> https://www.researchpad.co/article/elastic_article_14722 Inositol polyphosphate-4-phosphatase type II (INPP4B) is a dual-specificity phosphatase that acts as a tumor suppressor in multiple cancers. INPP4B dephosphorylates phospholipids at the 4th position of the inositol ring and inhibits AKT and PKC signaling by hydrolyzing of PI(3,4)P2 and PI(4,5)P2, respectively. INPP4B protein phosphatase targets include phospho-tyrosines on Akt and phospho-serine and phospho-threonine on PTEN. INPP4B is highly expressed in testes, suggesting its role in testes development and physiology. The objective of this study was to determine whether Inpp4b deletion impacts testicular function in mice. In testis, Inpp4b expression was the highest in postmeiotic germ cells in both mice and men. The testes of Inpp4b knockout male mice were significantly smaller compared to the testes of wild-type (WT) males. Inpp4b-/- males produced fewer mature sperm cells compared to WT, and this difference increased with age and high fat diet (HFD). Reduction in early steroidogenic enzymes and luteinizing hormone (LH) receptor gene expression was detected, although androgen receptor (AR) protein level was similar in WT and Inpp4b-/- testes. Germ cell apoptosis was significantly increased in the knockout mice, while expression of meiotic marker γH2A.X was decreased. Our data demonstrate that INPP4B plays a role in maintenance of male germ cell differentiation and protects testis functions against deleterious effects of aging and high fat diet.

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<![CDATA[Regional variation of hysterectomy for benign uterine diseases in Switzerland]]> https://www.researchpad.co/article/elastic_article_14622 Hysterectomy is the last treatment option for benign uterine diseases, and vaginal hysterectomy is preferred over more invasive techniques. We assessed the regional variation in hysterectomy rates for benign uterine diseases across Switzerland and explored potential determinants of variation.MethodsWe conducted a population-based analysis using patient discharge data from all Swiss hospitals between 2013 and 2016. Hospital service areas (HSAs) for hysterectomies were derived by analyzing patient flows. We calculated age-standardized mean procedure rates and measures of regional variation (extremal quotient [EQ], highest divided by lowest rate) and systematic component of variation [SCV]). We estimated the reduction in the variance of crude hysterectomy rates across HSAs in multilevel regression models, with incremental adjustment for procedure year, age, cultural/socioeconomic factors, burden of disease, and density of gynecologists.ResultsOverall, 40,211 hysterectomies from 54 HSAs were analyzed. The mean age-standardized hysterectomy rate was 298/100,000 women (range 186–456). While the variation in overall procedure rate was moderate (EQ 2.5, SCV 3.7), we found a very high procedure-specific variation (EQ vaginal 5.0, laparoscopic 6.3, abdominal 8.0; SCV vaginal 17.5, laparoscopic 11.2, abdominal 16.9). Adjusted for procedure year, demographic, cultural, and sociodemographic factors, a large share (64%) of the variance remained unexplained (vaginal 63%, laparoscopic 85%, abdominal 70%). The main determinants of variation were socioeconomic/cultural factors. Burden of disease and the density of gynecologists was not associated with procedure rates.ConclusionsSwitzerland has a very high regional variation in vaginal, laparoscopic, and abdominal hysterectomy for benign uterine disease. After adjustment for potential determinants of variation including demographic factors, socioeconomic and cultural factors, burden of disease, and the density of gynecologists, two thirds of the variation remain unexplained. ]]> <![CDATA[Prevalence of endosalpingiosis and other benign gynecologic lesions]]> https://www.researchpad.co/article/elastic_article_14492 Endosalpingiosis, traditionally regarded as an incidental pathological finding, was recently reported to have an association with gynecologic malignancies. To determine the prevalence of endosalpingiosis, we evaluated all benign appearing adnexal lesions using the Sectioning and Extensively Examining-Fimbria (SEE-Fim) protocol, and queried the pathology database for the presence of endosalpingiosis, gynecologic malignancy, endometriosis, Walthard nests, and paratubal cysts. Using the SEE-Fim protocol, the prevalence of endosalpingiosis, endometriosis, Walthard nests, and paratubal cysts were 22%, 45%, 33%, and 42% respectively, substantially higher than previously reported. All lesions were observed to increase with age except endometriosis which increased until menopause then decreased dramatically. Among specimens including ovarian tissue, the prevalence of implantation of at least one lesion type was ubiquitous in patients age 51 and older (93%). The clinical significance of endosalpingiosis should be a continued area of research with larger trials assessing prevalence, factors affecting incidence, and association with malignancy. Our findings contribute to elucidating the origin of ectopic lesions and gynecologic disease risk.

