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Sugar phosphates are potential sources of carbon and phosphate for bacteria. Despite that the process of internalization of Glucose-6-Phosphate (G6P) through plasma membrane remained elusive in several bacteria. VCA0625-27, made of periplasmic ligand binding protein (PLBP) VCA0625, an atypical monomeric permease VCA0626, and a cytosolic ATPase VCA0627, recently emerged as hexose-6-phosphate uptake system of Vibrio cholerae. Here we report high resolution crystal structure of VCA0625 in G6P bound state that largely resembles AfuA of Actinobacillus pleuropneumoniae. MD simulations on VCA0625 in apo and G6P bound states unraveled an 'open to close' and swinging bi-lobal motions, which are diminished upon G6P binding. Mutagenesis followed by biochemical assays on VCA0625 underscored that R34 works as gateway to bind G6P. Although VCA0627 binds ATP, it is ATPase deficient in the absence of VCA0625 and VCA0626, which is a signature phenomenon of type-I ABC importer. Further, modeling, docking and systematic sequence analysis allowed us to envisage the existence of similar atypical type-I G6P importer with fused monomeric permease in 27 other gram-negative bacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The continuously increasing level of atmospheric CO 2 in the atmosphere has led to global warming. Converting CO 2 into other carbon compounds could mitigate its atmospheric levels and produce valuable products, as CO 2 also serves as a plentiful and inexpensive carbon feedstock. However, the inert nature of CO 2 poses a major challenge for its reduction. To meet the challenge, nature has evolved metalloenzymes using transition metal ions like Fe, Ni, Mo, and W, as well as electron-transfer partners for their functions. Mimicking these enzymes, artificial metalloenzymes (ArMs) have been designed using alternative protein scaffolds and various metallocofactors like Ni, Co, Re, Rh, and FeS clusters. Both the catalytic efficiency and the scope of CO 2 -reduction product of these ArMs have been improved over the past decade. This review first focuses on the natural metalloenzymes that directly reduce CO 2 by discussing their structures and active sites, as well as the proposed reaction mechanisms. It then introduces the common strategies for electrochemical, photochemical, or photoelectrochemical utilization of these native enzymes for CO 2 reduction and highlights the most recent advancements from the past five years. We also summarize principles of protein design for bio-inspired ArMs, comparing them with native enzymatic systems and outlining challenges and opportunities in enzymatic CO 2 reduction., Competing Interests: Declaration of competing interest We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The current research endeavour aimed to synthesize ferulic acid grafted tamarind gum/guar gum (FA-g-TG/GG) based powders as wound dressings, which could form in situ gels upon contact with wound exudates. In this context, variable amounts of FA were initially grafted with TG via the Steglich esterification reaction protocol and the resulting conjugates were subsequently amalgamated with GG and lyophilized to produce dry powders (F-1 - -F-3) with average particle size within 5.10-5.54 μm and average angle of repose ∼30°. These powders were structurally characterized with 1 H NMR, FTIR, DSC, TGA, XRD and SEM analyses. Pristine TG, FA-g-TG and FA-g-TG/GG powders (F-2) revealed their distinct morphological structures and variable negative zeta potential values (-11.06 mV-25.50 mV). Among various formulation (F-1-F-3), F-2 demonstrated an acceptable powder-to-gel conversion time (within 20 min), suitable water vapour transmission rates (WVTR, 2564.94 ± 32.47 g/m 2 /day) and excellent water retention abilities and swelling profiles (4559.00 ± 41.57 %) in wound fluid. The powders were cytocompatible and conferred antioxidant activities. The powders also displayed fibroblast cell proliferation, migration and adhesion properties, implying their wound-healing potentials. Thus, the developed in situ gel-forming powders could be employed as promising dressings for wound management., Competing Interests: Declaration of competing interest All authors declare no personal relationships or conflicting interests, which have influenced the research activities presented in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Amino acid propensities for protein secondary structures are vital for protein structure prediction, understanding folding, and design, and have been studied using various theoretical and experimental methods. Traditional assessments of average propensities using statistical methods have been done on relatively smaller dataset for only a few secondary structures. They also involve averaging out the environmental factors and lack insights into consistency of preferences across diverse protein structures. While a few studies have explored variations in propensities across protein structural classes and folds, exploration of such variations across protein structures remains to be carried out. In this work, we have revised the average propensities for all six different secondary structures, namely α-helix, β-strand, 3 10 -helix, π-helix, turn and coil, analyzing the most exhaustive dataset available till date using two robust secondary structure assignment algorithms, DSSP and STRIDE. The propensities evaluated here can serve as a standard reference. Moreover, we present here, for the first time, the propensities within individual protein structures and investigated how the preferences of residues and more interestingly, of their groups formed based on their structural features, vary across different unique structures. We devised a novel approach- the minimal set analysis, based on the propensity distribution of residues, which along with the group propensities led us to the conclusion that a residue's preference for a specific secondary structure is primarily dictated by its side chain's structural features. The findings in this study provide a more insightful picture of residues propensities and can be useful in protein folding and design studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Amidst the Zn 2+ -dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett's Syndrome, Alzheimer's disease, Huntington's disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases. In this context, this study has been carried out to evaluate the potential structural contributors of quinazoline-cap-containing HDAC6 inhibitors via machine learning (ML), conventional classification-dependant QSAR, and MD simulation-based binding mode of interaction analysis toward HDAC6 binding. This combined conventional and modern molecular modeling study has revealed the significance of the quinazoline moiety, substitutions present at the quinazoline cap group, as well as the importance of molecular property, number of hydrogen bond donor-acceptor functions, carbon-chlorine distance that significantly affects the HDAC6 binding of these inhibitors, subsequently affecting their potency . Interestingly, the study also revealed that the substitutions such as the chloroethyl group, and bulky quinazolinyl cap group can affect the binding of the cap function with the amino acid residues present in the loops proximal to the catalytic site of HDAC6. Such contributions of cap groups can lead to both stabilization and destabilization of the cap function after occupying the hydrophobic catalytic site by the aryl hydroxamate linker-ZBG functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that can influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A mucoadhesive polyelectrolyte complex (PEC) nanoparticles were developed for ocular moxifloxacin (Mox) delivery in Bacterial Keratitis (BK). Moxifloxacin-loaded G/CG-Alg NPs were prepared by an amalgamation of cationic polymers (gelatin (G)/cationized gelatin (CG)), and anionic polymer (sodium alginate (Alg)) along with Mox respectively. Mox@CG-Alg NPs were characterized for physicochemical parameters such as particle size (DLS technique), morphology (SEM analysis), DSC, XRD, encapsulation efficiency, drug loading, mucoadhesive study (by texture analyzer), mucin turbidity, and viscosity assessment. The NPs uptake and toxicity of the formulation were analyzed in the Human Corneal Epithelial (HCE) cell line and an ocular irritation study was performed on the HET-CAM. The results indicated that the CG-Alg NPs, with optimal size (217.2 ± 4 nm) and polydispersity (0.22 ± 0.05), have shown high cellular uptake in monolayer and spheroids of HCE. The drug-loaded formulation displayed mucoadhesiveness, trans-corneal permeation, and sustained the release of the Mox. The anti-bacterial efficacy studied on planktonic bacteria/biofilms of P. aeruginosa and S. aureus (in vitro) indicated that the Mox@CG-Alg NPs displayed low MIC, higher zone of bacterial growth inhibition, and cell death compared to free Mox. A significant reduction of bacterial load was observed in the BK-induced mouse model., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Nanomedicines have emerged as a potential strategy to reduce the toxic effect