Role of direct antiglobulin test in anemia under evaluation: Its prevalence, laboratory workup, and significance in further patient management-a study from eastern India.

INTRODUCTION AND AIMS: The direct antiglobulin test (DAT) is an important diagnostic tool for immune hemolytic anemia (IHA). The present study was primarily aimed to identify the prevalence of DAT positivity in anemia patients along with its specificity . A three months follow up of the DAT positive patients were performed for the response during course of illness in terms of transfusion requirement, hemoglobin level, persistence of DAT. MATERIALS AND METHODS: This cross sectional study was performed at a government medical college on symptomatic anemia patients. At initial evaluation, complete blood count (CBC), blood grouping and DAT were performed in the EDTA blood. DAT positive blood samples were analyzed for their immunoglobulin specificity, auto or alloantibody type. Acid elution and red cell phenotyping were performed wherever applicable. Their clinical presentation, hematological and biochemical parameters of hemolysis were evaluated. Statistical analysis was performed on the results on SPSS (Version 23.0;.USA) and Graph pad Prism version 9. P value <0.05 was considered significant. RESULTS: DAT was present in 64 out of 501 patients with male female ratio 1: 4. Warm AIHA (WAIHA) was 93.7% with secondary WAIHA 60%. IgG was associated in 86% DAT positive samples, Only C3d was 14%. All the 4 cold AIHA (6.3%) had a higher antibody titre and thermal amplitude.DAT strength was directly proportional to the degree of hemolysis. During 3 months follow up, persistence of DAT and blood transfusion requirement was more in secondary WAIHA . Hemoglobin increment was more in primary WAIHA (75%). CONCLUSION: DAT played a significant role in the diagnosis as well as evaluation of AIHA.

CD38-RyR2 axis-mediated signaling impedes CD8+ T cell response to anti-PD1 therapy in cancer.

PD1 blockade therapy, harnessing the cytotoxic potential of CD8+ T cells, has yielded clinical success in treating malignancies. However, its efficacy is often limited due to the progressive differentiation of intratumoral CD8+ T cells into a hypofunctional state known as terminal exhaustion. Despite identifying CD8+ T cell subsets associated with immunotherapy resistance, the molecular pathway triggering the resistance remains elusive. Given the clear association of CD38 with CD8+ T cell subsets resistant to anti-PD1 therapy, we investigated its role in inducing resistance. Phenotypic and functional characterization, along with single-cell RNA sequencing analysis of both in vitro chronically stimulated and intratumoral CD8+ T cells, revealed that CD38-expressing CD8+ T cells are terminally exhausted. Exploring the molecular mechanism, we found that CD38 expression was crucial in promoting terminal differentiation of CD8+ T cells by suppressing TCF1 expression, thereby rendering them unresponsive to anti-PD1 therapy. Genetic ablation of CD38 in tumor-reactive CD8+ T cells restored TCF1 levels and improved the responsiveness to anti-PD1 therapy in mice. Mechanistically, CD38 expression on exhausted CD8+ T cells elevated intracellular Ca2+ levels through RyR2 calcium channel activation. This, in turn, promoted chronic AKT activation, leading to TCF1 loss. Knockdown of RyR2 or inhibition of AKT in CD8+ T cells maintained TCF1 levels, induced a sustained anti-tumor response, and enhanced responsiveness to anti-PD1 therapy. Thus, targeting CD38 represents a potential strategy to improve the efficacy of anti-PD1 treatment in cancer.

Exploring the resistome and virulome in major sequence types of Acinetobacter baumannii genomes: Correlations with genome divergence and sequence types.