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<![CDATA[Placental transfer of Letermovir &amp; Maribavir in the <i>ex vivo</i> human cotyledon perfusion model. New perspectives for <i>in utero</i> treatment of congenital cytomegalovirus infection]]> https://www.researchpad.co/article/elastic_article_11236 Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment.MethodsThe objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)).ResultsFor LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively.ConclusionsDrugs’ concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules. ]]> <![CDATA[SYGL-1 and LST-1 link niche signaling to PUF RNA repression for stem cell maintenance in Caenorhabditis elegans]]> https://www.researchpad.co/article/5ab4e873463d7e0cbd0422dd

Central questions in regenerative biology include how stem cells are maintained and how they transition from self-renewal to differentiation. Germline stem cells (GSCs) in Caeno-rhabditis elegans provide a tractable in vivo model to address these questions. In this system, Notch signaling and PUF RNA binding proteins, FBF-1 and FBF-2 (collectively FBF), maintain a pool of GSCs in a naïve state. An open question has been how Notch signaling modulates FBF activity to promote stem cell self-renewal. Here we report that two Notch targets, SYGL-1 and LST-1, link niche signaling to FBF. We find that SYGL-1 and LST-1 proteins are cytoplasmic and normally restricted to the GSC pool region. Increasing the distribution of SYGL-1 expands the pool correspondingly, and vast overexpression of either SYGL-1 or LST-1 generates a germline tumor. Thus, SYGL-1 and LST-1 are each sufficient to drive “stemness” and their spatial restriction prevents tumor formation. Importantly, SYGL-1 and LST-1 can only drive tumor formation when FBF is present. Moreover, both proteins interact physically with FBF, and both are required to repress a signature FBF mRNA target. Together, our results support a model in which SYGL-1 and LST-1 form a repressive complex with FBF that is crucial for stem cell maintenance. We further propose that progression from a naïve stem cell state to a state primed for differentiation relies on loss of SYGL-1 and LST-1, which in turn relieves FBF target RNAs from repression. Broadly, our results provide new insights into the link between niche signaling and a downstream RNA regulatory network and how this circuitry governs the balance between self-renewal and differentiation.

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<![CDATA[Deep learning assessment of breast terminal duct lobular unit involution: Towards automated prediction of breast cancer risk]]> https://www.researchpad.co/article/N8ae86a5e-90c1-41b1-ba31-58a5a939e3bc

Terminal duct lobular unit (TDLU) involution is the regression of milk-producing structures in the breast. Women with less TDLU involution are more likely to develop breast cancer. A major bottleneck in studying TDLU involution in large cohort studies is the need for labor-intensive manual assessment of TDLUs. We developed a computational pathology solution to automatically capture TDLU involution measures. Whole slide images (WSIs) of benign breast biopsies were obtained from the Nurses’ Health Study. A set of 92 WSIs was annotated for acini, TDLUs and adipose tissue to train deep convolutional neural network (CNN) models for detection of acini, and segmentation of TDLUs and adipose tissue. These networks were integrated into a single computational method to capture TDLU involution measures including number of TDLUs per tissue area, median TDLU span and median number of acini per TDLU. We validated our method on 40 additional WSIs by comparing with manually acquired measures. Our CNN models detected acini with an F1 score of 0.73±0.07, and segmented TDLUs and adipose tissue with Dice scores of 0.84±0.13 and 0.87±0.04, respectively. The inter-observer ICC scores for manual assessments on 40 WSIs of number of TDLUs per tissue area, median TDLU span, and median acini count per TDLU were 0.71, 0.81 and 0.73, respectively. Intra-observer reliability was evaluated on 10/40 WSIs with ICC scores of >0.8. Inter-observer ICC scores between automated results and the mean of the two observers were: 0.80 for number of TDLUs per tissue area, 0.57 for median TDLU span, and 0.80 for median acini count per TDLU. TDLU involution measures evaluated by manual and automated assessment were inversely associated with age and menopausal status. We developed a computational pathology method to measure TDLU involution. This technology eliminates the labor-intensiveness and subjectivity of manual TDLU assessment, and can be applied to future breast cancer risk studies.