of drugs administered via conventional approaches. Nanomedicines undergo passive and active targeting of the tumor tissues, thereby causing localized drug delivery and reducing drug demand and side effects. Here, we prepared reduction-sensitive oxaliplatin-conjugated human serum albumin nanoparticles with a small size, uniform surfaces, and a satisfactory encapsulation coefficient. The findings of cellular studies demonstrate that utilizing human serum albumin is effective for active tumor targeting. The presence of glutathione-sensitive disulfide linkers in the crosslinking agent and between Pt(IV) and HSA provided dual reduction sensitivity. Cytotoxicity and cell death were enhanced compared to free Oxaliplatin. The outcomes demonstrate that the approach maximized Oxaliplatin's ability to control tumor growth, induced apoptosis, and reduced drug resistance. Therefore, for the first time, our results imply that OXA-SS-HSA NPs were biocompatible, smart, and effective anticancer nanomedicine for triple-negative breast cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Histone deacetylase 3 (HDAC3) is an epigenetic regulator that involves gene expression, apoptosis, and cell cycle progression, and the overexpression of HDAC3 is accountable for several cancers, neurodegeneracy, and many other diseases. Therefore, HDAC3 emerged as a promising drug target for the novel drug design. Here, we carried out the pharmacophore modeling using 50 benzamide-based HDAC3 selective inhibitors and utilized it for PHASE ligand screening to retrieve the hits with similar pharmacophore features. The dataset inhibitors of best hypotheses used to build the 3D QSAR model and the generated 3D QSAR model resulted in good PLS statistics with a regression coefficient (R 2 ) of 0.89, predictive coefficient (Q 2 ) of 0.88, and Pearson-R factor of 0.94 indicating its excellent predictive ability. The hits retrieved from pharmacophore-based virtual screening were subjected to docking against HDAC3 for the identification of potential inhibitors. A total of 10 hitsM1 to M10 were ranked using their scoring functions and further subject to lead optimization. The Prime MM/GBSA, AutoDock binding free energies, and ADMET studies were implemented for the selection of lead candidates. The four ligand molecules M1, M2, M3, and M4 were identified as potential leads against HDAC3 after lead optimization. The top two leads M1 and M2 were subjected to MD simulations for their stability evaluation with HDAC3. The newly designed leads M11 and M12 were identified as HDAC3 potential inhibitors from MD simulations studies. Therefore, the outcomes of the present study could provide insights into the discovery of new potential HDAC3 inhibitors with improved selectivity and activity against a variety of cancers and neurodegenerative diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that can influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To date, various agents and molecules have been developed to treat post-stroke neuroinflammation; however, none of them are clinically successful. Post-stroke neuroinflammation is primarily attributed to microglial polarization as the generation of inflammasome complexes shifts microglia to their M1 phenotype and regulates the downstream cascade. Inosine, an adenosine derivative reported to maintain cellular energy homeostasis in stressed conditions. Although the exact mechanism is still unexplored, various studies have reported that it can stimulate axonal sprouting in different neurodegenerative diseases. Hence, our present study aims to decipher the molecular mechanism of inosine mediated neuroprotection by modulating inflammasome signaling towards altered microglial polarization in ischemic stroke. Inosine was administered intraperitoneally to male Sprague Dawley rats at 1 h post-ischemic stroke and was further evaluated for neurodeficit score, motor coordination and long-term neuroprotection. Brains were harvested for infarct size estimation, biochemical assays and molecular studies. Inosine administration at 1 h post ischemic stroke decreased infarct size, neurodeficit score, and improved motor co-ordination. Normalization of biochemical parameters were achieved in the treatment groups. Microglial polarization towards its anti-inflammatory phenotype and modulation of inflammation were evident by relevant gene and protein expression studies. The outcome provides preliminary evidence of inosine mediated alleviation of post-stroke neuroinflammation via modulation of microglial polarization towards its anti-inflammatory form through regulating the inflammasome activation., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Here, we report the effect of histone deacetylase 3 (HDAC3) inhibition associated with macrophage activation, IL-1β expression, angiogenesis and wound healing in diabetic mice., Main Methods: To determine the expression of HDAC3 in diabetic mice wounds, hyperglycemia was induced in C57BL/6 mice with streptozotocin followed by induction of 6 mm wounds. To understand the effect of HDAC3 selective inhibitor, BG45, wound tissues were isolated for analysing M1/M2 markers expression, immune cells infiltration, angiogenesis and healing factors expression. CD11b + F4/80 + cells were sorted from the wound tissues and analysed for the expression of M1/M2 markers using RT-qPCR and flow cytometer. In cell based assays, HDAC3 expression was measured in macrophages stimulated with high glucose (HG) plus LPS. Macrophages treated with BG45 and HG + LPS were analysed for the expression of pro-IL-1β, mature IL-1β, oxidative stress and pro-inflammatory (M1) and anti-inflammatory (M2) factors., Key Findings: HDAC3 was found to be upregulated in impaired diabetic mice wounds and in macrophages stimulated with HG + LPS. Topical application of BG45 loaded gel accelerated the wound healing in diabetic mice and was evident by improved expression of Collagen-1A, IL-10, TGF-β, and angiogenesis (CD31, VEGF). BG45 treatment decreased the expression of IL-1β, TNF-α, and IL-6 (M1 phenotype), reduced oxidative stress and promoted the expression of Arginase-1 and YM1/2 (M2 phenotype) in macrophages treated with HG + LPS. BG45 also improved the expression of CD11b + F4/80 + CD206 + cells in wound tissues and reduced expression of inflammatory markers., Significance: HDAC3 is upregulated in diabetic mice wounds and HDAC3 selective inhibitor promotes the wound healing by regulating macrophage activation, angiogenesis and IL-1β., Competing Interests: Declaration of competing interest Authors does not have any conflict of interest with anyone., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aeromonas hydrophila (Ah) is a Gram-negative bacterium and a serious global pathogen causing Motile Aeromonas Septicaemia (MAS) in fish leading to global loss in aquaculture. Investigation of the molecular alterations of host tissues such as liver could be a powerful approach to identify mechanistic and diagnostic immune signatures of disease pathogenesis. We performed a proteomic analysis of Labeo rohita liver tissue to examine the protein dynamics in the host cells during Ah infection. The proteomic data was acquired using two strategies; discovery and targeted proteomics. Label-free quantification was performed between Control and challenged group (AH) to identify the differentially expressed proteins (DEPs). A total of 2525 proteins were identified and 157 were DEPs. DEPs include metabolic enzymes (CS, SUCLG2), antioxidative proteins, cytoskeletal proteins and immune related proteins (TLR3, CLEC4E). Pathways like lysosome pathway, apoptosis, metabolism of xenobiotics by cytochrome P450 were enriched by downregulated proteins. However, upregulated proteins majorly mapped to innate immune system, signaling of B cell receptor, proteosome pathway, ribosome, carbon metabolism and protein processing in ER. Our study would help in exploring the role of Toll-like receptors, C-type lectins and, metabolic intermediates like citrate and succinate in Ah pathogenesis to understand the Ah infection in fish. SIGNIFICANCE: Bacterial diseases such as motile aeromonas septicaemia (MAS) are among the most serious problems in aquaculture industry. Small molecules that target the metabolism of the host have recently emerged as potential treatment possibilities in infectious diseases. However, the ability to develop new therapies is hampered due to lack of knowledge about pathogenesis mechanisms and host-pathogen interactions. We examined alterations in the host proteome during MAS caused by Aeromonas hydrophila (Ah) infection, in Labeo rohita liver tissue to find cellular proteins and processes affected by Ah infection. Upregulated proteins belong to innate immune system, signaling of B cell receptor, proteosome pathway, ribosome, carbon metabolism and protein processing. Our work is an important step towards leveraging host metabolism in targeting the disease by providing a bigger picture on proteome pathology correlation during Ah infection., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19., Competing Interests: The authors declare that there is no conflict of interest., (© 2022 Elsevier B.V. All rights reserved.)

