Additively Manufactured Carbon-Reinforced ABS Honeycomb Composite Structures and Property Prediction by Machine Learning.

The expansive utility of polymeric 3D-printing technologies and demand for high- performance lightweight structures has prompted the emergence of various carbon-reinforced polymer composite filaments. However, detailed characterization of the processing-microstructure-property relationships of these materials is still required to realize their full potential. In this study, acrylonitrile butadiene styrene (ABS) and two carbon-reinforced ABS variants, with either carbon nanotubes (CNT) or 5 wt.% chopped carbon fiber (CF), were designed in a bio-inspired honeycomb geometry. These structures were manufactured by fused filament fabrication (FFF) and investigated across a range of layer thicknesses and hexagonal (hex) sizes. Microscopy of material cross-sections was conducted to evaluate the relationship between print parameters and porosity. Analyses determined a trend of reduced porosity with lower print-layer heights and hex sizes compared to larger print-layer heights and hex sizes. Mechanical properties were evaluated through compression testing, with ABS specimens achieving higher compressive yield strength, while CNT-ABS achieved higher ultimate compressive strength due to the reduction in porosity and subsequent strengthening. A trend of decreasing strength with increasing hex size across all materials was supported by the negative correlation between porosity and increasing print-layer height and hex size. We elucidated the potential of honeycomb ABS, CNT-ABS, and ABS-5wt.% CF polymer composites for novel 3D-printed structures. These studies were supported by the development of a predictive classification and regression supervised machine learning model with 0.92 accuracy and a 0.96 coefficient of determination to help inform and guide design for targeted performance.

Interfacial Tension-Temperature-Pressure-Salinity Relationship for the Hydrogen-Brine System under Reservoir Conditions: Integration of Molecular Dynamics and Machine Learning.

Hydrogen (H2) underground storage has attracted considerable attention as a potentially efficient strategy for the large-scale storage of H2. Nevertheless, successful execution and long-term storage and withdrawal of H2 necessitate a thorough understanding of the physical and chemical properties of H2 in contact with the resident fluids. As capillary forces control H2 migration and trapping in a subsurface environment, quantifying the interfacial tension (IFT) between H2 and the resident fluids in the subsurface is important. In this study, molecular dynamics (MD) simulation was employed to develop a data set for the IFT of H2-brine systems under a wide range of thermodynamic conditions (298-373 K temperatures and 1-30 MPa pressures) and NaCl salinities (0-5.02 mol·kg-1). For the first time to our knowledge, a comprehensive assessment was carried out to introduce the most accurate force field combination for H2-brine systems in predicting interfacial properties with an absolute relative deviation (ARD) of less than 3% compared with the experimental data. In addition, the effect of the cation type was investigated for brines containing NaCl, KCl, CaCl2, and MgCl2. Our results show that H2-brine IFT decreases with increasing temperature under any pressure condition, while higher NaCl salinity increases the IFT. A slight decrease in IFT occurs when the pressure increases. Under the impact of cation type, Ca2+ can increase IFT values more than others, i.e., up to 12% with respect to KCl. In the last step, the predicted IFT data set was used to provide a reliable correlation using machine learning (ML). Three white-box ML approaches of the group method of data handling (GMDH), gene expression programming (GEP), and genetic programming (GP) were applied. GP demonstrates the most accurate correlation with a coefficient of determination (R2) and absolute average relative deviation (AARD) of 0.9783 and 0.9767%, respectively.

Elucidation of Structural Determinants Delineates the Residues Playing Key Roles in Differential Dynamics and Selective Inhibition of Sirt1-3.

Sirt1-3 are the most studied sirtuins, playing a key role in caloric-dependent epigenetic modifications. Since they are localized in distinct cellular compartments and act differently under various pathological conditions, selective inhibition would be a promising strategy to understand their biological function and to discover effective therapeutics. Here, sirtuin's inhibitor Ex527* is used as a probe to speculate the possible root cause of selective inhibition and differential structural dynamics of Sirt1-3. Comparative energetics and mutational studies revealed the criticality of residues I279 and I316 for the Sirt1 selectivity toward Ex527*. Furthermore, essential dynamics and residue network analysis revealed that the side-chain reorientation in residue F190 due to nonconserved residue Y191 played a major role in the formation of an extended selectivity pocket in Sirt2. These changes at the dynamical and residual level, which impact the internal wiring significantly, might help in rationally designing selective inhibitors against Sirt1-3.