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<![CDATA[Towards a fully automated surveillance of well-being status in laboratory mice using deep learning: Starting with facial expression analysis]]> https://www.researchpad.co/article/N201121b9-bfe0-423d-91d1-e349ea424365

Assessing the well-being of an animal is hindered by the limitations of efficient communication between humans and animals. Instead of direct communication, a variety of parameters are employed to evaluate the well-being of an animal. Especially in the field of biomedical research, scientifically sound tools to assess pain, suffering, and distress for experimental animals are highly demanded due to ethical and legal reasons. For mice, the most commonly used laboratory animals, a valuable tool is the Mouse Grimace Scale (MGS), a coding system for facial expressions of pain in mice. We aim to develop a fully automated system for the surveillance of post-surgical and post-anesthetic effects in mice. Our work introduces a semi-automated pipeline as a first step towards this goal. A new data set of images of black-furred laboratory mice that were moving freely is used and provided. Images were obtained after anesthesia (with isoflurane or ketamine/xylazine combination) and surgery (castration). We deploy two pre-trained state of the art deep convolutional neural network (CNN) architectures (ResNet50 and InceptionV3) and compare to a third CNN architecture without pre-training. Depending on the particular treatment, we achieve an accuracy of up to 99% for the recognition of the absence or presence of post-surgical and/or post-anesthetic effects on the facial expression.

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<![CDATA[The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study]]> https://www.researchpad.co/article/N6fc22072-15f3-4c64-b34f-34474f5cf931

The new type of pneumonia caused by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) has been declared as a global public health concern by WHO. As of April 3, 2020, more than 1,000,000 human infections have been diagnosed around the world, which exhibited apparent person-to-person transmission characteristics of this virus. The capacity of vertical transmission in SARS-CoV-2 remains controversial recently. Angiotensin-converting enzyme 2 (ACE2) is now confirmed as the receptor of SARS-CoV-2 and plays essential roles in human infection and transmission. In present study, we collected the online available single-cell RNA sequencing (scRNA-seq) data to evaluate the cell specific expression of ACE2 in maternal-fetal interface as well as in multiple fetal organs. Our results revealed that ACE2 was highly expressed in maternal-fetal interface cells including stromal cells and perivascular cells of decidua, and cytotrophoblast and syncytiotrophoblast in placenta. Meanwhile, ACE2 was also expressed in specific cell types of human fetal heart, liver and lung, but not in kidney. And in a study containing series fetal and post-natal mouse lung, we observed ACE2 was dynamically changed over the time, and ACE2 was extremely high in neonatal mice at post-natal day 1~3. In summary, this study revealed that the SARS-CoV-2 receptor was widely spread in specific cell types of maternal-fetal interface and fetal organs. And thus, both the vertical transmission and the placenta dysfunction/abortion caused by SARS-CoV-2 need to be further carefully investigated in clinical practice.

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<![CDATA[Reproductive life-history strategies in a species-rich assemblage of Amazonian electric fishes]]> https://www.researchpad.co/article/N810c6abb-a507-4d5b-89ae-f4ccddeb69e1

The reproductive biology of only a small fraction of Neotropical freshwater fishes has been described, and detailed comparative studies of reproductive life-history variation in the Neotropical ichthyofauna are lacking. Here we describe interspecific variation in reproductive life history for a multi-species assemblage of the electric knifefish genus Brachyhypopomus (Hypopomidae: Gymnotiformes: Ostariophysi) from Amazonian floodplain and terra firme stream systems. During a year-round quantitative sampling program, we collected and measured key life-history traits from 3,410 individuals. Based on oocyte size distributions, and on circannual variation in gonadosomatic indices, hepatosomatic indices, and capture-per-unit-effort abundance of reproductive adults, we concluded that all species exhibit a single protracted annual breeding season during which females spawn fractionally. We found small clusters of post-larval individuals in one floodplain species and one terra firme stream species, but no signs of parental care. From analyses of body size-frequency distributions and otolith growth increments, we concluded that five species in our study area have approximately one-year (annual) semelparous life history with a single reproductive period followed by death, while two species have a two-year iteroparous life history, with breeding in both year-groups. Despite predictions from life-history theory we found no salient correlations between life history strategy (semelparity or iteroparity) and habitat occupancy (floodplain or terra firme stream). In the iteroparous species B. beebei, we documented evidence for reproductive restraint in the first breeding season relative to the second breeding season and argue that this is consistent with age-regulated terminal investment.

