The tumour-derived extracellular vesicle proteome varies by endometrial cancer histology and is confounded by an obesogenic environment.

Endometrial cancer, the most common gynaecological cancer worldwide, is closely linked to obesity and metabolic diseases, particularly in younger women. New circulating biomarkers have the potential to improve diagnosis and treatment selections, which could significantly improve outcomes. Our approach focuses on extracellular vesicle (EV) biomarker discovery by directly profiling the proteome of EVs enriched from frozen biobanked endometrial tumours. We analysed nine tissue samples to compare three clinical subgroups-low BMI (Body Mass Index) Endometrioid, high BMI Endometrioid, and Serous (any BMI)-identifying proteins related to histological subtype, BMI, and shared secreted proteins. Using collagenase digestion and size exclusion chromatography, we successfully enriched generous quantities of EVs (range 204.8-1291.0 µg protein: 1.38 × 1011-1.10 × 1012 particles), characterised by their size (∼150 nm), expression of EV markers (CD63/81), and proposed endometrial cancer markers (L1CAM, ANXA2). Mass spectrometry-based proteomic profiling identified 2075 proteins present in at least one of the 18 samples. Compared to cell lysates, EVs were successfully depleted for mitochondrial and blood proteins and enriched for common EV markers and large secreted proteins. Further analysis highlighted significant differences in EV protein profiles between the high BMI subgroup and others, underlining the impact of comorbidities on the EV secretome. Interestingly, proteins differentially abundant in tissue subgroups were largely not also differential in matched EVs. This research identified secreted proteins known to be involved in endometrial cancer pathophysiology and proposed novel diagnostic biomarkers (EIF6, MUC16, PROM1, SLC26A2).

The population-specific Thr44Met OCT3 coding variant affects metformin pharmacokinetics with subsequent effects on insulin sensitivity in C57Bl/6J mice.

AIMS/HYPOTHESIS: Metformin is an important first-line treatment for type 2 diabetes and acts by increasing the body's ability to dispose of glucose. Metformin's efficacy can be affected by genetic variants in the transporters that regulate its uptake into cells. The SLC22A3 gene (also known as EMT; EMTH; OCT3) codes for organic cation transporter 3 (OCT3), which is a broad-specificity cation transporter that also transports metformin. Most SLC22A3 variants reduce the rate of metformin transport but the rs8187715 variant (p.Thr44Met) is reported to increase uptake of metformin in vitro. However, the impact of this on in vivo metformin transport and efficacy is unknown. Very few carriers of this variant have been reported globally, but, notably, all were of Pacific Island descent. Therefore, this study aims to understand the prevalence of this variant in Polynesian peoples (Maori and Pacific peoples) and to understand its impact on metformin transport and efficacy in vivo. METHODS: rs8187715 was genotyped in 310 individuals with Maori and Pacific ancestry recruited in Aotearoa New Zealand. To study this variant in a physiological context, an orthologous knockin mouse model with C57BL/6J background was used. Pharmacokinetic analysis compared uptake rate of metformin into tissues. Plasma growth/differentiation factor 15 (GDF-15) was also measured as a marker of metformin efficacy. Glucose and insulin tolerance was assessed after acute or sustained metformin treatment in knockin and wild-type control mice to examine the impact of the variant on metformin's glycaemic control. RESULTS: The minor allele frequency of this variant in the Maori and Pacific participants was 15.4%. There was no association of the variant with common metabolic parameters including diabetes status, BMI, blood pressure, lipids, or blood glucose and HbA1c. However, in the orthologous knockin mouse model, the rate of metformin uptake into the blood and tissues was increased. Acute metformin dosing increased insulin sensitivity in variant knockin mice but this effect was lost after longer-term metformin treatment. Metformin's effects on GDF-15 levels were also lost in variant knockin mice with longer-term metformin treatment. CONCLUSIONS/INTERPRETATION: These data provide evidence that the SLC22A3 rs8187715 variant accelerates metformin uptake rate in vivo. While this acutely improves insulin sensitivity, there was no increased effect of metformin with longer-term dosing. Thus, our finding of a high prevalence of this variant specifically in Maori and Pacific peoples identifies it as a potential population-specific pharmacogenetic marker with potential to guide metformin therapy in these peoples.