This study analyzes the relationship between clean and dirty energy sources and energy metals during the COVID-19 pandemic. We document a sharp increase in connectedness after the COVID-19 pandemic, that is asymmetric at the lower and upper quantiles, with stronger dependence among the variables at the upper quantiles. Among the energy metals, cobalt is the least connected to the energy markets. Finally, our empirical results show a switch in the net connectedness indexes of energy metals and clean energy after January 2021. Our results have implication for investors and policy makers for energy and metal under various market conditions., (© 2022 Elsevier B.V. All rights reserved.)

Oral cancer is one of the most prevalent malignancies worldwide. Here, to prepare a biocompatible tumor-targeted nanoformulation capable of efficient loading of the hydrophobic drug, DTX, human serum albumin was conjugated to poly(lactide) at different HSA: PLA ratios (1:1, 2, 3). The HSA-(PLA) 1 - 3 conjugates were physicochemically characterized by UV, IR, NMR, GPC, pyrene incorporation, and surface tension analysis. Next, the DTX-loaded DTX@HSA-(PLA) 1 - 3 NPs were prepared by the desolvation-self-assembly technique, which was further optimized by DOE. The NPs were characterized by DLS, SEM, DSC, XRD, CD spectroscopy, SDS-PAGE, drug entrapment and loading efficiencies, kinetic stability, drug release, and hemolysis assays. Murine and human oral cancer cell lines, MOC2 and FaDu, were used in monolayers/multicellular spheroids to assess cellular uptake, the extent of cell viability, and apoptosis induction following NPs treatment. The DTX@HSA-(PLA) 1 - 3 NPs were ~ 149-212 nm size range, drug entrapment, ~75-96 %, and loading efficiency, ~21-27 %. The selected DTX@HSA-(PLA) 2 NPs showed time-dependent improved targetability towards cancer cells than HSA NPs, indicating the benefit of HSA polymerization in NPs internalization. A time-dependent decrease in cell viability was observed for both the cell lines with IC50 values, 7.12 ± 1.84 and 6.38 ± 1.63 μg/mL, for FaDu and MOC2 cell lines, respectively (48 h post-treatment). The DTX@ HSA-(PLA) 2 NPs treatment induced higher apoptotic marker expressions, cell-cycle arrest in the G2/M-phase, DNA damage, and mitochondrial depolarization than free DTX and DTX@HSA NPs. Further, DTX@HSA-(PLA) 2 NPs (iv) showed significantly reduced plasma clearance (p < 0.05) and volume of distribution (V d ) than DTX and DTX@HSA NPs. Therefore, the developed polyprotein NPs offer superior therapeutic effect due to their stable drug incorporation, improved cell internalization, and long circulation, revealing their potential as an effective nanomedicine for oral cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The novel enveloped β-coronavirus SARS-CoV-2 (COVID-19) has offered a surprising health challenge all over the world. It develops severe pneumonia leading to acute respiratory distress syndrome (ARDS). Like SARS-COV-2, other encapsulated viruses like HIV, HSV, and influenza have also offered a similar challenge in the past. In this regard, many antiviral drugs are being explored with varying degrees of success to combat the associated pathological conditions. Therefore, upon scientific validation & development, these antiviral phytochemicals can attain a futuristic nutraceutical prospect in managing different encapsulated viruses. Houttuynia cordata (HC) is widely reported for activities such as antioxidant, anti-inflammatory, and antiviral properties. The major antiviral bioactive components of HC include essential oils (methyl n-nonyl ketone, lauryl aldehyde, capryl aldehyde), flavonoids (quercetin, rutin, hyperin, quercitrin, isoquercitrin), and alkaloids (norcepharadione B) & polysaccharides. HC can further be explored as a potential nutraceutical agent in the therapy of encapsulated viruses like HIV, HSV, and influenza. The review listed various conventional and green technologies that are being employed to extract potent phytochemicals with diverse activities from the HC. It was indicated that HC also inhibited molecular targets like 3C-like protease (3CLPRO) and RNA-dependent RNA polymerase (RdRp) of COVID-19 by blocking viral RNA synthesis and replication. Antioxidant and hepatoprotective effects of HC have been evident in impeding complications from marketed drugs during antiviral therapies. The use of HC as a nutraceutical is localized within some parts of Southeast Asia. Further technological advances can establish it as a nutraceutical-based functional food against pathogenic enveloped viruses like COVID 19., Competing Interests: The authors declare no conflicts of interest., (© 2022 Elsevier Ltd. All rights reserved.)

