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AbstractMalaria still threatens half the globe population despite successful Artemisinin-based combination therapy. One of the reasons for our inability to eradicate malaria is the emergence of resistance to current antimalarials. Thus, there is a need to develop new antimalarials targeting Plasmodiumproteins. The present study reported the design and synthesis of 4, 6 and 7-substituted quinoline-3-carboxylates 9(a–o)and carboxylic acids 10(a–b)for the inhibition of PlasmodiumN-Myristoyltransferases (NMTs) using computational biology tools followed by chemical synthesis and functional analysis. The designed compounds exhibited a glide score of −9.241 to −6.960 kcal/mol for PvNMT and −7.538 kcal/mol for PfNMT model proteins. Development of the synthesized compounds was established via NMR, HRMS and single crystal X-ray diffraction study. The synthesized compounds were evaluated for their in vitroantimalarial efficacy against CQ-sensitive Pf3D7 and CQ-resistant PfINDO lines followed by cell toxicity evaluation. In silicoresults highlighted the compound ethyl 6-methyl-4-(naphthalen-2-yloxy)quinoline-3-carboxylate (9a) as a promising inhibitor with a glide score of −9.084 kcal/mol for PvNMT and −6.975 kcal/mol for PfNMT with IC50values of 6.58 µM for Pf3D7 line. Furthermore, compounds 9nand 9oexhibited excellent anti-plasmodial activity (Pf3D7 IC50= 3.96, 6.71 µM, and PfINDO IC50= 6.38, 2.8 µM, respectively). The conformational stability of 9awith the active site of the target protein was analyzed through MD simulation and was found concordance with in vitroresults. Thus, our study provides scaffolds for the development of potent antimalarials targeting both Plasmodium vivaxand Plasmodium falciparum.Communicated by Ramaswamy H. Sarma

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is related with the COVID-19 pandemic. Recent spike protein variations have had an effect on the transmission of the virus. In addition to ACE-2, spike proteins can employ DC-SIGN and its analogous receptor, DC-SIGNR, for host evasion. Spike variations in the DC-SIGN interaction region and role of DC-SIGN in immune evasion have not been well defined. To understand the spike protein variations and their binding mode, phylogenetic analysis of the complete GISAID (Global Initiative for Sharing Avian Influenza Data) data of the SARS-CoV-2 spike protein was considered. In addition, an in silico knockout network evaluation of the SARS-CoV-2 single-cell transcriptome was conducted to determine the key role of DC-SIGN/R in immunological dysregulation. Within the DC-SIGN-interacting region of the SARS-CoV spike protein, the spike protein of SARS-CoV-2 displayed remarkable similarity to the SARS-CoV spike protein. Surprisingly, the phylogenetic analysis revealed that the SARS-CoV-2’s spike exhibited significantly diverse variants in the DC-SIGN interaction domain, which altered the frequency of these variants. The variation within the DC-SIGN-interacting domain of spike proteins affected the binding of a limited number of variants with DC-SIGN and DC-SIGNR and affected their evolution. MMGBSA binding free energies evaluation differed for variants from those of the wild type, suggesting the influence of substitution mutations on the interaction pattern. In silico knockout network analysis of the single-cell transcriptome of Bronchoalveolar Lavage and peripheral blood mononuclear cells revealed that SARS-CoV-2 altered DC-SIGN/R signaling. Early surveillance of diverse SARS-CoV-2 strains could preclude a worsening of the pandemic and facilitate the development of an optimum vaccine against variations. The spike Receptor Binding Domain genetic variants are thought to boost SARS CoV-2 immune evasion, resulting in its higher longevity.

Background: Emerging evidence has shown that SARS-CoV-2 may affect the circulatory system in addition to the human respiratory system. However, no study has indicated whether patients with leukemia have a greater likelihood of SARS-CoV-2 infection or have poor treatment outcomes. Objective: The study aimed to demonstrate the relationship between essential blood proteins and the major SARS-CoV-2 proteins by network pharmacology bioinformatics analysis. Methods: Bioinformatics analysis was used to establish eight differentially expressed gene hubs in leukemia through differential gene screening, protein–protein interaction network analysis, and gene enrichment analysis. Molecular docking analysis was also conducted to dock the two up-regulated proteins with the spike glycoprotein in leukemia and the critical protease enzyme (Mpro) of SARS-CoV-2. Results: We identified two up-regulated genes (PTPRC and BCL6) among the eight differentially expressed genes. The PTPRC and BCL6 also docked perfectly with the main SARS-CoV-2 structural proteins. Conclusion and Recommendation: This study indicates that SARS-CoV-2 is likely to affect with the blood in patients with chronic leukemia. Therefore, patients with chronic leukemia require greater medical attention and precautions during the COVID-19 pandemic.

