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The document is a collection of summaries of various research studies related to HIV prevention and treatment. The studies cover a range of topics, including the use of pre-exposure prophylaxis (PrEP), the development of HIV vaccines and antibodies, and the implementation of long-acting HIV prevention methods. The studies provide valuable insights into different strategies and interventions aimed at increasing HIV testing, prevention, and treatment outcomes. [Extracted from the article]

Degeneracy is defined as multiple sets of solutions that can produce very similar system performance. Degeneracy is seen across phylogenetic scales, in all kinds of organisms. In neuroscience, degeneracy can be seen in the constellation of biophysical properties that produce a neuron’s characteristic intrinsic properties and/or the constellation of mechanisms that determine circuit outputs or behavior. Here, we present examples of degeneracy at multiple levels of organization, from single-cell behavior, small circuits, large circuits, and, in cognition, drawing conclusions from work ranging from bacteria to human cognition. Degeneracy allows the individual-to-individual variability within a population that creates potential for evolution. [ABSTRACT FROM AUTHOR]

Owing to unique structural features, triazine-based covalent organic polymers (COPs) have attracted significant attention and emerged as novel catalysts or support materials for an array of applications. Typically formed by reacting triazine-based monomers or the in situ creation of triazine rings from nitrile monomers, these COPs possess 2D/3D meso/microporous structures held together via strong covalent linkages. The quest for efficient, stable and recyclable catalytic systems globally necessitates the need for a well-structured and comprehensive review summarizing the synthetic methodologies and applications of triazine-based COPs. This review explores the various synthetic routes and applications of these COPs in photocatalysis, heterogeneous catalysis, electrocatalysis, adsorption and sensing. By exploring the latest advancements and future directions, this review offers valuable insights into the synthesis and applications of triazine-based COPs. [ABSTRACT FROM AUTHOR]

Introduction: Blood group antigens of the RH system (formerly known as "Rhesus") play an important role in transfusion medicine because of the severe haemolytic consequences of antibodies to these antigens. No crystal structure is available for RhD proteins with its partner RhAG, and the precise stoichiometry of the trimer complex remains unknown. Methods: To analyse their structural properties, the trimers formed by RhD and/ or RhAG subunits were generated by protein modelling and molecular dynamics simulations were performed. Results: No major differences in structural behaviour were found between trimers of different compositions. The conformation of the subunits is relatively constant during molecular dynamics simulations, except for three large disordered loops. Discussion: This work makes it possible to propose a reasonable stoichiometry and demonstrates the potential of studying the structural behaviour of these proteins to investigate the hundreds of genetic variants relevant to transfusion medicine. [ABSTRACT FROM AUTHOR]

The ability to view structures of proteins at atomic resolution, facilitated by the rise of macromolecular crystallography, has had a tremendous impact in many areas of sciences, including molecular pharmacology, drug discovery and biotechnology. However, the teaching of macromolecular crystallography in universities across the globe has been less than optimal. This could be attributed to the interdisciplinary nature of this subject, making it appear esoteric and incomprehensible, at least at first glance, for students who have exclusive training in only one specific discipline. For the instructor, this problem is compounded further by the plethora of complex concepts and specialized terminologies that the science of macromolecular crystallography has accumulated over the course of its evolution. Moreover, the advent of robotics and several sophisticated software algorithms have reduced the incentive to understand the beautiful conceptual bedrock on which this subject is based. As a way of addressing some of the challenges delineated above, this Words of Advice article attempts to formulate the broad framework within which the teaching and learning of macromolecular crystallography should be approached. It advocates the acknowledgement that this is an interdisciplinary field, with substantial contributions from chemical, physical, biological and mathematical sciences, requiring the evolution of teaching approaches that acknowledge this reality. Moreover, it suggests the use of visual tools, use of computational resources and history to make the subject more relatable to students. [ABSTRACT FROM AUTHOR]

