Life Sciences

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Background/Objective: There is a paucity of data on the management of gastrointestinal (GI) bleeding in patients with Coronavirus disease -2019 (COVID-19) amid concerns about the risk of transmission during endoscopic procedures. We aimed to study the outcomes of conservative treatment for GI bleeding in patients with COVID-19. Methods: In this retrospective analysis, 24 of 1342 (1.8%) patients with COVID-19, presenting with GI bleeding from 22nd April to 22nd July 2020, were included. Results: The mean age of patients was 45.8 ± 12.7 years; 17 (70.8%) were males; upper GI (UGI) bleeding: lower GI (LGI) 23:1. Twenty-two (91.6%) patients had evidence of cirrhosis- 21 presented with UGI bleeding while one had bleeding from hemorrhoids. Two patients without cirrhosis were presumed to have non-variceal bleeding. The medical therapy for UGI bleeding included vasoconstrictors-somatostatin in 17 (73.9%) and terlipressin in 4 (17.4%) patients. All patients with UGI bleeding received proton pump inhibitors and antibiotics. Packed red blood cells (PRBCs), fresh frozen plasma (FFPs) and platelets were transfused in 14 (60.9%), 3 (13.0%) and 3 (13.0%), respectively. The median PRBCs transfused was 1 (0–3) unit(s). The initial control of UGI bleeding was achieved in all 23 patients and none required an emergency endoscopy. At 5-day follow-up, none rebled or died. Two patients later rebled, one had intermittent bleed due to gastric antral vascular ectasia, while another had rebleed 19 days after discharge. Three (12.5%) cirrhosis patients succumbed to acute hypoxemic respiratory failure during hospital stay. Conclusion: Conservative management strategies including pharmacotherapy, restrictive transfusion strategy, and close hemodynamic monitoring can successfully manage GI bleeding in COVID-19 patients and reduce need for urgent endoscopy. The decision for proceeding with endoscopy should be taken by a multidisciplinary team after consideration of the patient's condition, response to treatment, resources and the risks involved, on a case to case basis. © 2020 Indian National Association for Study of the Liver

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(SoNS) School of Natural Sciences

Fulltext

Journal of Clinical and Experimental Hepatology

Outcome of Conservative Therapy in Coronavirus disease-2019 Patients Presenting With Gastrointestinal Bleeding

The aluminum industrial waste red mud was successfully utilized as a novel adsorbent for the removal of arsenic (As) ions from water. The arsenate (As (V)) adsorption efficacy of red mud nanoparticles was also investigated. Red mud nanoparticles were prepared by ball milling raw red mud for 10 h, yielding particles’ size of 20 nm on average. The As (V) adsorption on these nanoparticles strongly depended on the size of the nanoparticles. As (V) removal increased from 58 to 83\% by reducing the size of red mud particles from 200 to 20 nm. Detail kinetics and transport study confirmed the pseudo-second-order kinetic process which was governed by external mass transport. The Freundlich (and Langmuir) isotherms confirm that the arsenate adsorption capacity changes from 2.28 mg/g (1.84 mg/g) to 2.54 mg/g (1.96 mg/g) for reduction of particles from size 200 nm to 20 nm. Water filter columns made with red mud nanoparticles prepared by ball milling for 10 h showed better filtration performance than the filter packed with raw red mud. Both the hydraulic conductivity and the As (V) removal (8 mm/h and 61\% respectively) of influent 1 mg/L As (V) by red mud nanoparticles were greater than the raw red mud (3.2 mm/h and 54\%). The modified red mud column filters also exhibited a higher efficiency than the raw red mud filters to remove Escherichia coli and Staphylococcus aureus from the water. Overall, this research shows that nanomaterials derived from aluminum processing waste can be a promising material for water filtration. © 2020, Springer Nature Switzerland AG.

Physics

SN Applied Sciences

Potential use of smartly engineered red mud nanoparticles for removal of arsenate and pathogens from drinking water

Primary cardiac neoplasms are extremely rare and are far outnumbered by metastases. These are difficult to diagnose and differentiate clinically due to lack of specific clinical manifestations. Technological advances have revolutionised cardiac imaging, with the cardiac magnetic resonance imaging (CMRI) showing promising results in the non-invasive evaluation of cardiac masses. Further, CMRI may envisage the malignant potential of a lesion based on its location, morphology, and signal characteristics, in addition to determining its impact on cardiac function. With the ever-increasing application of CMRI in the evaluation of neoplasms, comprehensive knowledge of their imaging characteristics becomes crucial. © 2019 The Royal College of Radiologists