AbstractObjective:The medicinal plant Betula albahas been used for prevention and treatment of kidney stones. Betulin is one of the main phytochemicals of Betula alba.The aim of this study is to investigate the antioxidant and antiurolithiatic activity of betulin in vitroand in silico. For antioxidant activity, 2, 2-diphenyl-1-picrylhydrazyl (DPPH), total reducing capacity, nitric oxide (NO) radical scavenging assay, and superoxide radical scavenging assay were studied.Method:In order to study antiurolithiatic activity, three assays such as crystallization, nucleation, and aggregation of oxalate crystal in urine were performed. In silicoexperiments were performed by using AutoDock 4.2 tools in order to establish affinity of phytochemicals toward antioxidant enzyme and matrix metalloproteinase (MMP-2 and 9).Results:The results obtained clearly demonstrate the significant scavenging activity of betulin and cystone against DPPH, NO, and superoxide radicals in comparison to standard antioxidant L-ascorbate (L-AA). It has also been observed that betulin has the capacity to inhibit the crystallization, nucleation, and aggregation in comparison to cystone. On the other hand, betulin and L-AA showed strong affinity toward antioxidant enzymes and matrix metalloproteinase as determined by in silicoexperiments.Conclusions:From this, it may be concluded that the antiurolithiatic activity of betulin is, at least in part, mediated by its antioxidant property.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are lung complications diagnosed by impaired gaseous exchanges leading to mortality. From the diverse etiologies, sepsis is a prominent contributor to ALI/ARDS. In the present study, we retrieved sepsis-induced ARDS mRNA expression profile and identified 883 differentially expressed genes (DEGs). Next, we established an ARDS-specific weighted gene co-expression network (WGCN) and picked the blue module as our hub module based on highly correlated network properties. Later we subjected all hub module DEGs to form an ARDS-specific 3-node feed-forward loop (FFL) whose highest-order subnetwork motif revealed one TF (STAT6), one miRNA (miR-34a-5p), and one mRNA (TLR6). Thereafter, we screened a natural product library and identified three lead molecules that showed promising binding affinity against TLR6. We then performed molecular dynamics simulations to evaluate the stability and binding free energy of the TLR6-lead molecule complexes. Our results suggest these lead molecules may be potential therapeutic candidates for treating sepsis-induced ALI/ARDS. In-silico studies on clinical datasets for sepsis-induced ARDS indicate a possible positive interaction between miR-34a and TLR6and an antagonizing effect on STAT6to promote inflammation. Also, the translational study on septic mice lungs by IHC staining reveals a hike in the expression of TLR6. We report here that miR-34a actively augments the effect of sepsis on lung epithelial cell apoptosis. This study suggests that miR-34a promotes TLR6 to heighten inflammation in sepsis-induced ALI/ARDS.

Dichelobacter nodosusis an anaerobic bacterium with fastidious growth requirements that is the principal cause of footrot associated with lameness in sheep and goats. In India, D. nodosusserogroups B and E have been recorded as major causes of footrot. Here we report the draft genome sequence of a D. nodosusserogroup E strain (JKS-07) from a case of virulent footrot in India.

Tuberculosis (T.B.) is an infectious disease caused primarily by the bacterial pathogen Mycobacterium tuberculosis(Mtb) in humans. The emergence of various drug-resistant Mtb strains threatens to disrupt worldwide attempts to control the infection. The state of disease can be attributed to the host–pathogen protein interaction network. Hence in this study, we have analyzed the protein interaction network at the intra-species level, i.e., within Mtb using the Louvain community detection and at the inter-species level, i.e., between human and Mtb proteins. We observed a higher inter-connectedness in the intra-species protein network as compared to the inter-species network. This reflects a critical role of protein interaction network modulation during host–pathogenesis conditions. After analyzing 269 Mtb proteins and 2287 human proteins using the interlog approach, we observed a total of 640 host–pathogen protein interaction pairing involving 120 humans and 90 Mtb proteins. The H.P.I.s were filtered using functional protein annotations and publicly available experimental results. In the Mtb PPI network, Rv1286, Rv0462, Rv2215, Rv3559c, Rv3504, and Rv3523 are associated as a motif (a governing unit in a network) and identified as key proteins. This interaction network will help researchers better understand host–pathogen protein–protein interactions, as well as shed light on how Mtb interacts with its host.