Elasticity of the HIV-1 core facilitates nuclear entry and infection.

HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid. Recent studies have shown that HIV-1 cores enter the nucleus prior to capsid disassembly. Interactions of the viral capsid with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown.

Elasticity of the HIV-1 Core Facilitates Nuclear Entry and Infection.

HIV-1 infection requires passage of the viral core through the nuclear pore of the cell, a process that depends on functions of the viral capsid . Recent studies have shown that HIV- 1 cores enter the nucleus prior to capsid disassembly . Interactions with the nuclear pore complex are necessary but not sufficient for nuclear entry, and the mechanism by which the viral core traverses the comparably sized nuclear pore is unknown.

Multidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization.

HIV-1 capsid (CA) stability is important for viral replication. E45A and P38A mutations enhance and reduce core stability, thus impairing infectivity. Second-site mutations R132T and T216I rescue infectivity.

Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining.

Dimensionality reduction via coarse grain modeling is a valuable tool in biomolecular research. For large assemblies, ultra coarse models are often knowledge-based, relying on a priori information to parameterize models thus hindering general predictive capability. Here, we present substantial advances to the shape based coarse graining (SBCG) method, which we refer to as SBCG2.

Recognition of the TDP-43 nuclear localization signal by importin α1/β.

Cytoplasmic mislocalization of the TAR-DNA binding protein of 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find that the NLS makes extensive contacts with importin α1, especially at the minor NLS-binding site.

HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration.

HIV-1 replication is durably controlled without antiretroviral therapy (ART) in certain infected individuals called elite controllers (ECs). These individuals express specific human leukocyte antigens (HLA) that tag HIV-infected cells for elimination by presenting viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In HIV-infected individuals expressing HLA-B27, CTLs primarily target the viral capsid protein (CA)-derived KK10 epitope.

Varicella-zoster virus reactivation is frequently detected in HIV-infected individuals presenting with stroke.

Infections are an underappreciated cause of stroke, particularly in young and immunocompromised individuals. Varicella-zoster virus (VZV) reactivation, particularly ophthalmic zoster, has been linked to increased risk of stroke but diagnosing VZV-associated cerebral vasculopathy is challenging as neither a recent zoster rash, nor detectable levels of VZV DNA are universally present at stroke presentation. Detection of VZV IgG in cerebrospinal fluid (CSF-VZVG) presents a promising alternative, but requires evaluation of individual blood-CSF dynamics, particularly in the setting of chronic inflammatory states such as HIV infection.

Full scale structural, mechanical and dynamical properties of HIV-1 liposomes.

Enveloped viruses are enclosed by a lipid membrane inside of which are all of the components necessary for the virus life cycle; viral proteins, the viral genome and metabolites. Viral envelopes are lipid bilayers that adopt morphologies ranging from spheres to tubes. The envelope is derived from the host cell during viral replication.

Deep-learning in situ classification of HIV-1 virion morphology.

Transmission electron microscopy (TEM) has a multitude of uses in biomedical imaging due to its ability to discern ultrastructure morphology at the nanometer scale. Through its ability to directly visualize virus particles, TEM has for several decades been an invaluable tool in the virologist's toolbox. As applied to HIV-1 research, TEM is critical to evaluate activities of inhibitors that block the maturation and morphogenesis steps of the virus lifecycle.

Molecular dynamics of the viral life cycle: progress and prospects.

Molecular dynamics (MD) simulations across spatiotemporal resolutions are widely applied to study viruses and represent the central technique uniting the field of computational virology. We discuss the progress of MD in elucidating the dynamics of the viral life cycle, including the status of modeling intact extracellular virions and leveraging advanced simulations to mimic active life cycle processes. We further remark on the prospects of MD for continued contributions to the basic science characterization of viruses, especially given the increasing availability of high-quality experimental data and supercomputing power.

Curvature of the Retroviral Capsid Assembly Is Modulated by a Molecular Switch.

During the maturation step, the retroviral capsid proteins (CAs) assemble into polymorphic capsids. Their acute curvature is largely determined by 12 pentamers inserted into the hexameric lattice. However, how the CA switches its conformation to control assembly curvature remains unclear.