The increasing global prevalence of antimicrobial resistance in Acinetobacter baumannii has led to concerns regarding the effectiveness of infection treatment. Moreover, the critical role of virulence factor genes in A. baumannii's pathogenesis and its propensity to cause severe disease is of particular importance. Comparative genomics, including multi-locus sequence typing (MLST), enhances our understanding of A. baumannii epidemiology. While there is substantial documentation on A. baumannii, a comprehensive study of the antibiotic-resistant mechanisms and the virulence factors contributing to pathogenesis, and their correlation with Sequence Types (STs) remains incompletely elucidated. In this study, we aim to explore the relationship between antimicrobial resistance genes, virulence factor genes, and STs using genomic data from 223 publicly available A. baumannii strains. The core phylogeny analysis revealed five predominant STs in A. baumannii genomes, linked to their geographical sources of isolation. Furthermore, the resistome and virulome of A. baumannii followed an evolutionary pattern consistent with their pan-genome evolution. Among the major STs, we observed significant variations in resistant genes against "aminoglycoside" and "sulphonamide" antibiotics, highlighting the role of genotypic variations in determining resistance profiles. Furthermore, the presence of virulence factor genes, particularly exotoxin and nutritional / metabolic factor genes, played a crucial role in distinguishing the major STs, suggesting a potential link between genetic makeup and pathogenicity. Understanding these associations can provide valuable insights into A. baumannii's virulence potential and clinical outcomes, enabling the development of effective strategies to combat infections caused by this opportunistic pathogen.

Exploring Cyclic Peptide Nanotube Stability Across Diverse Lipid Bilayers and Unveiling Water Transport Dynamics.

Cyclic Peptide Nanotubes (CPNTs) have emerged as compelling candidates for various applications, particularly as nanochannels within lipid bilayers. In this study, the stability of two CPNTs, namely 8 × [(Cys-Gly-Met-Gly)2] and 8 × [(Gly-Leu)4], are comprehensively investigated across different lipid bilayers, including 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), a mixed model membrane (POPE/POPG), and a realistic yeast model membrane. The results demonstrate that both CPNTs maintain their tubular structures in all lipid bilayers, with [(Cys-Gly-Met-Gly)2] showing increased stability over an extended period in these lipid membranes. The insertion of CPNTs shows negligible impact on lipid bilayer properties, including area per lipid, volume per lipid, and bilayer thickness. The study demonstrates that the CPNT preserves its two-line water movement pattern within all the lipid membranes, reaffirming their potential as water channels. The MSD curves further reveal that the dynamics of water molecules inside the nanotube are similar for all the bilayer systems with minor differences that arise due to different lipid environments.

Microbiome Metabolome Integration Platform (MMIP): a web-based platform for microbiome and metabolome data integration and feature identification.

A microbial community maintains its ecological dynamics via metabolite crosstalk. Hence, knowledge of the metabolome, alongside its populace, would help us understand the functionality of a community and also predict how it will change in atypical conditions. Methods that employ low-cost metagenomic sequencing data can predict the metabolic potential of a community, that is, its ability to produce or utilize specific metabolites. These, in turn, can potentially serve as markers of biochemical pathways that are associated with different communities. We developed MMIP (Microbiome Metabolome Integration Platform), a web-based analytical and predictive tool that can be used to compare the taxonomic content, diversity variation and the metabolic potential between two sets of microbial communities from targeted amplicon sequencing data. MMIP is capable of highlighting statistically significant taxonomic, enzymatic and metabolic attributes as well as learning-based features associated with one group in comparison with another. Furthermore, MMIP can predict linkages among species or groups of microbes in the community, specific enzyme profiles, compounds or metabolites associated with such a group of organisms. With MMIP, we aim to provide a user-friendly, online web server for performing key microbiome-associated analyses of targeted amplicon sequencing data, predicting metabolite signature, and using learning-based linkage analysis, without the need for initial metabolomic analysis, and thereby helping in hypothesis generation.

Pathways of hLL-3717-29 Aggregation Give Insight into the Mechanism of α-Amyloid Formation.