Structural role of a conserved active site cis proline in the Thermotoga maritima acetyl esterase from the carbohydrate esterase family 7.

A conserved cis proline residue located in the active site of Thermotoga maritima acetyl esterase (TmAcE) from the carbohydrate esterase family 7 (CE7) has been substituted by alanine. The residue was known to play a crucial role in determining the catalytic properties of the enzyme. To elucidate the structural role of the residue, the crystal structure of the Pro228Ala variant (TmAcEP228A ) was determined at 2.1 Å resolution. The replacement does not affect the overall secondary, tertiary, and quaternary structures and moderately decreases the thermal stability. However, the wild type cis conformation of the 227-228 peptide bond adopts a trans conformation in the variant. Other conformational changes in the tertiary structure are restricted to residues 222-226, preceding this peptide bond and are located away from the active site. Overall, the results suggest that the conserved proline residue is responsible for the cis conformation of the peptide and shapes the geometry of the active site. Elimination of the pyrrolidine ring results in the loss of van der Waals and hydrophobic interactions with both the alcohol and acyl moeities of the ester substrate, leading to significant impairment of the activity and perturbation of substrate specificity. Furthermore, a cis-to-trans conformational change arising out of residue changes at this position may be associated with the evolution of divergent activity, specificity, and stability properties of members constituting the CE7 family. Proteins 2017; 85:694-708. © 2016 Wiley Periodicals, Inc.

An extended loop in CE7 carbohydrate esterase family is dispensable for oligomerization but required for activity and thermostability.

The carbohydrate esterase family 7 (CE7) belonging to the α/ß hydrolase superfamily contains a structurally conserved loop extension element relative to the canonical α/ß hydrolase fold. This element called the ß-interface loop contributes 20-30% of the total buried surface area at intersubunit interfaces of the functional hexameric state. To test whether this loop is an enabling region for the structure and function of the oligomeric assembly, we designed a truncation variant of the thermostable CE7 acetyl esterase from Thermotoga maritima (TmAcE). Although deletion of 26 out of 40 residues in the loop had little impact on the hexamer formation, the variant exhibited altered dynamics of the oligomeric assembly and a loss of thermal stability. Furthermore, the mutant lacked catalytic activity. Crystal structures of the variant and a new crystal form of the wild type protein determined at 2.75Å and 1.76Å, respectively, provide a rationale for the properties of the variant. The hexameric assembly in the variant is identical to that of the wild type and differed only in the lack of buried surface area interactions at the original intersubunit interfaces. This is accompanied by disorder in an extended region of the truncated loop that consequently induces disorder in the neighboring oxyanion hole loop. Overall, the results suggest that the ß-interface loop in CE7 enzymes is dispensable for the oligomeric assembly. Rather, the loop extension event was evolutionarily selected to regulate activity, conformational flexibility and thermal stability.

Crystal structure of Thermotoga maritima acetyl esterase complex with a substrate analog: Insights into the distinctive substrate specificity in the CE7 carbohydrate esterase family.

The carbohydrate esterase family 7 (CE7) members are acetyl esterases that possess unusual substrate specificity for cephalosporin C and 7-amino-cephalosporanic acid. This family containing the α/ß hydrolase fold has a distinctive substrate profile that allows it to carry out hydrolysis of esters containing diverse alcohol moieties while maintaining narrow specificity for an acetate ester. Here we investigate the structural basis of this preference for small acyl groups using the crystal structure of the thermostable Thermotoga maritima CE7 acetyl esterase (TmAcE) complexed with a non-cognate substrate analog. The structure determined at 1.86 Å resolution provides direct evidence for the location of the largely hydrophobic and rigid substrate binding pocket in this family. Furthermore, a three-helix insertion domain near the catalytic machinery shapes the substrate binding site. The structure reveals two residues (Pro228 and Ile276) which constitute a hydrophobic rigid binding surface for the acyl group of the ester and thus restricts the size of the acyl group that be accommodated. In combination with previous literature on kinetic properties of the enzyme, our studies suggest that these residues determine the unique specificity of the TmAcE for short straight chain esters. The structure provides a template for focused attempts to engineer the CE7 enzymes for enhanced stability, selectivity or activity for biocatalytic applications.

