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AIMS: The main objective of the current study is to investigate the pathways and therapeutic targets linked to stevioside in the management of T2D using computational approaches. METHODS: We collected RNA-seq datasets from NCBI, then employed GREIN to retrieve differentially expressed genes (DEGs). Computer-assisted techniques DAVID, STRING and NetworkAnalyst were used to explore common significant pathways and therapeutic targets associated with T2D and stevioside. Molecular docking and dynamics simulations were conducted to validate the interaction between stevioside and therapeutic targets. RESULTS: Gene ontology and KEGG analysis revealed that prostaglandin synthesis, IL-17 signaling, inflammatory response, and interleukin signaling were potential pathways targeted by stevioside in T2D. Protein-protein interactions (PPI) analysis identified six common hub proteins (PPARG, PTGS2, CXCL8, CCL2, PTPRC, and EDN1). Molecular docking results showed best binding of stevioside to PPARG (-8 kcal/mol) and PTGS2 (-10.1 kcal/mol). Finally, 100 ns molecular dynamics demonstrated that the binding stability between stevioside and target protein (PPARG and PTGS2) falls within the acceptable range. CONCLUSIONS: This study reveals that stevioside exhibits significant potential in controlling T2D by targeting key pathways and stably binding to PPARG and PTGS2. Further research is necessary to confirm and expand upon these significant computational results.

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BACKGROUND: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023). RESULTS: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]. CONCLUSION: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis.

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Background: The role of rapid on-site evaluation (ROSE) for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic lesions is debatable. In this study, we aimed to compare the diagnostic yield of ROSE vs. non-ROSE in solid pancreatic lesions. Methods: This retrospective single-center study included patients undergoing EUS-FNA of solid pancreatic lesions from 2019-2021. Patients with cystic lesions, those undergoing fine-needle core biopsy, those undergoing repeat procedures, and patients with non-diagnostic smears with less than 6-month follow up were excluded. The diagnostic yield, need for repeat procedures and number of passes required with and without ROSE were analyzed in these patients. Results: Of the 111 patients included, 56 underwent ROSE. The majority of lesions were malignant in both groups (79.6% ROSE vs. 75% non-ROSE). The diagnostic yield was 96.4% in the ROSE group and 94.5% in the non-ROSE group. Repeat samples were needed in 1 ROSE and 2 non-ROSE patients. The median number of passes made was significantly fewer in the ROSE group (3.5, interquartile range - 3,4) compared with the non-ROSE group (4, interquartile range - 3,5) P=0.01. However, the frequency of procedure-related complications was similar in both groups. Conclusion: The utilization of ROSE during EUS-FNA of solid pancreatic lesions does not affect the diagnostic yield or the need for repeat samples, but reduces the number of passes needed for acquiring samples.

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Extracting information-bearing signal from a noisy environment has been a practical challenge in both classical and quantum computing formalism, especially in critical signal processing applications. To filter out the effect of noise, we propose a quantum smoothing filter built upon quantum formalism-based circuits applied for electrocardiogram signal denoising. The proposed quantum filter is a conceptually novel framework with an advantage in computational complexity as compared to the existing classical filters, such as discrete wavelet transform and empirical mode decomposition, whereas it achieves similar performance metrics for the accuracy of the filter. Further, we exploit the penta-diagonal Toeplitz structure of the smoothing filter, which gives approximately 48 % gate cost reduction for 10 qubit circuit compared to the standard Hamiltonian simulation without structure. The run-time complexity using the quantum matrix inversion technique for the structured matrix is given by O ~ κ 2 poly ( log N ) ε P for condition number κ of the N × N filter matrix within precision ε P . Embedding fixed sparsity of the banded matrix, the quantum filter shows potentially better run-time complexity than classical filtering techniques. For the quantifiable research results of our work, we have shown several performance metrics, such as mean-square error and peak signal-to-noise ratio analysis, with a bound of error due to observation noise, simulation error and quantum measurement uncertainty.

