MDFF_NM: Improved Molecular Dynamics Flexible Fitting into Cryo-EM Density Maps with a Multireplica Normal Mode-Based Search.

Molecular Dynamics Flexible Fitting (MDFF) is a widely used tool to refine high-resolution structures into cryo-EM density maps. Despite many successful applications, MDFF is still limited by its high computational cost, overfitting, accuracy, and performance issues due to entrapment within wrong local minima. Modern ensemble-based MDFF tools have generated promising results in the past decade. In line with these studies, we present MDFF_NM, a stochastic hybrid flexible fitting algorithm combining Normal Mode Analysis (NMA) and simulation-based flexible fitting. Initial tests reveal that, besides accelerating the fitting process, MDFF_NM increases the diversity of fitting routes leading to the target, uncovering ensembles of conformations in closer agreement with experimental data. The potential integration of MDFF_NM with other existing methods and integrative modeling pipelines is also discussed.

Cooperative mechanics of PR65 scaffold underlies the allosteric regulation of the phosphatase PP2A.

PR65, a horseshoe-shaped scaffold composed of 15 HEAT (observed in Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats, forms, together with catalytic and regulatory subunits, the heterotrimeric protein phosphatase PP2A. We examined the role of PR65 in enabling PP2A enzymatic activity with computations at various levels of complexity, including hybrid approaches that combine full-atomic and elastic network models. Our study points to the high flexibility of this scaffold allowing for end-to-end distance fluctuations of 40-50 Å between compact and extended conformations. Notably, the intrinsic dynamics of PR65 facilitates complexation with the catalytic subunit and is retained in the PP2A complex enabling PR65 to engage the two domains of the catalytic subunit and provide the mechanical framework for enzymatic activity, with support from the regulatory subunit. In particular, the intra-repeat coils at the C-terminal arm play an important role in allosterically mediating the collective dynamics of PP2A, pointing to target sites for modulating PR65 function.

Sampling of Protein Conformational Space Using Hybrid Simulations: A Critical Assessment of Recent Methods.

Recent years have seen several hybrid simulation methods for exploring the conformational space of proteins and their complexes or assemblies. These methods often combine fast analytical approaches with computationally expensive full atomic molecular dynamics (MD) simulations with the goal of rapidly sampling large and cooperative conformational changes at full atomic resolution. We present here a systematic comparison of the utility and limits of four such hybrid methods that have been introduced in recent years: MD with excited normal modes (MDeNM), collective modes-driven MD (CoMD), and elastic network model (ENM)-based generation, clustering, and relaxation of conformations (ClustENM) as well as its updated version integrated with MD simulations (ClustENMD). We analyzed the predicted conformational spaces using each of these four hybrid methods, applied to four well-studied proteins, triosephosphate isomerase (TIM), 3-phosphoglycerate kinase (PGK), HIV-1 protease (PR) and HIV-1 reverse transcriptase (RT), which provide extensive ensembles of experimental structures for benchmarking and comparing the methods. We show that a rigorous multi-faceted comparison and multiple metrics are necessary to properly assess the differences between conformational ensembles and provide an optimal protocol for achieving good agreement with experimental data. While all four hybrid methods perform well in general, being especially useful as computationally efficient methods that retain atomic resolution, the systematic analysis of the same systems by these four hybrid methods highlights the strengths and limitations of the methods and provides guidance for parameters and protocols to be adopted in future studies.

Identification, pathogenicity and histopathology of Colletotrichum sansevieriae causing anthracnose of Sansevieria trifasciata in Malaysia.

AIMS: To characterize causal pathogen of Sansevieria trifasciata anthracnose through morphology and molecular analysis; to evaluate the host range of the pathogen; and to explicate the infection process by the pathogen histopathologically. METHODS AND RESULTS: Symptomatic leaves of S. trifasciata were collected from five states in Malaysia. The causal pathogen was isolated and identified for the first time in Malaysia as C. sansevieriae based on morphological and multi-gene phylogenetic analyses using ITS, TUB2 and GAPDH sequences. Pathogenicity tests were conducted on different hosts. Colletotrichum sansevieriae was not pathogenic towards S. cylindrica, S. masoniana, Furcraea foetida, Chlorophytum comosum, Aloe vera and Gasteria carinata, confirming the exceptionally high host specificity for a species of Colletotrichum. Histopathology was performed using light microscope and scanning electron microscopy to study the infection process of C. sansevieriae on S. trifasciata. Colonization of host leaves by the pathogen was observed 2 days after inoculation. CONCLUSIONS: Colletotrichum sansevieriae caused anthracnose of S. trifasciata in Malaysia. It is a host-specific pathogen and colonized the host intracellularly. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of C. sansevieriae causing anthracnose of S. trifasciata in Malaysia. The host range test and understanding of the infection process will provide better understanding of the host-pathogen relationship and beneficial for effective disease management.

[COVID-19] Syndrome coronarien aigu et COVID-19 : Quelles particularités ?