Thrombosis, or the formation of blood clots, can lead to serious medical conditions such as stroke, heart attack, and deep vein thrombosis. The purinoreceptor P2Y12 plays a critical role in the thrombotic pathway and is targeted for therapy to prevent clot formation. However, it is essential to balance the regulation of thrombosis to avoid adverse situations. This study focuses on the P2Y12 receptor and aims to discern the protein residue network and differentiate residues based on their intramolecular interactions. The study utilized a statistical analysis to characterize the significant residues involved in ligand interaction, which helps to identify critical residues that are essential for the function of the receptor. A parametric analysis of interactions of residues in the intraprotein interaction was conducted, which revealed significant residue‐based contacts that facilitate protein interactions. By examining the interactions between residues, the mechanisms underlying protein interactions were studied and the importance of specific residues in facilitating these interactions was determined. This research provides important information on P2Y12, and the findings based on the network based significance of interacting residues may contribute to the development of new therapies that target the receptor to prevent clot formation while maintaining a balance in thrombosis regulation to avoid adverse outcomes. Ultimately, this study could lead to improved treatments for thrombotic disorders and better patient outcomes. [ABSTRACT FROM AUTHOR]

How do neurons that implement cell-autonomous self-regulation of calcium react to knockout of individual ion-channel conductances? To address this question, we used a heterogeneous population of 78 conductance-based models of hippocampal pyramidal neurons that maintained cell-autonomous calcium homeostasis while receiving theta-frequency inputs. At calcium steadystate, we individually deleted each of the 11 active ion-channel conductances from each model. We measured the acute impact of deleting each conductance (one at a time) by comparing intrinsic electrophysiological properties before and immediately after channel deletion. The acute impact of deleting individual conductances on physiological properties (including calcium homeostasis) was heterogeneous, depending on the property, the specific model, and the deleted channel. The underlying many-to-many mapping between ion channels and properties pointed to ion-channel degeneracy. Next, we allowed the other conductances (barring the deleted conductance) to evolve towards achieving calcium homeostasis during theta-frequency activity. When calcium homeostasis was perturbed by ion-channel deletion, post-knockout plasticity in other conductances ensured resilience of calcium homeostasis to ion-channel deletion. These results demonstrate degeneracy in calcium homeostasis, as calcium homeostasis in knockout models was implemented in the absence of a channel that was earlier involved in the homeostatic process. Importantly, in reacquiring homeostasis, ion-channel conductances and physiological properties underwent heterogenous plasticity (dependent on the model, the property, and the deleted channel), even introducing changes in properties that were not directly connected to the deleted channel. Together, post-knockout plasticity geared towards maintaining homeostasis introduced heterogenous off-target effects on several channels and properties, suggesting that extreme caution be exercised in interpreting experimental outcomes involving channel knockouts. [ABSTRACT FROM AUTHOR]

Thermus thermophilus is an extremely thermophilic organism that thrives at a temperature of 65°C. T. thermophilus genome has ~2218 genes, out of which 66% (1482 genes) have been annotated, and the remaining 34% (736 genes) are assigned as hypothetical proteins. In this work, biochemical and biophysical experiments were performed to characterize the hypothetical protein TTHA1873 from T. thermophilus. The hypothetical protein TTHA1873 acts as a nuclease, which indiscreetly cuts methylated and non‐methylated DNA in divalent metal ions and relaxes the plasmid DNA in the presence of ATP. The chelation of metal ions with EDTA inhibits its activity. These results suggest that the hypothetical protein TTHA1873 would be a CRISPR‐associated protein with non‐specific DNase activity and ATP‐dependent DNA‐relaxing activity. [ABSTRACT FROM AUTHOR]