Compressive Properties of Additively Manufactured Metal-Reinforced PLA and ABS Composites.

The development of multi-material filaments has enabled fused filament fabrication-based additive manufacturing to address demand for high-performance lightweight multifunctional components. In this study, polylactic acid (PLA) and acrylonitrile butadiene styrene based filaments with metallic reinforcements of magnetic iron (MI), stainless steel (SS), bronze (Br), copper (Cu), Bismuth (Bi), and Tungsten (W) were investigated to elucidate their complex processing-structure-property relationships. The microstructure of 3D-printed materials were characterized by microscopy and analyzed to determine the metal cross-sectional area percentage and the relationship between metal reinforcement, the polymer matrix, and porosity. Compression testing was conducted in directions parallel and perpendicular to the build direction in order to evaluate the effect of orientation and metal reinforcement on the mechanical properties. 3D-printed specimens experienced either fracture through print layers or layer-wise interfacial rupture for loads applied perpendicular and parallel to the print layers, respectively. A dependence of yield strength on loading orientation was observed for Br-PLA, Cu-PLA, SS-PLA, Bi-ABS, and W-ABS; however, MI-PLA and pure ABS specimens did not exhibit this sensitivity. Metal reinforcement also influenced the magnitude of compressive yield strength, with MI-PLA and SS-PLA demonstrating increased strength over Br-PLA and Cu-PLA, while ABS demonstrated increased strength over Bi-ABS and W-ABS. These results demonstrate the importance of considering orientation in printing and applications, the trade-off between various metallic reinforcements for added multifunctionality, and the potential of these tailored polymer composites for novel 3D-printed structures.

Mango Leaves (Mangifera indica)-Derived Highly Florescent Green Graphene Quantum Dot Nanoprobes for Enhanced On-Off Dual Detection of Cholesterol and Fe2+ Ions Based on Molecular Logic Operation.

In the present study, we have engineered a molecular logic gate system employing both Fe2+ ions and cholesterol as bioanalytes for innovative detection strategies. We utilized a green-synthesis method employing the mango leaves extract to create fluorescent graphene quantum dots termed "mGQDs". Through techniques like HR-TEM, i.e., high-resolution transmission electron microscopy, Raman spectroscopy, and XPS, i.e., X-ray photoelectron spectroscopy, the successful formation of mGQDs was confirmed. The photoluminescence (PL) characteristics of mGQDs were investigated for potential applications in metal ion detection, specifically Fe2+ traces in water, by using fluorescence techniques. Under 425 nm excitation, mGQDs exhibited emission bands at 495 and 677 nm in their PL spectrum. Fe2+-induced notable quenching of mGQDs' PL intensity decreased by 97% with 2.5 µM Fe2+ ions; however, adding 20 mM cholesterol resulted in a 92% recovery. Detection limits were established through a linear Stern-Volmer (S-V) plot at room temperature, yielding values of 4.07 µM for Fe2+ ions and 1.8 mM for cholesterol. Moreover, mGQDs demonstrated biocompatibility, aqueous solubility, and nontoxicity, facilitating the creation of a rapid nonenzymatic cholesterol detection method. Selectivity and detection studies underscored mGQDs' reliability in cholesterol level monitoring. Additionally, a molecular logic gate system employing Fe2+ metal ions and cholesterol as a bioanalyte was established for detection purposes. Overall, this research introduces an ecofriendly approach to craft mGQDs and highlights their effectiveness in detecting metal ions and cholesterol, suggesting their potential as versatile nanomaterials for diverse analytical and biomedical applications.

Mild and efficient cyanuric chloride catalyzed Pictet-Spengler reaction.

