Unexpected activity of a novel kunitz-type inhibitor Inhibition of cysteine proteases but not serine proteases

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Kunitz-type (KT) protease inhibitors are low molecular weight proteins classically defined as serine protease inhibitors. We identified a novel secreted KT inhibitor associated with the gut and parenchymal tissues of the infective juvenile stage of Fasciola hepatica, a helminth parasite of medical and veterinary importance. Unexpectedly, recombinant KT inhibitor (rFhKT1) exhibited no inhibitory activity toward serine proteases but was a potent inhibitor of the major secreted cathepsin L cysteine proteases of F. hepatica, FhCL1 and FhCL2, and of human cathepsins L and K (Ki ô 0.4-27 nM). FhKT1 prevented the autocatalytic activation of FhCL1 and FhCL2 and formed stable complexes with the mature enzymes. Pulldown experiments from adult parasite culture medium showed that rFhKT1 interacts specifically with native secreted FhCL1, FhCL2, and FhCL5. Substitution of the unusual P1 Leu15 within the exposed reactive loop of FhKT1 for the more commonly found Arg (FhKT1Leu15 / Arg15 ) had modest adverse effects on the cysteine protease inhibition but conferred potent activity against the serine protease trypsin (Ki ô 1.5 nM). Computational docking and sequence analysis provided hypotheses for the exclusive binding of FhKT1 to cysteine proteases, the importance of the Leu15 in anchoring the inhibitor into the S2 active site pocket, and the inhibitor's selectivity toward FhCL1, FhCL2, and human cathepsins L and K. FhKT1 represents a novel evolutionary adaptation of KT protease inhibitors by F. hepatica, with its prime purpose likely in the regulation of the major parasite-secreted proteases and/or cathepsin L-like proteases of its host

Methodological problem with comparing increases in different measures of body weight

<p>Abstract</p> <p>Background</p> <p>A number of studies have compared proportional increases over time in waist circumference (WC) and body mass index (BMI). However this method is flawed. Here, we explain why comparisons of WC and BMI must take into account the relationship between them. We used data from two cross-sectional US surveys (NHANES 1988-94 and 2005-06), and calculated the percentage change in the average BMI and the average WC between the two surveys, comparing the results with a regression analysis of changes in WC relative to BMI.</p> <p>Findings</p> <p>The crude percentage change in BMI (5.8%) was marginally greater than for WC (5.1%). But these percentages cannot be directly compared, as the relationship between the measures is described by a regression equation with an intercept term that does not equal zero. The coefficient of time from the regression equation will determine whether or not WC is on average larger for a given BMI at the second compared with the first time point.</p> <p>Conclusion</p> <p>Differences in the percentage change in WC and the percentage change in BMI cannot be usefully directly compared. Comparisons of increases in the two measures must account for the relationship between them as described by the regression equation.</p

Theoretically optimal forms for very long span bridges under gravity loading

Electronic supplementary material is available online at https://doi.org/10.6084/m9. figshare.c.4218686.© 2018 The Authors. Long-span bridges have traditionally employed suspension or cable-stayed forms, comprising vertical pylons and networks of cables supporting a bridge deck. However, the optimality of such forms over very long spans appears never to have been rigorously assessed, and the theoretically optimal form for a given span carrying gravity loading has remained unknown. To address this we here describe a new numerical layout optimization procedure capable of intrinsically modelling the self-weight of the constituent structural elements, and use this to identify the form requiring the minimum volume of material for a given span. The bridge forms identified are complex and differ markedly to traditional suspension and cable-stayed bridge forms. Simplified variants incorporating split pylons are also presented. Although these would still be challenging to construct in practice, a benefit is that they are capable of spanning much greater distances for a given volume of material than traditional suspension and cable-stayed forms employing vertical pylons, particularly when very long spans (e.g. over 2 km) are involved.Engineering and Physical Sciences Research Council and Expedition Engineering Lt

Hepatitis E Virus Seroprevalence among Blood Donors in Southwest Switzerland

Aim: The aim of this study was to determine the seroprevalence of Hepatitis E virus (HEV) among blood donors in southwest Switzerland.Background: HEV is recognized as a food-borne disease in industrialized countries, transmitted mainly through pork meat. Cases of transmission through blood transfusion have also been reported. Recent studies have revealed seroprevalence rates of 13.5%, 16.6% and 20.6% among blood donors in England, France and Denmark, respectively.Methods: We analyzed 550 consecutive blood donor samples collected in the region of Lausanne, canton of Vaud, Switzerland, for the presence of anti-HEV IgG, using the MP Diagnostics HEV ELISA kit. For each donor, we documented age, sex and alanine aminotransferase (ALT) value.Results: The study panel was composed of 332 men (60.4%) and 218 women (39.6%). Overall, anti-HEV IgG was found in 27 of 550 samples (4.9%). The seroprevalence was 5.4% (18/332) in men and 4.1% (9/218) in women. The presence of anti-HEV IgG was not correlated with age, gender or ALT values. However, we observed a peak in seroprevalence of 5.3% in individuals aged 51 to 70 years old.Conclusions: Compared with other European countries, HEV seroprevalence among blood donors in southwest Switzerland is low. The low seroprevalence may be explained by the sensitivity of commercial tests used and/or the strict regulation of animal and meat imports. Data regarding HEV prevalence in Swiss livestock are lacking and merit exploration