Mental Health Experiences of Adolescents and Young Adults with Inflammatory Bowel Disease During Transition to Adult Care: A Qualitative Descriptive Study.

OBJECTIVE: To explore the mental health experiences of adolescents and young adults (AYA) with inflammatory bowel disease (IBD) enrolled in a randomized controlled trial evaluating the impact of a multimodal transition intervention. STUDY DESIGN: Virtual semistructured interviews were held with 21 AYA aged 16 through 18 years with IBD. Guided by qualitative description, interviews were digitally recorded, transcribed verbatim, and analyzed using an inductive approach to reflexive thematic analysis. RESULTS: Three themes were generated from the data: (1) a continuum of integration between IBD and personal identity in adolescence and young adulthood; (2) manifestations of the mind-gut connection among AYA with IBD; and (3) hopes and priorities for addressing mental health in IBD care. CONCLUSIONS: AYA with IBD endorsed the criticality of incorporating mental health discussions into routine care during the transition to adult care, given the co-occurrence of psychosocial stressors throughout this period. A series of factors promoting and hindering the integration of IBD into one's identity were identified and could be explored in clinical encounters.

A high-density linkage map reveals broad- and fine-scale sex differences in recombination in the hihi (stitchbird; Notiomystis cincta).

Recombination, the process of DNA exchange between homologous chromosomes during meiosis, plays a major role in genomic diversity and evolutionary change. Variation in recombination rate is widespread despite recombination often being essential for progression of meiosis. One such variation is heterochiasmy, where recombination rates differ between sexes. Heterochiasmy has been observed across broad taxonomic groups, yet it remains an evolutionary enigma. We used Lep-MAP3, a pedigree-based software that is efficient in handling large datasets, to generate linkage maps for the hihi or stitchbird (Notiomystis cincta), utilising information from >36 K SNPs and 36 families. We constructed 29 linkage maps, including for the previously unscaffolded Z chromosome. The hihi is an endangered passerine endemic to Aotearoa New Zealand that is sexually dimorphic and exhibits high levels of sexual conflict, including sperm competition. Patterns in recombination in the hihi are consistent with those in other birds, including higher recombination rates in micro-chromosomes. Heterochiasmy in the hihi is male-biased, in line with predictions of the Haldane-Huxley rule, with the male linkage map being 15% longer. Micro-chromosomes exhibit heterochiasmy to a greater extent, contrary to that reported in other birds. At the intra-chromosomal level, heterochiasmy is higher nearer to chromosome ends and in gene-rich regions. Regions of extreme heterochiasmy are enriched for genes implicated in cell structure. This study adds an important contribution in assessing evolutionary theories of heterochiasmy and provides a framework for future studies investigating fine-scale heterochiasmy.

Impact of Biologics and Small-Molecule Agents on Postoperative Complications in IBD: A Systematic Review.