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<![CDATA[Drosophila melanogaster tPlus3a and tPlus3b ensure full male fertility by regulating transcription of Y-chromosomal, seminal fluid, and heat shock genes]]> https://www.researchpad.co/article/5c8accf0d5eed0c48499037d

Spermatogenesis in Drosophila melanogaster is characterized by a specific transcriptional program during the spermatocyte stage. Transcription of thousands of genes is regulated by the interaction of several proteins or complexes, including a tTAF-containing TFIID variant, tMAC, Mediator, and chromatin interactors, e.g., bromodomain proteins. We addressed how distinct subsets of target genes are selected. We characterized the highly similar proteins tPlus3a and tPlus3b, which contain a Plus3 domain and are enriched in the testis, mainly in spermatocytes. In tPlus3a and tplus3b deletion mutants generated using the CRISPR/Cas9 system, fertility was severely reduced and sperm showed defects during individualization. tPlus3a and tPlus3b heterodimerized with the bromodomain protein tBRD-1. To elucidate the role of the tPlus3a and tPlus3b proteins in transcriptional regulation, we determined the transcriptomes of tplus3a-tplus3b and tbrd-1 deletion mutants using next-generation sequencing (RNA-seq) and compared them to that of the wild-type. tPlus3a and tPlus3b positively or negatively regulated the expression of nearly 400 genes; tBRD-1 regulated 1,500 genes. Nearly 200 genes were regulated by both tPlus3a and tPlus3b and tBRD-1. tPlus3a and tPlus3b activated the Y-chromosomal genes kl-3 and kl-5, which indicates that tPlus3a and tPlus3b proteins are required for the function of distinct classes of genes. tPlus3a and tPlus3b and tBRD-1 repress genes relevant for seminal fluid and heat shock. We hypothesize that tPlus3a and tPlus3b proteins are required to specify the general transcriptional program in spermatocytes.

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<![CDATA[Characterization of an intratracheal aerosol challenge model of Brucella melitensis in guinea pigs]]> https://www.researchpad.co/article/5c8823ccd5eed0c48463903c

B. melitensis is considered the most virulent of the Brucella species, and a need exists for an improved laboratory animal model of infection that mimics natural transmission and disease. Guinea pigs are highly susceptible to infection with Brucella spp. and develop a disease syndrome that mimics natural disease after aerosol inoculation. Intratracheal inoculation is a targeted means of generating aerosols that offer advantages over aerosol chamber delivery. To establish this delivery method, female, Hartley guinea pigs were infected via intratracheal inoculation with PBS or 16M B. melitensis at low dose (101 to 103) or high dose (106 to 108) and monitored for 30 days for signs of disease. Guinea pigs in the high dose groups developed fever between 12–17 days post-inoculation. Bacteria were recovered from the spleen, liver, lymph nodes, lung, and uterus at 30-days post-inoculation and demonstrated dose dependent mean increases in colonization and pathologic changes consistent with human brucellosis. To study the kinetics of extrapulmonary dissemination, guinea pigs were inoculated with 107 CFU and euthanized at 2-hours post inoculation and at weekly intervals for 3 weeks. 5.8x105 to 4.2x106 CFU were recovered from the lung 2 hours post-inoculation indicating intratracheal inoculation is an efficient means of infecting guinea pigs. Starting at 1-week post inoculation bacteria were recovered from the aforementioned organs with time dependent mean increases in colonization. This data demonstrates that guinea pigs develop a disease syndrome that models the human manifestation of brucellosis, which makes the guinea pig a valuable model for pathogenesis studies.

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<![CDATA[A DNA repair protein and histone methyltransferase interact to promote genome stability in the Caenorhabditis elegans germ line]]> https://www.researchpad.co/article/5c79a3e8d5eed0c4841d1c27

Histone modifications regulate gene expression and chromosomal events, yet how histone-modifying enzymes are targeted is poorly understood. Here we report that a conserved DNA repair protein, SMRC-1, associates with MET-2, the C. elegans histone methyltransferase responsible for H3K9me1 and me2 deposition. We used molecular, genetic, and biochemical methods to investigate the biological role of SMRC-1 and to explore its relationship with MET-2. SMRC-1, like its mammalian ortholog SMARCAL1, provides protection from DNA replication stress. SMRC-1 limits accumulation of DNA damage and promotes germline and embryonic viability. MET-2 and SMRC-1 localize to mitotic and meiotic germline nuclei, and SMRC-1 promotes an increase in MET-2 abundance in mitotic germline nuclei upon replication stress. In the absence of SMRC-1, germline H3K9me2 generally decreases after multiple generations at high culture temperature. Genetic data are consistent with MET-2 and SMRC-1 functioning together to limit replication stress in the germ line and in parallel to promote other germline processes. We hypothesize that loss of SMRC-1 activity causes chronic replication stress, in part because of insufficient recruitment of MET-2 to nuclei.