α-amyloids present a novel self-assembly principle that can be utilized to prepare functional biomaterials. Evidence of α-amyloid formation in the active core of the human LL-37 protein (comprising residues 17 to 29) was associated with this peptide's membranolytic property. Though mechanistic pathways of ß-amyloid formation are known, such studies are scarce in α-amyloids. Modern computational techniques allow such mechanistic studies in molecular detail. Here, we propose aggregation pathways in hLL-3717-29 through molecular dynamics simulations. We first identified oligomers among peptides based on a distance criterion. The distribution of oligomers was then used to build Markov state models from which pathways were obtained using the framework of transition path theory. We checked the structural stability of the peptides during oligomerization, which is crucial from their functional point of view. We also investigated the key residues that participate in oligomer formation, the interactions between them, and the effect of residue mutations on the binding free energy of the peptides. Our findings suggest that larger oligomers are produced from the association of smaller and intermediate oligomers. The peptides retain their helical structure during aggregation with transient occurrences of 3-10 helix and turns. Hydrophobic interactions are vital in the aggregation of these peptides with Ile24 playing a crucial role. Mutation of this residue to alanine decreases the peptides' binding free energy, resulting in reduced aggregation tendency.

Exploring the Curvature-Dependence of Boron Nitride Nanoparticles on the Inhibition of hIAPP Aggregation.

Nanoparticles, particularly carbon nanoparticles, have gathered significant interest in the field of anti-aggregation research. However, due to their cytotoxicity, the exploration of biocompatible nanoparticles has become a new frontier in the quest for drugs against human amyloid diseases. The application of non-cytotoxic and biocompatible boron nitride (BN) nanoparticles against amyloid aggregation has been probed to tackle this issue. BN nanoparticles displayed inhibitory activity against the aggregation of Aß and α-syn peptides. In this work, the effect of BN nanoparticles on the dimerization of hIAPP, which is associated with the pathogenesis of type 2 diabetes, is studied. BN nanoparticles prevent the misfolding of hIAPP into ß-sheet-rich aggregates. On varying the curvature, the nanoparticles display variation in the interaction preference with hIAPP. Interestingly, as the hydrophobicity of the nanoparticles increases from (5,5) BN nanotube to BN nanosheet, the interaction propensity shifts from N-terminal to the amyloid prone C-terminal of hIAPP. The hydrophobic and aromatic stacking interactions are a contributing factor toward the binding between hIAPP and BN. Due to this, the flat surface of the nanosheet shows better interaction potential toward hIAPP, compared to the nanotubes. Further, the nanoparticles can also disassemble preformed hIAPP fibrils, and the effect is more pronounced for (5,5) nanotube and the nanosheet. This study provides insight into the inhibitory mechanism of hIAPP aggregation by boron nitride nanoparticles and also an understanding of the significance of the curvature of nanoparticles in their interaction with amyloid peptides, which is valuable for the design of antiamyloid drugs.

Butyrate limits inflammatory macrophage niche in NASH.

Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.

Integrating Multi-Omics Data to Construct Reliable Interconnected Models of Signaling, Gene Regulatory, and Metabolic Pathways.

Alteration of the status of the metabolic enzymes could be a probable way to regulate metabolic reprogramming, which is a critical cellular adaptation mechanism especially for cancer cells. Coordination among biological pathways, such as gene-regulatory, signaling, and metabolic pathways is crucial for regulating metabolic adaptation. Also, incorporation of resident microbial metabolic potential in human body can influence the interplay between the microbiome and the systemic or tissue metabolic environments. Systemic framework for model-based integration of multi-omics data can ultimately improve our understanding of metabolic reprogramming at holistic level. However, the interconnectivity and novel meta-pathway regulatory mechanisms are relatively lesser explored and understood. Hence, we propose a computational protocol that utilizes multi-omics data to identify probable cross-pathway regulatory and protein-protein interaction (PPI) links connecting signaling proteins or transcription factors or miRNAs to metabolic enzymes and their metabolites using network analysis and mathematical modeling. These cross-pathway links were shown to play important roles in metabolic reprogramming in cancer scenarios.