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BACKGROUND: Bile cultures are often sent with blood cultures in patients with acute bacterial cholangitis. AIMS: To assess the yield of blood and bile cultures in patients with cholangitis and the clinical utility of bile cultures in guiding therapy. METHODS: All patients diagnosed with cholangitis, based on the Tokyo 2013/2018 guidelines were recruited retrospectively over ten years. The clinical and investigation details were recorded. The results of bile and blood cultures including antibiotic sensitivity patterns were noted. The concordance of microorganisms grown in blood and bile cultures and their sensitivity pattern were assessed. RESULTS: A total of 1063 patients with cholangitis were included. Their mean age was 52.7 ± 14 years and 65.4% were males. Blood cultures were positive in 372 (35%) patients. Bile culture was performed in 384 patients with 84.4% being positive, which was significantly higher than the yield of blood culture (p < 0.001). Polymicrobial growth was more in bile (59.3%) than in blood cultures (13.5%, p < 0.001). E.coli, Klebsiella, Enterococcus and Pseudomonas were the four most common organisms isolated from both blood and bile. Extended spectrum betalactamase producing organisms were isolated in 57.7% and 58.8% of positive blood and bile cultures, respectively. Among 127 patients with both blood and bile cultures positive, complete or partial concordance of organisms was noted in about 90%. CONCLUSION: Bile and blood cultures have a similar microbial profile in most patients with cholangitis. As bile cultures have a significantly higher yield than blood cultures, they could effectively guide antimicrobial therapy, especially in those with negative blood cultures.

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Leucine-rich repeat (LRR)-containing proteins have been identified in diverse species, including plants. The diverse intracellular and extracellular LRR variants are responsible for numerous biological processes. We analyzed the expression patterns of Arabidopsis thaliana extracellular LRR (AtExLRR) genes, 10 receptor-like proteins, and 4 additional genes expressing the LRR-containing protein by a promoter: ß-glucuronidase (GUS) study. According to in silico expression studies, several AtExLRR genes were expressed in a tissue- or stage-specific and abiotic/hormone stress-responsive manner, indicating their potential participation in specific biological processes. Based on the promoter: GUS assay, AtExLRRs were expressed in different cells and organs. A quantitative real-time PCR investigation revealed that the expressions of AtExLRR3 and AtExLRR9 were distinct under various abiotic stress conditions. This study investigated the potential roles of extracellular LRR proteins in plant growth, development, and response to various abiotic stresses.

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Protein A affinity chromatography is widely used as a capture step for monoclonal antibodies (mAb) and molecules that possess an Fc-domain, such as fusion proteins and bispecific antibodies. However, the use of low pH (3.0-4.0) to elute the molecule and achieve acceptable yield (>85 %) can lead to product degradation (e.g. fragmentation, aggregation) for molecules sensitive to low pH. In this paper, we describe a comprehensive evaluation of two protein A resins with ligands designed to elute at a milder pH as a result of modified sequences in their Fc and VH3 binding regions. One of the evaluated resins has been made commercially available by Purolite and named Praesto Jetted A50 HipH. Results demonstrated that Jetted A50 HipH could elute the Fc-fusion protein and most mAbs evaluated with an elution pH at or above 4.6. Elution and wash optimization determined run conditions for high recovery (>90 % monomer yield), reduction of high molecular weight (HMW) species (>50 %), and significant host cell protein (HCP) clearance at the mildest elution pH possible. For a pH-stable mAb and a pH-sensitive fusion protein, cell culture material was purified with optimized conditions and demonstrated the mild elution pH resins' ability to purify product with acceptable yield, comparable or better impurity clearance, and significantly milder native eluate pH compared to traditional resins. The benefits of the mild elution pH resins were clearly exemplified for the pH-sensitive protein, where a milder elution buffer and native eluate pH resulted in only 2 % HMW in the eluate that remained stable over 48 h. In contrast, a traditional protein A resin requiring low pH elution led to eluate HMW levels of 8 %, which increased to 16 % over the same hold time. Additionally, these resins have high dynamic binding capacity and allow the use of traditional HCP washes. Therefore, Jetted A50 HipH is an ideal candidate for a platform protein A resin and provides flexibility for pH-sensitive proteins and stable mAbs, while preserving product quality, recovery, and seamless integration into a downstream process.