BACKGROUND: Patients with IBD may require colectomy for severe disease unresponsive or refractory to pharmacological therapy. The question of the impact of biologic use on postoperative complications is a topic of active investigation. OBJECTIVE: A systematic literature review was performed to describe the current state of knowledge of the impact of perioperative biologic and tofacitinib use on postoperative complications in patients with IBD. DATA SOURCES: PubMed and Cochrane databases were searched. STUDY SELECTION: Studies between January 2000 and January 2023, in any language, were searched, followed by a snowball search identifying further studies in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Articles regarding pediatric or endoscopic management were excluded. INTERVENTIONS: Preoperative or perioperative exposure to biologics in IBD was included. MAIN OUTCOME MEASURES: Infectious and noninfectious complications, including anastomotic leaks, surgical site infections, urinary tract infections, pneumonia, sepsis, septic shock, postoperative length of stay, readmission, and reoperation, were the main outcomes measured. RESULTS: A total of 28 studies were included for analysis in this review, including 7 meta-analyses or systematic reviews and 5 randomized studies. Snowball search identified 11 additional studies providing topical information. Overall, tumor necrosis factor inhibitors likely do not increase the risk of postoperative adverse outcomes, while data on other biologics and small-molecule agents are emerging. LIMITATIONS: This is a qualitative review including all study types. The varied nature of study types precludes quantitative comparison. CONCLUSIONS: Although steroids increase postoperative infectious and noninfectious complications, tumor necrosis factor inhibitors do not appear to increase postoperative infectious and noninfectious complications. There is a need for further perioperative data for other agents. See video from symposium .

Scaling of Activity Space in Marine Organisms across Latitudinal Gradients.

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.

Risk of corticosteroid treatment and hospitalization after checkpoint inhibitor and radiation therapy in patients with cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. ICIs have contributed significantly to improved survival and thereby provide more opportunity for the development of local disease symptomatology requiring palliative radiation. Radiation therapy (RT) has also recently shown benefit in the oligometastatic setting. Data on the interaction and safety of concurrent ICIs and RT are limited. METHODS: In this retrospective cohort study using a large medical claims database from 2010 to 2017, the need for corticosteroid therapy and the risk of hospitalization within 180 days of treatment with an ICI were determined for patients with a diagnosis of malignant melanoma or lung cancer. Patients were stratified by the use of RT within the 30 days before and after ICI therapy. RESULTS: In all, 2020 patients (218 with RT and 1802 without RT) met the inclusion criteria for prednisone analysis, whereas 3519 patients (361 with RT and 3158 without RT) met the inclusion criteria for all other analyses. In a univariable analysis, RT was not associated with the need for prednisone (relative risk [RR], 1.2; 95% confidence interval [CI], 0.8-1.9) or methylprednisolone (RR, 1.1; 95% CI, 0.7-2.0). When the end point was hospitalization, RT was significantly associated with hospitalization after ICI therapy for certain cancer/drug combinations (RR for lung cancer/programmed death 1 receptor inhibitors, 1.4; 95% CI, 1.2-1.6; P < .001; RR for melanoma/ipilimumab, 2.0; 95% CI, 1.0-3.5; P = .03). CONCLUSIONS: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring corticosteroid therapy in comparison with not receiving RT. However, RT was associated with a higher risk of hospitalization, although this finding may be a result of differences in the underlying patient illness severity or oncologic disease burden at the baseline. LAY SUMMARY: Data on the interaction of immunotherapy (immune checkpoint inhibitors) and radiation therapy and the safety of combining them are limited. Using a large database, this study has found that patients treated concurrently with immune checkpoint inhibitors and radiation therapy are not at increased risk for requiring corticosteroid therapy (which is used as a proxy for immune-related adverse events). However, concurrent therapy is associated with a higher risk of hospitalization, although this finding may be due to differences in the underlying patient illness severity (sicker patients may require both immunotherapy and radiation therapy).

Endoscopic Therapy for Pouch Leaks and Strictures: A Systematic Review.