Hydrophobic Deep Eutectic Solvents as Greener Substitutes for Conventional Extraction Media: Examples and Techniques.

Deep eutectic solvents (DESs) are multicomponent designer solvents that exist as stable liquids over a wide range of temperatures. Over the last two decades, research has been dedicated to developing noncytotoxic, biodegradable, and biocompatible DESs to replace commercially available toxic organic solvents. However, most of the DESs formulated until now are hydrophilic and disintegrate via dissolution on coming in contact with the aqueous phase. To expand the repertoire of DESs as green solvents, hydrophobic DESs (HDESs) were prepared as an alternative. The hydrophobicity is a consequence of the constituents and can be modified according to the nature of the application. Due to their immiscibility, HDESs induce phase segregation in an aqueous solution and thus can be utilized as an extracting medium for a multitude of compounds. Here, we review literature reporting the usage of HDESs for the extraction of various organic compounds and metal ions from aqueous solutions and absorption of gases like CO2. We also discuss the techniques currently employed in the extraction processes. We have delineated the limitations that might reduce the applicability of these solvents and also discussed examples of how DESs behave as reaction media. Our review presents the possibility of HDESs being used as substitutes for conventional organic solvents.

Nested DWT-Based CNN Architecture for Monocular Depth Estimation.

Applications such as medical diagnosis, navigation, robotics, etc., require 3D images. Recently, deep learning networks have been extensively applied to estimate depth. Depth prediction from 2D images poses a problem that is both ill-posed and non-linear. Such networks are computationally and time-wise expensive as they have dense configurations. Further, the network performance depends on the trained model configuration, the loss functions used, and the dataset applied for training. We propose a moderately dense encoder-decoder network based on discrete wavelet decomposition and trainable coefficients (LL, LH, HL, HH). Our Nested Wavelet-Net (NDWTN) preserves the high-frequency information that is otherwise lost during the downsampling process in the encoder. Furthermore, we study the effect of activation functions, batch normalization, convolution layers, skip, etc., in our models. The network is trained with NYU datasets. Our network trains faster with good results.

Influence of salt and temperature on the self-assembly of cyclic peptides in water: a molecular dynamics study.

It is found in the literature that cyclic peptides (CPs) are able to self-assemble in water to form cyclic peptide nanotubes (CPNTs) and are used extensively in the field of nanotechnology. Several factors influence the formation and stability of these nanotubes in water. However, an extensive study of the contribution of several important factors is still lacking. The purpose of this study is to explore the effect of temperature and salt (NaCl) on the association tendency of CPs. Furthermore, the self-association behavior of CPs in aqueous solutions at various temperatures is also thoroughly discussed. Cyclo-[(Asp-D-Leu-Lys-D-Leu)2] is considered for this study and a series of classical molecular dynamics (MD) simulations at three different temperatures, viz. 280 K, 300 K, and 320 K, both in pure water and in NaCl solutions of different concentrations are carried out. The calculations of radial distribution functions, preferential interaction parameters, cluster formation and hydrogen bonding properties suggest a strong influence of NaCl concentration on the association propensity of CPs. Low NaCl concentration hinders CP association while high NaCl concentration facilitates the association of CPs. Besides this, the association of CPs is found to be enhanced at low temperature. Furthermore, the thermodynamics of CP association is predominantly found to be enthalpy driven in both the presence and absence of salt. No crossover between enthalpy and entropy in CP association is observed. In addition, the MM-GBSA method is used to investigate the binding free energies of the CP rings that self-assembled to form nanotube like structures at all three temperatures.

Elucidating the Hydrotropic Mechanism of the Antagonistic Salt PPh4Cl.

