RTL551 Treatment of EAE Reduces CD226 and T-bet+ CD4 T Cells in Periphery and Prevents Infiltration of T-bet+ IL-17, IFN-γ Producing T Cells into CNS

Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1–5 daily injections of RTL551 (two-domain I-Ab covalently linked to MOG-35-55 peptide), but not the control RTL550 (“empty” two-domain I-Ab without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE

Immunolocalization of dually phosphorylated MAPKs in dividing root meristem cells of Vicia faba, Pisum sativum, Lupinus luteus and Lycopersicon esculentum

Key message In plants, phosphorylated MAPKs display constitutive nuclear localization; however, not all studied plant species show co-localization of activated MAPKs to mitotic microtubules. Abstract The mitogen-activated protein kinase (MAPK) signaling pathway is involved not only in the cellular response to biotic and abiotic stress but also in the regulation of cell cycle and plant development. The role of MAPKs in the formation of a mitotic spindle has been widely studied and the MAPK signaling pathway was found to be indispensable for the unperturbed course of cell division. Here we show cellular localization of activated MAPKs (dually phosphorylated at their TXY motifs) in both interphase and mitotic root meristem cells of Lupinus luteus, Pisum sativum, Vicia faba (Fabaceae) and Lycopersicon esculentum (Solanaceae). Nuclear localization of activated MAPKs has been found in all species. Colocalization of these kinases to mitotic microtubules was most evident in L. esculentum, while only about 50 % of mitotic cells in the root meristems of P. sativum and V. faba displayed activated MAPKs localized to microtubules during mitosis. Unexpectedly, no evident immunofluorescence signals at spindle microtubules and phragmoplast were noted in L. luteus. Considering immunocytochemical analyses and studies on the impact of FR180204 (an inhibitor of animal ERK1/2) on mitotic cells, we hypothesize that MAPKs may not play prominent role in the regulation of microtubule dynamics in all plant species

INCF/OCNS Software Working Group

Neuroscience cannot exist without its ecosystem of community-developed software tools that many of us rely heavily upon. The newly established Software Working Group, a community working group shared by the International Neuroinformatics Coordinating Facility (INCF) and the Organization for Computational Neurosciences (OCNS), aims to undertake activities that focus on these software tools. Members of the working group will find and discuss relevant software tools, learn and teach how to use them, test and review them, and report bugs to inform tool developers of issues when required. The working group will also strive to learn how these tools work to get involved in their development and maintenance. The aim is to ensure that the tools that our community depends on continue to be maintained by actively engaged community members, and to bring end users into close collaboration with tool developers. Since the working group includes many tool developers, it also serves as a platform to exchange design and development ideas, and will assist in improving interoperability between related tools. Another related goal of the working group is to help members define, improve, and teach transferable skills in the area of modern research software development, particularly in but not limited to, computational neuroscience. The working group is designed to be flexible, instead of being linked to a particular goal. This approach allows the group to pursue timely projects that its members value and are interested in working on. The current goals of the working group are: - To set up and maintain a living document of the current best practices in research software development to serve as a reference for the research community, especially tool developers - To host regular “developer sessions” where developer teams of various tools discuss their development pipelines (or workflows)—to disseminate various development practices, and help potential contributors get started. The activities of the working group can be followed on its website at https://ocns.github.io/SoftwareWG

A specialized learner for inferring structured cis-regulatory modules

BACKGROUND: The process of transcription is controlled by systems of transcription factors, which bind to specific patterns of binding sites in the transcriptional control regions of genes, called cis-regulatory modules (CRMs). We present an expressive and easily comprehensible CRM representation which is capable of capturing several aspects of a CRM's structure and distinguishing between DNA sequences which do or do not contain it. We also present a learning algorithm tailored for this domain, and a novel method to avoid overfitting by controlling the expressivity of the model. RESULTS: We are able to find statistically significant CRMs more often then a current state-of-the-art approach on the same data sets. We also show experimentally that each aspect of our expressive CRM model space makes a positive contribution to the learned models on yeast and fly data. CONCLUSION: Structural aspects are an important part of CRMs, both in terms of interpreting them biologically and learning them accurately. Source code for our algorithm is available at

Ultrasonic partial glossectomy

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Self-Reported and Actual Beta-Blocker Prescribing for Heart Failure Patients: Physician Predictors