BACKGROUND: Patients with ulcerative colitis refractory to medication or familial adenomatous polyposis may require ileal pouch-anal anastomosis after a colectomy. IPAA is generally well tolerated. However, patients can experience posttreatment complications, including pouch strictures and leaks. Medical therapy has a limited role in mechanical fibrotic strictures, whereas surgery is invasive and costly. In the past few decades, endoscopic therapies have provided a less invasive and less costly intervention for pouch strictures and leaks. OBJECTIVE: This systematic literature review aimed to describe the status of advancements in endoscopic therapy for pouch leaks and strictures. DATA SOURCES: The sources used were PubMed and Cochrane databases. STUDY SELECTION: Studies between January 1990 and January 2022, in any language, were included. Articles regarding surgical management or pouches other than adult ileal pouch-anal anastomosis were excluded. INTERVENTIONS: Endoscopic management of acute and chronic leaks and strictures ileal pouch-anal anastomosis was included. MAIN OUTCOME MEASURES: Successful management (including persistent leak or stricture, pouch failure, subsequent endoscopy, or surgery) was measured. RESULTS: Sixty-one studies were included in this review, including 4 meta-analyses or systematic reviews, 11 reviews, 17 cohort studies, and 18 case series. LIMITATIONS: The limitations include qualitative review of all study types, with no randomized controlled studies available. CONCLUSION: Ileal pouch-anal anastomosis leaks are various in configuration, and endoscopic therapies have included clipping leaks at the tip of the "J" as well as endoscopic sinusotomy. Endoscopic therapies for pouch strictures have included endoscopic balloon dilation, endoscopic stricturotomy, and endoscopic stricturoplasty, which are now considered first-line therapies for pouch strictures. Endoscopic balloon dilation has shown safety and efficacy in single, short, and straight strictures and endoscopic stricturotomy for refractory long, fibrotic, anastomotic strictures. Endoscopic therapies can delay or prevent invasive surgeries. Key tenets of successful endoscopic therapy include patient and lesion candidacy, an experienced endoscopist, and adequate rescue surgery plans.

Perioperative Management of Ulcerative Colitis: A Systematic Review.

BACKGROUND: Patients with ulcerative colitis may require colectomy for severe disease unresponsive or refractory to pharmacological therapy. Managing ulcerative colitis is complicated because there are many factors at play, including patient optimization and treatment, as the guidance varies on the ideal perioperative use of corticosteroids, immunomodulators, biologics, and small molecule agents. OBJECTIVE: A systematic literature review was performed to describe the current status of perioperative management of ulcerative colitis. DATA SOURCES: PubMed and Cochrane databases were used. STUDY SELECTION: Studies published between January 2000 and January 2022, in any language, were included. Articles regarding pediatric or endoscopic management were excluded. INTERVENTIONS: Perioperative management of ulcerative colitis was included. MAIN OUTCOME MEASURES: Successful management, including reducing surgical complication rates, was measured. RESULTS: A total of 121 studies were included in this review, including 23 meta-analyses or systematic reviews, 25 reviews, and 51 cohort studies. LIMITATIONS: Qualitative review including all study types. The varied nature of study types precludes quantitative comparison. CONCLUSION: Indications for colectomy in ulcerative colitis include severe disease unresponsive to medical treatment and colitis-associated neoplasia. Urgent colectomy has a higher mortality rate than elective colectomy. Corticosteroids are associated with postsurgical infectious complications and should be stopped or weaned before surgery. Biologics are not associated with adverse postoperative effects and do not necessarily need to be stopped preoperatively. Additionally, the clinician must assess individuals' comorbidities, nutrition status, and risk of venous thromboembolism. Nutritional imbalance should be corrected, ideally at the preoperative period. Postoperatively, corticosteroids can be tapered on the basis of the length of preoperative corticosteroid use.

Multimodal intervention to improve the transition of patients with inflammatory bowel disease from pediatric to adult care: protocol for a randomized controlled trial.