PPh4Cl is an antagonistic salt that recently showed promise as a hydrotropic agent. Here, we give mechanistic insights into the PPh4Cl-assisted solubility of a dye molecule using molecular dynamics simulations. Our findings reveal that dye molecules aggregate into a cluster which leads to an accumulation of PPh4+ ions in its vicinity and subsequent exclusion of water molecules from the region. The structural organization is attributed to the preferential interaction of dye molecules and PPh4Cl. The origin of such preference arises from the difference in π-π and CH-π interaction among the pairs. The hydrodynamic radius of PPh4Cl indicates a low propensity for cluster formation, which enhances its hydrotropic behavior. The process of dye dissolution is thermodynamically favored and occurs through a cooperative mechanism. Our studies provide molecular insight into experimental observations crucial for the design of novel hydrotropes with enhanced solubilizing properties.

Illustrating the Effect of Small Molecules Derived from Natural Resources on Amyloid Peptides.

The onset of amyloidogenic diseases is associated with the misfolding and aggregation of proteins. Despite extensive research, no effective therapeutics are yet available to treat these chronic degenerative diseases. Targeting the aggregation of disease-specific proteins is regarded as a promising new approach to treat these diseases. In the past few years, rapid progress in this field has been made in vitro, in vivo, and in silico to generate potential drug candidates, ranging from small molecules to polymers to nanoparticles. Small molecular probes, mostly those derived from natural sources, have been of particular interest among amyloid inhibitors. Here, we summarize some of the most important natural small molecular probes which can inhibit the aggregation of Aß, hIAPP, and α-syn peptides and discuss how their binding efficacy and preference for the peptides vary with their structure and conformation. This provides a comprehensive idea of the crucial factors which should be incorporated into the future design of novel drug candidates useful for the treatment of amyloid diseases.

Disparate Effect of Hybrid Peptidomimetics Containing Isomers of Aminobenzoic Acid on hIAPP Aggregation.

The abnormal misfolding of human islet amyloid polypeptide (hIAPP) in pancreatic ß-cells is implicated in the progression of type II diabetes (T2D). With the prevalence of T2D increasing worldwide, preventing the aggregation of hIAPP has been recognized as a promising therapeutic strategy to control this disease. Recently, a class of novel conformationally restricted ß-sheet breaker hybrid peptidomimetics (BSBHps) was found to demonstrate efficient inhibitory ability toward amyloid formation of hIAPP. One (Ile26) or more (Gly24 and Ile26) residues in these six-membered peptide sequences, which have been extracted from the amyloidogenic core of hIAPP, N22FGAIL27, are substituted by three different isomers of the conformationally restricted aromatic amino acid, i.e., aminobenzoic acid (ß, γ, and δ), to generate these BSBHps. The presence of the nonproteinogenic aminobenzoic acid moiety renders the BSBHps to be more stable toward proteolytic degradation. The different isomeric BSBHps exhibit contrasting influence on the self-assembly of hIAPP. The BSBHps containing ß- and γ-aminobenzoic acid can sufficiently prevent hIAPP aggregation, but those with the δ-aminobenzoic group stabilize the ß-sheet-rich aggregate of hIAPP. The difference in the angle between the amino and carboxyl groups in the isomers of the aminobenzoic moiety causes the BSBHps to attain discrete conformation and hence leads to variation in their binding preference with hIAPP and ultimately their inhibitory potency. This guides the pathway for the dissimilar effect of BSBHps on peptide aggregation and, therefore, provides insights into the design considerations for novel drugs against T2D.

Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8+ T Cells.