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<![CDATA[FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele]]> https://www.researchpad.co/article/5c89776ad5eed0c4847d2c3f

FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4–16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage.

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<![CDATA[Heterochrony of puberty in the European badger (Meles meles) can be explained by growth rate and group-size: Evidence for two endocrinological phenotypes]]> https://www.researchpad.co/article/5c897769d5eed0c4847d2c1b

Puberty is a key stage in mammalian ontogeny, involving endocrinological, physiological and behavioural changes, moderated by intrinsic and extrinsic factors. Thus, not all individuals within one population achieve sexual maturity simultaneously. Here, using the European badger (Meles meles) as a model, we describe male testosterone and female oestrone profiles (using Enzyme-immunoassays) from first capture (3 months, post-weaning) until 28 months (attaining sexual maturity and final body size), along with metrics of somatic growth, scent gland development and maturation of external reproductive organs as well as intra-specific competition. In both sexes, endocrinological puberty commenced at ca. 11 months. Thereafter, cub hormone levels followed adult seasonal hormone patterns but at lower levels, with the majority of cubs reaching sexual maturity during their second mating season (22–28 months). Interestingly, there was evidence for two endocrinological phenotypes among male cubs (less evident in females), with early developers reaching sexual maturity at 11 months (first mating season) and late developers reaching sexual maturity at 22–26 months (second mating season). Early developers also attained a greater proportion of their ultimate adult size by 11 months, exhibiting faster growth rates than late developers (despite having similar adult size). Male cubs born into larger social groups tended to follow the late developer phenotype. Our results support the hypothesis that a minimum body size is required to reach sexual maturity, which may be achieved at different ages, even within a single population, where early maturity can confer individual fitness advantages and enhance population growth rate.

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<![CDATA[Integrated structural variation and point mutation signatures in cancer genomes using correlated topic models]]> https://www.researchpad.co/article/5c99020ad5eed0c484b97533

Mutation signatures in cancer genomes reflect endogenous and exogenous mutational processes, offering insights into tumour etiology, features for prognostic and biologic stratification and vulnerabilities to be exploited therapeutically. We present a novel machine learning formalism for improved signature inference, based on multi-modal correlated topic models (MMCTM) which can at once infer signatures from both single nucleotide and structural variation counts derived from cancer genome sequencing data. We exemplify the utility of our approach on two hormone driven, DNA repair deficient cancers: breast and ovary (n = 755 samples total). We show how introducing correlated structure both within and between modes of mutation can increase accuracy of signature discovery, particularly in the context of sparse data. Our study emphasizes the importance of integrating multiple mutation modes for signature discovery and patient stratification, and provides a statistical modeling framework to incorporate additional features of interest for future studies.

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<![CDATA[The role of embryo contact and focal adhesions during maternal recognition of pregnancy]]> https://www.researchpad.co/article/5c8823f5d5eed0c484639429

Maternal recognition of pregnancy (MRP) in the mare is an unknown process. In a non-pregnant mare on day 14 post-ovulation (PO), prostaglandin F (PGF) is secreted by the endometrium causing regression of the corpus luteum. Prior to day 14, MRP must occur in order to attenuate secretion of PGF. The embryo is mobile throughout the uterus due to uterine contractions from day of entry to day 14. It is unknown what signaling is occurring. Literature stated that infusing oil or placing a glass marble into the equine uterus prolongs luteal lifespan and that in non-pregnant mares, serum exosomes contain miRNA that are targeting the focal adhesion (FA) pathway. The hypothesis of this study is embryo contact with endometrium causes a change in abundance of focal adhesion molecules (FA) in the endometrium leading to decrease in PGF secretion. Mares (n = 3/day) were utilized in a cross-over design with each mare serving as a pregnant and non-pregnant (non-mated) control on days 9 and 11 PO. Mares were randomly assigned to collection day and endometrial samples and embryos were collected on the specified day. Biopsy samples were divided into five pieces, four for culture for 24 hours and one immediately snap frozen. Endometrial biopsies for culture were placed in an incubator with one of four treatments: [1] an embryo in contact on the luminal side of the endometrium, [2] beads in contact on the luminal side of the endometrium, [3] peanut oil in contact on the luminal side of the endometrium or [4] the endometrium by itself. Biopsies and culture medium were frozen for further analysis. RNA and protein were isolated from biopsies for PCR and Western blot analysis for FA. PGF assays were performed on culture medium to determine concentration of PGF. Statistics were performed using SAS (P ≤ 0.05 indicated significance). The presence of beads on day 9 impacted samples from pregnant mares more than non-pregnant mares and had very little impact on day 11. Presence of oil decreased FA in samples from pregnant mares on day 9. On day 11, oil decreased FA abundance in samples from non-pregnant mares. Embryo contact caused multiple changes in RNA and protein abundance in endometrium from both pregnant and non-pregnant mares. The PGF secretion after 24 hours with each treatment was also determined. On day 9, there was no change in PGF secretion compared to any treatments. On day 11, presence of peanut oil increased PGF secretion in samples from non-pregnant mares. In samples from non-pregnant mares, presence of an embryo decreased PGF secretion compared to control samples from non-pregnant mares. Results revealed that while beads and peanut oil may impact abundance of FA RNA and protein in endometrial samples, it does not appear to impact PGF secretion. Conversely, embryo contact for 24 hours with endometrium from a non-pregnant mare causes a decrease in PGF secretion. These results suggest that it is not just contact of any substance/object causing attenuation of PGF secretion, but the embryo itself is necessary to decrease PGF secretion.