BACKGROUND: Transition in care is defined as the "purposeful and planned movement of adolescents and young adults with a chronic medical condition from pediatric to adult-oriented healthcare systems/care providers." Currently, there are no Level 1 evidence-based interventions to improve the care of transitioning adolescents and young adults (AYAs) with inflammatory bowel disease (IBD). The development of a transition program using a biopsychosocial approach will improve the standards for healthcare delivery to transitioning IBD patients. This is a protocol for a structured randomized controlled trial (RCT) to assess the clinical and implementation effectiveness of a multimodal intervention focused on improving patient function, transition readiness and outcomes among AYA patients with IBD being cared for at pediatric centers in Canada. METHODS: This multi-center RCT is a type 1 hybrid effectiveness-implementation trial to evaluate effectiveness of the intervention and how it can be implemented more widely after the trial. We will include patients aged 16.0-17.5 years. The intervention program consists of 4 core components: (1) individualized assessment, (2) transition navigator, (3) virtual patient skills-building with a focus on building resilience, self-management and self-efficacy, and (4) a virtual structured education program. The control group will undergo standard-of-care defined by each participating center. The primary outcome will be the IBD Disability Index, a validated measure to assess patient functioning. Secondary outcomes include transition readiness and success, anxiety and depression scales, and health service utilization rates. Additionally, we will measure implementation outcomes and related barriers and facilitators for the intervention program. DISCUSSION: The type 1 hybrid effectiveness-implementation design will allow for the development of a feasible, sustainable, and acceptable final intervention model. The intervention will consist of modules that can be accessed in an online, virtual platform. The implementation will allow centralization of interventions and funding in order to minimize the impact on local clinical practice or hospital resources. The authors anticipate that the main study limitation will relate to study subjects not completely adhering to every component of the intervention, which will be evaluated and addressed using the implementation science approach. TRIAL REGISTRATION: NCT05221281. Registry: ClinicalTrials.gov. Date of registration: February 2, 2022. https://clinicaltrials.gov/ct2/show/NCT05221281 .

Deep learning on time series laboratory test results from electronic health records for early detection of pancreatic cancer.

The multi-modal and unstructured nature of observational data in Electronic Health Records (EHR) is currently a significant obstacle for the application of machine learning towards risk stratification. In this study, we develop a deep learning framework for incorporating longitudinal clinical data from EHR to infer risk for pancreatic cancer (PC). This framework includes a novel training protocol, which enforces an emphasis on early detection by applying an independent Poisson-random mask on proximal-time measurements for each variable. Data fusion for irregular multivariate time-series features is enabled by a "grouped" neural network (GrpNN) architecture, which uses representation learning to generate a dimensionally reduced vector for each measurement set before making a final prediction. These models were evaluated using EHR data from Columbia University Irving Medical Center-New York Presbyterian Hospital. Our framework demonstrated better performance on early detection (AUROC 0.671, CI 95% 0.667 - 0.675, p < 0.001) at 12 months prior to diagnosis compared to a logistic regression, xgboost, and a feedforward neural network baseline. We demonstrate that our masking strategy results greater improvements at distal times prior to diagnosis, and that our GrpNN model improves generalizability by reducing overfitting relative to the feedforward baseline. The results were consistent across reported race. Our proposed algorithm is potentially generalizable to other diseases including but not limited to cancer where early detection can improve survival.

Endoscopic Balloon Dilation Is Cost-Effective for Crohn's Disease Strictures.

BACKGROUND: Endoscopic balloon dilation (EBD) has emerged as an alternative intervention to manage Crohn's disease (CD) strictures. We determined the cost-effectiveness of EBD versus resection surgery for patients with short (< 4-5 cm) primary or secondary/anastomotic small or large bowel strictures. METHODS: A microsimulation state-transition model analyzed the benefits and risks of EBD and resection surgery for patients with primary or anastomotic CD strictures. Our primary outcome was quality-adjusted life years (QALYs) over ten years, and strategies were compared using a willingness to pay of $100,000/QALY from a societal perspective. Costs (2021 $US) and incremental cost-effectiveness ratios (ICER) were calculated. Deterministic 1-way and probabilistic analyses assessed model uncertainty. RESULTS: The EBD strategy cost $19,822 and resulted in 6.18 QALYs while the surgery strategy cost $41,358 and resulted in 6.37 QALYs. Surgery had an ICER of $113,332 per QALY, making EBD a cost-effective strategy. The median number of EBDs was 5 in the EBD strategy and 0 in the surgery strategy. The median number of surgeries was 2 in the surgery strategy and 1 in the EBD strategy. Of individuals who initially received EBD, 50.4% underwent subsequent surgery. One-way sensitivity analyses showed that the probabilities of requiring repeated interventions, surgery mortality (< 0.7%), and quality of life after interventions were the most influential model parameters. Probabilistic sensitivity analyses favored EBD in 50.9% of iterations. CONCLUSIONS: EBD is a cost-effective strategy for managing CD strictures. Differences in patient risk and quality of life after intervention impact cost-effectiveness. Intervention decisions should consider cost-effectiveness, patient risks, and quality of life.