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BACKGROUND: Early-onset idiopathic chronic pancreatitis (EOICP) is a disease that affects young individuals. Data on pregnancy outcomes in EOICP are limited. AIM: To assess the pregnancy outcomes in patients with EOICP and the effect of pregnancy on the course of EOICP. METHODS: Patients with EOICP with disease onset before their pregnancy were recruited. Data regarding demographic variables, disease duration, pregnancy outcomes, and course of illness were noted. RESULTS: 50 patients were included in the study contributing to a total of 86 pregnancies. The mean age of onset of symptoms and at the time of delivery was 17.95 (5.71) and 23.44 (4.28) years, respectively. Gestational diabetes (GD) and gestational hypertension (GH) noted in one (1.5%) each. 3 (4.5%) pregnancies were preterm. 19 (22.1%) pregnancies did not have successful outcomes (7 (8.1%) were induced abortions). 12 (15.2%) pregnancies had spontaneous pregnancy losses. 8 (10.1%) were spontaneous abortions and 4 (5.1%) were stillbirths. Of 67 successful pregnancies, 33 (49.3%) pregnancies were delivered by LSCS. Compared to average rates of LSCS in India, this was significantly higher (21.5% vs 49.3%-p ≤ 0.001). The average birth weight was 2.87 (0.48) kg. There was one (1.5%) neonatal death. Compared to the published Indian data, there was no significant difference in the incidence of spontaneous pregnancy losses, GD, GH, preterm labor, and birth weight. Pancreatic pain was reported by 21 (42%) women in total 27 (31.4%) pregnancies. There was no difference in maternal or fetal outcomes between pregnancies with or without pancreatic pain. There were no pancreatitis-related complications reported during the pregnancies. CONCLUSION: The present study shows that mothers affected with EOICP have pregnancy outcomes similar to healthy women in India.

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Antibiotic-resistant microbes have emerged around the world, presenting a risk to health. Plant-derived drugs have become a potential source for the production of antibiotic-resistant drugs and cancer therapies. In this study, we investigated the antibacterial, cytotoxic and antioxidant properties of Acalypha indica and Boerhavia diffusa, and conducted in silico molecular docking experiments against EGFR and VEGFR-2 proteins. The metabolic extract of A. indica inhibited Streptococcus iniae and Staphylococcus sciuri with inhibition zones of 21.66 ± 0.57 mm and 20.33 ± 0.57 mm, respectively. The B. diffusa leaf extract produced inhibition zones of 20.3333 ± 0.5773 mm and 20.33 ± 0.57 mm against Streptococcus iniae and Edwardsiella anguillarum, respectively. A. indica and B. diffusa extracts had toxicities of 162.01 µg/ml and 175.6 µg/ml, respectively. Moreover, B. diffusa (IC50 =154.42 µg/ml) leaf extract exhibited moderately higher antioxidant activity compared with the A. indica (IC50 = 218.97 µg/ml) leaf extract. Multiple interactions were observed at Leu694, Met769 and Leu820 sites for EGFR and at Asp1046 and Cys1045 sites for VEGFR during the molecular docking study. CID-235030, CID-70825 and CID-156619353 had binding energies of -7.6 kJ/mol, -7.5 kJ/mol and -7.6 kJ/mol, respectively, with EGFR protein. VEGFR-2 protein had docking energies of -7.5 kJ/mol, -7.6 kJ/mol and -7.3 kJ/mol, respectively, for CID-6420353, CID-156619353 and CID-70825 compounds. The MD simulation trajectories revealed the hit compound; CID-235030 and EGFR complex, CID-6420353 and VEGFR-2 exhibit stable profile in the root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), hydrogen bond and root mean square fluctuation (RMSF) and the binding free energy by MM-PBSA method. This study indicates that methanol extracts of A. indica and B. diffusa may play a crucial role in developing antibiotic-resistant and cancer drugs.Communicated by Ramaswamy H. Sarma.