ELK1 Uses Different DNA Binding Modes to Regulate Functionally Distinct Classes of Target Genes

Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP–seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled

Changes in Treatment Content of Services During Trauma-informed Integrated Services for Women with Co-occurring Disorders

The experience of trauma is highly prevalent in the lives of women with mental health and substance abuse problems. We examined how an intervention targeted to provide trauma-informed integrated services in the treatment of co-occurring disorders has changed the content of services reported by clients. We found that the intervention led to an increased provision of integrated services as well as services addressing each content area: trauma, mental health and substance abuse. There was no increase in service quantity from the intervention. Incorporation of trauma-specific element in the treatment of mental health and substance abuse may have been successfully implemented at the service level thereby better serve women with complex behavioral health histories

The Use of Herbal Medications and Dietary Supplements by People with Mental Illness

This study examined the relationship between herbal medication and dietary supplement (HMDS) use and mental health characteristics. Data are drawn from a national household survey of the United States’ civilian, non-institutionalized population (N = 9,585). Psychiatric medication and HMDS use, psychiatric diagnoses and treatment needs, utilization and satisfaction were assessed. Compared to non-users, HMDS users were more likely to perceive themselves as having mental health needs, to have received mental health and primary care treatment, and to be dissatisfied with their overall healthcare. Psychiatric medication use was not related to HMDS use, and in multivariate analyses, HMDS use was associated with perceived mental health needs. Differences in use of specific HMDS between those with and without a psychiatric disorder were also examined. The use of HMDS warrants particular attention in persons with perceived mental health problems as these individuals may be turning to HMDS use for treatment of their symptoms

Edging toward ‘reasonably’ good corporate governance

Over four decades, research and policy have created layers of understandings in the quest for “good” corporate governance. The corporate excesses of the 1970s sparked a search for market mechanisms and disclosure to empower shareholders. The UK-focused problems of the 1990s prompted board-centric, structural approaches, while the fall of Enron and many other companies in the early 2000s heightened emphasis on director independence and professionalism. With the financial crisis of 2007-09, however, came a turn in some policy approaches and in academic literature seeking a different way forward. This paper explores those four phases and the discourse each develops and then links each to assumptions about accountability and cognition. After the financial crisis came pointers n policy and practice away from narrow, rationalist prescriptions and toward what the philosopher Stephen Toulmin calls “reasonableness”. Acknowledging that heightens awareness of complexity and interdependence in corporate governance practice. The paper then articulates a research agenda concerning what “reasonable” corporate governance might entail

Altering the trajectory of early postnatal cortical development can lead to structural and behavioural features of autism

<p>Abstract</p> <p>Background</p> <p>Autism is a behaviourally defined neurodevelopmental disorder with unknown etiology. Recent studies in autistic children consistently point to neuropathological and functional abnormalities in the temporal association cortex (TeA) and its associated structures. It has been proposed that the trajectory of postnatal development in these regions may undergo accelerated maturational alterations that predominantly affect sensory recognition and social interaction. Indeed, the temporal association regions that are important for sensory recognition and social interaction are one of the last regions to mature suggesting a potential vulnerability to early maturation. However, direct evaluation of the emerging hypothesis that an altered time course of early postnatal development can lead to an ASD phenotype remains lacking.</p> <p>Results</p> <p>We used electrophysiological, histological, and behavioural techniques to investigate if the known neuronal maturational promoter valproate, similar to that in culture systems, can influence the normal developmental trajectory of TeA <it>in vivo</it>. Brain sections obtained from postnatal rat pups treated with VPA <it>in vivo </it>revealed that almost 40% of cortical cells in TeA prematurely exhibited adult-like intrinsic electrophysiological properties and that this was often associated with gross cortical hypertrophy and a reduced predisposition for social play behaviour.</p> <p>Conclusions</p> <p>The co-manifestation of these functional, structural and behavioural features suggests that alteration of the developmental time course in certain high-order cortical networks may play an important role in the neurophysiological basis of autism.</p

Abilities to explicitly and implicitly infer intentions from actions in adults with autism spectrum disorder

Previous research suggests that Autism Spectrum Disorder (ASD) might be associated with impairments on implicit but not explicit mentalizing tasks. However, such comparisons are made difficult by the heterogeneity of stimuli and the techniques used to measure mentalizing capabilities. We tested the abilities of 34 individuals (17 with ASD) to derive intentions from others’ actions during both explicit and implicit tasks and tracked their eye-movements. Adults with ASD displayed explicit but not implicit mentalizing deficits. Adults with ASD displayed typical fixation patterns during both implicit and explicit tasks. These results illustrate an explicit mentalizing deficit in adults with ASD, which cannot be attributed to differences in fixation patterns