Influence of membrane on the antigen presentation of the HIV-1 envelope membrane proximal external region (MPER).

The membrane proximal external region (MPER) of the HIV envelope glycoproteins has generated renewed interest after a recent phase I vaccine trial that presented MPER lipid-peptide epitopes demonstrated promise to elicit a broad neutralization response. The antigenicity of MPER is intimately associated with the membrane, and its presentation relies significantly on the lipid composition. This review brings together recent findings on the influence of membranes on the conformation of MPER and its recognition by broadly neutralizing antibodies. Specifically, the review highlights the importance of properly accounting for the balance between protein-protein and membrane-protein interactions in vaccine design.

Insertion and Anchoring of HIV-1 Fusion Peptide into Complex Membrane Mimicking Human T-cell.

A fundamental understanding of how HIV-1 envelope (Env) protein facilitates fusion is still lacking. The HIV-1 fusion peptide, consisting of 15 to 22 residues, is the N-terminus of the gp41 subunit of the Env protein. Further, this peptide, a promising vaccine candidate, initiates viral entry into target cells by inserting and anchoring into human immune cells. The influence of membrane lipid reorganization and the conformational changes of the fusion peptide during the membrane insertion and anchoring processes, which can significantly affect HIV-1 cell entry, remains largely unexplored due to the limitations of experimental measurements. In this work, we investigate the insertion of the fusion peptide into an immune cell membrane mimic through multiscale molecular dynamics simulations. We mimic the native T-cell by constructing a 9-lipid asymmetric membrane, along with geometrical restraints accounting for insertion in the context of gp41. To account for the slow timescale of lipid mixing while enabling conformational changes, we implement a protocol to go back and forth between atomistic and coarse-grained simulations. Our study provides a molecular understanding of the interactions between the HIV-1 fusion peptide and the T-cell membrane, highlighting the importance of conformational flexibility of fusion peptides and local lipid reorganization in stabilizing the anchoring of gp41 into the targeted host membrane during the early events of HIV-1 cell entry. Importantly, we identify a motif within the fusion peptide critical for fusion that can be further manipulated in future immunological studies.

Predicting permeation of compounds across the outer membrane of P. aeruginosa using molecular descriptors.

The ability Gram-negative pathogens have at adapting and protecting themselves against antibiotics has increasingly become a public health threat. Data-driven models identifying molecular properties that correlate with outer membrane (OM) permeation and growth inhibition while avoiding efflux could guide the discovery of novel classes of antibiotics. Here we evaluate 174 molecular descriptors in 1260 antimicrobial compounds and study their correlations with antibacterial activity in Gram-negative Pseudomonas aeruginosa. The descriptors are derived from traditional approaches quantifying the compounds' intrinsic physicochemical properties, together with, bacterium-specific from ensemble docking of compounds targeting specific MexB binding pockets, and all-atom molecular dynamics simulations in different subregions of the OM model. Using these descriptors and the measured inhibitory concentrations, we design a statistical protocol to identify predictors of OM permeation/inhibition. We find consistent rules across most of our data highlighting the role of the interaction between the compounds and the OM. An implementation of the rules uncovered in our study is shown, and it demonstrates the accuracy of our approach in a set of previously unseen compounds. Our analysis sheds new light on the key properties drug candidates need to effectively permeate/inhibit P. aeruginosa, and opens the gate to similar data-driven studies in other Gram-negative pathogens.

Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane.

The oncogene RAS, extensively studied for decades, presents persistent gaps in understanding, hindering the development of effective therapeutic strategies due to a lack of precise details on how RAS initiates MAPK signaling with RAF effector proteins at the plasma membrane. Recent advances in X-ray crystallography, cryo-EM, and super-resolution fluorescence microscopy offer structural and spatial insights, yet the molecular mechanisms involving protein-protein and protein-lipid interactions in RAS-mediated signaling require further characterization. This study utilizes single-molecule experimental techniques, nuclear magnetic resonance spectroscopy, and the computational Machine-Learned Modeling Infrastructure (MuMMI) to examine KRAS4b and RAF1 on a biologically relevant lipid bilayer. MuMMI captures long-timescale events while preserving detailed atomic descriptions, providing testable models for experimental validation. Both in vitro and computational studies reveal that RBDCRD binding alters KRAS lateral diffusion on the lipid bilayer, increasing cluster size and decreasing diffusion. RAS and membrane binding cause hydrophobic residues in the CRD region to penetrate the bilayer, stabilizing complexes through ß-strand elongation. These cooperative interactions among lipids, KRAS4b, and RAF1 are proposed as essential for forming nanoclusters, potentially a critical step in MAP kinase signal activation.