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In the modern world, wheat, a vital global cereal and the second most consumed, is vulnerable to climate change impacts. These include erratic rainfall and extreme temperatures, endangering global food security. Research on hydrogen-rich water (HRW) has gained momentum in plant and agricultural sciences due to its diverse functions. This study examined the effects of different HRW treatment durations on wheat, revealing that the 4-h treatment had the highest germination rate, enhancing potential, vigor, and germination indexes. This treatment also boosted relative water content, root and shoot weight, and average lengths. Moreover, the 4-h HRW treatment resulted in the highest chlorophyll and soluble protein concentrations in seeds while reducing cell death. The 4-h and 5-h HRW treatments significantly increased H2O2 levels, with the highest NO detected in both root and shoot after 4-h HRW exposure. Additionally, HRW-treated seeds exhibited increased Zn and Fe concentrations, along with antioxidant enzyme activities (CAT, SOD, APX) in roots and shoots. These findings suggest that HRW treatment could enhance wheat seed germination, growth, and nutrient absorption, thereby increasing agricultural productivity. Molecular analysis indicated significant upregulation of the Dreb1 gene with a 4-h HRW treatment. Thus, it shows promise in addressing climate change effects on wheat production. Therefore, HRW treatment could be a hopeful strategy for enhancing wheat plant drought tolerance, requiring further investigation (field experiments) to validate its impact on plant growth and drought stress mitigation.

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Proton pump inhibitors (PPIs) have been available for over three decades and are among the most commonly prescribed medications. They are effective in treating a variety of gastric acid-related disorders. They are freely available and based on current evidence, use of PPIs for inappropriate indications and duration appears to be common. Over the years, concerns have been raised on the safety of PPIs as they have been associated with several adverse effects. Hence, there is a need for PPI stewardship to promote the use of PPIs for appropriate indication and duration. With this objective, the Indian Society of Gastroenterology has formulated guidelines on the rational use of PPIs. The guidelines were developed using a modified Delphi process. This paper presents these guidelines in detail, including the statements, review of literature, level of evidence and recommendations. This would help the clinicians in optimizing the use of PPIs in their practice and promote PPI stewardship.

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Paederia foetida is valued for its folk medicinal properties. This research aimed to assess the acute toxicity, hypoglycemic and anti-hemostasis properties of the methanolic extract of P. foetida leaves (PFLE). Acute toxicity of PFLE was performed on a mice model. Hypoglycemic and anti-hemostasis properties of PFLE were investigated on normal and streptozotocin-induced mice models. Deep learning, molecular docking, density functional theory, and molecular simulation techniques were employed to understand the underlying mechanisms through in silico study. Oral administration of PFLE at a dosage of 300 µg/kg body weight (BW) showed no signs of toxicity. Treatment with PFLE (300 µg/kg/BW) for 14 days resulted in a hypoglycemic condition and a 30.47% increase in body weight. Additionally, PFLE mixed with blood exhibited a 44.6% anti-hemostasis effect. Deep learning predicted the inhibitory concentration (pIC50, nM) of Cleomiscosins against SGLT2 and FXa to be 7.478 and 6.017, respectively. Molecular docking analysis revealed strong binding interactions of Cleomiscosins with crucial residues of the target proteins, exhibiting binding energies of -8.2 kcal/mol and -7.1 kcal/mol, respectively. ADME/Tox predictions indicated favorable pharmacokinetic properties of Cleomiscosins, and DFT calculations of frontier molecular orbitals analyzed the stability and reactivity of these compounds. Molecular simulation dynamics, principal component analysis and MM-PBSA calculation demonstrated the stable, compact, and rigid nature of the protein-ligand complexes. The methanolic PFLE exhibited significant hypoglycemic and anti-hemostasis properties. Cleomiscosin may have inhibitory properties for the development of novel drugs to manage diabetes and thrombophilia in the near future.

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A worrying new outbreak of Monkeypox (Mpox) in humans is caused by the Mpox virus (MpoxV). The pathogen has roughly 28 hypothetical proteins of unknown structure, function, and pathogenicity. Using reliable bioinformatics tools, we attempted to analyze the MpoxV genome, identify the role of hypothetical proteins (HPs), and design a potential candidate vaccine. Out of 28, we identified seven hypothetical proteins using multi-server validation with high confidence for the occurrence of conserved domains. Their physical, chemical, and functional characterizations, including molecular weight, theoretical isoelectric point, 3D structures, GRAVY value, subcellular localization, functional motifs, antigenicity, and virulence factors, were performed. We predicted possible cytotoxic T cell (CTL), helper T cell (HTL) and linear and conformational B cell epitopes, which were combined in a 219 amino acid multiepitope vaccine with human ß defensin as a linker. This multi-epitopic vaccine was structurally modelled and docked with toll-like receptor-3 (TLR-3). The dynamical stability of the vaccine-TLR-3 docked complexes exhibited stable interactions based on RMSD and RMSF tests. Additionally, the modelled vaccine was cloned in-silico in an E. coli host to check the appropriate expression of the final vaccine built. Our results might conform to an immunogenic and safe vaccine, which would require further experimental validation.Communicated by Ramaswamy H. Sarma.