A microtubule is a cylindrical biological polymer that plays key roles in cellular structure, transport, and signalling. In this work, based on studies of electronic properties of polyacetelene and mechanical properties of microtubules themselves (Spakowitz A. J., Phys. Rev. Lett., 103 (2009) 248101), we explore the possibility that microtubules could act as topological insulators that are gapped to electronic excitations in the bulk but possess robust electronic bounds states at the tube ends. Through analyses of structural and electronic properties, we model the microtubule as a cylindrical stack of Su-Schrieffer-Heeger chains (originally proposed in the context of polyacetylene) describing electron hopping between the underlying dimerized tubulin lattice sites. We postulate that the microtubule is mostly uniform, dominated purely by GDP-bound dimers, and is capped by a disordered regime due to the presence of GTP-bound dimers as well. In the uniform region, we identify the electron hopping parameter regime in which the microtubule is a topological insulator. We then show the manner in which these topological features remain robust when the hopping parameters are disordered. We briefly mention possible biological implications for these microtubules to possess topologically robust electronic bound states. [ABSTRACT FROM AUTHOR]

Lysosomal storage diseases (LSDs) consist of about 60 different monogenic disorders. Most of them occur due to protein misfolding. Only a few of those have been treated with molecular chaperones; the remaining either have limited treatment options or only management therapies. About 1860 single amino-acid substitutions (SAS) have been identified under LSDs. Merely, a handful of mutations have been studied experimentally. Availability of computational tools has made researchers turn toward genetic disorders to focus light on unexplored disorders and their mutations. Since all the LSDs are rare genetic disorders, not much research is carried out in this area. However, a mutational effect on protein function could be predicted, through bioinformatics tools. On that note, out of 1860 SAS, 58 predictions were neutral and 778 were predicted to be disease associated by all programs included in this study. The result of the prediction analysis of all mutations in each of the LSDs is curated into a database. This would make researchers know the deleterious nature of a mutation causing LSD. The database is available at http://lsddb.vit.ac.in:3000/. Lysosomal storage diseases (LSDs) are rare yet cytotoxic inherent metabolic aberrations, elucidated by excess accumulation of biomolecular substrates in cells of various organs, due to lysosomal defective functioning. To formulate effective analeptics against this detrimental and potentially life-threatening affliction, and to better comprehend the pathological mechanism behind LSDs, it is essential to know the integral detrimental mutations that actuate LSDs. To make researchers and the general populace aware of this pertinent information, we have designed a database that includes all the disorders categorized under LSDs. [ABSTRACT FROM AUTHOR]

Studying the straw lignocellulose strengthening mechanism during simultaneous degradation has important practical significance for improving resource utilization and reducing environmental pollution. In this paper, the degradation ability of four straw lignocellulose-degrading enzymes was evaluated by molecular docking and molecular dynamics. Using the significantly binds to straw lignocellulose-degrading enzyme as a template, a multifunctional lignocellulose-degrading enzyme 3CBH-1KS5-4XQD-1B85 was constructed based on amino acid recombination and homologous modeling. Five efficient degrading enzymes (3CBH-1, 3CBH-2, 3CBH-3, 3CBH-4, and 3CBH-5) were designed by site-directed mutagenesis of 3CBH-1KS5-4XQD-1B85 amino acid at position 346. Molecular dynamics showed that the degradation ability of 3CBH-1 was significant and it was 1.45 times higher than 3CBH-1KS5-4XQD-1B85. Moreover, the mechanism of enhanced degradability and the stability of the enzymes were explored. With the aid of Taguchi experiments, the suitable external environment for degrading straw was determined. In the presence of inhibitors (organic acids and phenolic compounds), the binding energy of 3CBH-1 (238.46 ± 30.96 kJ/mol) is 36.42% higher than that of 3CBH-1KS5-4XQD-1B85 (174.79 ± 20.35 kJ/mol) without external environmental stimulation. Based on homology modeling, this paper constructed a site-directed mutagenesis scheme of multifunctional enzymes, and the aim was to obtain multifunctional and efficient straw lignocellulose-degrading enzymes through protein engineering, which provided a feasible scheme for straw biodegradation. [ABSTRACT FROM AUTHOR]