Beta-blockers reduce mortality among patients with systolic heart failure (HF), yet primary care provider prescription rates remain low.To examine the association between primary care physician characteristics and both self-reported and actual prescription of beta-blockers among patients with systolic HF.Cross-sectional survey with supplementary retrospective chart review.Primary care providers at three New York City Veterans Affairs medical centers.Main outcomes were: 1) self-reported prescribing of beta-blockers, and 2) actual prescribing of beta-blockers among HF patients. Physician HF practice patterns and confidence levels, as well as socio-demographic and clinical characteristics, were also assessed.Sixty-nine of 101 physicians (68%) completed the survey examining self-reported prescribing of beta-blockers. Physicians who served as inpatient ward attendings self-reported significantly higher rates of beta-blocker prescribing among their HF patients when compared with physicians who did not attend (78% vs. 58%; p = 0.002), as did physicians who were very confident in managing HF patients when compared with physicians who were not (82% vs. 68%; p = 0.009). Fifty-one of these 69 surveyed physicians (74%) were successfully matched to 287 HF patients for whom beta-blocker prescribing data was available. Physicians with greater self-reported rates of prescribing beta-blockers were significantly more likely to actually prescribe beta-blockers (p = 0.02); however, no other physician characteristics were significantly associated with actual prescribing of beta-blockers among HF patients.Physician teaching responsibilities and confidence levels were associated with self-reported beta-blocker prescribing among their HF patients. Educational efforts focused on improving confidence levels in HF care and increasing exposure to teaching may improve beta-blocker presciption in HF patients managed in primary care

Cortactin and phagocytosis in isolated Sertoli cells

BACKGROUND: Cortactin, an actin binding protein, has been associated with Sertoli cell ectoplasmic specializations in vivo, based on its immunolocalization around the heads of elongated spermatids, but not previously identified in isolated Sertoli cells. In an in vitro model of Sertoli cell-spermatid binding, cortactin was identified around debris and dead germ cells. Based on this observation, we hypothesized that this actin binding protein may be associated with a non-junction-related physiological function, such as phagocytosis. The purpose of this study was to identify the presence and distribution of cortactin in isolated rat Sertoli cells active in phagocytic activity following the addition of 0.8 μm latex beads. RESULTS: Sertoli cell monocultures were incubated with or without follicle stimulating hormone (FSH; 0.1 μg/ml) in the presence or absence of cytochalasin D (2 μM), as an actin disrupter. Cortactin was identified by standard immunostaining with anti-cortactin, clone 4F11 (Upstate) after incubation times of 15 min, 2 hr, and 24 hr with or without beads. Cells exposed to no hormone and no beads appeared to have a ubiquitous distribution of cortactin throughout the cytoplasm. In the presence of cytochalasin D, cortactin immunostaining was punctate and distributed in a pattern similar to that reported for actin in cells exposed to cytochalasin D. Sertoli cells not exposed to FSH, but activated with beads, did not show cortactin immunostaining around the phagocytized beads at any of the time periods. FSH exposure did not alter the distribution of cortactin within Sertoli cells, even when phagocytic activity was upregulated by the presence of beads. CONCLUSION: Results of this study suggest cortactin is not associated with peripheralized actin at junctional or phagocytic sites. Further studies are necessary to clarify the role of cortactin in Sertoli cells

Identifying Cis-Regulatory Sequences by Word Profile Similarity

Recognizing regulatory sequences in genomes is a continuing challenge, despite a wealth of available genomic data and a growing number of experimentally validated examples.We discuss here a simple approach to search for regulatory sequences based on the compositional similarity of genomic regions and known cis-regulatory sequences. This method, which is not limited to searching for predefined motifs, recovers sequences known to be under similar regulatory control. The words shared by the recovered sequences often correspond to known binding sites. Furthermore, we show that although local word profile clustering is predictive for the regulatory sequences involved in blastoderm segmentation, local dissimilarity is a more universal feature of known regulatory sequences in Drosophila.Our method leverages sequence motifs within a known regulatory sequence to identify co-regulated sequences without explicitly defining binding sites. We also show that regulatory sequences can be distinguished from surrounding sequences by local sequence dissimilarity, a novel feature in identifying regulatory sequences across a genome. Source code for WPH-finder is available for download at http://rana.lbl.gov/downloads/wph.tar.gz