The hydrophilic nature and resultant persistence of neonicotinoids in aquatic systems increase the exposure duration for non-target organisms. The sublethal toxicity of the neonicotinoid Thiamethoxam® spanning sub-chronic and chronic durations was investigated in Clarias batrachus, a non-target freshwater fish species. 96 h LC 50 value of Thiamethoxam® on Clarias batrachus was 138.60 mg L -1 . Pre-determined exposure concentrations of Thiamethoxam® (6.93 and 13.86 mg L -1 ) were used and effects were assessed at days 15, 30, and 45 exposure intervals. Biomarker effects were evaluated using antioxidant enzyme responses (CAT, SOD) neurotransmission (acetylcholinesterase activity), haematological and serum biochemistry changes (including haemoglobin content, total erythrocyte count, and serum albumin total leukocyte count, total serum protein, serum globulin, triglyceride, cholesterol, high-density lipoprotein, very low-density lipoprotein, low-density lipoprotein, phospholipid, and total serum glucose), histopathological alterations (gill and liver). Thiamethoxam®-exposed fish showed a marked reduction in haemoglobin content, total erythrocyte count, and serum albumin levels compared to control fish. Similarly, gill and liver antioxidant enzyme activity (CAT, SOD) and neurotransmission (acetylcholinesterase) also showed altered responses between sub-chronic exposure on day-15 and chronic responses on day-45. Histopathological observations in gill tissue revealed alterations ranging from vacuolation, hypertrophy, disruption of primary lamellar architecture, haemorrhage, the fusion of secondary lamella, and sloughing of outer epithelia. For liver tissue of exposed fish histopathological observations included increased sinusoidal spaces (ISS), necrosis of hepatocytes (NOH), nuclear degeneration (ND), disruption of architecture (DOA), macrophage infiltration of the central vein, vacuolation (V), hypertrophied hepatocytes, and haemorrhages. The gradients of toxic responses across exposure concentrations and depictions of impaired fish health with increasing thiamethoxam® exposure duration portend lowered physiological capacity for survival in the wild., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rehabilitation of a post-exenterated orbital defect is a necessity, to restore a patient's esthetic appearance and help overcome the associated psychosocial stigma. An implant supported prosthesis enjoys a better patient acceptance due to its superior retention and stability. This clinical report highlights the challenges faced in planning, designing and placement of maxillofacial implants in the supra-orbital rim of an exenterated socket post-radiotherapy along with the management of the unexpected complications which developed subsequently. Administration of hyperbaric oxygen therapy, fabrication of a digitally designed surgical guide to ensure predictable implant placement, selection of surface treated implants for better biomechanical anchorage, and a gentler surgical technique for recovery of irradiated hard and soft tissues were measures undertaken during the treatment phase. An effort has been made to point-out the fact that despite the various approaches adopted in an irradiated patient, success of implant placement in such a situation remains a challenge., Competing Interests: The authors report no conflict of interest., (© 2022 Craniofacial Research Foundation. Published by Elsevier B.V. All rights reserved.)

Due to COVID-19, the whole world is undergoing a devastating situation, but treatment with no such drug candidates still has been established exclusively. In that context, 69 diverse chemicals with potential SARS-CoV-2 3CL pro inhibitory property were taken into consideration for building different internally and externally validated linear (SW-MLR and GA-MLR), non-linear (ANN and SVM) QSAR, and HQSAR models to identify important structural and physicochemical characters required for SARS-CoV-2 3CL pro inhibition. Importantly, 2-oxopyrrolidinyl methyl and benzylester functions, and methylene (hydroxy) sulphonic acid warhead group, were crucial for retaining higher SARS-CoV-2 3CL pro inhibition. These GA-MLR and HQSAR models were also applied to predict some already repurposed drugs. As per the GA-MLR model, curcumin, ribavirin, saquinavir, sepimostat, and remdesivir were found to be the potent ones, whereas according to the HQSAR model, lurasidone, saquinavir, lopinavir, elbasvir, and paritaprevir were the highly effective SARS-CoV-2 3CL pro inhibitors. The binding modes of those repurposed drugs were also justified by the molecular docking, molecular dynamics (MD) simulation, and binding energy calculations conducted by several groups of researchers. This current work, therefore, may be able to find out important structural parameters to accelerate the COVID-19 drug discovery processes in the future., Competing Interests: The authors declare no conflict of interests., (© 2021 Elsevier B.V. All rights reserved.)

VpsR, the master regulator of biofilm formation in Vibrio cholerae, is an atypical NtrC1 type bEBP lacking residues essential for σ 54 -RNAP binding and REC domain phosphorylation. Moreover, transcription from P vpsL , a promoter of biofilm biosynthesis, has been documented in presence of σ 70 -RNAP/VpsR/c-di-GMP complex. It was proposed that c-di-GMP and VpsR together form an active transcription complex with σ 70 -RNAP. However, the impact of c-di-GMP imparted on VpsR that leads to transcription activation with σ 70 -RNAP remained elusive, largely due to the lack of the structure of VpsR and knowledge about c-di-GMP:VpsR interactions. In this direction we have solved the crystal structure of VpsR RA , containing REC and AAA + domains, in apo, AMPPNP/GMPPNP and c-di-GMP bound states. Structures of VpsR RA unveiled distinctive REC domain orientation that leads to a novel dimeric association and noncanonical ATP/GTP binding. Moreover, we have demonstrated that at physiological pH VpsR remains as monomer having no ATPase activity but c-di-GMP imparted cooperativity to convert it to dimer with potent activity. Crystal structure of c-di-GMP:VpsR RA complex reveals that c-di-GMP binds near the C-terminal end of AAA + domain. Trp quenching studies on VpsR R , VpsR A , VpsR RA , VpsR AD with c-di-GMP additionally demonstrated that c-di-GMP could potentially bind VpsR D . We propose that c-di-GMP mediated tethering of VpsR D with VpsR A could likely favor generating the specific protein-DNA architecture for transcription activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Bacterial keratitis (BK) is a leading cause of visual impairment. The fluoroquinolone antibiotic moxifloxacin (Mox), being highly water-soluble, suffers from poor corneal penetration leading to unsatisfactory therapeutic outcomes in BK. Here, we prepared Mox-loaded co-polymeric nanoparticles (NPs) by entrapping the drug in co-polymeric NPs constituted by the self-assembly of a water-soluble copolymer, poly(ethylene glycol)-b-p(hydroxypropyl) methacrylamide (mPH). The polymer (mPH) was prepared using a radical polymerization technique at different mPEG: HPMA ratios of 1:70/100/150. The polymer/nanoparticles were characterized by GPC, CAC, DLS, SEM, XRD, DSC, FTIR, % DL, % EE, and release studies. The ex vivo muco-adhesiveness and corneal permeation ability were judged using a texture analyzer and Franz Diffusion Cells. In vitro cellular uptake, cytotoxicity, and safety assessment were performed using HCE cells in monolayers, spheroids, and multilayers in transwells. The DOE-optimized colloidal solution of Mox-mPH NPs (1:150) displayed a particle size of ~116 nm, superior drug loading (8.3%), entrapment (83.2%), robust mucoadhesion ex vivo, and ocular retention in vivo (~6 h) (judged by in vivo image analysis). The non-irritant formulation, Mox-mPH NPs (1:150) (proven by HET-CAM test) exhibited intense antimicrobial activity against P. aeruginosa, S. pneumoniae, and S. aureus in vitro analyzed by live-dead cells assay, zone of inhibition studies, and by determining the minimum inhibitory and bactericidal concentrations. The polymeric nanoparticles, mPH (1:150), decreased the opacity and the bacterial load compared to the other treatment groups. The studies warrant the safe and effective topical application of the Mox-mPH NPs solution in bacterial keratitis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Histone deacetylase 3 (HDAC3) is one of the most promising targets to develop anticancer therapeutics. In continuation of our quest for selective HDAC3 inhibitors, a series of small molecules having o-hydroxy benzamide as the novel zinc binding group (ZBG) has been introduced for the first time that can be able to produce good HDAC3-selectivity over other HDACs. The most promising HDAC3 inhibitors, 11a and 12b, displayed promising in vitro anticancer activities with less toxicity to normal kidney cells. These compounds significantly upregulate histone acetylation and induce apoptosis with a G2/M phase arrest in B16F10 cells. Compound 11a exhibited potent antitumor efficacy in 4T1-Luc breast cancer xenograft mouse model in female Balb/c mice. It also showed significant tumor growth