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[This corrects the article DOI: 10.1039/C5RA19442C.].

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BACKGROUND: Proton pump inhibitors (PPI) may impact the absorption of vitamin B12. We performed a systematic review to ascertain if PPI use increases risk of vitamin B12 deficiency. METHODS: Electronic databases (PubMed, Embase, Scopus) were searched on first of September 2022. We selected studies that compared the frequency of vitamin B12 deficiency in PPI users and non-users. Pooled Odds Ratio (OR) was calculated for the occurrence of vitamin B12 deficiency in PPI users compared to non-users. The risk of bias was assessed using the Newcastle Ottawa scale. RESULTS: Twenty-five studies were included. The pooled OR of vitamin B12 deficiency among PPI users (2852 participants) was higher than non-users (28070 participants) (OR 1.42, 95% CI: 1.16-1.73; I2 = 54%). Overall risk of PPI use among vitamin B12 deficient individuals was higher than those without deficiency (OR 1.49, 1.20-1.85; I2 = 68%). Most studies found no difference between serum vitamin B12 levels among PPI users compared to non-users. CONCLUSION: Although the pooled OR of vitamin B12 deficiency was slightly increased in PPI users, but there was significant heterogeneity, and the pooled OR was too low to imply an association clearly. Better-designed prospective studies in long-term users may clarify the issue. REGISTRATION: This study was not registered on PROSPERO.

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MAIN CONCLUSION: Targeted expression of bgl23-D, a dominant-negative allele of ATCSLD5, is a useful genetic approach for functional analysis of ATCSLDs in specific cells and tissues in plants. Stomata are key cellular structures for gas and water exchange in plants and their development is influenced by several genes. We found the A. thaliana bagel23-D (bgl23-D) mutant showing abnormal bagel-shaped single guard cells. The bgl23-D was a novel dominant mutation in the A. thaliana cellulose synthase-like D5 (ATCSLD5) gene that was reported to function in the division of guard mother cells. The dominant character of bgl23-D was used to inhibit ATCSLD5 function in specific cells and tissues. Transgenic A. thaliana expressing bgl23-D cDNA with the promoter of stomata lineage genes, SDD1, MUTE, and FAMA, showed bagel-shaped stomata as observed in the bgl23-D mutant. Especially, the FAMA promoter exhibited a higher frequency of bagel-shaped stomata with severe cytokinesis defects. Expression of bgl23-D cDNA in the tapetum with SP11 promoter or in the anther with ATSP146 promoter induced defects in exine pattern and pollen shape, novel phenotypes that were not shown in the bgl23-D mutant. These results indicated that bgl23-D inhibited unknown ATCSLD(s) that exert the function of exine formation in the tapetum. Furthermore, transgenic A. thaliana expressing bgl23-D cDNA with SDD1, MUTE, and FAMA promoters showed enhanced rosette diameter and increased leaf growth. Taken together, these findings suggest that the bgl23-D mutation could be a helpful genetic tool for functional analysis of ATCSLDs and manipulating plant growth.

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In this review, after providing the basic physical concept behind quantum annealing (or adiabatic quantum computation), we present an overview of some recent theoretical as well as experimental developments pointing to the issues which are still debated. With a brief discussion on the fundamental ideas of continuous and discontinuous quantum phase transitions, we discuss the Kibble-Zurek scaling of defect generation following a ramping of a quantum many body system across a quantum critical point. In the process, we discuss associated models, both pure and disordered, and shed light on implementations and some recent applications of the quantum annealing protocols. Furthermore, we discuss the effect of environmental coupling on quantum annealing. Some possible ways to speed up the annealing protocol in closed systems are elaborated upon: we especially focus on the recipes to avoid discontinuous quantum phase transitions occurring in some models where energy gaps vanish exponentially with the system size. This article is part of the theme issue 'Quantum annealing and computation: challenges and perspectives'.