Targeting MarA N-terminal domain dynamics to prevent DNA binding.

Efflux is one of the mechanisms employed by Gram-negative bacteria to become resistant to routinely used antibiotics. The inhibition of efflux by targeting their regulators is a promising strategy to re-sensitize bacterial pathogens to antibiotics. AcrAB-TolC is the main resistance-nodulation-division efflux pump in Enterobacteriaceae.

Essential Functional Interplay of the Catalytic Groups in Acid Phosphatase.

The cooperative interplay between the functional devices of a preorganized active site is fundamental to enzyme catalysis. An in-depth understanding of this phenomenon is central to elucidating the remarkable efficiency of natural enzymes and provides an essential benchmark for enzyme design and engineering. Here, we study the functional interconnectedness of the catalytic nucleophile (His18) in an acid phosphatase by analyzing the consequences of its replacement with aspartate.

The N-terminal Helix-Turn-Helix Motif of Transcription Factors MarA and Rob Drives DNA Recognition.

DNA-binding proteins play an important role in gene regulation and cellular function. The transcription factors MarA and Rob are two homologous members of the AraC/XylS family that regulate multidrug resistance. They share a common DNA-binding domain, and Rob possesses an additional C-terminal domain that permits binding of low-molecular weight effectors.

Recent Advances in Understanding Biological GTP Hydrolysis through Molecular Simulation.

GTP hydrolysis is central to biology, being involved in regulating a wide range of cellular processes. However, the mechanisms by which GTPases hydrolyze this critical reaction remain controversial, with multiple mechanistic possibilities having been proposed based on analysis of experimental and computational data. In this mini-review, we discuss advances in our understanding of biological GTP hydrolysis based on recent computational studies and argue in favor of solvent-assisted hydrolysis as a conserved mechanism among GTPases.

Social cognition and interaction training for recent-onset schizophrenia: A preliminary randomized trial.

Comprehensive social cognition training programs have been effective to improve social cognition in people with chronic schizophrenia, although there is insufficient quality evidence for recent-onset psychosis. The aim of this study was to assess the effects of Social Cognition and Interaction Training (SCIT) in a sample of recent-onset schizophrenia outpatients. Sixteen participants who had their first psychotic episode for less than 2 years were randomly allocated to the SCIT group during 20 weeks (weekly sessions) or to a psychoeducation group and completed baseline and post-training assessment for cognitive biases, social cognition, clinical symptoms and functioning.

Migration of Junior Doctors: The Case of Psychiatric Trainees in Portugal.

Introduction: In the last few decades, the rates of international medical migration have continuously risen. In Psychiatry, there is great disparity in the workforce between high and low-income countries. Yet, little is known about the 'push' and 'pull' factors and the migratory intentions of trainees.

The role of ligand-gated conformational changes in enzyme catalysis.

Structural and biochemical studies on diverse enzymes have highlighted the importance of ligand-gated conformational changes in enzyme catalysis, where the intrinsic binding energy of the common phosphoryl group of their substrates is used to drive energetically unfavorable conformational changes in catalytic loops, from inactive open to catalytically competent closed conformations. However, computational studies have historically been unable to capture the activating role of these conformational changes. Here, we discuss recent experimental and computational studies, which can remarkably pinpoint the role of ligand-gated conformational changes in enzyme catalysis, even when not modeling the loop dynamics explicitly.

Pink- and orange-pigmented Planctomycetes produce saproxanthin-type carotenoids including a rare C carotenoid.

Planctomycetes are ubiquitous and environmentally important Gram-negative aquatic bacteria with key roles in global carbon and nitrogen cycles. Many planctomycetal species have a pink or orange colour and have been suggested to produce carotenoids. Potential applications as food colorants or anti-oxidants have been proposed.

GTP Hydrolysis Without an Active Site Base: A Unifying Mechanism for Ras and Related GTPases.

GTP hydrolysis is a biologically crucial reaction, being involved in regulating almost all cellular processes. As a result, the enzymes that catalyze this reaction are among the most important drug targets. Despite their vital importance and decades of substantial research effort, the fundamental mechanism of enzyme-catalyzed GTP hydrolysis by GTPases remains highly controversial.

Anxiety, Depression and Academic Performance: A Study Amongst Portuguese Medical Students Versus Non-Medical Students.

Introduction: The aim of the study is to assess the prevalence of anxiety and depressive symptoms in Portuguese medical students compared to students of other faculties, and the possible impact those symptoms have on academic performance.

Material And Methods: A cross-sectional study was conducted in a sample of 750 students: 512 medical students and 238 nonmedical students. All students anonymously completed a socio-demographic survey and the Hospital Anxiety and Depression Scale (HADS).

Functional ability in younger and older elderlies after discharge from the intensive care unit. A prospective cohort.

Objective: To compare the functional capacity of younger elderly individuals (60 to 79 years old) with that of older elderly individuals (≥ 80 years old) during the first 6 months after discharge from the intensive care unit.

Methods: A multicenter prospective cohort study was conducted, in which data on intensive care unit admission and outcomes after hospital discharge (immediate post-discharge, after 3 months and after 6 months) were collected. Muscle strength was evaluated through the protocol of the Medical Research Council and dynamometry (handgrip); the ability to perform activities of daily life and functional independence were assessed by the Barthel index and the usual level of physical activity (International Physical Activity Questionnaire); and quality of life was assessed by the 12-Item Short-Form Health Survey Version 2.

