140 research outputs found
Exploring the Free Energy Landscape: From Dynamics to Networks and Back
The knowledge of the Free Energy Landscape topology is the essential key to
understand many biochemical processes. The determination of the conformers of a
protein and their basins of attraction takes a central role for studying
molecular isomerization reactions. In this work, we present a novel framework
to unveil the features of a Free Energy Landscape answering questions such as
how many meta-stable conformers are, how the hierarchical relationship among
them is, or what the structure and kinetics of the transition paths are.
Exploring the landscape by molecular dynamics simulations, the microscopic data
of the trajectory are encoded into a Conformational Markov Network. The
structure of this graph reveals the regions of the conformational space
corresponding to the basins of attraction. In addition, handling the
Conformational Markov Network, relevant kinetic magnitudes as dwell times or
rate constants, and the hierarchical relationship among basins, complete the
global picture of the landscape. We show the power of the analysis studying a
toy model of a funnel-like potential and computing efficiently the conformers
of a short peptide, the dialanine, paving the way to a systematic study of the
Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press
Providing alcohol-related screening and brief interventions to adolescents through health care systems: Obstacles and solutions
Duncan Clark and Howard Moss identify obstacles to alcohol-related screening and treatment for adolescents and propose policy solutions
Anthrax Lethal Toxin Disrupts Intestinal Barrier Function and Causes Systemic Infections with Enteric Bacteria
A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activity and is partially attenuated by co-administration of broad spectrum antibiotics, indicating that it is both a cause and an effect of infection. These findings indicate that targeting of MAPK signaling pathways by anthrax LT compromises the structural integrity of the mucosal layer, serving to undermine the effectiveness of the intestinal barrier. Combined with the well-described immunosuppressive effects of LT, this disruption of the intestinal barrier provides a potential mechanism for host invasion via the enteric route, a common portal of entry during the natural infection cycle of Bacillus anthracis
Evaluation of emotion processing in HIV-infected patients and correlation with cognitive performance
Background: Facial emotion recognition depends on cortical and subcortical networks. HIV infection of the central
nervous system can damage these networks, leading to impaired facial emotion recognition.
Methods: We performed a cross-sectional single cohort study consecutively enrolling HIV + subjects during routine
outpatient visits. Age, gender and education-matched HIV-negative healthy individuals were also selected. Subjects
were submitted to a Facial Emotion Recognition Test, which assesses the ability to recognize six basic emotions
(disgust, anger, fear, happiness, surprise, sadness). The score for each emotion and a global score (obtained by
summing scores for each emotion) were analyzed. General cognitive status of patients was also assessed.
Results: A total of 49 HIV + and 20 HIVβsubjects were enrolled. On the Facial Emotion Recognition Test, ANOVA
revealed a significantly lower performance of HIV + subjects than healthy controls in recognizing fear. Moreover,
fear facial emotion recognition was directly correlated with Immediate Recall of Rey Words. The lower the patientsβ
neurocognitive performance the less accurate they were in recognizing happiness. AIDS-defining events were
negatively related to the correct recognition of happiness.
Conclusions: Fear recognition deficit in HIV + patients might be related to the impaired function of neural
networks in the frontostriatal system. AIDS events, including non-neurological ones, may have a negative effect on
this system. Inclusion of an emotion recognition test in the neuropsychological test battery could help clinicians
during the long term management of HIV-infected patients, to better understand the cognitive mechanisms
involved in the reduction of emotion recognition ability and the impact of this impairment on daily lif
Auditory Feedback Control of Vocal Pitch during Sustained Vocalization: A Cross-Sectional Study of Adult Aging
Background: Auditory feedback has been demonstrated to play an important role in the control of voice fundamental frequency (F0), but the mechanisms underlying the processing of auditory feedback remain poorly understood. It has been well documented that young adults can use auditory feedback to stabilize their voice F0 by making compensatory responses to perturbations they hear in their vocal pitch feedback. However, little is known about the effects of aging on the processing of audio-vocal feedback during vocalization. Methodology/Principal Findings: In the present study, we recruited adults who were between 19 and 75 years of age and divided them into five age groups. Using a pitch-shift paradigm, the pitch of their vocal feedback was unexpectedly shifted 650 or 6100 cents during sustained vocalization of the vowel sound/u/. Compensatory vocal F0 response magnitudes and latencies to pitch feedback perturbations were examined. A significant effect of age was found such that response magnitudes increased with increasing age until maximal values were reached for adults 51β60 years of age and then decreased for adults 61β75 years of age. Adults 51β60 years of age were also more sensitive to the direction and magnitude of the pitch feedback perturbations compared to younger adults. Conclusion: These findings demonstrate that the pitch-shift reflex systematically changes across the adult lifespan. Understanding aging-related changes to the role of auditory feedback is critically important for our theoretica
Comorbid substance abuse and brain morphology in recent-onset psychosis
The aim of the presented study was to compare schizophrenia and schizoaffective patients early in the course of the disease with and without comorbid substance abuse disorder (SUD vs. NSUD) with regard to brain morphology. In a prospective design 41 patients (20 SUD vs. 21 NSUD) diagnosed as recent-onset schizophrenia or schizoaffective disorder consecutively admitted to hospital received standardized psychopathological evaluation (BPRS, SANS, MADRS, CGI, GAF) and MRI scanning with volumetric measurement of superior temporal gyrus (STG), amygdala-hippocampal complex, and cingulum. Patients with SUD (primarily cannabis) were significantly younger, predominantly male and had a lower socioeconomic status. Despite less attentional impairment (SANS subscore) and elevated anxiety/depression (BPRS subscore) in patients with SUD compared to NSUD, no other psychopathological differences could be detected. There were no differences in the assessed temporolimbic brain morphology between the two subgroups. In conclusion, in this study substance abuse in recent-onset psychosis had no effect on brain morphology and the earlier onset of psychosis in patients with comorbid SUD could not be explained by supposed accentuated brain abnormalities in temporolimbic regions
Disorders of compulsivity: a common bias towards learning habits.