A practical, mild and efficient protocol for the Pictet-Spengler reaction catalyzed by cyanuric chloride (trichloro-1,3,5-triazine, TCT) is described. The 6-endo cyclization of tryptophan/tryptamine and modified Pictet-Spengler substrates with both electron-withdrawing and electron-donating aldehydes was carried out by using a catalytic amount of TCT (10 mol %) in DMSO under a nitrogen atmosphere. TCT catalyzed the Pictet-Spengler reaction involving electron-donating aldehydes in excellent yield. Thus, it has a distinct advantage over the existing methodologies where electron-donating aldehydes failed to undergo 6-endo cyclization. Our methodology provided broad substrate scope and diversity. This is indeed the first report of the use of TCT as a catalyst for the Pictet-Spengler reaction.

SARS-CoV-2 envelope protein attain Kac mediated dynamical interaction network to adopt 'histone mimic' at BRD4 interface.

Interface mimicry, achieved by recognition of host-pathogen interactions, is the basis by which pathogen proteins can hijack the host machinery. The envelope (E) protein of SARS-CoV-2 is reported to mimic the histones at the BRD4 surface via establishing the structural mimicry; however, the underlying mechanism of E protein mimicking the histones is still elusive. To explore the mimics at dynamic and structural residual network level an extensive docking, and MD simulations were carried out in a comparative manner between complexes of H3-, H4-, E-, and apo-BRD4. We identified that E peptide is able to attain an 'interaction network mimicry', as its acetylated lysine (Kac) achieves orientation and residual fingerprint similar to histones, including water-mediated interactions for both the Kac positions. We identified Y59 of E, playing an anchor role to escort lysine positioning inside the binding site. Furthermore, the binding site analysis confirms that E peptide needs a higher volume, similar to the H4-BRD4 where both the lysine's (Kac5 and Kac8) can accommodate nicely, however, the position of Kac8 is mimicked by two additional water molecules other than four water-mediated bridging's, strengthening the possibility that E peptide could hijack host BRD4 surface. These molecular insights seem pivotal for mechanistic understanding and BRD4-specific therapeutic intervention. KEY POINTSMolecular mimicry is reported in hijacking and then outcompeting the host counterparts so that pathogens can rewire their cellular function by overcoming the host defense mechanism.The molecular recognition process is the basis of molecular mimicry. The E peptide of SARS-CoV-2 is reported to mimic host histone at the BRD4 surface by utilizing its C-terminally placed acetylated lysine (Kac63) to mimic the N-terminally placed acetylated lysine Kac5GGKac8 histone (H4) by interaction network mimicry identified through microsecond molecular dynamics (MD) simulations and post-processing extensive analysis.There are two steps to mimic: firstly, tyrosine residues help E to anchor at the BRD4 surface to position Kac and increase the volume of the pocket. Secondary, after positioning of Kac, a common durable interaction network N140:Kac5; Kac5:W1; W1:Y97; W1:W2; W2:W3; W3:W4; W4:P82 is established between Kac5, with key residues P82, Y97, N140, and four water molecules through water mediate bridge. Furthermore, the second acetylated lysine Kac8 position and its interaction as polar contact with Kac5 were also mimicked by E peptide through interaction network P82:W5; W5:Kac63; W5:W6; W6:Kac63.The binding event at BRD4/BD1 seems an induced-fit mechanism as a bigger binding site volume was identified at H4-BRD4 on which E peptide attains its better stability than H3-BRD4.We identified the tyrosine residue Y59 of E that acts like an anchor on the BRD4 surface to position Kac inside the pocket and attain the interaction network by using aromatic residues of the BRD4 surface.Communicated by Ramaswamy H. Sarma.

FÓ§rster resonance energy transfer (FRET) between CdSe quantum dots and ABA phosphorus(V) corroles.

