The Brain-Gut-Microbiome Axis.

Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases

Characterizing a Histidine Switch Controlling pH-Dependent Conformational Changes of the Influenza Virus Hemagglutinin

AbstractDuring the fusion of the influenza virus to the host cell, bending of the HA2 chain of hemagglutinin into a hairpin-shaped structure in a pH-dependent manner facilitates the fusion of the viral envelope and the endosomal membrane. To characterize the structural and dynamical responses of the hinge region of HA2 to pH changes and examine the role of a conserved histidine in this region (the hinge histidine), we have performed an extensive set of molecular dynamics (MD) simulations of 26-residue peptides encompassing the hinge regions of several hemagglutinin subtypes under both neutral and low pH conditions, modeled by the change of the protonation state of the hinge histidine. More than 70 sets of MD simulations (collectively amounting to 25.1 μs) were performed in both implicit and explicit solvents to study the effect of histidine protonation on structural dynamics of the hinge region. In both explicit and implicit solvent simulations, hinge bending was consistently observed upon the protonation of the histidine in all the simulations starting with an initial straight helical conformation, whereas the systems with a neutral histidine retained their primarily straight conformation throughout the simulations. Conversely, the MD simulations starting from an initially bent conformation resulted in the formation of a straight helical structure upon the neutralization of the hinge histidine, whereas the bent structure was maintained when the hinge histidine remained protonated. Finally, mutation of the hinge histidine to alanine abolishes the bending response of the peptide altogether. A molecular mechanism based on the interaction of the hinge histidine with neighboring acidic residues is proposed to be responsible for its role in controlling the conformation of the hinge. We propose that this might present a common mechanism for pH-controlled structural changes in helical structures when histidines act as the pH sensor

The knowledge and the use of psychological skills of anger management skills at the bedside by the physicians and nurses of Jahrom University of Medical Sciences in 2013

Although all individuals could be exposed to the outburst of anger, a group of them are more at risk than others because of the nature of their work and responsibilities, that the physicians and nurses are placed in this group. In the field of psychology, different skills such as social protection systems, problem-solving skills, self-relaxation system, use of humor skills and communication and negotiation skills have been proposed to control anger. Given the importance of anger management in the prevention of job violence in the health environment and its impact on psychological health of psychiatrists and nurses and also the lack of information and research on the topic, this study aimed to study the knowledge and the use of psychological skills of anger management at the bedside by the physicians and nurses of Jahrom University of Medical Sciences.Methodology: This study is a cross-sectional and descriptive research, its studied sample included 259 general practitioners, specialists and nurses working in two general hospitals affiliated to Jahrom University of Medical Sciences. They were included in the study by the census method. The data was collected by the self-report method and two researcher-made questionnaires: a questionnaire of the knowledge of the psychological skills of anger management and a questionnaire of the use of anger management skills at the bedside and their validity (face and content) and reliability were examined before performing the research. Data analysis was performed with descriptive statistics (mean, frequency, percentage) using SPSS software.Results: The mean of the knowledge of the physicians and nurses of Jahrom University of Medical Sciences from the psychological skills of anger management was 30.2 (standard deviation is equal to 1.53) that based on the classification of the scores of related questionnaire, it was at a good level. Also, the results showed that the mean of the use of psychological skills of anger management at the bedside by the physicians and nurses working in Jahrom University of Medical Sciences was 39.54 (standard deviation is equal to 1.28) that based on the classification of the scores of related questionnaire, it was at a good level.Conclusion: According to the results, the knowledge and the use of psychological skills of anger management skills at the bedside by the physicians and nurses of Jahrom University of Medical Sciences were at the desired level, however, it is proposed to use other evaluation and assessment methods which have no limitations of self-report method in future studies.Keywords: anger management skill, nurses, physician

Targeting Listeria monocytogenes consensus sequence of internalin genes using an antisense molecule

As an intracellular pathogen, Listeria monocytogenes can enter host cells where it can replicate and escape detection and eradication by the host immune response making the clearance of infection very challenging. Furthermore, with the advent of antimicrobial resistance, the need for alternative targets is inevitable. Internalin proteins are crucial to this bacterium as they contribute to bacterial entry to the systemic circulation. In this study, we targeted a highly conserved region of these proteins by an antisense sequence that was covalently conjugated to the cell penetrating peptides (CPP) to overcome the challenging delivery barriers. Then, we evaluated the efficiency of this construct in vitro. We also assessed the antigenicity, cytotoxicity, and probability of apoptosis induction by this construct. The studied CPP-PNA inhibited bacterial growth and suppressed the mRNA expression of internalins in a dose-dependent manner. In addition, at all studied concentrations, CPP-PNA significantly reduced the invasion rate of L. monocytogenes in the examined cell lines. Moreover, different concentrations of CPP-PNA did not have a significant antigenic, cytotoxic, and apoptotic properties compared to the control. These results suggest the effectiveness of CPP-antisense in targeting the mRNAs of internalins for various research, therapeutic and preventive purposes. However, additional research is required to evaluate the potency, safety, and pharmacokinetics of this compound for the prevention and treatment of listeriosis

COVID-19: The Immune Responses and Clinical Therapy Candidates.