suppression with no general toxicity and extended survival rates post-tumor resection. It significantly induced higher ROS generation, leading to apoptosis. No considerable toxicity was noticed in major organs isolated from the compound 11a-treated mice. Compound 11a also induced the upregulation of acH3K9, acH4K12, caspase-3 and caspase-7 as analyzed by immunoblotting with treated tumor tissue. Overall, HDAC3 selective inhibitor 11a might be a potential lead for the clinical translation as an emerging drug candidate., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This exposition reveals the effect of glucose as a molecular crowder on the solvent environment in proximity of the protein surface in putative folded (Ubiquitin) and intrinsically disordered (dimeric Amyloid beta) states. Atomistic simulations reveal markedly higher structural perturbation in the disordered systems due to crowding effects, while the folded state retains overall structural fidelity. Key hydrophobic contacts in the disordered dimer are lost. However, glucose induced crowding results in elevated hydration on surfaces of both protein systems. Despite evident differences in their structural responses, the hydration layer of both the folded and disordered states display a distinct enhancement in lifetimes of mean residence and rotational relaxation under the hyperglycemic conditions. The results are crucial in the light of emergent co-solvent induced biological phenomena in crowded media., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Neelanjana Sengupta reports financial support was provided by Science and Engineering Research Board. Brataraj Ghosh reports financial support was provided by University Grants Commission., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The outbreak of COVID-19 had already shown its harmful impact on mankind, especially on health sectors, global economy, education systems, cultures, politics, and other important fields. Like most of the affected countries in the globe, India is now facing serious crisis due to COVID-19 in the recent times. The evaluation of the present status of the provinces affected by COVID-19 is very much essential to the government authorities to impose preventive strategies in controlling the spread of COVID-19 and to take necessary measures. In this article, a computational methodology is developed to estimate the present status of states and provinces which are affected due to COVID-19 using a fuzzy inference system. The factors such as population density, number of COVID-19 tests, confirmed cases of COVID-19, recovery rate, and mortality rate are considered as the input parameters of the proposed methodology. Considering positive and negative factors of the input parameters, the rule base is developed using triangular fuzzy numbers to capture uncertainties associated with the model. The application potentiality is validated by evaluating Pearson's correlation coefficient. A sensitivity analysis is also performed to observe the changes of final output by varying the tolerance ranges of the inputs. The results of the proposed method show that some of the provinces have very poor performance in controlling the spread of COVID-19 in India. So, the government needs to take serious attention to deal with the pandemic situation of COVID-19 in those provinces., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier B.V. All rights reserved.)

A series of novel linker-less benzamides with different aryl and heteroaryl cap groups have been designed, synthesized, and screened as potent histone deacetylase (HDAC) inhibitors with promising anticancer activity. Two lead compounds 5e and 5f were found as potent and highly selective HDAC3 inhibitors over other Class-I HDACs and HDAC6. Compound 5e bearing a 6-quinolinyl moiety as the cap group was found to be a highly potent HDAC3 inhibitor (IC 50  = 560 nM) and displayed 46-fold selectivity for HDAC3 over HDAC2, and 33-fold selectivity for HDAC3 over HDAC1. The synthesized compounds possess antiproliferative activities against different cancer cell lines and significantly less cytotoxic to normal cells. Molecular Docking studies of compounds 5e and 5f reveal a similar binding mode of interactions as CI994 at the HDAC3 active site. These observations agreed with the in vitro HDAC3 inhibitory activities. Significant enhancement of the endogenous acetylation level on H3K9 and H4K12 was found when B16F10 cells were treated with compounds 5e and 5f in a dose-dependent manner. The compounds induced apoptotic cell death in Annexin-V/FITC-PI assay and caused cell cycle arrest at G2/M phase of cell cycle in B16F10 cells. These compounds may serve as potential HDAC3 inhibitory anticancer therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The habit of chewing arecanut leads to fibrosis in the oral tissues, which can lead to cancer. Despite high mortality, fibrosis has limited clinical success owing to organ-specific variations, genetic predispositions, and slow progression. Fibrosis is a progressive condition that is unresponsive to medications in the severe phase. To understand underlying macromolecular changes we studied the extracellular matrix's (ECM) key molecular modifications in the early and late phase of arecanut-induced fibrosis in skin. To study the fibrosis, we topically applied arecanut extract on the mice skin. We observed that the matrix changes observe early and late phases based on ECM characteristics including the matrix proteins and the glycans. A spike in the levels of proteoglycans and β-sheet structures are noted in the early phase. A significant drop in the proteoglycans and strengthening of amide covalent interactions is observed in the late phase. Although, almost no physical changes are noticeable only in the early phase; the late phase observes thick collagen bundling and a 4-fold stiffening of the skin tissue. The study indicates that the temporal interplay of proteins and glycans determine the matrix's severity state while opening avenues to research directed towards the phase-specific clinical discovery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In the present study, polymeric micelles constituted of N-(2-hydroxypropyl)methacrylamide (HPMA) and methoxypoly(ethylene glycol) (mPEG)-based copolymer, mPEG-b-HPMA was studied for the delivery of an anticancer drug, doxorubicin (DOX) by physically loading the drug into its core. A series of mPEG-b-HPMA copolymers of different molecular weights (MWs, ∼4000-25,000 Da) by using various initiator: monomer feed ratios (1:25/75/125/175) were synthesized by radical polymerization technique. The DOX-loaded micelles were prepared at different drug to polymer ratios by thin film hydration method. Block copolymers were structurally characterized by gel permeation chromatography (GPC), 1 H-NMR spectroscopy, fourier transform infrared spectroscopy (FTIR), and critical micelles concentration studies. The DLS and SEM studies indicated that the micelles were spherical with diameters ∼20-100 nm. The DOX-loaded mPEG-b-HPMA micelles, P6-M1, prepared by the polymer synthesized using initiator: monomer feed ratios of 1:175 and at polymer to drug ratios of 10:1 exhibited low particle sizes (∼46.8 nm), highest drug loading and encapsulation efficiencies (5.6 %, and 63.3 %, respectively) compared to the other tested formulations. Confocal microscopy study indicated that the P6-M1 was taken up by breast cancer cell lines, 4T1, MCF-7, and MDA-MB-231in a time-dependent manner. P6-M1 displayed lower half maximal inhibitory concentration (IC 50 ) compared to free drug in all tested treatment durations compared to free DOX. P6-M1 was safe in hemolysis studies with sustained DOX residence in circulation compared to free DOX. The results indicated that mPEG-b-HPMA could be utilized to load DOX effectively, and the optimized nano-micelles, P6-M1 could serve as a promising nanomedicine to treat breast cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A series of thirty-one novel 7-(5-((amino)-methyl)-thiophen-2-yl)-spiro-[chroman-2,4'-piperidin]-4-one hydrochloride analogues (Cst 1 - 31) have been designed, synthesized and characterized by 1 H NMR, 13 C NMR and MS spectral analysis. Here, we evaluated the anticancer potential and biological results of low-molecular-weight bridgehead oxygen and nitrogen-containing spirochromanones on proliferation and apoptosis of the human breast cancer cell line (MCF-7) and Murine melanoma (B16F10). The anticancer activity ranged from 2.9 to 35.0 µM. The most potent compounds Cst-22, Cst-24 and Cst-31 were found to be less toxic against human embryonic kidney (HEK-293) cell lines. Cst-24 and Cst-31 were found to be causing significant cytotoxicity through apoptotic cell death and also G2 phase arrest of cell cycle in B16F10 cells. In-silico ADME prediction stidies of the titled compounds were found within the rules outlined, and these compounds may not face any pharmacokinetic associated issues in the mere future upon developmental stage. These conjugates may serve as a lead for the discovery of potential anticancer drug candidate with better therapeutic profile., (Copyright © 2021 Elsevier Inc. All rights reserved.)