Molecular docking analysis of a dermatan sulfate tetra-saccharide to human alpha-L-iduronidase.

Human alpha-L-iduronidase (IDUA) is a 653 amino acid protein involved in the sequential degradation of glycos-amino-glycans (GAG), heparan sulfate (HS), and dermatan sulfate (DS). Some variants in the IDUA gene produce a deficient enzyme that causes un-degraded DS and HS to accumulate in multiple tissues, leading to an organ dysfunction known as muco-poly-saccharidosis type I (MPS I). Molecular and catalytic activity assays of new or rare variants of IDUA do not predict the phenotype that a patient will develop. Therefore, it is of interest to describe the molecular docking analysis, to locate binding regions of DS to IDUA to better understand the effect of a variant on MPS I development. The results presented herein demonstrate the presence of a polar/acidic catalytic site and a basic region in the putative binding site of DS to IDUA. Further, synthetic substrate docking with the enzyme could help in the predictions of the MPS I phenotype.

Type 2 Diabetes Mellitus and Nonvalvular Atrial Fibrillation in Mexico: National Registries Raise a Red Flag

ABSTRACT Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide and is highly prevalent in Mexico, as 10.2% of the adult population harbors this condition. T2DM is usually associated with cardiovascular comorbidities, including arrhythmias. Metabolic impairment is one of the mechanisms that contribute to tissue remodeling that affects atrial structure, and concomitant, the cardiac conduction system, both could result in atrial fibrillation (AF). AF is estimated to affect more than a half million Mexicans, and its incidence is expected to keep rising. According to national registries, T2DM is present in 28.4% of Mexican patients with AF and the coexistence of both diseases is associated with a higher risk of stroke. In clinical practice, the CHA2DS2-VASc risk score is useful for stroke risk stratification in patients with AF to facilitate the adequate use of anticoagulation therapy. T2DM is among the items of the CHA2DS2-VASc score because it correlates with an intrinsic prothrombotic state. In this narrative review, we present information that highlights the need for optimal glucose control and adequate anticoagulation in subjects with T2DM and AF.

Trauma hepático / Hepátic trauma

Objetivo: Evaluar las causas, grados de lesión y localización del trauma hepático en las injurias tóraco-abdominales: solución quirúrgica y sus resultados, así como explicar el mecanismo de daño hepático según la causa de la injuria. Sumario: Los pacientes con trauma tóraco-abdominal presentan lesiones hepáticas con gran frecuencia, las que deben ser tratadas en forma rápida y oportuna. Método: Estudio retrospectivo de los casos de trauma hepático operados durante los años 1995 -2000 en el Hospital de Emergencias "José Casimiro Ulloa" en Lima Perú. Resultados: Se operaron 164 pacientes con 13.4 por ciento (22) de mortalidad. Los traumas fueron causados por contusión directa en 58 por ciento y agresión en 42 por ciento. La reparación hepática fue: Con sutura en 212 casos, taponamiento en 40 casos, hepatectomía en 1 caso y sin tratamiento en 2 casos. Hubieron 38 reintervenciones: La relación entre los grados de lesión hepática y la mortalidad fueron: Grado I:9 casos, sin ningún muerto Grado II: 97 casos con 4 muertos (4.1 por ciento); Grado III:37 casos con 2 muertos (5 por ciento), Grado IV: 12 casos con 7 muertos (58 por ciento); Grado V: 9 casos con 9 muertos (100 por ciento). Conclusión: El compromiso hepático en las injurias toráco-abdominales es alto, en nuestra experiencia, la mortalidad global fue de 13.6 por ciento, de estas el 70 por ciento por trauma cerrado y el 30 por ciento por trauma abierto. La resucitación, el soporte vital, la intervención quirúrgica oportuna y rápida , cualquiera sea la técnica usada para amainar el sangrado hepático, de buenos resultados. Muchas veces las lesiones acompañantes determinan la evolución del paciente. Los mecanismos de la lesión hepática son predecibles en los casos de trauma directo o desaceleración. En las lesiones por proyectiles o punzo penetrantentes, la trayectoria define el daño anatómico.

Cirugía de control de daños: a propósito de un caso / Damage control surgery: a case

La cirugía de control de daños constituye uno de los mayores y más complejos problemas en el tratamiento del paciente severamente traumatizado. La decisión de la instauración de una cirugía de control de daños se la debe tomar en el contexto de un paciente hemodinámicamente inestable con la premisa de controlar la hemorragia y diferir la reparación de otras lesiones para un segundo tiempo cuando el paciente se encuentre más estable. El principal objetivo de la cirugía de control de daños (CCD) es evitar la aparición de la triada letal.