Molecular motion regulates the activity of the Mitochondrial Serine Protease HtrA2.

HtrA2 (high-temperature requirement 2) is a human mitochondrial protease that has a role in apoptosis and Parkinson's disease. The structure of HtrA2 with an intact catalytic triad was determined, revealing a conformational change in the active site loops, involving mainly the regulatory LD loop, which resulted in burial of the catalytic serine relative to the previously reported structure of the proteolytically inactive mutant. Mutations in the loops surrounding the active site that significantly restricted their mobility, reduced proteolytic activity both in vitro and in cells, suggesting that regulation of HtrA2 activity cannot be explained by a simple transition to an activated conformational state with enhanced active site accessibility.

Compulsory psychiatric treatment checklist: Instrument development and clinical application.

Instruments designed to evaluate the necessity of compulsory psychiatric treatment (CPT) are scarce to non-existent. We developed a 25-item Checklist (scoring 0 to 50) with four clusters (Legal, Danger, Historic and Cognitive), based on variables identified as relevant to compulsory treatment. The Compulsory Treatment Checklist (CTC) was filled with information on case (n=324) and control (n=251) subjects, evaluated under the Portuguese Mental Health Act (Law 36/98), in three hospitals.

A low fermentable oligo-di-mono saccharides and polyols (FODMAP) diet reduced pain and improved daily life in fibromyalgia patients.

Background And Aims: Fibromyalgia (FM) is a chronic, rheumatic disease characterized by widespread myofascial pain, of unknown aetiology, having a major impact on quality of life (QOL). Available pharmacotherapy for FM is marginally effective. FM is associated with co-morbidities of gastrointestinal (GI) disorders and Irritable Bowel Syndrome (IBS).

A low fermentable oligo-di-mono-saccharides and polyols (FODMAP) diet is a balanced therapy for fibromyalgia with nutritional and symptomatic benefits.

Introduction: Fibromyalgia is a chronic rheumatic disease producing widespread pain, associated to a major comorbidity -irritable bowel syndrome. Low FODMAPS diet (low fermentable oligo-di-mono-saccharides and polyols diet) has been effective in controlling irritable bowel syndrome symptoms. Overweight is an aggravating factor for fibromyalgia.

Clarifying the Catalytic Mechanism of Human Glutamine Synthetase: A QM/MM Study.

Glutamine synthetase (GS) is a crucial enzyme responsible for the elimination of both neurotoxic glutamate and toxic ammonium, by combining them into glutamine. Alterations on the GS activity are associated with severe liver and neurodegenerative diseases and its absence or malformation results in death. In this work, the catalytic mechanism of human GS has been investigated with high-level QM/MM calculations, showing a two-phase reaction cycle.

The Proximity between Hallucination and Delusion Dimensions: An Observational, Analytic, Cross-Sectional, Multicentre Study.

In psychiatric classifications, hallucinations (mainly auditory hallucinations) are one of the fundamental criteria for establishing a schizophrenia diagnosis or any of the related psychotic disorder's diagnoses. The conceptual proximity between delusions and hallucinations was maintained until the end of the XIX century, with several supporters during the XX century. Their limits were not yet definitely defined in terms of Descriptive Psychopathology, and much less so in terms of biochemical and anatomical models.

Cholesterol Biosynthesis: A Mechanistic Overview.

Cholesterol is an essential component of cell membranes and the precursor for the synthesis of steroid hormones and bile acids. The synthesis of this molecule occurs partially in a membranous world (especially the last steps), where the enzymes, substrates, and products involved tend to be extremely hydrophobic. The importance of cholesterol has increased in the past half-century because of its association with cardiovascular diseases, which are considered one of the leading causes of death worldwide.

Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets.

Background: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition.

Reaction Mechanism of Mycobacterium Tuberculosis Glutamine Synthetase Using Quantum Mechanics/Molecular Mechanics Calculations.

This paper is devoted to the understanding of the reaction mechanism of mycobacterium tuberculosis glutamine synthetase (mtGS) with atomic detail, using computational quantum mechanics/molecular mechanics (QM/MM) methods at the ONIOM M06-D3/6-311++G(2d,2p):ff99SB//B3LYP/6-31G(d):ff99SB level of theory. The complete reaction undergoes a three-step mechanism: the spontaneous transfer of phosphate from ATP to glutamate upon ammonium binding (ammonium quickly loses a proton to Asp54), the attack of ammonia on phosphorylated glutamate (yielding protonated glutamine), and the deprotonation of glutamine by the leaving phosphate. This exothermic reaction has an activation free energy of 21.

Structure of a truncated form of leucine zipper II of JIP3 reveals an unexpected antiparallel coiled-coil arrangement.

JIP3 and JIP4, two highly related scaffolding proteins for MAP kinases, are binding partners for two molecular motors as well as for the small G protein ARF6. The leucine zipper II (LZII) region of JIP3/4 is the binding site for these three partners. Previously, the crystal structure of ARF6 bound to JIP4 revealed LZII in a parallel coiled-coil arrangement.

Assessing the relation between career satisfaction in psychiatry with lifelong learning and scientific activity.

Lifelong learning (LLL) is an essential feature for the doctor to keep clinically updated and has been described as an indicator of competence and professionalism. The aim of this study was to evaluate the association between career satisfaction in psychiatry, lifelong learning, and commitment in scientific activities, taking into account other personal and professional effects. The survey was sent to 453 national psychiatrists and 190 surveys (41.