Clinical Radiology

Cardiac MRI for the evaluation of cardiac neoplasms

Scaffold proteins play pivotal role as modulators of cellular processes by operating as multipurpose conformation clamps. 14-3-3 proteins are gold-standard scaffold modules that recognize phosphoSer/Thr (pS/pT) containing conserved motifs, and confer conformational changes leading to modulation of functional parameters of their target proteins. Modulation in functional activity of kinases has been attributed to their interaction with 14-3-3 proteins. Herein, we have annotated and characterized PF3D7_0818200 as 14-3-3 isoform I in Plasmodium falciparum 3D7, and its interaction with one of the key kinases of the parasite, Calcium-Dependent Protein Kinase 1 (CDPK1) by performing various analytical biochemistry and biophysical assays. Molecular dynamics simulation studies indicated that CDPK1 polypeptide sequence (61KLGpS64) behaves as canonical Mode I-type (RXXpS/pT) consensus 14-3-3 binding motif, mediating the interaction. The 14-3-3I/CDPK1 interaction was validated in vitro with ELISA and SPR, which confirmed that the interaction is phosphorylation dependent, with binding affinity constant of 670 ± 3.6 nM. The interaction of 14-3-3I with CDPK1 was validated with well characterized optimal 14-3-3 recognition motifs: Mode I-type ARSHpSYPA and Mode II-type RLYHpSLPA, by simulation studies and ITC. This interaction was found to marginally enhance CDPK1 functional activity. Furthermore, interaction antagonizing peptidomimetics showed growth inhibitory impact on the parasite indicating crucial physiological role of 14-3-3/CDPK1 interaction. Overall, this study characterizes 14-3-3I as a scaffold protein in the malaria parasite and unveils CDPK1 as its previously unidentified target. This sets a precedent for the rational design of 14-3-3 based PPI inhibitors by utilizing 14-3-3 recognition motif peptides, as a potential antimalarial strategy. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal

Molecular dynamics simulations and biochemical characterization of Pf14-3-3 and PfCDPK1 interaction towards its role in growth of human malaria parasite

Upon Plasmodium falciparum merozoites exposure to low [K+] environment in blood plasma, there is escalation of cytosolic [Ca2+] which activates Ca2+-Dependent Protein Kinase 1 (CDPK1), a signaling hub of intra-erythrocytic proliferative stages of parasite. Given its high abundance and multidimensional attributes in parasite life-cycle, this is a lucrative target for designing antimalarials. Towards this, we have virtually screened MyriaScreenII diversity collection of 10,000 drug-like molecules, which resulted in 18 compounds complementing ATP-binding pocket of CDPK1. In vitro screening for toxicity in mammalian cells revealed that these compounds are non-toxic in nature. Furthermore, SPR analysis demonstrated differential binding affinity of these compounds towards recombinantly purified CDPK1 protein. Selection of lead compound 1 was performed by evaluating their inhibitory effects on phosphorylation and ATP binding activities of CDPK1. Furthermore, in vitro biophysical evaluations by ITC and FS revealed that binding of compound 1 is driven by formation of energetically favorable non-covalent interactions, with different binding constants in presence and absence of Ca2+, and TSA authenticated stability of compound 1 bound CDPK1 complex. Finally, compound 1 strongly inhibited intra-erythrocytic growth of P. falciparum in vitro. Conceivably, we propose a novel CDPK1-selective inhibitor, step towards developing pan-CDPK kinase inhibitors, prerequisite for cross-stage anti-malarial protection. © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society

Development of novel anti-malarial from structurally diverse library of molecules, targeting plant-like CDPK1, a multistage growth regulator of P. falciparum

C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC50 = 0.67–4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery. © 2020, The Author(s).

Scientific Reports

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

In eukaryotes, Hsp110s are unambiguous cognates of the Hsp70 chaperones, in primary sequence, domain organization, and structure. Hsp110s function as nucleotide exchange factors (NEFs) for the Hsp70s although their apparent loss of Hsp70-like chaperone activity, nature of interdomain communication, and breadth of domain functions are still puzzling. Here, by combining single-molecule FRET, small angle X-ray scattering measurements (SAXS), and MD simulation, we show that yeast Hsp110, Sse1 lacks canonical Hsp70-like interdomain allostery. However, the protein exhibits unique noncanonical conformational changes within its domains. Sse1 maintains an open-lid substrate-binding domain (SBD) in close contact with its nucleotide-binding domain (NBD), irrespective of its ATP hydrolysis status. To further appreciate such ATP-hydrolysis-independent exhaustive interaction between two domains of Hsp110s, NBD-SBD chimera was constructed between Hsp110 (Sse1) and Hsp70 (Ssa1). In Sse1/Ssa1 chimera, we observed undocking of two domains leading to complete loss of NEF activity of Sse1. Interestingly, chimeric proteins exhibited significantly enhanced ATPase rate of Sse1-NBD compared to wild-type protein, implying that intrinsic ATPase activity of the protein remains mostly repressed. Apart from repressing the high ATPase activity of its NBD, interactions between two domains confer thermal stability to Sse1 and play critical role in the (co)chaperoning function of Sse1 in Ssa1-mediated disaggregation activity. Altogether, Sse1 exhibits a unique interdomain interaction, which is essential for its NEF activity, suppression of high intrinsic ATPase activity, co-chaperoning activity in disaggregase machinery, and stability of the protein. © 2019 Federation of European Biochemical Societies