Risk of Postpartum Flare Hospitalizations in Patients with Inflammatory Bowel Disease Persists After Six Months.

BACKGROUND: Although patients with IBD are at higher risk for flares during the postpartum period, little is known about the risk factors, timeline, and healthcare-associated costs of a readmission flare. AIMS: To ascertain the timeline in which patients are hospitalized for postpartum inflammatory bowel disease (IBD) flares, and the associated risk factors. METHODS: This is a nationwide retrospective cohort study of 7054 patients with IBD who delivered between 2010-2014 obtained from the National Readmissions Database. The presence of IBD was defined using previously validated International Classification of Diseases codes, and univariable and multivariable regression models were performed to assess risk factors associated with a postpartum flare hospitalization over the nine-month observation period. RESULTS: A total of 353 (5.0%) patients were hospitalized for a postpartum IBD flare, with approximately one-third (30.0%) readmitted after 6 months. On multivariable analysis, having Crohn's disease (aRR 1.47, 95%CI 1.16-1.88), Medicare insurance (aRR 3.30, 95%CI 2.16-5.02), and ≥ 2 comorbidities (aRR 1.34, 95%CI 1.03-1.74) were independently associated with a higher risk of an IBD flare hospitalization. Compared to patients aged 25-29, those 20-24 were at higher risk for an IBD flare readmission (aRR 1.58, 95%CI 1.17-2.13), whereas patients aged 35-39 years were at lower risk (aRR 0.63, 95%CI 0.43-0.92). CONCLUSIONS: Among patients with IBD, Crohn's disease, Medicare insurance, multiple comorbidities, and younger age were independent risk factors for a postpartum IBD flare hospitalization. As approximately one-third of these readmissions occurred after 6 months, it is imperative to ensure adequate follow-up and treatment for postpartum IBD patients, particularly in the extended postpartum period.

Family history recording in UK general practice: the lIFeLONG study.

BACKGROUND: In order to integrate genomic medicine into routine patient care and stratify personal risk, it is increasingly important to record family history (FH) information in general/family practice records. This is true for classic genetic disease as well as multifactorial conditions. Research suggests that FH recording is currently inadequate. OBJECTIVES: To provide an up-to-date analysis of the frequency, quality, and accuracy of FH recording in UK general/family practice. METHODS: An exploratory study, based at St Leonard's Practice, Exeter-a suburban UK general/family practice. Selected adult patients registered for over 1 year were contacted by post and asked to complete a written FH questionnaire. The reported information was compared with the patients' electronic medical record (EMR). Each EMR was assessed for its frequency (how often information was recorded), quality (the level of detail included), and accuracy (how closely the information matched the patient report) of FH recording. RESULTS: Two hundred and forty-one patients were approached, 65 (27.0%) responded and 62 (25.7%) were eligible to participate. Forty-three (69.4%) EMRs contained FH information. The most commonly recorded conditions were bowel cancer, breast cancer, diabetes, and heart disease. The mean quality score was 3.64 (out of 5). There was little negative recording. 83.2% of patient-reported FH information was inaccurately recorded or missing from the EMRs. CONCLUSION: FH information in general/family practice records should be better prepared for the genomic era. Whilst some conditions are well recorded, there is a need for more frequent, higher quality recording with greater accuracy, especially for multifactorial conditions.