In this article, highly fluorescent phosphorus(V) corrole was synthesised which was then combined with CdSe quantum dots (QDs) in order to study Förster resonance energy transfer (FRET) mechanism between CdSe QDs (donor) and phosphorus corrole (acceptor). Spectral overlap between QD's emission profile and corrole's absorption profile was found to be significant enough to result into Förster resonance energy transfer (FRET). The UV-vis spectrum experienced increase in the absorption bands on addition of phosphorus corrole to CdSe QDs suggesting QD-corrole conjugation. In the steady state fluorescence measurements, emission spectrum observed quenching in the fluorescence intensity of prepared CdSe QDs on addition of phosphorus corrole. Likewise, in case of time-resolved fluorescence measurements it was noticed that the CdSe QD's lifetime was greatly quenched by the presence of a corrole acceptor. Stern-Volmer plot was made to show quenching in this case was dynamic in nature. Based on the results of UV-vis, steady state and time-resolved fluorescence measurements the plausible mechanism behind such observations is considered to be FRET.

Multi-Material Additive Manufacturing of High Temperature Polyetherimide (PEI)-Based Polymer Systems for Lightweight Aerospace Applications.

Rapid innovations in 3-D printing technology have created a demand for multifunctional composites. Advanced polymers like amorphous thermoplastic polyetherimide (PEI) can create robust, lightweight, and efficient structures while providing high-temperature stability. This work manufactured ULTEM, a PEI-based polymer, and carbon-fiber-infused ULTEM multi-material composites with varying layering patterns (e.g., AAABBB vs. ABABAB) using fused filament fabrication (FFF). The microstructure of fractured surfaces and polished cross-sections determined that the print quality of layers printed closer to the heated bed was higher than layers closer to the top surface, primarily due to the thermal insulating properties of the material itself. Mechanical properties of the multi-material parts were between those of the single-material parts: an ultimate tensile strength and elastic modulus of 59 MPa and 3.005 GPa, respectively. Multi-material parts from the same filaments but with different layering patterns showed different mechanical responses. Prints were of higher quality and demonstrated a higher elastic modulus (3.080 GPa) when consecutive layers were printed from the same filament (AAABBB) versus parts with printed layers of alternating filaments (ABABAB), which showed a higher ultimate strength (62.04 MPa). These results demonstrate the potential for creatively designing multi-material printed parts that may enhance mechanical properties.

Structure-based pharmacophore mapping and virtual screening of natural products to identify polypharmacological inhibitor against c-MET/EGFR/VEGFR-2.

Three receptor tyrosine kinases (RTKs), c-MET, EGFR, and VEGFR-2 have been identified as potential oncogenic targets involved in tumor development, metastasis, and invasion. Designing inhibitors that can simultaneously interact with multiple targets is a promising approach, therefore, inhibiting these three RTKs with a single chemical component might give an effective chemotherapeutic strategy for addressing the disease while limiting adverse effects. The in-silico methods have been developed to identify the polypharmacological inhibitors particularly for drug repurposing and multitarget drug design. Here, to find a viable inhibitor from natural source against these three RTKs, structure-based pharmacophore mapping and virtual screening of SN-II database were carried out. The filtered compound SN00020821, identified as Cedeodarin, from different computational approaches, demonstrated good interactions with all the three targets, c-MET/EGFR/VEGFR-2, with interaction energies of -42.35 kcal/mol, -49.32 kcal/mol and -44.83 kcal/mol, respectively. SN00020821displayed stable key interactions with critical amino acids of all the three receptors' kinase catalytic domains including "DFG motif" explored through the MD simulations. Furthermore, it also met the ADMET requirements and was determined to be drug-like as predicted from the Lipinski's rule of five and Veber's rule. Finally, SN00020821 provides a novel molecular scaffold that could be investigated further as a polypharmacological anticancer therapeutic candidate that targets the three RTKs.Communicated by Ramaswamy H. Sarma.

Intradermal Immunization of Soluble Influenza HA Derived from a Lethal Virus Induces High Magnitude and Breadth of Antibody Responses and Provides Complete Protection In Vivo.

