Timing is Everything: PTTH Mediated DHR4 Nucleocytoplasmic Trafficking Sets the Tempo of Drosophila Steroid Production

During development, multicellular organisms must become sexually mature in order to reproduce. The developmental timing of this transition is controlled by pulses of steroid hormones, but how these pulses are generated have remained unclear? A recent paper shows that in Drosophila larvae, nucleocytoplasmic trafficking of DHR4, a nuclear receptor, in response to prothoracicotropic hormone signaling, is critical for producing the correct temporal pulses of steroid hormones that coordinate the juvenile–adult transition

Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5 - 10 minutes. Following a brief training phase, our studies shown that iMD-VR novices were able to generate unbinding and rebinding pathways on similar timescales as iMD-VR experts, with the majority able to recover binding poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These results indicate that iMD-VR affords sufficient control for users to carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and recover crystallographic poses, offering an interesting new approach for simulating drug docking and generating binding hypotheses.Comment: PLOS ON

Following the banking cycle of umbilical cord blood in India: the disparity between prebanking persuasion and post-banking utilization

To address critique of the rare uptake of umbilical cord blood (UCB) in private banks, hybrid-banking models would combine the advantages of ‘public UCB banking’ and private UCB banking by responding to both market forces and public needs. We question both by following the cycle of UCB banking in India: the circulation and stagnation of UCB as waste, gift, biological insurance, enclaved good, source of saving lives, and commodity through various practices of public, private and hybrid UCB banking. Making the journey from ‘recruitment’, ‘collection’ and ‘banking’ to ‘research’ and ‘therapy’ allowed us to identify concerns about the transparency of this cycle. Drawing on archival research and fieldwork interviews with different stakeholders in UCB banks in India, this article shows how private/hybrid cord blood banks are competing for their market share and its implication for the circulation of UCB: speculation, stagnation and opacity

Predictors of Successful Decannulation Using a Tracheostomy Retainer in Patients with Prolonged Weaning and Persisting Respiratory Failure

Background: For percutaneously tracheostomized patients with prolonged weaning and persisting respiratory failure, the adequate time point for safe decannulation and switch to noninvasive ventilation is an important clinical issue. Objectives: We aimed to evaluate the usefulness of a tracheostomy retainer (TR) and the predictors of successful decannulation. Methods: We studied 166 of 384 patients with prolonged weaning in whom a TR was inserted into a tracheostoma. Patients were analyzed with regard to successful decannulation and characterized by blood gas values, the duration of previous spontaneous breathing, Simplified Acute Physiology Score (SAPS) and laboratory parameters. Results: In 47 patients (28.3%) recannulation was necessary, mostly due to respiratory decompensation and aspiration. Overall, 80.6% of the patients could be liberated from a tracheostomy with the help of a TR. The need for recannulation was associated with a shorter duration of spontaneous breathing within the last 24/48 h (p < 0.01 each), lower arterial oxygen tension (p = 0.025), greater age (p = 0.025), and a higher creatinine level (p = 0.003) and SAPS (p < 0.001). The risk for recannulation was 9.5% when patients breathed spontaneously for 19-24 h within the 24 h prior to decannulation, but 75.0% when patients breathed for only 0-6 h without ventilatory support (p < 0.001). According to ROC analysis, the SAPS best predicted successful decannulation {[}AUC 0.725 (95% CI: 0.634-0.815), p < 0.001]. Recannulated patients had longer durations of intubation (p = 0.046), tracheostomy (p = 0.003) and hospital stay (p < 0.001). Conclusion: In percutaneously tracheostomized patients with prolonged weaning, the use of a TR seems to facilitate and improve the weaning process considerably. The duration of spontaneous breathing prior to decannulation, age and oxygenation describe the risk for recannulation in these patients. Copyright (c) 2012 S. Karger AG, Base

Four Levels of Hierarchical Organization, Including Noncovalent Chainmail, Brace the Mature Tumor Herpesvirus Capsid against Pressurization

SummaryLike many double-stranded DNA viruses, tumor gammaherpesviruses Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus withstand high internal pressure. Bacteriophage HK97 uses covalent chainmail for this purpose, but how this is achieved noncovalently in the much larger gammaherpesvirus capsid is unknown. Our cryoelectron microscopy structure of a gammaherpesvirus capsid reveals a hierarchy of four levels of organization: (1) Within a hexon capsomer, each monomer of the major capsid protein (MCP), 1,378 amino acids and six domains, interacts with its neighboring MCPs at four sites. (2) Neighboring capsomers are linked in pairs by MCP dimerization domains and in groups of three by heterotrimeric triplex proteins. (3) Small (∼280 amino acids) HK97-like domains in MCP monomers alternate with triplex heterotrimers to form a belt that encircles each capsomer. (4) One hundred sixty-two belts concatenate to form noncovalent chainmail. The triplex heterotrimer orchestrates all four levels and likely drives maturation to an angular capsid that can withstand pressurization

'Mindless markers of the nation': The routine flagging of nationhood across the visual environment

The visual environment has increasingly been used as a lens with which to understand wider processes of social and economic change with studies employing in-depth qualitative approaches to focus on, for example, gentrification or trans-national networks. This exploratory paper offers an alternative perspective by using a novel method, quantitative photo mapping, to examine the extent to which a particular socio-cultural marker, the nation, is ‘flagged’ across three contrasting sites in Britain. As a multi-national state with an increasingly diverse population, Britain offers a particularly fruitful case study, drawing in debates around devolution, European integration and Commonwealth migration. In contributing to wider debates around banal nationalism, the paper notes the extent to which nations are increasingly articulated through commerce, consumption and market exchange and the overall significance of everyday markers (signs, objects, infrastructure) in naturalising a national view of the world