The crystal structures of an L‐type lectin domain from Methanocaldococcus jannaschii in apo and mannose‐bound forms have been determined. A thorough investigation of L‐type lectin domains from several organisms provides insight into the differences in these domains from different kingdoms of life. While the overall fold of the L‐type lectin domain is conserved, differences in the lengths of the carbohydrate‐binding loops and significant variations in the Mn2+‐binding site compared to the Ca2+‐binding site are observed. Furthermore, the sequence and phylogenetic analyses suggest that the archaeal L‐type lectin domain is evolutionarily closer to the plant legume lectins than to its bacterial or animal counterparts. This is the first report of the biochemical, structural, sequence, and phylogenetic analyses of an L‐type lectin domain from archaea and serves to enhance our understanding of the species‐specific differences and evolution of L‐type lectin domains. [ABSTRACT FROM AUTHOR]

Synapse associated protein-97/Human Disk Large (SAP97/hDLG) is a conserved, alternatively spliced, modular, scaffolding protein critical in regulating the molecular organization of cell-cell junctions in vertebrates. We confirm that the molecular determinants of first order phase transition of SAP97/hDLG is controlled by morpho-functional changes in its nanoscale organization. Furthermore, the nanoscale molecular signatures of these signalling islands and phase transitions are altered in response to changes in cytosolic Ca2+. Additionally, exchange kinetics of alternatively spliced isoforms of the intrinsically disordered region in SAP97/hDLG C-terminus shows differential sensitivities to Ca2+ bound Calmodulin, affirming that the molecular signatures of local phase transitions of SAP97/hDLG depends on their nanoscale heterogeneity and compositionality of isoforms. SAP97/hDLG is a ubiquitous, alternatively spliced, and conserved modular scaffolding protein involved in the organization cell junctions and excitatory synapses. Here, authors confirm that SAP97/hDLG condenses in to nanosized molecular domains in both heterologous cells and hippocampal pyramidal neurons. Authors demonstrate that in vivo and in vitro condensation, molecular signatures of nanoscale condensates and exchange kinetics of SAP97/hDLG is modulated by the local availability of alternatively spliced isoforms. Additionally, SAP97/hDLG isoforms exhibits a differential sensitivity to Ca2+ bound Calmodulin, resulting in altered properties of nanocondensates and their real-time regulation [ABSTRACT FROM AUTHOR]

Of the 10 paralogs of MazEF Toxin-Antitoxin system in Mycobacterium tuberculosis, MazEF6 plays an important role in multidrug tolerance, virulence, stress adaptation and Non Replicative Persistant (NRP) state establishment. The solution structures of the DNA binding domain of MazE6 and of its complex with the cognate operator DNA show that transcriptional regulation occurs by binding of MazE6 to an 18 bp operator sequence bearing the TANNNT motif (-10 region). Kinetics and thermodynamics of association, as determined by NMR and ITC, indicate that the nMazE6-DNA complex is of high affinity. Residues in N-terminal region of MazE6 that are key for its homodimerization, DNA binding specificity, and the base pairs in the operator DNA essential for the protein-DNA interaction, have been identified. It provides a basis for design of chemotherapeutic agents that will act via disruption of TA autoregulation, leading to cell death. The dimeric MazE6 antitoxin binds to a specific sequence in its cognate operator DNA for autoregulation, and the key residues for dimerization and DNA binding are identified. [ABSTRACT FROM AUTHOR]