Effector CD8+ T cells rely primarily on glucose metabolism to meet their biosynthetic and functional needs. However, nutritional limitations in the tumor microenvironment can cause T-cell hyporesponsiveness. Therefore, T cells must acquire metabolic traits enabling sustained effector function at the tumor site to elicit a robust antitumor immune response. Here, we report that IL12-stimulated CD8+ T cells have elevated intracellular acetyl CoA levels and can maintain IFNγ levels in nutrient-deprived, tumor-conditioned media (TCM). Pharmacological and metabolic analyses demonstrated an active glucose-citrate-acetyl CoA circuit in IL12-stimulated CD8+ T cells supporting an intracellular pool of acetyl CoA in an ATP-citrate lyase (ACLY)-dependent manner. Intracellular acetyl CoA levels enhanced histone acetylation, lipid synthesis, and IFNγ production, improving the metabolic and functional fitness of CD8+ T cells in tumors. Pharmacological inhibition or genetic knockdown of ACLY severely impaired IFNγ production and viability of CD8+ T cells in nutrient-restricted conditions. Furthermore, CD8+ T cells cultured in high pyruvate-containing media in vitro acquired critical metabolic features of IL12-stimulated CD8+ T cells and displayed improved antitumor potential upon adoptive transfer in murine lymphoma and melanoma models. Overall, this study delineates the metabolic configuration of CD8+ T cells required for stable effector function in tumors and presents an affordable approach to promote the efficacy of CD8+ T cells for adoptive T-cell therapy. SIGNIFICANCE: IL12-mediated metabolic reprogramming increases intracellular acetyl CoA to promote the effector function of CD8+ T cells in nutrient-depleted tumor microenvironments, revealing strategies to potentiate the antitumor efficacy of T cells.

Phenylpropanoids on the Inhibition of ß-Amyloid Aggregation and the Movement of These Molecules through the POPC Lipid Bilayer.

Alzheimer's disease (AD), caused by Aß aggregation, is a major concern in medical research. It is a neurodegenerative disorder, leading to a loss of cognitive abilities, which is still claiming the lives of many people all over the world. This poses a challenge before the scientific community to discover effective drugs which can prevent such toxic aggregation. Recent experimental findings suggest the potency of two naturally-occurring phenylpropanoids, Schizotenuin A (SCH) and Lycopic Acid B (LAB) which can effectively combat the deleterious effects of Aß aggregation, although nothing is known about their mechanism of inhibition. In this work, we deal with an extensive computational study on the inhibitory effects of these inhibitors by using an all-atom molecular dynamics simulation to interpret the underlying mechanism of their inhibitory processes. A series of investigations is carried out while studying the various structural and conformational changes of the peptide chains in the absence and presence of inhibitors. To investigate the details of the interactions between the peptide residues and inhibitors, nonbonding energy calculations, the radial distribution function, the coordination number of water and inhibitor molecules around the peptide residues, and hydrogen-bonding interactions are calculated. The potential of mean force (PMF) is calculated to estimate aggregate formation from their free-energy profiles. It is seen that the hydrophobic core of the KLVFFAE undergoes aggregation and that these inhibitors show great promise in preventing the onset of AD in the future by preventing Aß aggregation. Also, the translocation studies on these inhibitors through a model POPC lipid bilayer shed light on their permeation properties and biocompatibility.

The chaotropic effect of ions on the self-aggregating propensity of Whitlock's molecular tweezers.