Why do we repeat choices that we know are bad for us? Decision making is characterized by the parallel engagement of two distinct systems, goal-directed and habitual, thought to arise from two computational learning mechanisms, model-based and model-free. The habitual system is a candidate source of pathological fixedness. Using a decision task that measures the contribution to learning of either mechanism, we show a bias towards model-free (habit) acquisition in disorders involving both natural (binge eating) and artificial (methamphetamine) rewards, and obsessive-compulsive disorder. This favoring of model-free learning may underlie the repetitive behaviors that ultimately dominate in these disorders. Further, we show that the habit formation bias is associated with lower gray matter volumes in caudate and medial orbitofrontal cortex. Our findings suggest that the dysfunction in a common neurocomputational mechanism may underlie diverse disorders involving compulsion.This study was funded by the WT fellowship grant for VV (093705/Z/
10/Z) and Cambridge NIHR Biomedical Research Centre. VV and NAH are Wellcome
Trust (WT) intermediate Clinical Fellows. YW is supported by the Fyssen Fondation
and MRC Studentships. PD is supported by the Gatsby Charitable Foundation. JEG has
received grants from the National Institute of Drug Abuse and the National Center for
Responsible Gaming. TWR and BJS are supported on a WT Programme Grant
(089589/Z/09/Z). The BCNI is supported by a WT and MRC grant.This is the final published version. It's also available from Molecular Psychiatry at http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201444a.html
The Peter Pan paradigm
Genetic and environmental agents that disrupt organogenesis are numerous and well described. Less well established, however, is the role of delay in the developmental processes that yield functionally immature tissues at birth. Evidence is mounting that organs do not continue to develop postnatally in the context of these organogenesis insults, condemning the patient to utilize under-developed tissues for adult processes. These poorly differentiated organs may appear histologically normal at birth but with age may deteriorate revealing progressive or adult-onset pathology. The genetic and molecular underpinning of the proposed paradigm reveals the need for a comprehensive systems biology approach to evaluate the role of maternal-fetal environment on organogenesis
Early indicators of exposure to biological threat agents using host gene profiles in peripheral blood mononuclear cells
<p>Abstract</p> <p>Background</p> <p>Effective prophylaxis and treatment for infections caused by biological threat agents (BTA) rely upon early diagnosis and rapid initiation of therapy. Most methods for identifying pathogens in body fluids and tissues require that the pathogen proliferate to detectable and dangerous levels, thereby delaying diagnosis and treatment, especially during the prelatent stages when symptoms for most BTA are indistinguishable flu-like signs.</p> <p>Methods</p> <p>To detect exposures to the various pathogens more rapidly, especially during these early stages, we evaluated a suite of host responses to biological threat agents using global gene expression profiling on complementary DNA arrays.</p> <p>Results</p> <p>We found that certain gene expression patterns were unique to each pathogen and that other gene changes occurred in response to multiple agents, perhaps relating to the eventual course of illness. Nonhuman primates were exposed to some pathogens and the <it>in vitro</it> and <it>in vivo</it> findings were compared. We found major gene expression changes at the earliest times tested post exposure to aerosolized <it>B. anthracis </it>spores and 30 min post exposure to a bacterial toxin.</p> <p>Conclusion</p> <p>Host gene expression patterns have the potential to serve as diagnostic markers or predict the course of impending illness and may lead to new stage-appropriate therapeutic strategies to ameliorate the devastating effects of exposure to biothreat agents.</p
Adolescent Brain Development and the Risk for Alcohol and Other Drug Problems
Dynamic changes in neurochemistry, fiber architecture, and tissue composition occur in the adolescent brain. The course of these maturational processes is being charted with greater specificity, owing to advances in neuroimaging and indicate grey matter volume reductions and protracted development of white matter in regions known to support complex cognition and behavior. Though fronto-subcortical circuitry development is notable during adolescence, asynchronous maturation of prefrontal and limbic systems may render youth more vulnerable to risky behaviors such as substance use. Indeed, binge-pattern alcohol consumption and comorbid marijuana use are common among adolescents, and are associated with neural consequences. This review summarizes the unique characteristics of adolescent brain development, particularly aspects that predispose individuals to reward seeking and risky choices during this phase of life, and discusses the influence of substance use on neuromaturation. Together, findings in this arena underscore the importance of refined research and programming efforts in adolescent health and interventional needs
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