HDAC6, a class IIB HDAC isoenzyme, stands unique in its structural and physiological functions. Besides histone modification, largely due to its cytoplasmic localization, HDAC6 also targets several non-histone proteins including Hsp90, α-tubulin, cortactin, HSF1, etc. Thus, it is one of the key regulators of different physiological and pathological disease conditions. HDAC6 is involved in different signaling pathways associated with several neurological disorders, various cancers at early and advanced stage, rare diseases and immunological conditions. Therefore, targeting HDAC6 has been found to be effective for various therapeutic purposes in recent years. Though several HDAC6 inhibitors (HDAC6is) have been developed till date, only two ACY-1215 (ricolinostat) and ACY-241 (citarinostat) are in the clinical trials. A lot of work is still needed to pinpoint strictly selective as well as potent HDAC6i. Considering the recent crystal structure of HDAC6, novel HDAC6is of significant therapeutic value can be designed. Notably, the canonical pharmacophore features of HDAC6is consist of a zinc binding group (ZBG), a linker function and a cap group. Significant modifications of cap function may lead to achieve better selectivity of the inhibitors. This review details the study about the structural biology of HDAC6, the physiological and pathological role of HDAC6 in several disease states and the detailed structure-activity relationships (SARs) of the known HDAC6is. This detailed review will provide key insights to design novel and highly effective HDAC6i in the future., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Oral sub-mucous fibrosis (OSF) is a pathophysiological state of oral cavity or oropharynx having a high chance of conversion to oral squamous cell carcinoma (OSCC). It involves fibrotic transformation of sub-epithelial matrix along with epithelial abnormalities. The present work aims to unveil the mechanistic domain regarding OSF to OSCC conversion exploring the scenario of hypoxia associated oxidative stress, epithelial-mesenchymal transition (EMT), metastasis and stemness acquisition. The study involves histopathological analysis of the diseased condition along with the exploration of oxidative stress status, assessment of mitochondrial condition, immunohistochemical analysis of HIF-1α, E-cadherin, vimentin, ERK, ALDH-1, CD133, Shh, Gli-1 and survivin expressions in the oral epithelial region together with the quantitative approach towards collagen deposition in the sub-epithelial matrix. Oxidative stress was found to be associated with type-II EMT in case of OSF attributing the development of sub-epithelial fibrosis and type-III EMT in case of OSCC favoring malignancy associated metastasis. Moreover, the acquisition of stemness during OSCC can also be correlated with EMT. Alteration of Shh and Gli-1 expression pattern revealed the mechanistic association of hypoxia with the phenotypic plasticity and disease manifestation in case of OSF as well as OSCC. Shh/ Gli-1 signaling can also be correlated with survivin mediated cytoprotective phenomenon under oxidative stress. Overall, the study established the correlative network of hypoxia associated oxidative stress, EMT and manifestation of oral pre-cancerous and cancerous condition in a holistic approach that may throw rays of hope in the therapeutic domain of the concerned diseases., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The objective of the work was to improve the intestinal stability and pH sensitive release of quercetin in the gastrointestinal tract. To achieve this aim, novel quercetin loaded pH sensitive hydrogel beads of gellan gum were developed through an ionic cross-linking technique using calcium chloride (CaCl 2 ) as cross-linking agents. Field emission scanning electron microscopy (FESEM) was used to characterize the morphological appearance of the prepared hydrogel beads. Drug-polymer and drug-CaCl 2 interaction were studied by using infrared spectroscopy. The important finding of the study was the formation of stable hydrogel beads at a very low concentration of CaCl 2 (0.3 % w/v). There was a drug polymer interaction in addition to polymer and CaCl 2 interaction that is confirmed by infrared spectroscopy. All the formulation shows good entrapment efficiencies within the range of 58.56-93.71 %. The prepared beads exhibited a pH responsive swelling behavior with maximum swelling at the simulated intestinal fluid (pH 7.4) (SIF). Hydrogel beads also showed a pH responsive release behavior and sustained release of drug at SIF. Moreover, the intestinal stability of quercetin was improved when encapsulated in gellan gum hydrogel beads in comparison to the solution containing quercetin., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Delayed wound healing in diabetes is characterized by sustained activation of inflammasome and increased expression of IL-1β in macrophages. Identification and validation of novel pathways to regulate IL-1β expression will provide therapeutic targets for diabetic wounds. Here we report sustained over-expression of histone deacetylase 6 (HDAC6) in wounds of diabetic mice and its role in delayed wound healing. Topical application of HDAC6 inhibitor; Tubastatin A (TSA) gel promoted the wound healing in diabetic mice. TSA hydrogel reduced the infiltration of neutrophils, T-cells and macrophages in the early phase of wound healing. TSA treatment promoted the wound healing by inducing collagen deposition, angiogenesis (CD31) and fibrotic factors (TGF-β1) in the late phase of healing. Protein analysis of the diabetic wounds treated with TSA showed increased acetylated α-tubulin and decreased levels of mature IL-1β with no significant effect on the expression of pro-IL-1β, pro-caspase-1 and active caspase-1. In in vitro assays, macrophages exhibited upregulation of HDAC6, IL-1β and downregulation of IL-10 upon stimulation with high glucose and LPS. TSA inhibited the IL-1β secretion and promoted IL-10 in stimulated macrophages with high glucose and LPS. Further investigations showed that TSA inhibits IL-1β release by inhibiting tubulin dependent lysosomal exocytosis without affecting its transcription and maturation. Nocodazole (known acetylation inhibitor) pre-treatment inhibited TSA effect on IL-1β secretion in high glucose stimulated macrophages. Overall, our findings indicate that sustained HDAC6 expression in diabetic wounds contributes to impaired healing responses and HDAC6 may represent a new therapeutic target for diabetic wounds., Competing Interests: Declaration of competing interest With the submission of this manuscript we would like to undertake that the above mentioned manuscript has not been published elsewhere, accepted for publication elsewhere or under editorial review for publication elsewhere; and that my Institute's BITS-Pilani, Hyderabad campus and co-authors are fully aware of this submission. The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epithelial mesenchymal transition (EMT) in development, tissue repair and carcinogenesis involves cellular plasticity with varying degrees of epithelial and mesenchymal properties. Several recent studies have focused on EMT phenotypic dynamism; however, information on cellular interaction in the context of EMT is inadequate. In our previous study, we investigated EMT phenotypic plasticity and anticipated it as a population driven interactive process. Present study has characterized cellular connectivity as a representative of interactivity during EMT in epithelial normal and cancer cell. It has also explored dynamism of connectivity and phenotype employing Markov model. Further, plasticity was substantiated with cell surface microvilli and molecular marker. The study unveiled interplay between phenotype and connectivity too. Findings have revealed that intercellular connectivity fueled EMT plasticity and its dynamism was more prominent in cancer