Taking a family history (FH) of disease can be a quick, cost-effective way of gathering genetic information. Genetic medicine is beginning to transform healthcare, so it is important to gather FH information. General practitioners, also known as family physicians, are in the best position to gather FH information as they regularly see multiple family members. Research suggests that FH recording in general/family practice is not yet good enough. This study aimed to find the areas for improvement by measuring the frequency, quality, and accuracy of FH recording. This study looked at 62 patients' records in one UK general practice. Patients were asked to give up-to-date FH information in a questionnaire which was compared with their record. The study found that some conditions were often recorded. The most commonly recorded condition was heart disease. The conditions that are more likely to reflect the family environment, such as depression, were less frequently recorded. Recordings often included the side of the family the condition affected. Recordings rarely included the age that the relative was affected. The information was not very accurate, as most of the information from patient questionnaires was missing from the records. Research should now focus on how to improve recording.

A role for PAK1 mediated phosphorylation of ß-catenin Ser552 in the regulation of insulin secretion.

The presence of adherens junctions and the associated protein ß-catenin are requirements for the development of glucose-stimulated insulin secretion (GSIS) in ß-cells. Evidence indicates that modulation of ß-catenin function in response to changes in glucose levels can modulate the levels of insulin secretion from ß-cells but the role of ß-catenin phosphorylation in this process has not been established. We find that a Ser552Ala version of ß-catenin attenuates glucose-stimulated insulin secretion indicating a functional role for Ser552 phosphorylation of ß-catenin in insulin secretion. This is associated with alterations F/G actin ratio but not the transcriptional activity of ß-catenin. Both glucose and GLP-1 stimulated phosphorylation of the serine 552 residue on ß-catenin. We investigated the possibility that an EPAC-PAK1 pathway might be involved in this phosphorylation event. We find that reduction in PAK1 levels using siRNA attenuates both glucose and GLP-1 stimulated phosphorylation of ß-catenin Ser552 and the effects of these on insulin secretion in ß-cell models. Furthermore, both the EPAC inhibitor ESI-09 and the PAK1 inhibitor IPA3 do the same in both ß-cell models and mouse islets. Together this identifies phosphorylation of ß-catenin at Ser552 as part of a cell signalling mechanism linking nutrient and hormonal regulation of ß-catenin to modulation of insulin secretory capacity of ß-cells and indicates this phosphorylation event is regulated downstream of EPAC and PAK1 in ß-cells.

Regulation of host-infection ability in the grass-symbiotic fungus Epichloë festucae by histone H3K9 and H3K36 methyltransferases.

Recent studies have identified key genes that control the symbiotic interaction between Epichloë festucae and Lolium perenne. Here we report on the identification of specific E. festucae genes that control host infection. Deletion of setB, which encodes a homologue of the H3K36 histone methyltransferase Set2/KMT3, reduced histone H3K36 trimethylation and led to severe defects in colony growth and hyphal development. The E. festucae ΔclrD mutant, which lacks the gene encoding the homologue of the H3K9 methyltransferase KMT1, displays similar developmental defects. Both mutants are completely defective in their ability to infect L. perenne. Alleles that complement the culture and plant phenotypes of both mutants also complement the histone methylation defects. Co-inoculation of either ΔsetB or ΔclrD with the wild-type strain enables these mutants to colonize the host. However, successful colonization by the mutants resulted in death or stunting of the host plant. Transcriptome analysis at the early infection stage identified four fungal candidate genes, three of which encode small-secreted proteins, that are differentially regulated in these mutants compared to wild type. Deletion of crbA, which encodes a putative carbohydrate binding protein, resulted in significantly reduced host infection rates by E. festucae.

α-catenin isoforms are regulated by glucose and involved in regulating insulin secretion in rat clonal ß-cell models.