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<![CDATA[Molecular and genetic characterization of partial masculinization in embryonic ovaries grafted into male nude mice]]> https://www.researchpad.co/article/5c8977afd5eed0c4847d330e

In most of mammalian embryos, gonadal sex differentiation occurs inside the maternal uterus before birth. In several fetal ovarian grafting experiments using male host mice, an experimental switch from the maternal intrauterine to male-host environment gradually induces partial masculinization of the grafted ovaries even under the wild-type genotype. However, either host-derived factors causing or molecular basis underlying this masculinization of the fetal ovaries are not clear. Here, we demonstrate that ectopic appearance of SOX9-positive Sertoli cell-like cells in grafted ovaries was mediated by the testosterone derived from the male host. Neither Sox8 nor Amh activity in the ovarian tissues is essential for such ectopic appearance of SOX9-positive cells. The transcriptome analyses of the grafted ovaries during this masculinization process showed early downregulation of pro-ovarian genes such as Irx3, Nr0b1/Dax1, Emx2, and Fez1/Lzts1 by days 7–10 post-transplantation, and subsequent upregulation of several pro-testis genes, such as Bhlhe40, Egr1/2, Nr4a2, and Zc3h12c by day 20, leading to a partial sex reversal with altered expression profiles in one-third of the total numbers of the sex-dimorphic pre-granulosa and Sertoli cell-specific genes at 12.5 dpc. Our data imply that the paternal testosterone exposure is partially responsible for the sex-reversal expression profiles of certain pro-ovarian and pro-testis genes in the fetal ovaries in a temporally dependent manner.

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<![CDATA[Voluntary medical male circumcision (VMMC) for prevention of heterosexual transmission of HIV and risk compensation in adult males in Soweto: Findings from a programmatic setting]]> https://www.researchpad.co/article/5c8acc83d5eed0c48498f8f2

Background

Clinical trials have clearly shown a reduction in HIV acquisition through voluntary medical male circumcision (VMMC). However, data assessing risk compensation under programmatic conditions is limited.

Methods

This was a prospective cohort of HIV seronegative males aged 18–40 years receiving VMMC between November 2012 and July 2014. HIV serostatus was determined pre and post VMMC. Risk compensation was defined as a decrease in condom use at last sex act and/or an increase in concurrent sexual relationships, both measured twelve months post-circumcision.

Results

A total of 233 males were enrolled and underwent voluntary medical male circumcision (VMMC) for prevention against HIV. There was no evidence of risk compensation post-circumcision as defined in this study. Significant increases in proportion of participants in the 18–24 years age group who knew the HIV status of their sexual partner (39% to 56%, p = 0.0019), self-reported condom use at last sex act (21% to 34%, p = 0.0106) and those reporting vaginal sexual intercourse in the past 12 months (67% to 79%, p-value = <0.0001) were found. In both 18–24 and 25–40 years age groups, there was a significant increase in perception of being at risk of contracting HIV (70% to 84%, p-value = <0.0001).

Conclusion

No significant risk compensation was observed in this study on comparing pre-and post-circumcision behaviour. An increase in proportion of participants in the 18–24 years age group who had vaginal intercourse in the first 12 months post-circumcision as a possibility of risk compensation was minimal and negated by an increase in proportion of those reporting using a condom at the last sex act, increase in knowledge of partner’s HIV status and lack of increase in alcohol post-circumcision.

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