A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

Complete Genome Sequence of Treponema paraluiscuniculi, Strain Cuniculi A: The Loss of Infectivity to Humans Is Associated with Genome Decay.

Treponema paraluiscuniculi is the causative agent of rabbit venereal spirochetosis. It is not infectious to humans, although its genome structure is very closely related to other pathogenic Treponema species including Treponema pallidum subspecies pallidum, the etiological agent of syphilis. In this study, the genome sequence of Treponema paraluiscuniculi, strain Cuniculi A, was determined by a combination of several high-throughput sequencing strategies. Whereas the overall size (1,133,390 bp), arrangement, and gene content of the Cuniculi A genome closely resembled those of the T. pallidum genome, the T. paraluiscuniculi genome contained a markedly higher number of pseudogenes and gene fragments (51). In addition to pseudogenes, 33 divergent genes were also found in the T. paraluiscuniculi genome. A set of 32 (out of 84) affected genes encoded proteins of known or predicted function in the Nichols genome. These proteins included virulence factors, gene regulators and components of DNA repair and recombination. The majority (52 or 61.9%) of the Cuniculi A pseudogenes and divergent genes were of unknown function. Our results indicate that T. paraluiscuniculi has evolved from a T. pallidum-like ancestor and adapted to a specialized host-associated niche (rabbits) during loss of infectivity to humans. The genes that are inactivated or altered in T. paraluiscuniculi are candidates for virulence factors important in the infectivity and pathogenesis of T. pallidum subspecies.

A cardiovascular mathematical model of graded head-up tilt

A lumped parameter model of the cardiovascular system has been developed and optimized using experimental data obtained from 13 healthy subjects during graded head-up tilt (HUT) from the supine position to [Formula: see text]. The model includes descriptions of the left and right heart, direct ventricular interaction through the septum and pericardium, the systemic and pulmonary circulations, nonlinear pressure volume relationship of the lower body compartment, arterial and cardiopulmonary baroreceptors, as well as autoregulatory mechanisms. A number of important features, including the separate effects of arterial and cardiopulmonary baroreflexes, and autoregulation in the lower body, as well as diastolic ventricular interaction through the pericardium have been included and tested for their significance. Furthermore, the individual effect of parameter associated with heart failure, including LV and RV contractility, baseline systemic vascular resistance, pulmonary vascular resistance, total blood volume, LV diastolic stiffness and reflex gain on HUT response have also been investigated. Our fitted model compares favorably with our experimental measurements and published literature at a range of tilt angles, in terms of both global and regional hemodynamic variables. Compared to the normal condition, a simulated congestive heart failure condition produced a blunted response to HUT with regards to the percentage changes in cardiac output, stroke volume, end diastolic volume and effector response (i.e., heart contractility, venous unstressed volume, systemic vascular resistance and heart rate) with progressive tilting.

Vulnerability and Growth. Developmental dynamics and differential effects of the loss of an intimate partner in the second half of life. IP 12: Study outline and first results

This working report gives an overview of the Individual Project 12 “Vulnerability and growth. Developmental dynamics and differential effects of the loss of an intimate partner in the second half of life” of the Swiss National Centre of Competence in Research LIVES led by Pasqualina Perrig-Chiello, University of Bern. This longitudinal and interdisciplinary project aims at examining vulnerability and personal growth after a critical life event, namely the break-up of a long-term intimate relationship in the second half of life, be it due to divorce or due to bereavement. In this report we present details about the rationale, the main research questions, the hypotheses and the methods of the study. Special attention is given to the methodological approach. The authors give a first sample description and report on the validity of the data by comparing the sample with Swiss Labour Force Survey and Swiss Health Survey data.

Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration

Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.

Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target?

Loss of appetite and ensuing weight loss is a key feature of severe illnesses. Protein-energy malnutrition (PEM) contributes significantly to the adverse outcome of these conditions. Pharmacological interventions to target appetite stimulation have little efficacy but considerable side effects. Therefore nutritional therapy appears to be the logical step to combat inadequate nutrition. However, clinical trial data demonstrating benefits are sparse and there is no current established standard algorithm for use of nutritional support in malnourished, acutely ill medical inpatients. Recent high-quality evidence from critical care demonstrating harmful effects when parenteral nutritional support is used indiscriminately has led to speculation that loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification. Outside critical care, there is an important gap in high quality clinical trial data shedding further light on these important issues. The selection, timing, and doses of nutrition should be evaluated as carefully as with any other therapeutic intervention, with the aim of maximising efficacy and minimising adverse effects and costs. In light of the current controversy, a reappraisal of how nutritional support should be used in acutely ill medical inpatients outside critical care is urgently required. The aim of this review is to discuss current pathophysiological concepts of PEM and to review the current evidence for the efficacy of nutritional support regarding patient outcomes when used in an acutely ill medical patient population outside critical care.

Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer

Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC.

Ego depletion and attention regulation under pressure: Is a temporary loss of self-control strength indeed related to impaired attention regulation?

In the current study we investigated whether ego depletion negatively affects attention regulation under pressure in sports by assessing participants' dart throwing performance and accompanying gaze behavior. According to the strength model of self-control, the most important aspect of self-control is attention regulation. Because higher levels of state anxiety are associated with impaired attention regulation, we chose a mixed design with ego depletion (yes vs. no) as between-subjects and anxiety level (high vs. low) as within-subjects factor. Participants performed a perceptual-motor task requiring selective attention, namely, dart throwing. In line with our expectations, depleted participants in the high-anxiety condition performed worse and displayed a shorter final fixation on bull's eye, demonstrating that when one's self-control strength is depleted, attention regulation under pressure cannot be maintained. This is the first study that directly supports the general assumption that ego depletion is a major factor in influencing attention regulation under pressure.

Ego depletion and attention regulation under pressure: Is a temporary loss of self-control strength indeed related to impaired attention regulation?

In the present study we investigated whether ego depletion negatively affects attention regulation under pressure in sports by assessing participants’ dart throwing performance and accompanying gaze behavior. According to the strength model of self-control the most important aspect of self-control is attention regulation (Schmeichel & Baumeister, 2010). As higher levels of state anxiety are associated with impaired attention regulation (Nieuwenhuys & Oudejans, 2012) we chose a mixed design with ego depletion (yes vs. no) as between-subjects and anxiety level (high vs. low) as within-subjects factor. A total of 28 right-handed students participated in our study (Mage = 23.4, SDage = 2.5; 10 female; no professional dart experience). Participants performed a perceptual-motor task requiring selective attention, namely, dart throwing. The task was performed while participants were positioned high and low on a climbing wall (i.e., with high and low levels of anxiety). In line with our expectations, a mixed-design ANOVA revealed that depleted participants in the high anxiety condition performed worse (p < .001) and displayed a shorter final fixation on bull’s eye (p < .01) than in the low anxiety condition, demonstrating that when one is depleted attention regulation under pressure cannot be maintained. This is the first study that directly supports the general assumption that ego depletion is a major factor in influencing attention regulation under pressure.

Ectodysplasin-1 deficiency in a German Holstein bull associated with loss of respiratory mucous glands and chronic rhinotracheitis

A 2-year-old German Holstein bull was identified as a carrier of a mutation within the X-chromosomal ED1 gene, which encodes a TNF-related signalling molecule mainly involved in ectodermal development. The clinicopathological appearance was associated with hypotrichosis, hypodontia, and a reduced number of eccrine glands, in addition to chronic rhinotracheitis and partial squamous metaplasia. Furthermore, for the first time in an ED1-deficient animal, a complete lack of respiratory mucous glands was observed. This suggests that the ED1 gene plays a role in the development of mucous glands, the absence of which resembles a feature of X-linked anhidrotic ectodermal dysplasia (ED1) in human patients.

Land use intensification alters ecosystem multifunctionality via loss of biodiversity and changes to functional composition

Global change, especially land-use intensification, affects human well-being by impacting the deliv-ery of multiple ecosystem services (multifunctionality). However, whether biodiversity loss is amajor component of global change effects on multifunctionality in real-world ecosystems, as inexperimental ones, remains unclear. Therefore, we assessed biodiversity, functional compositionand 14 ecosystem services on 150 agricultural grasslands differing in land-use intensity. We alsointroduce five multifunctionality measures in which ecosystem services were weighted according torealistic land-use objectives. We found that indirect land-use effects, i.e. those mediated by biodi-versity loss and by changes to functional composition, were as strong as direct effects on average.Their strength varied with land-use objectives and regional context. Biodiversity loss explainedindirect effects in a region of intermediate productivity and was most damaging when land-useobjectives favoured supporting and cultural services. In contrast, functional composition shifts,towards fast-growing plant species, strongly increased provisioning services in more inherentlyunproductive grasslands.