The pandemic of coronavirus disease 2019 (COVID-19), with rising numbers of patients worldwide, presents an urgent need for effective treatments. To date, there are no therapies or vaccines that are proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several potential candidates or repurposed drugs are under investigation, including drugs that inhibit SARS-CoV-2 replication and block infection. The most promising therapy to date is remdesivir, which is US Food and Drug Administration (FDA) approved for emergency use in adults and children hospitalized with severe suspected or laboratory-confirmed COVID-19. Herein we summarize the general features of SARS-CoV-2's molecular and immune pathogenesis and discuss available pharmacological strategies, based on our present understanding of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Finally, we outline clinical trials currently in progress to investigate the efficacy of potential therapies for COVID-19

Effects of sub-inhibitory concentrations of antibiotics and oxidative stress on the expression of type II toxin-antitoxin system genes in Klebsiella pneumoniae

Objectives: Sub-inhibitory concentrations (sub-MICs) of antibiotics reflect the conditions that bacteria encounter in tissues and the natural environment. Sub-MICs of antibiotics can induce stress and alter the expression of different bacterial genes. Bacteria react to stress conditions using different mechanisms, one of which is the toxin-antitoxin (TA) system. This study investigated the expression of the TA system genes under oxidative and antibiotic stresses in Klebsiella pneumoniae (K. pneumoniae). Methods: To determine the effects of sub-MICs of gentamicin, nalidixic acid, ceftazidime, and certain concentrations of H2O2 on bacterial survival and growth, colony forming units were quantitated and turbidity was assessed following the treatment of K. pneumoniae with ½ MICs of antibiotics and 5 mM H2O2 at different time intervals. The expression of TA system genes in K. pneumoniae was evaluated 1 h after treatment using the quantitative real-time PCR (qRT-PCR) method. Results: The results revealed reduced K. pneumoniae growth in the presence of sub-MICs of antibiotics and 5 mM H2O2 compared to the control. Furthermore, according to the results of the qRT-PCR assay, only the presence of gentamicin could increase the expression of TA system genes. Conclusion: Although the exact role of the TA systems in response to stress is still unclear, this study provided information on the effect of the type II TA systems under oxidative and antibiotic stress conditions. © 2019 International Society for Antimicrobial Chemotherap

Exploring the dynamics of adult Axin2 cell lineage integration into dentate gyrus granule neurons

The Wnt pathway plays critical roles in neurogenesis. The expression of Axin2 is induced by Wnt/β-catenin signaling, making this gene a reliable indicator of canonical Wnt activity. We employed pulse-chase genetic lineage tracing with the Axin2-CreERT2 allele to follow the fate of Axin2+ lineage in the adult hippocampal formation. We found Axin2 expressed in astrocytes, neurons and endothelial cells, as well as in the choroid plexus epithelia. Simultaneously with the induction of Axin2 fate mapping by tamoxifen, we marked the dividing cells with 5-ethynyl-2′-deoxyuridine (EdU). Tamoxifen induction led to a significant increase in labeled dentate gyrus granule cells three months later. However, none of these neurons showed any EdU signal. Conversely, six months after the pulse-chase labeling with tamoxifen/EdU, we identified granule neurons that were positive for both EdU and tdTomato lineage tracer in each animal. Our data indicates that Axin2 is expressed at multiple stages of adult granule neuron differentiation. Furthermore, these findings suggest that the integration process of adult-born neurons from specific cell lineages may require more time than previously thought

Ultra-High Carrier Mobilities in Ferroelectric Domain Wall Corbino Cones at Room Temperature

Recently, electrically conducting heterointerfaces between dissimilar band-insulators (such as lanthanum aluminate and strontium titanate) have attracted considerable research interest. Charge transport has been thoroughly explored and fundamental aspects of conduction firmly established. Perhaps surprisingly, similar insights into conceptually much simpler conducting homointerfaces, such as the domain walls that separate regions of different orientations of electrical polarisation within the same ferroelectric band-insulator, are not nearly so well-developed. Addressing this disparity, we herein report magnetoresistance in approximately conical 180° charged domain walls, which occur in partially switched ferroelectric thin film single crystal lithium niobate. This system is ideal for such measurements: firstly, the conductivity difference between domains and domain walls is extremely and unusually large (a factor of at least 1013) and hence currents driven through the thin film, between planar top and bottom electrodes, are overwhelmingly channelled along the walls; secondly, when electrical contact is made to the top and bottom of the domain walls and a magnetic field is applied along their cone axes (perpendicular to the thin film surface), then the test geometry mirrors that of a Corbino disc, which is a textbook arrangement for geometric magnetoresistance measurement. Our data imply carriers at the domain walls with extremely high room temperature Hall mobilities of up to ~ 3,700cm2V-1s-1. This is an unparalleled value for oxide interfaces (and for bulk oxides too) and is most comparable to mobilities in other systems typically seen at cryogenic, rather than at room, temperature