Leucine-glycine and carnosine dipeptides prevent diabetes induced by multiple low-dose streptozotocin in experimental model of adult mice

Aims/Introduction Peptides are considered as quasi‐hormones and effective molecules for regulation of the cells function and metabolic disorders prevention. Di‐ and tripeptides with the ability to gastrointestinal absorption have been proposed to prevent diabetes progression. Materials and Methods Small peptides with different sequences of specific amino acids were synthesized based on a solid phase peptide synthesis (SPPS) protocol as well as carnosine (A) and glutathione (B) were examined for the prevention of diabetes induced by multiple low‐dose of streptozotocin (MLDS) in mice. Results The peptides A, Leu‐Gly (D) and Pro‐Pro (F) exhibited a preventive effects on blood glucose elevation and impairment of the signaling and performance of beta cells. The beta cells function assessed by immunofluorescence and blood glucose level in mice exposed to diabetes treated by the peptides A and D was similar to the normal mice. The peptide D prevented from body weight loss caused by diabetes induction. The use of D and A peptides dramatically prevents the incidence of disruption in beta cells signaling by maintaining the natural balance of intracellular Akt‐2 and cAMP. Conclusions The results proved that peptide D (Leu‐Gly) named Hannaneh inhibits the body weight loss caused by diabetes induction. The Hannaneh and carnosine dipeptides with preservation of normal beta cell signalling and anti DPP‐4 activity were prevented from increasing the blood glucose in mice at risk of diabetes. These dipeptides may be regarded as the pharmaceutical agents for the prevention of diabetes

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Signal Detection on the Battlefield: Priming Self-Protection vs. Revenge-Mindedness Differentially Modulates the Detection of Enemies and Allies

Detecting signs that someone is a member of a hostile outgroup can depend on very subtle cues. How do ecology-relevant motivational states affect such detections? This research investigated the detection of briefly-presented enemy (versus friend) insignias after participants were primed to be self-protective or revenge-minded. Despite being told to ignore the objectively nondiagnostic cues of ethnicity (Arab vs. Western/European), gender, and facial expressions of the targets, both priming manipulations enhanced biases to see Arab males as enemies. They also reduced the ability to detect ingroup enemies, even when these faces displayed angry expressions. These motivations had very different effects on accuracy, however, with self-protection enhancing overall accuracy and revenge-mindedness reducing it. These methods demonstrate the importance of considering how signal detection tasks that occur in motivationally-charged environments depart from results obtained in conventionally motivationally-inert laboratory settings.National Institute of Mental Health (U.S.) (Grant MH64734)U.S. Army Research Institute for the Behavioral and Social Sciences (Grant W74V8H-05-K-0003)National Science Foundation (U.S.) (Grant BCS-0642873

The Role of Fibrocytes in Sickle Cell Lung Disease

<div><h3>Background</h3><p>Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.</p> <h3>Methodology/Principal Findings</h3><p>Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.</p> <h3>Conclusions</h3><p>These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.</p> </div

Death and Science: The Existential Underpinnings of Belief in Intelligent Design and Discomfort with Evolution

The present research examined the psychological motives underlying widespread support for intelligent design theory (IDT), a purportedly scientific theory that lacks any scientific evidence; and antagonism toward evolutionary theory (ET), a theory supported by a large body of scientific evidence. We tested whether these attitudes are influenced by IDT's provision of an explanation of life's origins that better addresses existential concerns than ET. In four studies, existential threat (induced via reminders of participants' own mortality) increased acceptance of IDT and/or rejection of ET, regardless of participants' religion, religiosity, educational background, or preexisting attitude toward evolution. Effects were reversed by teaching participants that naturalism can be a source of existential meaning (Study 4), and among natural-science students for whom ET may already provide existential meaning (Study 5). These reversals suggest that the effect of heightened mortality awareness on attitudes toward ET and IDT is due to a desire to find greater meaning and purpose in science when existential threats are activated

iTRAQ Identification of Candidate Serum Biomarkers Associated with Metastatic Progression of Human Prostate Cancer

A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n = 5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer ‘BPH’, (ii) localised cancer with no evidence of progression, ‘non-progressing’ (iii) localised cancer with evidence of biochemical progression, ‘progressing’, and (iv) bone metastasis at presentation ‘metastatic’. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (p<0.001). Comparisons of metastatic versus progressing groups identified the significant differential expression of 23 proteins. Mapping the differentially expressed proteins onto the prostate cancer progression pathway revealed the dysregulated expression of individual proteins, pairs of proteins and ‘panels’ of proteins to be associated with particular stages of disease development and progression. The median immunostaining intensity of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p = 0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation

Non-Invasive Mapping of the Gastrointestinal Microbiota Identifies Children with Inflammatory Bowel Disease

