Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples

Background Many studies have demonstrated that lifestyle factors can affect sperm quality and fertility. Sperm telomere length (STL) has been reported as potential biomarker or sperm quality. However, no studies have investigated how lifestyle factors can affect STL and associated clinical outcomes. Objectives The purpose of this manuscript is to investigate any association between STL with lifestyle factors, semen parameters and clinical outcomes. Materials and methods Sperm telomere length was measured using real‐time PCR in normozoospermic male partners (n = 66) of couples undergoing ART treatment. Each participant also completed a detailed questionnaire about general lifestyle. Linear regression univariate analysis and ANCOVA were performed to respectively determine correlations between STL and study parameters or identify statistically significant differences in STL while controlling for age, BMI and other factors. Results Using a linear regression model, STL is positively correlated with in vitro fertilization success (n = 65, r = 0.37, P = .004) but not with embryo cleavage rates and post‐implantation clinical outcomes including gestational age‐adjusted birth weight. No associations were observed between STL and sperm count, concentration or progressive motility. We further found that STL did not associate age, BMI, health or lifestyle factors. Discussion In somatic cells, the rate of telomere shortening is influenced by a number of lifestyle factors such as smoking, diet and occupation. However, little is known about how lifestyle factors affect STL and subsequently reproductive outcome. Out data suggest that STL might have an important role mechanistically for fertilization rate regardless of sperm parameters and lifestyle factors. Conclusion The results of this study demonstrate that STL is associated with in vitro fertilization rates, but not with semen parameters nor lifestyle factors. Further investigations are warranted to identify the potential variation of STL overtime to clarify its significance as a potential biomarker in ART

The biogeography of the Plastisphere : implications for policy

Author Posting. © Ecological Society of America, 2015. This article is posted here by permission of Ecological Society of America for personal use, not for redistribution. The definitive version was published in Frontiers in Ecology and the Environment 13 (2015): 541–546, doi:10.1890/150017.Microplastics (particles less than 5 mm) numerically dominate marine debris and occur from coastal waters to mid-ocean gyres, where surface circulation concentrates them. Given the prevalence of plastic marine debris (PMD) and the rise in plastic production, the impacts of plastic on marine ecosystems will likely increase. Microscopic life (the “Plastisphere”) thrives on these tiny floating “islands” of debris and can be transported long distances. Using next-generation DNA sequencing, we characterized bacterial communities from water and plastic samples from the North Pacific and North Atlantic subtropical gyres to determine whether the composition of different Plastisphere communities reflects their biogeographic origins. We found that these communities differed between ocean basins – and to a lesser extent between polymer types – and displayed latitudinal gradients in species richness. Our research reveals some of the impacts of microplastics on marine biodiversity, demonstrates that the effects and fate of PMD may vary considerably in different parts of the global ocean, and suggests that PMD mitigation will require regional management efforts.This work was supported by a US National Science Foundation (NSF) collaborative grant to LAA-Z (OCE-1155571), ERZ (OCE-1155379), and TJM (OCE-1155671), and was partially funded by an NSF TUES grant (DUE-1043468) to LAA-Z and ERZ, and by the Richard Saltonstall Charitable Foundation to TJM. GP was funded through the OCE-1155379 grant and assisted with identification of plastic resins via ATR-FTIR

Similarities in the immunoglobulin response and V(H )gene usage in rhesus monkeys and humans exposed to porcine hepatocytes

BACKGROUND: The use of porcine cells and organs as a source of xenografts for human patients would vastly increase the donor pool; however, both humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose α (1,3) galactose (αGal) present on the surface of many porcine cells. We previously examined the xenoantibody response in patients exposed to porcine hepatocytes via treatment(s) with bioartficial liver devices (BALs), composed of porcine cells in a support matrix. We determined that xenoantibodies in BAL-treated patients are predominantly directed at porcine αGal carbohydrate epitopes, and are encoded by a small number of germline heavy chain variable region (V(H)) immunoglobulin genes. The studies described in this manuscript were designed to identify whether the xenoantibody responses and the IgV(H )genes encoding antibodies to porcine hepatocytes in non-human primates used as preclinical models are similar to those in humans. Adult non-immunosuppressed rhesus monkeys (Macaca mulatta) were injected intra-portally with porcine hepatocytes or heterotopically transplanted with a porcine liver lobe. Peripheral blood leukocytes and serum were obtained prior to and at multiple time points after exposure, and the immune response was characterized, using ELISA to evaluate the levels and specificities of circulating xenoantibodies, and the production of cDNA libraries to determine the genes used by B cells to encode those antibodies. RESULTS: Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the V(H)3 family, with a minor contribution from the V(H)4 family. Immunoglobulin heavy-chain gene (V(H)) cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, V(H)3-11(cyno), has not been previously identified, and encodes xenoantibodies at later time points post-transplant. Sequencing of IgG clones revealed increased usage of the monkey germline progenitor most similar to human IGHV3-11 and the onset of mutations. CONCLUSION: The small number of IGV(H )genes encoding xenoantibodies to porcine hepatocytes in non-human primates and humans is highly conserved. Rhesus monkeys are an appropriate preclinical model for testing novel reagents such as those developed using structure-based drug design to target and deplete antibodies to porcine xenografts

Diminished Neural and Cognitive Responses to Facial Expressions of Disgust in Patients with Psoriasis: A Functional Magnetic Resonance Imaging Study

Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (P<0.005) smaller signal responses to disgusted faces in the bilateral insular cortex compared with healthy controls. These data were corroborated by FERT, in that patients were less able than controls to identify all intensities of disgust tested. We hypothesize that patients with psoriasis, in this case male patients, develop a coping mechanism to protect them from stressful emotional responses by blocking the processing of disgusted facial expressions

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell's Diverticulum

Background: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch. Methods: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions. Results: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change. Conclusions: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality

Corrigendum: CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes

Presentation of peptide:MHCII by ​RORγ-expressing group 3 innate lymphoid cells (ILC3s), which are enriched within gut tissue, is required for control of ​CD4 T-cell responses to commensal bacteria. It is not known whether ILC populations migrate from their mucosal and peripheral sites to local draining secondary lymphoid tissues. Here we demonstrate that ILC3s reside within the interfollicular areas of mucosal draining lymph nodes, forming a distinct microenvironment not observed in peripheral lymph nodes. By photoconverting intestinal cells in Kaede mice we reveal constitutive trafficking of ILCs from the intestine to the draining mesenteric lymph nodes, which specifically for the LTi-like ILC3s was ​CCR7-dependent. Thus, ILC populations traffic to draining lymph nodes using different mechanisms

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 co-infection are high. DFT1 gradually accumulates copy number variants (CNVs) and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.This work was supported by grants from Wellcome (102942/Z/13/A), the National Science Foundation (DEB-1316549), the University of Tasmania Foundation (Eric Guiler Tasmanian Devil Research Grants), the Australian Research Council (DE 170101116) and a Philip Leverhulme Prize from the Leverhulme Trust. YMK was supported by a Herchel Smith Postgraduate Fellowship

Lactoferrin impact on gut microbiota in preterm infants with late-onset sepsis or necrotising enterocolitis: the MAGPIE mechanisms of action study

Background: Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives: The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods: Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results: We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42 at aged 7–9 days to only 2 at aged 30–60 days (p < 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R2 = 0.005; p = 0.04). Staphylococcus (p < 0.01), Haemophilus (p < 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations: Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion: We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work: We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration: Current Controlled Trials ISRCTN12554594. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information