population. However, normal cells are more vibrant in transition and phenotypic plasticity. We have proposed connectivity plasticity as a hallmark of EMT and needs to be studied in depth. Present study also paves the way in translating in vitro EMT findings in histopathological practices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A series of thirty one novel 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-3-methylquinoxaline-1,4-dioxide (7a-l), 3-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6-chloro-2-methylquinoxaline-1,4-dioxide (8a-l) and 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6,7-dichloro-3-methylquinoxaline-1,4-dioxide (9a-g) analogues were synthesized, characterized using various analytical techniques and single crystal was developed for the compounds 8 g and 9f. Synthesized compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two clinical isolates Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 30.35 to 252.00 µM. Among the tested compounds, 8e, 8 l, 9c and 9d exhibited moderate activity (MIC = 47.6 - 52.0 µM) and 8a exhibited significant anti-tubercular activity (MIC = 30.35 µM). Furthermore, 8e, 8 l, and 9d were found to be less toxic against human embryonic kidney, HEK 293 cell lines. Finally, a docking study was also performed using MTB DNA Gyrase (PDB ID: 5BS8) for the significantly active compound 8a to know the exact binding pattern within the active site of the target enzyme., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyloidogenic disorders are currently rising as a global health issue, prompting more and more studies dedicated to the development of effective targeted therapeutics. The innate affinity of these amyloidogenic proteins towards the biomembranes adds further complexities to the systems. Our previous studies have shown that biologically active peptides can effectively target amyloidogenesis serving as an efficient therapeutic alternative in several amyloidogenic disorders. The structural uniqueness of the PWWP motif in the de novo designed heptapeptide, KR7 (KPWWPRR-NH 2 ) was demonstrated to target insulin fiber elongation specifically. By working on insulin, an important model system in amyloidogenic studies, we gained several mechanistic insights into the inhibitory actions at the protein-peptide interface. Here, we report a second-generation non-toxic and serum stable cyclic peptide, based primarily on the PWWP motif that resulted in complete inhibition of insulin fibrillation both in the presence and absence of the model membranes. Using both low- and high-resolution spectroscopic techniques, we could delineate the specific mechanism of inhibition, at atomistic resolution. Our studies put forward an effective therapeutic intervention that redirects the default aggregation kinetics towards off-pathway fibrillation. Based on the promising results, this novel cyclic peptide can be considered an excellent lead to design pharmaceutical molecules against amyloidogenesis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: To develop a photosensitizer, chlorin e6 (Ce6)-based amphiphilic polymer, DP-Ce6, where DOPE and PEG are conjugated to Ce6, which would self-assemble to form polymeric micelles (DP-Ce6-M) in aqueous environment., Methods: DP-Ce6-M were characterized for particle size, zeta potential, and singlet oxygen ( 1 O 2 ) generation. Cellular internalization, phototoxicity were investigated against monolayer and 3D spheroids of human lung adenocarcinoma cells (A549)., Results and Conclusions: DP-Ce6-M formed stable micelles with particles size of 58.2 ± 1.6 nm. Solubility of Ce6 was improved. Photoactivity of DP-Ce6-M was sustained in regard to 1 O 2 generation compared to free Ce6. The DP-Ce6-M showed enhanced internalization and growth inhibition in monolayer and spheroidal cells. Overall, DP-Ce6-M demonstrated the potential for further exploration as PDT agent for cancer treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Human carbonic anhydrase-II (hCA-II) is the most dominant physiologic isoform amongst the sixteen reported hCA isoforms. Because of its high availability in the different anatomical, and cellular sites of the eye like retina and lens, it plays a more prominent role in the regulation of intraocular pressure than the other twelve catalytically active hCA isoforms. This isoform is also located in the brain, kidney, gastric mucosa, osteoclasts, RBCs, skeletal muscle, testes, pancreas, lungs, etc. Earlier, hCA-II inhibitors were designed based on the sulfonamides e.g. acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide, etc. and they were used systemically in antiglaucoma therapy. Many successful attempts have been made by the researchers in order to design more potent and effective inhibitors by incorporating various moieties in sulphonamides. Some novel scaffolds like chalcones, thiophenes, organotellurium compounds, dithiocarbamate, selenide, and 2-benzylpyrazine, etc. were also designed as hCA-II inhibitors and their inhibitory efficacy was proved in the nanomolar range. In order to obtain relevant information from the insights of their structure-activity relationship, the reported hCA-II inhibitors from the year 1989 to 2019 were critically analysed. It gave a complete insight into the relationship between their structure-activity and hCA-II inhibition. The broad spectrum of our investigation may help researchers to summarize all the crucial structural information required for the development of more potent hCA-II inhibitors for glaucoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rho-dependent transcription termination is a well-conserved process in bacteria. The Psu and YaeO proteins are the two established inhibitors of the ATP-dependent RNA helicase Rho protein of Escherichia coli. Here, we show a detailed sequence and phylogenetic analysis demonstrating that Vibrio cholerae YaeO (VcYaeO) is significantly distinct from its E. coli counterpart. VcYaeO induces significant growth defect on in vivo expression and inhibits in vitro functions of the V. cholerae Rho on directly binding to the latter. Through various biophysical techniques, we showed that interaction of VcYaeO disrupts the oligomeric state of the VcRho. Structure of VcYaeO solved at 1.75 Å resolution, the first crystal structure of a YaeO protein, demonstrates a beta-sandwich fold distinct from the NMR structure of the EcYaeO. Interestingly, VcYaeO structurally resembles the Hfq protein, and like the latter, it exhibits ssDNA/RNA-binding properties. Docking studies demonstrate probable interactions of VcYaeO with VcRho and mode of inhibition of RNA binding to Rho. We propose that VcYaeO inhibits the function of the Rho protein via disruption of the latter's hexameric assembly and also likely by sequestering the RNA from the Rho primarybinding sites., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: This study sought to evaluate the prognostic value of post-percutaneous coronary intervention (PCI) distal coronary pressure to aortic pressure ratio (Pd/Pa) in predicting long-term clinical outcomes and to determine whether Pd/Pa combined with fractional flow reserve (FFR) post-intervention provides additional prognostic information superior to either marker alone., Background: Post-PCI FFR has been shown to be a predictor of long-term outcomes in numerous studies. The role of post-PCI resting Pd/Pa has not been previously studied in this setting., Methods: Consecutive patients undergoing PCI who had pre- and post-PCI Pd/Pa and FFR were followed for major adverse cardiovascular events (MACE) including death, myocardial infarction, and target vessel revascularization., Results: A total of 574 patients were followed for 30 months (25th to 75th percentile 18 to 46 months). Using receiver-operating characteristic curve analysis post-stenting FFR cutoff of ≤0.86 had the best predictive accuracy of MACE (17% vs. 23%; log-rank p = 0.02), whereas post-stenting