Molecular tweezers feature the first class of artificial receptors to pique the interest of researchers and emerge as an effective therapeutic candidate. The exceptional structure and exquisite binding specificity of tweezers establish this overall class of receptors as a promising tool, with abundant applications. However, their inclination to self-aggregate by mutual π-π stacking interactions of their aromatic arms diminishes their efficacy as a therapeutic candidate. Therefore, following up on sporadic studies, since the discovery of the Hofmeister series, on the ability of ions to either solvate (salting-in) or induce aggregation (salting-out) of hydrophobic solutes, the notions of ion-specificity effects are utilized on tweezer moieties. The impacts of three different aluminum salts bearing anions Cl-, ClO4- and SCN- on the self-association propensity of Whitlock's caffeine-pincered molecular tweezers are investigated, with a specific emphasis placed on elucidating the varied behavior of the ions on the hydration ability of tweezers. The comparative investigation is conducted employing a series of all-atom molecular dynamics simulations of five tweezer molecules in pure water and three salt solutions, at two different concentrations each, maintaining a temperature of 300 K and a pressure of 1 atm, respectively. Radial distribution functions, coordination numbers, and SASA calculations display a steady reduction in the aggregation proclivity of the receptor molecules with an increase in salt concentration, as progressed along the Hofmeister series. Orientational preferences between the tweezer arms reveal a disruptive effect in the regular π-π stacking interactions, in the presence of high concentrations of ClO4- and SCN- ions, while preferential interactions and tetrahedral order parameters unveil the underlying mechanism, by which the anions alter the solubility of the hydrophobic molecules. Overall, it is observed that SCN- exhibits the highest salting-in effect, followed by ClO4-, with both anions inhibiting tweezer aggregation through different mechanisms. ClO4- ions impart an effect by moderately interacting with the solute molecules as well as modifying the water structure of the bulk solution promoting solvation, whereas, SCN- ions engage entirely in interaction with specific tweezer sites. Cl- being the most charge-dense of the three anionic species experiences stronger hydration and therefore, imparts a very negligible salting-in effect.

Deciphering the Role of ATP on PHF6 Aggregation.

The aggregation of Tau protein, which are involved in Alzheimer's disease, are associated with the self-assembly of the hexapeptide sequence, paired helical filament 6 (PHF6) from repeat 3 of Tau. In order to treat Alzheimer's disease and other such tauopathies, one of the therapeutic strategies is to inhibit aggregation of Tau and its nucleating segments. Therefore, we have studied the effect of adenosine triphosphate (ATP) on the aggregation of PHF6. ATP has, interestingly, demonstrated its ability to inhibit and dissolve protein aggregates. Using classical molecular dynamics simulations, we observed that the hydrophobic core of PHF6 segment displays extended ß-sheet conformation, which stabilizes PHF6 aggregates. However, the distribution of ATP around the vicinity of the peptides enables PHF6 to remain discrete and attain random coil conformers. The interpeptide interactions are substituted by PHF6-ATP interactions through hydrogen bonding and hydrophobic interactions (including π-π stacking). Furthermore, the adenosine moiety of ATP contributes more than the triphosphate chain toward PHF6-ATP interaction. Ultimately, this work establishes the inhibitory activity of ATP against Tau aggregation; hence, the therapeutic effect of ATP should be explored further in regard to the effective treatment of Alzheimer's disease.

Inhibition of Aß16-22 Peptide Aggregation by Small Molecules and Their Permeation through POPC Lipid Bilayer: Insight from Molecular Dynamics Simulation Study.

Alzheimer's Disease is a rapidly progressing irreversible neurodegenerative disorder characterized by neuronal cell deterioration that endangers human health. With its proper therapeutic treatment being unavailable, several research groups throughout the world are involved in designing efficient drug molecules. However, the elusive mechanism of action of the drugs as well as their debilitating side effects pose major challenges in this regard. In the present article, we investigated the inhibitory effect of an indanone-carbamate-based molecule on Aß16-22 peptide aggregation by employing a series of all-atom molecular dynamics simulation study. To gain explicit insights, we studied the role of inhibitor molecules on the disruption of highly arranged ß-sheet of peptides by various types of analyses such as structural analysis, Cα-Cα-atom distance, residue-wise contact map, and solvent accessible surface area. The results obtained from various analyses revealed that the inhibitor molecules interacted with Aß16-22 peptides to destabilize its arranged ß-sheet conformer via hydrophobic interaction. To further comprehend the effect of inhibitors on amyloid aggregation, we also determined interaction energy, hydration number, radial distribution function, hydrogen bonding, and potential of mean forces. In addition, the permeability of the inhibitors through model POPC lipid bilayer via passive diffusion was also analyzed. Our study is noteworthy in that it elucidates the strong interaction between inhibitors and the central hydrophobic core of peptides comprising aromatic phenylalanine residues, as well as the passive translocation of inhibitors across POPC lipid bilayers.