Shortfall in stroke care: A study of ischaemic stroke care practices in a South African metropole.

Background: In recent years there have been significant advances in the management of stroke. In particular, reperfusion therapies have been shown to confer significant benefit, with the possibility of reversing ischaemic stroke or reducing disability when administered to suitable patients. However, these therapies also carry significant risk, including death.

Viral protein R polymorphisms in the pathogenesis of HIV-associated acute ischaemic stroke: a case-control study.

HIV-1 viral proteins have been implicated in endothelial dysfunction, which is a major determinant of ischaemic stroke risk in HIV-infected individuals. Polymorphisms in HIV-1 viral protein R (Vpr) may alter its potential to promote endothelial dysfunction, by modifying its effects on viral replication, reactivation of latent cells, upregulation of pro-inflammatory cytokines and infection of macrophages. We analysed Vpr polymorphisms and their association with acute ischaemic stroke by comparing Vpr signature amino acids between 54 HIV-infected individuals with acute ischaemic stroke, and 80 age-matched HIV-infected non-stroke controls.

Coronavirus through Delaware's Computational Microscope.

The Perilla/Hadden-Perilla research team at the University of Delaware presents an overview of computational structural biology, their efforts to model the SARS-CoV-2 viral particle, and their perspective on how their work and training endeavors can contribute to public health.

Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone).

High-Performance Analysis of Biomolecular Containers to Measure Small-Molecule Transport, Transbilayer Lipid Diffusion, and Protein Cavities.

Compartmentalization is a central theme in biology. Cells are composed of numerous membrane-enclosed structures, evolved to facilitate specific biochemical processes; viruses act as containers of genetic material, optimized to drive infection. Molecular dynamics simulations provide a mechanism to study biomolecular containers and the influence they exert on their environments; however, trajectory analysis software generally lacks knowledge of container interior versus exterior.

Structural basis for the homotypic fusion of chlamydial inclusions by the SNARE-like protein IncA.

Many intracellular bacteria, including Chlamydia, establish a parasitic membrane-bound organelle inside the host cell that is essential for the bacteria's survival. Chlamydia trachomatis forms inclusions that are decorated with poorly characterized membrane proteins known as Incs. The prototypical Inc, called IncA, enhances Chlamydia pathogenicity by promoting the homotypic fusion of inclusions and shares structural and functional similarity to eukaryotic SNAREs.

Impact of Low Ankle-Brachial Index on the Risk of Recurrent Vascular Events.

Background and Purpose- Low ankle-brachial index (ABI) identifies a stroke subgroup with high risk of recurrent stroke, cardiovascular events, and death. However, limited data exist on the relationship between low ABI and stroke in low and middle-income countries. Therefore, we evaluated the prevalence of ABI ≤0.

Poor anticoagulation control in patients taking warfarin at a tertiary and district-level prothrombin clinic in Cape Town, South Africa.

Background: Warfarin is the most commonly used anticoagulant for both primary and secondary prevention of thromboembolism. For anticoagulation efficacy, the international normalised ratio (INR) needs to be within the therapeutic range for at least 65% of time on warfarin.

Objectives: To describe INR control in patients on long-term warfarin and identified predictors of good INR control at two dedicated warfarin follow-up clinics in Cape Town, South Africa (SA).

Clinical and genetic analysis of spinocerebellar ataxia type 7 (SCA7) in Zambian families.

Background: To date, 43 types of Spinocerebellar Ataxias (SCAs) have been identified. A subset of the SCAs are caused by the pathogenic expansion of a CAG repeat tract within the corresponding gene. Ethnic and geographic differences are evident in the prevalence of the autosomal dominant SCAs.

Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial.

Background: Embolic strokes of undetermined source comprise up to 20% of ischemic strokes. The stroke recurrence rate is substantial with aspirin, widely used for secondary prevention. The New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source international trial will compare the efficacy and safety of rivaroxaban, an oral factor Xa inhibitor, versus aspirin for secondary prevention in patients with recent embolic strokes of undetermined source.