Pd/Pa ≤0.96 was the best predictor of MACE (15% vs. 24%; log rank p = 0.0006). There was a significant interaction between post-PCI Pd/Pa and FFR on MACE risk such that patients with Pd/Pa ≤0.96 and FFR ≤0.86 had the highest event rate (25%), whereas those with Pd/Pa >0.96 and FFR >0.86 had the lowest event rate (15%), which was not different from patients with Pd/Pa >0.96 and FFR ≤0.86 (17%). In a fully adjusted Cox regression analysis, Pd/Pa was an independent predictor of MACE (hazard ratio: 2.07; 95% confidence interval: 1.3 to 3.3; p = 0.002)., Conclusions: Post-PCI resting Pd/Pa is a powerful prognostic tool for MACE prediction. It adds complementary and incremental risk stratification over established factors including post-PCI FFR., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Due to the severe water pollution from effluent dyes, the need of the hour is to find a suitable dye degradation technology, and appropriate catalyst materials. Semiconducting ZnO was produced by pyrolysis of ZIF-8 template. The materials were well characterized with in situ and ex situ XRD and TGA, FE-SEM, HRTEM, UV-DRS, PL, and FRET. The results showed that upon calcination the body centered cubic ZIF-8 produces hexagonal primitive ZnO while retaining the truncated cubic shaped particles. The materials were screened for photo- and electro-catalytic oxidation of methylene blue. In both the different degradation technologies, ZnO synthesized from ZIF-8 outperformed the ZIF-8. The FRET dynamics showed significant spectral overlap of ZnO emission and the methylene blue absorption. It was found to be responsible for the better photocatalytic efficacy of ZnO samples than ZIF-8. The proposed reaction mechanism showed that the surface-bound reactive oxygen species produced either by light exposure or due to applied bias is key to dye degradation. The cytotoxicity of the untreated and ZnO and ZIF-8 treated dye over melanoma cells was evaluated, and it was found that the cytotoxicity of the degraded dye from ZIF-derived ZnO was less compared to that of ZIF-8 treated one., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this article, we compare the two ecological services known as yield and resilience, for a tri-trophic food chain model consisting of a prey, an intermediate predator and a top predator. For this comparison process, we use both analytical and numerical techniques. It is shown that a variety of patterns are possible based on the intensity of efforts distributed among different trophic levels. Thus we may suggest that fishing down the food chain, as suggested by Pauly et al. (1998) is not bound to happen. Our analysis also shows that balancing the harvest between prey, intermediate predator and top predator could give more yield and stabilizing the ecosystem, than the selective harvesting of any one species. This balanced harvesting may not be a win-win situation for yield and resilience, but it could be a most favourable strategy to balance them. This research would help to correlate resilience with yield and determines the desirable selection of two policies, resilience maximizing yield or maximum sustainable yield to safeguard ecological communities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The nature and profile of different modes of poisoning vary significantly in different parts of India. The assessment of the magnitude of suicidal poisoning is an area of paramount importance not only for appropriate management but also for raising social awareness and framing government policies for the prevention of same., Objectives: We aimed to determine the pattern of poisoning, the sociodemographic profile of patients who poison themselves, and the in-hospital outcome of self-poisoned patients over a 1-year period., Methods: This was a cross-sectional observational study conducted between May 2015 and April 2016 that included 492 patients >12 years of age who were admitted to our hospital after consuming poison with the intention of deliberate self-harm. Relevant history with respect to the nature and amount of poison ingested were taken and recorded, and the patients' sociodemographic profiles and outcome (as either discharge or death) were noted., Results: Most of the patients were 13-28 years of age (69%). Males (n = 293 [59.55%]) predominated over females and the majority were farmers (n = 193 [39.23%]). Rural cases (n = 373 [75.81%]) outnumbered urban cases. The major causes of deliberate self-harm attempts were impulsive actions (n = 442 [89.84%]). Pesticides (n = 393 [79.88%]) were the most commonly consumed poison. The overall mortality rate was 12%, with paraquat (94.74%) topping the list of fatal substances., Conclusion: Young adults and males constitute majority of the population in this study. Agricultural poisons made up the bulk of the cases, mostly taken by rural population. Paraquat, an herbicide banned in several countries, had the highest mortality rate in this study., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Acyl carrier proteins (ACPs) play crucial roles in the biosynthesis of fatty acids, non-ribosomal polypeptides and polyketides. The three-dimensional NMR structure of Leishmania major holo-LmACP, belonging to the type II pathway, has been reported previously, but the structure of its apo-form and its conformational differences with the holo-form remain to be explored. Here we report the crystal structures of apo-LmACP (wild-type and S37A mutant) at 2.0 Å resolution and compare their key features with the structures of holo-LmACP (wild-type) and other type II ACPs from Escherichia coli and Plasmodium falciparum. The crystal structure of apo-LmACP, which is homologous to other type II ACPs, displays some key structural rearrangements as compared to its holo-structure. Contrary to holo-form, which exists predominantly as a monomer, the apo-form exists as a mixture of monomeric and dimeric population in solution. In contrast to the closed structure of apo-LmACP, holo-LmACP structure was observed in an open conformation as a result of reorganization of specific helices and loops. We propose that the structural changes exhibited by LmACP occur due to the attachment of the phosphopantetheine arm and may be a prerequisite for the initiation of fatty acid synthesis. The movement of helix 3 may also play a role in the dissociation of holo-LmACP from its cognate enzymes of the FAS II pathway., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Low molecular weight protein tyrosine phosphatases (LMWPTPs) are ubiquitously found as small cytoplasmic enzymes which act on phospho-tyrosine containing proteins that are engaged in various cellular functions. Vibrio cholerae O395 contains two LMWPTPs having widely different sequence. Phylogenetic analysis based on a non redundant set of 124 LMWPTP sequences, designate that LMWPTP-2 from Vibrio choleraeO395 (VcLMWPTP-2) is a single taxon. We have determined the crystal structure of VcLMWPTP-2 at 2.6 Å with MOPS bound in the active site. Tertiary structure analysis indicates that VcLMWPTP-2 forms dimer. Studies in solution state also confirm exclusive presence of a dimeric form. Kinetic studies demonstrate that VcLMWPTP-2 dimer is catalytically active while inactivation through oligomerisation was reported as one of the regulatory mechanism in case of mammalian LMWPTP viz., Bos taurus LMWPTP, BPTP. Kinetic studies using p-nitrophenyl phosphate (p-NPP) as a substrate demonstrate active participation of both the P-loop cysteine in catalysis. Vicinal Cys17, in addition plays a role of protecting the catalytic Cys12 under oxidative stress. Structural analysis and MD simulations allowed us to propose the role of several conserved residues around the active site. Distribution of surface charges and grooves around the active site delineates unique features of VcLMWPTP-2 which could be utilized to design specific inhibitor., (Copyright © 2018 Elsevier B.V. All rights reserved.)