Immunogens mimicking the native-like structure of surface-exposed viral antigens are considered promising vaccine candidates. Influenza viruses are important zoonotic respiratory viruses with high pandemic potential. Recombinant soluble hemagglutinin (HA) glycoprotein-based protein subunit vaccines against Influenza have been shown to induce protective efficacy when administered intramuscularly. Here, we have expressed a recombinant soluble trimeric HA protein in Expi 293F cells and purified the protein derived from the Inf A/Guangdong-Maonan/ SWL1536/2019 virus which was found to be highly virulent in the mouse. The trimeric HA protein was found to be in the oligomeric state, highly stable, and the efficacy study in the BALB/c mouse challenge model through intradermal immunization with the prime-boost regimen conferred complete protection against a high lethal dose of homologous and mouse-adapted InfA/PR8 virus challenge. Furthermore, the immunogen induced high hemagglutinin inhibition (HI) titers and showed cross-protection against other Inf A and Inf B subtypes. The results are promising and warrant trimeric HA as a suitable vaccine candidate.

Effect of Reinforcements and 3-D Printing Parameters on the Microstructure and Mechanical Properties of Acrylonitrile Butadiene Styrene (ABS) Polymer Composites.

Fused filament fabrication (FFF) systems utilize a wide variety of commercially available filaments, including Acrylonitrile Butadiene Styrene (ABS), as well as their variants. However, the effect of filament composition, reinforcements (chopped fibers and nanotubes), and 3-D printing variables on the microstructure and thermomechanical behavior is not well understood, and systematic studies are needed. In this work, different types of ABS materials with and without carbon fiber and carbon nanotube reinforcements were printed with multiple print layer heights. The microstructure, elastic behavior, tensile behavior, and fracture toughness of 3-D printed materials were characterized. ABS material systems printed at a low print layer height of 0.1 mm outperformed those printed at a larger height of 0.2 mm. Carbon nanotube reinforcements result in significant improvement in the strength and elastic modulus of ABS materials. Printed coupons of ABS with carbon nanotubes achieve an ultimate strength of 34.18 MPa, while a premium grade ABS coupon achieved 28.75 MPa when printed with the same print layer heights. Samples of ABS with chopped carbon fiber show an ultimate strength of 27.25 MPa, due primarily to the significant porosity present in the filament. Elastic moduli and fracture toughness measured using dynamic and mechanical methods show similar trends as a function of layer height. The effects of different materials, reinforcements, and printing parameters on the microstructure and mechanical properties are discussed in detail.

Characterizing (un)binding mechanism of USP7 inhibitors to unravel the cause of enhanced binding potencies at allosteric checkpoint.

The ability to predict the intricate mechanistic behavior of ligands and associated structural determinants during protein-ligand (un)binding is of great practical importance in drug discovery. Ubiquitin specific protease-7 (USP7) is a newly emerging attractive cancer therapeutic target with bound allosteric inhibitors. However, none of the inhibitors have reached clinical trials, allowing opportunities to examine every aspect of allosteric modulation. The crystallographic insights reveal that these inhibitors have common properties such as chemical scaffolds, binding site and interaction fingerprinting. However, they still possess a broader range of binding potencies, ranging from 22 nM to 1,300 nM. Hence, it becomes more critical to decipher the structural determinants guiding the enhanced binding potency of the inhibitors. In this regard, we elucidated the atomic-level insights from both interacting partners, that is, protein-ligand perspective, and established the structure-activity link between USP7 inhibitors by using classical and advanced molecular dynamics simulations combined with linear interaction energy and molecular mechanics-Poisson Boltzmann surface area. We revealed the inhibitor potency differences by examining the contributions of chemical moieties and USP7 residues, the involvement of water-mediated interactions, and the thermodynamic landscape alterations. Additionally, the dissociation profiles aided in the establishment of a correlation between experimental potencies and structural determinants. Our study demonstrates the critical role of blocking loop 1 in allosteric inhibition and enhanced binding affinity. Comprehensively, our findings provide a constructive expansion of experimental outcomes and show the basis for varying binding potency using in-silico approaches. We expect this atomistic approach to be useful for effective drug design.

Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors.

Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases. Here, we report the structure-based designing and synthesis of two distinct series of novel Sirt1 inhibitors, benzimidazole mono-peptides and amino-acid derived 5-pyrazolyl methylidene rhodanine carboxylic acid. The compounds were evaluated for in vitro enzyme-based and cell-based Sirt1 inhibition assay, and cytotoxic-activity in both liver and breast cancer cells. The tryptophan conjugates i.e.13h (IC50 = 0.66 µM, ΔG bind = -1.1 kcal mol-1) and 7d (IC50 = 0.77 µM, ΔG bind = -4.4 kcal mol-1) demonstrated the maximum efficacy to inhibit Sirt1. The MD simulation unveiled that electrostatic complementarity at the substrate-binding-site through a novel motif "SLxVxP(V/F)A" could be a cause of increased Sirt1 inhibition by 13h and 13l over Sirt2 in cell-based assay, as compared to the control Ex527 and 7d. Finally, this study highlights novel molecules 7d and 13h, along with a new key hot-spot in Sirt1, which could be used as a starting lead to design more potent and selective sirtuin inhibitors as a potential anticancer molecule.

A common Matrix metalloproteinase 8 promoter haplotype enhances the risk for hypertension via diminished interactions with nuclear factor kappa B.

OBJECTIVES: Matrix metalloproteinase 8 (MMP8) has a prominent role in collagen turnover in blood vessels and vascular remodeling. The contribution of regulatory single nucleotide polymorphisms in MMP8 to cardiovascular diseases is unclear. We aimed to delineate the influence of MMP8 promoter variations on hypertension. METHODS: A case-control study in unrelated individuals ( n  = 2565) was carried out. Resequencing of the MMP8 proximal promoter, linkage disequilibrium analysis, genotyping of variants and regression analyses were performed. MMP8 promoter-reporter constructs were generated and expressed in human vascular endothelial cells under various conditions. RESULTS: We identified four single nucleotide polymorphisms (SNPs) in the promoter region of MMP8 : -1089A/G (rs17099452), -815G/T (rs17099451), -795C/T (rs11225395), -763A/T (rs35308160); these SNPs form three major haplotypes. Hap3 (viz., GTTT haplotype) carriers showed significant associations with hypertension in two geographically distinct human populations (e.g., Chennai: odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.16-1.86, P  = 2 × 10 -3 ; Chandigarh: OR = 1.85, 95% CI = 1.21-2.81, P  = 4 × 10 -3 ). Hap3 carriers also displayed elevated systolic blood pressure, diastolic blood pressure and mean arterial pressure levels. Hap3 promoter-reporter construct showed lower promoter activity than the wild-type (Hap1) construct. In silico analysis and molecular dynamics studies predicted diminished binding of the transcription factor nuclear factor kappa B (NF-κB) to the functional -815T allele of Hap3 compared to the -815G wild-type allele; this prediction was validated by in-vitro experiments. Hap3 displayed impaired response to tumor necrosis factor-alpha treatment, possibly due to weaker binding of NF-κB. Notably, MMP8 promoter haplotypes were identified as independent predictors of plasma MMP8 and endothelial dysfunction markers (von Willebrand factor and endothelin-1) levels. CONCLUSION: MMP8 promoter GTTT haplotype has a functional role in reducing MMP8 expression during inflammation via diminished interaction with NF-κB and in enhancing the risk of hypertension.

Sentiment analysis on the impact of coronavirus in social life using the BERT model.

Nowadays, the whole world is confronting an infectious disease called the coronavirus. No country remained untouched during this pandemic situation. Due to no exact treatment available, the disease has become a matter of seriousness for both the government and the public. As social distance is considered the most effective way to stay away from this disease. Therefore, to address the people eagerness about the Corona pandemic and to express their views, the trend of people has moved very fast towards social media. Twitter has emerged as one of the most popular platforms among those social media platforms. By studying the same eagerness and opinions of people to understand their mental state, we have done sentiment analysis using the BERT model on tweets. In this paper, we perform a sentiment analysis on two data sets; one data set is collected by tweets made by people from all over the world, and the other data set contains the tweets made by people of India. We have validated the accuracy of the emotion classification from the GitHub repository. The experimental results show that the validation accuracy is ≈ 94%.

Identification of potential molecules against COVID-19 main protease through structure-guided virtual screening approach.

The pandemic caused by novel coronavirus disease 2019 (COVID-19) infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (Mpro) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of Mpro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of Mpro. However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure- and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies.Communicated by Ramaswamy H. Sarma.