The recent finding that ß-catenin levels play an important rate-limiting role in processes regulating insulin secretion lead us to investigate whether its binding partner α-catenin also plays a role in this process. We find that levels of both α-E-catenin and α-N-catenin are rapidly up-regulated as levels of glucose are increased in rat clonal ß-cell models INS-1E and INS-832/3. Lowering in levels of either α-catenin isoform using siRNA resulted in significant increases in glucose stimulated insulin secretion (GSIS) and this effect was attenuated when ß-catenin levels were lowered indicating these proteins have opposing effects on insulin release. This effect of α-catenin knockdown on GSIS was not due to increases in insulin expression but was associated with increases in calcium influx into cells. Moreover, simultaneous depletion of α-E catenin and α-N catenin decreased the actin polymerisation to a similar degree as latrunculin treatment and inhibition of ARP 2/3 mediated actin branching with CK666 attenuated the α-catenin depletion effect on GSIS. This suggests α-catenin mediated actin remodelling may be involved in the regulation of insulin secretion. Together this indicates that α-catenin and ß-catenin can play opposing roles in regulating insulin secretion, with some degree of functional redundancy in roles of α-E-catenin and α-N-catenin. The finding that, at least in ß-cell models, the levels of each can be regulated in the longer term by glucose also provides a potential mechanism by which sustained changes in glucose levels might impact on the magnitude of GSIS.

Theorising rehabilitation: Actors and parameters shaping normality, liminality and depersonalisation in a UK hospital.

Sociological concern for rehabilitation remains limited. This paper aims to contribute to rehabilitation theory. It examines two units of a specialist rehabilitation hospital in the UK (amputee and neurological services) by focusing on the key actors involved - families, patients, staff - and the parameters shaping their relationships. The findings extend previous theoretical understandings of rehabilitation in three themes: normality, liminality and depersonalisation. We argue, first: normality is constantly negotiated amongst the different actors. This complicates existing works' critique of rehabilitation as reproducing the ideology of normality. Second, discourses produced during acute care shape the inpatient rehabilitation experience. This calls attention to the pre-rehabilitation phase and complicates existing works' emphasis on the transition from inpatient stay to the time of discharge. Finally, inpatient rehabilitation is notable in rendering the adverse effects of depersonalisation apparent. It combines the bureaucracy of a regular hospital ward, with institutionalising aspects of long-term care. These findings have a potential to enhance practice as well as knowledge. We call for a deeper sociological attention, combining theory-building with empirical data for a better understanding of inpatient rehabilitation.

Polygenic basis for adaptive morphological variation in a threatened Aotearoa | New Zealand bird, the hihi (Notiomystis cincta).

To predict if a threatened species can adapt to changing selective pressures, it is crucial to understand the genetic basis of adaptive traits, especially in species historically affected by severe bottlenecks. We estimated the heritability of three hihi (Notiomystis cincta) morphological traits known to be under selection (nestling tarsus length, body mass and head-bill length) using 523 individuals and 39 699 single nucleotide polymorphisms (SNPs) from a 50 K Affymetrix SNP chip. We then examined the genetic architecture of the traits via chromosome partitioning analyses and genome-wide association scans (GWAS). Heritabilities estimated using pedigree relatedness or genomic relatedness were low. For tarsus length, the proportion of genetic variance explained by each chromosome was positively correlated with its size, and more than one chromosome explained significant variation for body mass and head-bill length. Finally, GWAS analyses suggested many loci of small effect contributing to trait variation for all three traits, although one locus (an SNP within an intron of the transcription factor HEY2) was tentatively associated with tarsus length. Our findings suggest a polygenic nature for the morphological traits, with many small effect size loci contributing to the majority of the variation, similar to results from many other wild populations. However, the small effective population size, polygenic architecture and already low heritabilities suggest that both the total response and rate of response to selection are likely to be limited in hihi.