Improving psychological science: further thoughts, reflections and ways forward

Cogent Psychology is a pioneering and dynamic Open Access journal for the psychology community, publishing original research, reviews, and replications that span the full spectrum of psychological inquiry. In 2021, it relaunched with a new Editor-in-Chief and Section Editors with an exciting vision to combine open access publishing with open research practices. As such, the journal welcomes traditional and new article formats, including Registered Reports, Brief Replication Reports, Review Articles, and Brief Reports. This broader range of formats is designed to reflect the evolving nature of psychological research and open science approaches. To the best of our knowledge, no other psychology journal offers such a distinctive combination of article publishing formats. Moreover, we welcome submissions in nine key areas of psychological science: Clinical Psychology, Cognitive & Experimental Psychology, Developmental Psychology, Educational Psychology, Health Psychology, Neuropsychology, Personality & Individual Differences, Social Psychology and Work, Industrial & Organisational Psychology

The failure of suicide prevention in primary care: family and GP perspectives - a qualitative study

Background Although Primary care is crucial for suicide prevention, clinicians tend to report completed suicides in their care as non-preventable. We aimed to examine systemic inadequacies in suicide prevention from the perspectives of bereaved family members and GPs.Methods Qualitative study of 72 relatives or close friends bereaved by suicide and 19 General Practitioners who have experienced the suicide of patients.Results Relatives highlight failures in detecting symptoms and behavioral changes and the inability of GPs to understand the needs of patients and their social contexts. A perceived overreliance on anti-depressant treatment is a major source of criticism by family members. GPs tend to lack confidence in the recognition and management of suicidal patients, and report structural inadequacies in service provision.Conclusions Mental health and primary care services must find innovative and ethical ways to involve families in the decision-making process for patients at risk of suicide

DON ANTE DRAČEVAC (1920-1993)

<div><p>Diapause is an actively induced dormancy that has evolved in Metazoa to resist environmental stresses. In temperate regions, many diapausing insects overwinter at low temperatures by blocking embryonic, larval or adult development. Despite its Afro-tropical origin, <i>Drosophila melanogaster</i> migrated to temperate regions of Asia and Europe where females overwinter as adults by arresting gonadal development (reproductive diapause) at temperatures <13°C. Recent work in <i>D</i>. <i>melanogaster</i> has implicated the developmental hormones dILPs-2 and/or dILP3, and dILP5, homologues of vertebrate insulin/insulin-like growth factors (IGFs), in reproductive arrest. However, polymorphisms in <i>timeless (tim)</i> and <i>couch potato (cpo)</i> dramatically affect diapause inducibility and these dILP experiments could not exclude this common genetic variation contributing to the diapause phenotype. Here, we apply an extensive genetic dissection of the insulin signaling pathway which allows us to see both enhancements and reductions in egg development that are independent of <i>tim</i> and <i>cpo</i> variations. We show that a number of manipulations dramatically enhance diapause to ~100%. These include ablating, or reducing the excitability of the insulin-producing cells (IPCs) that express dILPs-2,3,5 employing the <i>dilp2</i>,<i>3</i>,<i>5</i>^<i>-/-</i> triple mutant, desensitizing insulin signaling using a <i>chico</i> mutation, or inhibiting dILP2 and 5 in the hemolymph by over-expressing Imaginal Morphogenesis Protein-Late 2 (Imp-L2). In addition, triple mutant <i>dilp2</i>,<i>3</i>,<i>5</i>^-/- females maintain high levels of diapause even when temperatures are raised in adulthood to 19°C. However at 22°C, these females all show egg development revealing that the effects are conditional on temperature and not a general female sterility. In contrast, over-expression of <i>dilps-2/5</i> or enhancing IPC excitability, led to levels of ovarian arrest that approached zero, underscoring dILPs-2 and 5 as key antagonists of diapause.</p></div

Human Tyrosine Hydroxylase Natural Allelic Variation: Influence on Autonomic Function and Hypertension

The catecholamine biosynthetic pathway consists of several enzymatic steps in series, beginning with the amino acids phenylalanine and tyrosine, and eventuating in the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline). Since the enzyme tyrosine hydroxylase (TH; tyrosine 3-mono-oxygenase; EC 1.14.16.2; chromosome 11p15.5) is generally considered to be rate-limiting in this pathway, probed as to whether common genetic variation at the TH gene occurred, and whether such variants contributed to inter-individual alterations in autonomic function, either biochemical or physiological. We began with sequencing a tetranucleotide (TCAT) repeat in the first intron, and found that the two most common versions, (TCAT)6 and (TCAT)10i, predicted heritable autonomic traits in twin pairs. We then conducted systematic polymorphism discovery across the ~8 kbp locus, and discovered numerous variants, principally non-coding. The proximal promoter block contained four common variants, and its haplotypes and SNPs (especially C-824T, rs10770141) predicted catecholamine secretion, environmental stress-induced BP increments, and hypertension. Finally, we found that two of the common promoter variants, C-824T (rs10770141) and A-581G (rs10770140), were functional in that they differentially affected transcriptional activity of the isolated promoter, disrupted recognition motifs for specific transcription factor binding, altered the promoter responses to the co-transfected (exogenous) factors, and bound the endogenous factors in the chromatin fraction of the nucleus. We concluded that common variation in the proximal TH promoter is functional, giving rise to changes in autonomic function and consequently cardiovascular risk