γ‐aminobutyric acid (GABA) is the major inhibitory neurotransmitter, and its levels in the synaptic space are controlled by the GABA transporter isoforms (GATs). GATs are structurally related to biogenic amine transporters but display interactions with distinct inhibitors used as anti‐epileptics. In this study, we engineer the binding pocket of Drosophila melanogaster dopamine transporter to resemble GAT1 and determine high‐resolution X‐ray structures of the modified transporter in the substrate‐free state and in complex with GAT1 inhibitors NO711 and SKF89976a that are analogs of tiagabine, a medication prescribed for the treatment of partial seizures. We observe that the primary binding site undergoes substantial shifts in subsite architecture in the modified transporter to accommodate the two GAT1 inhibitors. We also observe that SKF89976a additionally interacts at an allosteric site in the extracellular vestibule, yielding an occluded conformation. Interchanging SKF89976a interacting residue in the extracellular loop 4 between GAT1 and dDAT suggests a role for this motif in the selective control of neurotransmitter uptake. Our findings, therefore, provide vital insights into the organizational principles dictating GAT1 activity and inhibition. Synopsis: While γ‐aminobutyric acid (GABA) neurotransmitter release is vital to inhibitory synapse function and GABA transporters (GATs) are targeted by antiepileptic drugs, the mechanistic basis for their unique pharmacology remains elusive. Combining structural and biochemical analysis of engineered transporters, this study uncovers distinct features of the GAT binding pocket that dictate inhibitor interaction specificities. Substitution of 11 binding site residues results in a chimeric Drosophila melanogaster dopamine transporter with rat GAT1‐like inhibitor binding site (dDATGAT).Substrate‐free dDATGAT displays strongly altered binding site architecture with prominent subsites A and C′.GABA uptake inhibitors NO711 and SKF89976a bind dDATGAT within the primary binding site in the subsites A and C′.SKF89976a shows additional binding in the vestibule of dDAT displaying both competitive and noncompetitive inhibition.Modification of SKF89976a binding residues in the dDATGAT extracellular loop 4 affects neurotransmitter uptake activity. [ABSTRACT FROM AUTHOR]

Heme-biosynthetic pathway of malaria parasite is dispensable for asexual stages, but essential for mosquito and liver stages. Despite having backup mechanisms to acquire hemoglobin-heme, pathway intermediates and/or enzymes from the host, asexual parasites express heme pathway enzymes and synthesize heme. Here we show heme synthesized in asexual stages promotes cerebral pathogenesis by enhancing hemozoin formation. Hemozoin is a parasite molecule associated with inflammation, aberrant host-immune responses, disease severity and cerebral pathogenesis. The heme pathway knockout parasites synthesize less hemozoin, and mice infected with knockout parasites are protected from cerebral malaria and death due to anemia is delayed. Biosynthetic heme regulates food vacuole integrity and the food vacuoles from knockout parasites are compromised in pH, lipid unsaturation and proteins, essential for hemozoin formation. Targeting parasite heme synthesis by griseofulvin—a FDA-approved antifungal drug, prevents cerebral malaria in mice and provides an adjunct therapeutic option for cerebral and severe malaria. Malaria parasite heme pathway is non-essential for blood stages, but essential for mosquito and liver stages. Here, the authors show that heme pathway promotes cerebral pathogenesis by enhancing hemozoin formation and that targeting it with griseofulvin inhibits cerebral malaria in mice. [ABSTRACT FROM AUTHOR]

As existing vaccines fail to completely prevent COVID-19 infections or community transmission, there is an unmet need for vaccines that can better combat SARS-CoV-2 variants of concern (VOC). We previously developed highly thermo-tolerant monomeric and trimeric receptor-binding domain derivatives that can withstand 100 °C for 90 min and 37 °C for four weeks and help eliminate cold-chain requirements. We show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations and a 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for upcoming Phase I human clinical trials and that there is potential for increasing the efficacy with vaccine matching to improve the responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions, which show that, while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible and also carries the risk of eliciting unwanted antibodies against the oligomerisation domain. [ABSTRACT FROM AUTHOR]