Background: Pediatric inflammatory bowel disease (IBD) is challenging to diagnose because of the non-specificity of symptoms; an unequivocal diagnosis can only be made using colonoscopy, which clinicians are reluctant to recommend for children. Diagnosis of pediatric IBD is therefore frequently delayed, leading to inappropriate treatment plans and poor outcomes. We investigated the use of 16S rRNA sequencing of fecal samples and new analytical methods to assess differences in the microbiota of children with IBD and other gastrointestinal disorders. Methodology/Principal Findings: We applied synthetic learning in microbial ecology (SLiME) analysis to 16S sequencing data obtained from i) published surveys of microbiota diversity in IBD and ii) fecal samples from 91 children and young adults who were treated in the gastroenterology program of Children’s Hospital (Boston, USA). The developed method accurately distinguished control samples from those of patients with IBD; the area under the receiver-operating-characteristic curve (AUC) value was 0.83 (corresponding to 80.3% sensitivity and 69.7% specificity at a set threshold). The accuracy was maintained among data sets collected by different sampling and sequencing methods. The method identified taxa associated with disease states and distinguished patients with Crohn’s disease from those with ulcerative colitis with reasonable accuracy. The findings were validated using samples from an additional group of 68 patients; the validation test identified patients with IBD with an AUC value of 0.84 (e.g. 92% sensitivity, 58.5% specificity). Conclusions/Significance: Microbiome-based diagnostics can distinguish pediatric patients with IBD from patients with similar symptoms. Although this test can not replace endoscopy and histological examination as diagnostic tools, classification based on microbial diversity is an effective complementary technique for IBD detection in pediatric patients.Natural Sciences and Engineering Research Council of Canada (Award NSERC PGS D)National Institutes of Health (U.S.) (1-R21-A1084032-01A1

Characterization of Yeast Extracellular Vesicles: Evidence for the Participation of Different Pathways of Cellular Traffic in Vesicle Biogenesis

Background: Extracellular vesicles in yeast cells are involved in the molecular traffic across the cell wall. In yeast pathogens, these vesicles have been implicated in the transport of proteins, lipids, polysaccharide and pigments to the extracellular space. Cellular pathways required for the biogenesis of yeast extracellular vesicles are largely unknown. Methodology/Principal Findings: We characterized extracellular vesicle production in wild type (WT) and mutant strains of the model yeast Saccharomyces cerevisiae using transmission electron microscopy in combination with light scattering analysis, lipid extraction and proteomics. WT cells and mutants with defective expression of Sec4p, a secretory vesicleassociated Rab GTPase essential for Golgi-derived exocytosis, or Snf7p, which is involved in multivesicular body (MVB) formation, were analyzed in parallel. Bilayered vesicles with diameters at the 100–300 nm range were found in extracellular fractions from yeast cultures. Proteomic analysis of vesicular fractions from the cells aforementioned and additional mutants with defects in conventional secretion pathways (sec1-1, fusion of Golgi-derived exocytic vesicles with the plasm

Horizontal gene transfer in Histophilus somni and its role in the evolution of pathogenic strain 2336, as determined by comparative genomic analyses

<p>Abstract</p> <p>Background</p> <p>Pneumonia and myocarditis are the most commonly reported diseases due to <it>Histophilus somni</it>, an opportunistic pathogen of the reproductive and respiratory tracts of cattle. Thus far only a few genes involved in metabolic and virulence functions have been identified and characterized in <it>H. somni </it>using traditional methods. Analyses of the genome sequences of several <it>Pasteurellaceae </it>species have provided insights into their biology and evolution. In view of the economic and ecological importance of <it>H. somni</it>, the genome sequence of pneumonia strain 2336 has been determined and compared to that of commensal strain 129Pt and other members of the <it>Pasteurellaceae</it>.</p> <p>Results</p> <p>The chromosome of strain 2336 (2,263,857 bp) contained 1,980 protein coding genes, whereas the chromosome of strain 129Pt (2,007,700 bp) contained only 1,792 protein coding genes. Although the chromosomes of the two strains differ in size, their average GC content, gene density (total number of genes predicted on the chromosome), and percentage of sequence (number of genes) that encodes proteins were similar. The chromosomes of these strains also contained a number of discrete prophage regions and genomic islands. One of the genomic islands in strain 2336 contained genes putatively involved in copper, zinc, and tetracycline resistance. Using the genome sequence data and comparative analyses with other members of the <it>Pasteurellaceae</it>, several <it>H. somni </it>genes that may encode proteins involved in virulence (<it>e.g</it>., filamentous haemaggutinins, adhesins, and polysaccharide biosynthesis/modification enzymes) were identified. The two strains contained a total of 17 ORFs that encode putative glycosyltransferases and some of these ORFs had characteristic simple sequence repeats within them. Most of the genes/loci common to both the strains were located in different regions of the two chromosomes and occurred in opposite orientations, indicating genome rearrangement since their divergence from a common ancestor.</p> <p>Conclusions</p> <p>Since the genome of strain 129Pt was ~256,000 bp smaller than that of strain 2336, these genomes provide yet another paradigm for studying evolutionary gene loss and/or gain in regard to virulence repertoire and pathogenic ability. Analyses of the complete genome sequences revealed that bacteriophage- and transposon-mediated horizontal gene transfer had occurred at several loci in the chromosomes of strains 2336 and 129Pt. It appears that these mobile genetic elements have played a major role in creating genomic diversity and phenotypic variability among the two <it>H. somni </it>strains.</p

Understanding the nature and mechanism of foot pain

Approximately one-quarter of the population are affected by foot pain at any given time. It is often disabling and can impair mood, behaviour, self-care ability and overall quality of life. Currently, the nature and mechanism underlying many types of foot pain is not clearly understood. Here we comprehensively review the literature on foot pain, with specific reference to its definition, prevalence, aetiology and predictors, classification, measurement and impact. We also discuss the complexities of foot pain as a sensory, emotional and psychosocial experience in the context of clinical practice, therapeutic trials and the placebo effect. A deeper understanding of foot pain is needed to identify causal pathways, classify diagnoses, quantify severity, evaluate long term implications and better target clinical intervention