FEBS Journal

Interdomain communication suppressing high intrinsic ATPase activity of Sse1 is essential for its co-disaggregase activity with Ssa1

Among the different secondary structures that DNA can adopt, G-quadruplex is a noncanonical form that has recently started to garner attention about the possible layers of regulation they could introduce in cellular processes. Here, we outline how the presence of G-quadruplexes can be probed in legumes and other plant genomes. This chapter describes various in silico approaches that can be utilized to identify putative G-quadruplex forming sequences (GQSes) and validate their formation through in vitro experimental approaches. © Springer Science+Business Media, LLC, part of Springer Nature 2020.

Methods in Molecular Biology

Methods for identification and validation of G-quadruplex sequences in legumes

Background: Plateletpheresis procedures are generally safe and associated with low adverse reactions. Although donor reactions and injuries are self-limited events, they may discourage donors from future platelet donations. Aim: The purpose of this study was to determine the prevalence and predictors of adverse donor reactions in plateletpheresis donors, which could serve as targets for interventions to reduce reactions. Materials and Methods: The study included 106 platelet donors over a period of 2 years. The demographic, biometric, and clinical parameters were noted. The data were analyzed for predictors of adverse donor reactions. Statistical Analysis Used: The data were analyzed using independent sample t-test to correlate donor variables such as gender. To correlate other variables such as age, weight, and whole blood processed, Chi-square test was used. Results: A total of 106 plateletpheresis donations were performed and 13.2% of vasovagal reactions were observed. The significant predictive factors for reactions were young female donors with low body weight in which more than 2.5 L volume of whole blood was processed and more than 250 ml of acid, citrate, and dextrose-A was infused and with single venous access procedures. Conclusions: The results of this study are encouraging and helpful in identifying donors at risk for developing adverse reactions during plateletpheresis so that proper and close observation during and after donation as well as timely intervention can prevent most of the unpleasant events of plateletpheresis donors. © 2020 Asian Journal of Transfusion Science | Published by Wolters Kluwer-Medknow.

Asian Journal of Transfusion Science

Prevalence and predictors of adverse reactions in plateletpheresis donors with the perspective of donor safety in a tertiary care hospital of Northern India

Mature human erythrocytes contain a rich pool of microRNAs (miRNAs), which result from differentiation of the erythrocytes during the course of haematopoiesis. Recent studies have described the effect of erythrocytic miRNAs on the invasion and growth of the malaria parasite Plasmodium falciparum during the asexual blood stage of its life cycle. In this work, we have identified two erythrocytic miRNAs, miR-150-3p and miR-197-5p, that show favourable in silico hybridization with Plasmodium apicortin, a protein with putative microtubule-stabilizing properties. Co-expression of P. falciparum apicortin and these two miRNAs in a cell line model resulted in downregulation of apicortin at both the RNA and protein level. To create a disease model of erythrocytes containing miRNAs, chemically synthesized mimics of miR-150-3p and miR-197-5p were loaded into erythrocytes and subsequently used for invasion by the parasite. Growth of the parasite was hindered in miRNA-loaded erythrocytes, followed by impaired invasion; micronemal secretion was also reduced, especially in the case of miR-197-5p. Apicortin expression was found to be reduced in miRNA-loaded erythrocytes. To interpret the effect of downregulation of apicortin on parasite invasion to host erythrocytes, we investigated the secretion of the invasion-related microneme protein apical membrane antigen 1 (AMA1). AMA1 secretion was found to be reduced in miRNA-treated parasites. Overall, this study identifies apicortin as a novel target within the malaria parasite and establishes miR-197-5p as its miRNA inhibitor. This miRNA represents an unconventional nucleotide-based therapeutic and provides a new host factor-inspired strategy for the design of antimalarial molecular medicine. © 2020. Published by The Company of Biologists Ltd