Alcohol abuse causes severe metabolic abnormalities inducing hepatic damage and malnutrition. Since higher Fischer ratio proteins have therapeutic value in liver diseases, an investigation was undertaken to study the ameliorative effect of the enhanced Fischer ratio flaxseed protein hydrolysate (EFR-FPH) alone and in combination with antioxidant micronutrients on ethanol-induced hepatotoxicity in a rat model. The EFR-FPH was prepared by dual enzymatic hydrolysis and charcoal treatment of flaxseed protein. The ratio of the branched-chain:aromatic amino acids (Fischer ratio) was found to be 7·08. The EFR-FPH, characterised using LC-MS/MS, showed the abundance of free leucine and isoleucine compared with phenylalanine and tyrosine. The matrix-assisted laser desorption/ionisation-time of flight MS analysis revealed the larger peptides present in EFR-FPH with mass 2·3 kDa. The EFR-FPH improved the nutritional status, liver function and antioxidant defense in the ethanol hepatotoxicity-induced rat model. The hepatoprotective effect of EFR-FPH was significantly enhanced when combined with selenium or vitamin E. Ethanol-induced changes in the liver tissue were effectively suppressed in the groups receiving EFR-FPH. Flaxseed-based hepatoprotective dietary supplement was formulated incorporating an optimum level of EFR-FPH (10 %) based on sensory acceptability and was fortified with selenium and vitamin E. The hepatoprotective formulation significantly lowered aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin by 47, 61, 55 and 78 %, respectively, and improved the antioxidant defense in the ethanol hepatotoxicity-induced rat model. The current investigation suggests that EFR-FPH in synergy with antioxidant micronutrients is potent in ameliorating ethanol-induced hepatotoxicity and has a potential to form a hepatoprotective dietary supplement. [ABSTRACT FROM AUTHOR]

Carbon nano onion (CNO) from dried grass has been synthesized by carbonization in the size range, 20 to 100 nm. This shows catalytic property to transform aerial oxygen under visible light to generate reactive oxygen species (ROS). A concept has been presented herein to show that this CNO even under room light generates hydrogen peroxide which inhibits WSN influenza virus (H1N1). The advantage of introducing CNO, synthesized from a cheap source to cater to the global need, is to sterilize infected hospitals indoor and outdoor, aircraft carriers, air conditioner vents due to its sustained conversion of air to ROS. Thus, CNO use could prevent frequent evacuation as used by conventional sanitisers to sterilize infected places from other RNA virus and hospital pathogens under COVID-19 pandemic. Carbon nano onion (CNO) under aerial oxygen on exposure with visible light generates ROS which is capable to rupture the lipid envelope of SARS-CoV-2 followed by disintegrating its RNA. [ABSTRACT FROM AUTHOR]

Saturation suppressor mutagenesis was used to generate thermostable mutants of the SARS-CoV-2 spike receptor-binding domain (RBD). A triple mutant with an increase in thermal melting temperature of ~7°C with respect to the wild-type B.1 RBD and was expressed in high yield in both mammalian cells and the microbial host, Pichia pastoris , was downselected for immunogenicity studies. An additional derivative with three additional mutations from the B.1.351 (beta) isolate was also introduced into this background. Lyophilized proteins were resistant to high-temperature exposure and could be stored for over a month at 37°C. In mice and hamsters, squalene-in-water emulsion (SWE) adjuvanted formulations of the B.1-stabilized RBD were considerably more immunogenic than RBD lacking the stabilizing mutations and elicited antibodies that neutralized all four current variants of concern with similar neutralization titers. However, sera from mice immunized with the stabilized B.1.351 derivative showed significantly decreased neutralization titers exclusively against the B.1.617.2 (delta) VOC. A cocktail comprising stabilized B.1 and B.1.351 RBDs elicited antibodies with qualitatively improved neutralization titers and breadth relative to those immunized solely with either immunogen. Immunized hamsters were protected from high-dose viral challenge. Such vaccine formulations can be rapidly and cheaply produced, lack extraneous tags or additional components, and can be stored at room temperature. They are a useful modality to combat COVID-19, especially in remote and low-resource settings. [ABSTRACT FROM AUTHOR]

Obituary for Prof. Akira Ishihama: A MENTOR RAISING EPIGENETIC PRESENCE Akira established a biochemical system to purify each I E. coli i RNA polymerase subunit from wild-type or mutant cells, reconstitute the active polymerase and evaluate each subunit's contribution and effects of mutations. We mourn the departure of Prof. Akira Ishihama (Fig. [Extracted from the article]