identifying allosteric networks to fight antibiotics resistance

The rise of multi-drug resistance in bacterial pathogens is one of the grand challenges facing medical science. A major concern is the speed of development of β-lactamase-mediated resistance in Gram-negative species, thus putting at risk the efficacy of the most recently approved antibiotics and inhibitors, including carbapenems and avibactam, respectively. New strategies to overcome resistance are urgently required, which will ultimately be facilitated by a deeper understanding of the mechanisms that regulate the function of β-lactamases such as the Klebsiella Pneumoniae carbapenemases (KPCs). Using enhanced sampling computational methods together with site-directed mutagenesis, we report the identification of two “hydrophobic networks” in the KPC-2 enzyme, the integrity of which has been found to be essential for protein stability and corresponding resistance. Present throughout the structure, these networks are responsible for the structural integrity and allosteric signaling. Disruption of the networks leads to a loss of the KPC-2 mediated resistance phenotype, resulting in restored susceptibility to different classes of β-lactam antibiotics including carbapenems and cephalosporins. The ”hydrophobic networks” were found to be highly conserved among class-A β-lactamases, which implies their suitability for exploitation as a potential target for therapeutic intervention

IIGEO online magazine: History, database, statistical and forecasting

La Revista del Instituto de Investigación-IIGEO desde sus inicios ha cubierto líneas relevantes de la Minería, Medioambiente y Desarrollo Sostenible. Su incorporación como Revista Virtual a las Bases del Sistema de Bibliotecas (SISBIB) permitió cubrir un radio mayor de visitantes. Posteriormente se ingresó a las Bases Indexadas LATINDEX y SCIELO PERU lográndose una mayor presencia virtual en Internet. En estos últimos años se ha trabajado para ser parte de la Base OJS (Open Journal System), iniciativa que viene promoviendo el Vicerrectorado de Investigación–UNMSM para incorporar las publicaciones de los Institutos de Investigación de la Universidad. La IIGEO está considerada entre las mejores revistas virtuales de la UNMSM, junto a las revistas de Anales de Medicina, Revista Peruana de Biología y Revista de Investigaciones Peruanas de Veterinaria.The Institute of Investigation magazine IIGEO, from the beginning, is dealing with relevant subjects in mining, the environment and sustainable development. Its incorporation as virtual magazine into the system of libraries (SISBIB) allowed to spread it over a large number of visitors. Subsequently, the magazine was entered into the Indexed Bases like LATINDEC and SCIELO PERU, achieving a major virtual presence in internet. In recent years, we worked for sharing OJS Base (Open Journal System). This initiative is promoted by the UNMSM Vice Rector of investigation in order to incorporate the university institutes of investigationpublications. IIGEO is considered among the best UNMSM virtual magazines like Annals of Medicine (Anales de Medicina), Biological Peruvian Magazine (Revista Peruana de Biología) and Peruvian Investigations of Veterinary Magazine (Revista de Investigaciones Peruanas de Veterinaria)

NaViA: A Program for the Visual Analysis of Complex Mass Spectra

MOTIVATION: Native mass spectrometry is now a well-established method for the investigation of protein complexes, specifically their subunit stoichiometry and ligand binding properties. Recent advances allowing the analysis of complex mixtures lead to an increasing diversity and complexity in the spectra obtained. These spectra can be time consuming to tackle through manual assignment and challenging for automated approaches. RESULTS: Native Mass Spectrometry Visual Analyser (NaViA) is a web-based tool to augment the manual process of peak assignment. In addition to matching masses to the stoichiometry of its component subunits it allows raw data processing, assignment and annotation and permits mass spectra to be shared with their respective interpretation. AVAILABILITY: NaViA is open-source and can be accessed online under https://navia.ms. The source code and documentation can be accessed at https://github.com/d-que/navia, under the BSD 2-Clause license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

NaViA : a program for the visual analysis of complex mass spectra

Motivation: Native mass spectrometry is now a well-established method for the investigation of protein complexes, specifically their subunit stoichiometry and ligand binding properties. Recent advances allowing the analysis of complex mixtures lead to an increasing diversity and complexity in the spectra obtained. These spectra can be time-consuming to tackle through manual assignment and challenging for automated approaches. Results: Native Mass Spectrometry Visual Analyser is a web-based tool to augment the manual process of peak assignment. In addition to matching masses to the stoichiometry of its component subunits, it allows raw data processing, assignment and annotation and permits mass spectra to be shared with their respective interpretation. Availability and implementation: NaViA is open-source and can be accessed online under https://navia.ms. The source code and documentation can be accessed at https://github.com/d-que/navia, under the BSD 2-Clause licence. Supplementary information: Supplementary data are available at Bioinformatics online

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Deconstructing Allostery: Computational Assessment of the Binding Determinants of Allosteric PTP1B Modulators

It is currently challenging to predict whether fragment hits that do not bind to an orthosteric site could be elaborated into allosteric modulators, as in these cases binding does not necessarily translate into a functional effect. We propose a workflow using Markov State Models (MSMs) with steered molecular dynamics (sMD) to assess the allosteric potential of known binders. sMD simulations are employed to sample protein conformational space inaccessible to routine equilibrium MD timescales. Protein conformations sampled by sMD provide starting points for seeded MD simulations, which are combined into MSMs. The methodology is demonstrated on a dataset of protein tyrosine phosphatase 1B ligands. Experimentally confirmed allosteric inhibitors are correctly classified as inhibitors, whereas the deconstructed analogues show reduced inhibitory activity. Analysis of the MSMs provide insights into preferred protein-ligand arrangements that correlate with functional outcomes. The present methodology may find applications for progressing fragments towards lead molecules in FBDD campaigns

Reconstruction of apo A2A receptor activation pathways reveal ligand-competent intermediates and state-dependent cholesterol hotspots

G-protein coupled receptors (GPCRs) play a pivotal role in transmitting signals at the cellular level. Structural insights can be exploited to support GPCR structure-based drug discovery endeavours. Despite advances in GPCR crystallography, active state structures are scarce. Molecular dynamics (MD) simulations have been used to explore the conformational landscape of GPCRs. Efforts have been made to retrieve active state conformations starting from inactive structures, however to date this has not been possible without using an energy bias. Here, we reconstruct the activation pathways of the apo adenosine receptor (A2A), starting from an inactive conformation, by applying adaptive sampling MD combined with a goal-oriented scoring function. The reconstructed pathways reconcile well with experiments and help deepen our understanding of A2A regulatory mechanisms. Exploration of the apo conformational landscape of A2A reveals the existence of ligand-competent states, active intermediates and state-dependent cholesterol hotspots of relevance for drug discovery. To the best of our knowledge this is the first time an activation process has been elucidated for a GPCR starting from an inactive structure only, using a non-biased MD approach, opening avenues for the study of ligand binding to elusive yet pharmacologically relevant GPCR states