En Décembre 2019, une épidémie de pneumonie cau¬sée par un nouveau coronarvirus (COVID-19) est apparue à Wuhan et s'est rapidement étendue à tra¬vers la Chine et les différents autres pays. Le virus en cause, le SARS-CoV 2 (severe acute respiratory syndrome coronavirus 2) a un pouvoir de contagion très important. Bien que les manifestations cliniques de COVID-19 soient dominées par des symptômes respiratoires, certains patients peuvent également présenter des complications cardiovasculaires. Les atteintes cardio¬vasculaires les plus souvent observées en cas d'infec¬tion à COVID-19 sont les suivantes: les lésions myo¬cardiques (élévation des troponines), les myocardites, les syndromes coronaires aigus (SCA), les arythmies, les complications thromboemboliques veineuses et l'insuffisancecardiaque.Laphysiopathologie de cette atteinte cardiaque est encore mal élucidée au vu de la littérature actuelle re¬lative à la pandémie Covid-19. Dans cet article, nous aborderons les mécanismes physiopathologiques menant à l'atteinte coronaire, la particularité de la prise en charge du syndrome coro¬narien avec et sans sus décalage du segment ST (STE¬MI et NSTEMI) dans ce contexte pandémique

Water extraction and root traits in Oryza sativa × Oryza glaberrima introgression lines under different soil moisture regimes.

Drought is a major constraint to rainfed rice production in some parts of sub Saharan Africa (SSA) because of irregular and low rainfall. Improving root water uptake during progressive soil drying could contribute to terminal drought stress resistance. Two lysimeter experiments were conducted using 200 introgression lines (ILs) derived from Oryza sativa L.×Oryza glaberrima Steud. crosses (IR64/RAM54 and IR64/RAM90) to characterise water uptake and root traits under progressive soil drying and to assess genetic differences among these lines in relation to drought stress. The lysimeter facility setup and protocols for simultaneous monitoring of water uptake rates and leaf area are described. Significant genetic variability for water uptake and root traits among the ILs was observed under drought stress. Water uptake in the drought stress treatments was correlated with root length density (RLD) and root dry matter (RDM) at lower soil depths. The highest RLD values at depth were observed among the RAM90 ILs and genetic differences were observed between RAM90 and RAM54 populations, implying that accession RAM90 could be used as a source for improving drought avoidance in lowland rice. The ILs with greater water uptake identified in this study will be used in future research for improving drought resistance of rice in SSA.

Sexual dysfunction and depression: etiology, prevalence, and treatment.

Sexual dysfunction and depression are very common conditions that are age-related and chronic. In men, epidemiologic studies have confirmed a strong correlation between erectile dysfunction and symptoms of depression. Both conditions have a significant negative impact on the quality of life of patients and their partners. Several studies showed that restoration of normal sexual function improves the quality of life of patients and their partners, regardless of treatment method. The literature review and recent observations emphasize the multifactorial nature of sexual dysfunction and, more specifically, erectile dysfunction and underline the importance of the comorbidity and bidirectional relationship between erectile dysfunction and depression. Research is progressing on the possible link between andropause, sexual dysfunction, and depression, thus opening potential new opportunities to address issues of aging-related morbidities.

Common conditions of the aging male: erectile dysfunction, benign prostatic hyperplasia, cardiovascular disease and depression.

With increasing life expectancy, medical profession will be faced with the task of ensuring that the large, aging population remains healthy and vital despite the face of increasing healthcare costs. Naturally, urology as a specialty is concerned with important geriatric issues. This article will focus specifically on the aging male population and the health problems that most frequently plague them. Four major, non-cancer, disease states have been identified that adversely effect males over the age of 50. These conditions are: erectile dysfunction (ED), benign prostatic hyperplasia (BPH), cardiovascular disease (CVD) and depression. A literature search of PubMed was conducted using the key words ED, BPH, CVD and depression as well as ADAM (Androgen Decline in the Aging Male) and quality of life (QoL). NIH and WHO conference proceedings and publications were also referenced to insure detail and accuracy of data. Information was then organized and correlated in order to provide a detailed description of the key conditions and their interrelatedness. The spectrum of research performed thus far regarding this topic has done little to investigate the effects, causes and correlations between these conditions. Research has been done linking two or three of these conditions; however, there remains to be information discussing the four disease states in terms of their possible cause and effect relationships or the effectiveness of parallel, multi-disciplinary approach to their therapy. This report calls attention to the benefits of viewing and researching the above mentioned conditions as possibly interrelated, as opposed to the traditional view of them as separate, unrelated and independently treatable disease states. ED, BPH, CVD and depression are all common conditions that accompany aging and negatively impact QoL. They almost always develop with age and precipitate considerable morbidity and may even result in mortality. Furthermore, the presentation of one condition may correlate with the development of another. The inter-relation of these conditions, as evident from their underlying similarities, cause-and-effects relationships and therapeutic consequences, should be enough to warrant a multidisciplinary approach to their research. This approach, combined with careful choice of therapy, parallel and singular, will help providers reach their goal to keep patients healthy, and more importantly happy, late into their life, thus realizing the concept of "successful aging".