906 research outputs found
Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.
Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control
Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal
Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base
Unraveling the Phylogenetic Relationships of the Eccoptochilinae, an Enigmatic Array of Ordovician Cheirurid Trilobites
The Cheiruridae are a diverse group of trilobites and several subfamilies within the clade have been the focus of recent phylogenetic studies. This paper focuses on the relationships of one of those subfamilies, the Ordovician Eccoptochilinae. We analyze sixteen species from six genera within the traditionally defined group, using the pilekiid Anacheirurus frederici as an outgroup. To assess the monophyly of the Eccoptochilinae seven sphaerexochine species, Kawina arnoldi, Sphaerexochus arenosus, S. atacius, S. latifrons, S. mirus, S. parvus, and S. scabridus were included in the analysis as well. The results of this analysis show that the genus Eccoptochile represents a paraphyletic grade and species traditionally assigned to Parasphaerexochus and Skelipyx plot within Pseudosphaerexochus. Also, representative species of Sphaerexochinae plot within the traditionally defined Eccoptochilinae, suggesting Eccoptochilinae itself is paraphyletic. To resolve this, we propose all species of Pseudosphaerexochus be placed within Sphaerexochinae and Eccoptochilinae be restricted to a monotypic Eccoptochile clavigera.This research was supported by NSF DEB-0716162
Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy
How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures
Predictors of outcome in infant and toddlers functional or behavioral disorders after a brief parentâinfant psychotherapy
The efficacy of parentâchild psychotherapies is widely recognized today. There are, however, less data on predictive factors for outcome in infants and toddlers and their parents. The aim of this study was to highlight predictive factors for outcome after a brief psychotherapy in a population of 49 infants and toddlers aged 3â30Â months presenting functional or behavioral disorders. Two assessments were performed, the first before treatment and the second a month after the end of the therapy. These assessments included an evaluation of the childâs symptoms, and of depressive or anxiety symptoms in the parents. The assessments after therapy show complete or partial improvement in the childâs symptoms for nearly three quarters, and a decrease in the number of anxious and depressive mothers, and also in the number of depressive fathers. Three independent factors appear as predictive of unfavorable outcome for the child: frequency and intensity of behavioral problems and fears, and the absence of the father at more than two-thirds of consultations. The outcome for the mother is associated solely with her anxiety score at the start of the therapy. This study underlines the particular difficulties involved in the treatment of infants and toddlers presenting behavioral disturbances and emotional difficulties, and the value of involving the father in treatment
Niche as a determinant of word fate in online groups
Patterns of word use both reflect and influence a myriad of human activities
and interactions. Like other entities that are reproduced and evolve, words
rise or decline depending upon a complex interplay between {their intrinsic
properties and the environments in which they function}. Using Internet
discussion communities as model systems, we define the concept of a word niche
as the relationship between the word and the characteristic features of the
environments in which it is used. We develop a method to quantify two important
aspects of the size of the word niche: the range of individuals using the word
and the range of topics it is used to discuss. Controlling for word frequency,
we show that these aspects of the word niche are strong determinants of changes
in word frequency. Previous studies have already indicated that word frequency
itself is a correlate of word success at historical time scales. Our analysis
of changes in word frequencies over time reveals that the relative sizes of
word niches are far more important than word frequencies in the dynamics of the
entire vocabulary at shorter time scales, as the language adapts to new
concepts and social groupings. We also distinguish endogenous versus exogenous
factors as additional contributors to the fates of words, and demonstrate the
force of this distinction in the rise of novel words. Our results indicate that
short-term nonstationarity in word statistics is strongly driven by individual
proclivities, including inclinations to provide novel information and to
project a distinctive social identity.Comment: Supporting Information is available here:
http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0019009.s00
Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc â Activity in the Medial Prefrontal Cortex
Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc â, a cystineâglutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis.
Objectives: Our goal was to determine whether increased system xc â activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating.
Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc â, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3â3 mg/kg, sc). N-Acetylcysteine (10â100 ÎŒM) and the system xc â inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 ÎŒM) were used to increase and decrease system xc â activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc â activity.
Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10â100 ÎŒM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 ÎŒM), indicating an involvement of system xc â.
Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc â independent mechanisms, but that increasing cystineâglutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine
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Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor.
An amendment to this paper has been published and can be accessed via a link at the top of the paper
Changes in coagulation functions and hemorheological parameters may predict hematoma formation after total knee arthroplasty
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