Emergency endovascular and percutaneous urological interventions: A pictorial review.

Emergency endovascular and percutaneous urological interventions encompass various diagnostic and therapeutic procedures to address various genitourinary conditions. These urological interventions are life-saving in addressing complications following biopsy, post-nephrectomy, post-transplant, and post-trauma. Compared to other surgical fields, there are relatively fewer urological emergencies. However, they require prompt radiological diagnosis and urgent interventions. This pictorial essay emphasizes various urological emergencies and urgent interventional management.

Synthesis of Quinazolinones and Benzothiazoles Using α-Keto Acids under Ball Milling.

Mechanochemistry refers to the initiation of chemical reactions via mechanical forces such as milling, grinding, or shearing to achieve the chemical transformations. As a manifestation of mechanocatalysis, herein, an oxidant-free and solvent-free approach for the synthesis of quinazolinones (23 derivatives) and benzothiazoles (23 derivatives) has been developed through stainless-steel-driven decarboxylative acyl radical generation from α-keto acids. A library of 2-arylquinazolinones and 2-arylbenzothiazoles has been prepared in moderate to good yields at room temperature. Moreover, control experiments and XPS studies supported the reduction (by zerovalent iron) of molecular oxygen through the moderate abrasion of balls, which promoted the generation of a superoxide radical anion via a SET process.

Integrative experimental validation of concomitant miRNAs and transcription factors with differentially expressed genes in acute myocardial infarction.

Identification of concomitant miRNAs and transcription factors (TFs) with differential expression (DEGs) in MI is crucial for understanding holistic gene regulation, identifying key regulators, and precision in biomarker and therapeutic target discovery. We performed a comprehensive analysis using Affymetrix microarray data, advanced bioinformatic tools, and experimental validation to explore potential biomarkers associated with human pathology. The search strategy includes the identification of the GSE83500 dataset, comprising gene expression profiles from aortic wall punch biopsies of MI and non-MI patients, which were used in the present study. The analysis identified nine distinct genes exhibiting DEGs within the realm of MI. miRNA-gene/TF and TF-gene/miRNA regulatory relations were mapped to retrieve interacting hub genes to acquire an MI miRNA-TF co-regulatory network. Furthermore, an animal model of I/R-induced MI confirmed the involved gene based on quantitative RT-PCR and Western blot analysis. The consequences of the bioinformatic tool substantiate the inference regarding the presence of three key hub genes (UBE2N, TMEM106B, and CXADR), a central miRNA (hsa-miR-124-3p), and sixteen TFs. Animal studies support the involvement of predicted genes in the I/R-induced myocardial infarction assessed by RT-PCR and Western blotting. Thus, the final consequences suggest the involvement of promising molecular pathways regulated by TF (p53/NF-κB1), miRNA (hsa-miR-124-3p), and hub gene (UBE2N), which may play a key role in the pathogenesis of MI.

Mechanistic insights into sodium ion-mediated ligand binding affinity and modulation of 5-HT2B GPCR activity: implications for drug discovery and development.

PURPOSE: The G-protein coupled receptor (GPCR) family, implicated in neurological disorders and drug targets, includes the sensitive serotonin receptor subtype, 5-HT2B. The influence of sodium ions on ligand binding at the receptor's allosteric region is being increasingly studied for its impact on receptor structure. METHODS: High-throughput virtual screening of three libraries, specifically the Asinex-GPCR library, which contains 8,532 compounds and FDA-approved (2466 compounds) and investigational compounds (2731)) against the modeled receptor [4IB4-5HT2BRM] using the standard agonist/antagonist (Ergotamine/Methysergide), as previously selected from our studies based on ADMET profiling, and further on basis of binding free energy a single compound - dihydroergotamine is chosen. RESULTS: This compound displayed strong interactions with the conserved active site. Ions influence ligand binding, with stronger interactions (3-H-bonds and 1-π-bond around 3.35 Å) observed when an agonist and ions are present. Ions entry is guided by conserved motifs in helices III, IV, and VII, which regulate the receptor. Dihydroergotamine, the selected drug, showed binding variance based on ions presence/absence, affecting amino acid residues in these motifs. DCCM and PCA confirmed the stabilization of ligands, with a greater correlation (∼46.6%-PC1) observed with ions. Dihydroergotamine-modified interaction sites within the receptor necessary for activation, serving as a potential 5HT2BRM agonist. RDF analysis showed the sodium ions density around the active site during dihydroergotamine binding. CONCLUSION: Our study provides insights into sodium ion mobility's role in controlling ligand binding affinity in 5HT2BR, offering therapeutic development insights.

Co-overexpression of SWEET sucrose transporters modulates sucrose synthesis and defence responses to enhance immunity against bacterial blight in rice.

Enhancing carbohydrate export from source to sink tissues is considered to be a realistic approach for improving photosynthetic efficiency and crop yield. The rice sucrose transporters OsSUT1, OsSWEET11a and OsSWEET14 contribute to sucrose phloem loading and seed filling. Crucially, Xanthomonas oryzae pv. oryzae (Xoo) infection in rice enhances the expression of OsSWEET11a and OsSWEET14 genes, and causes leaf blight. Here we show that co-overexpression of OsSUT1, OsSWEET11a and OsSWEET14 in rice reduced sucrose synthesis and transport leading to lower growth and yield but reduced susceptibility to Xoo relative to controls. The immunity-related hypersensitive response (HR) was enhanced in the transformed lines as indicated by the increased expression of defence genes, higher salicylic acid content and presence of HR lesions on the leaves. The results suggest that the increased expression of OsSWEET11a and OsSWEET14 in rice is perceived as a pathogen (Xoo) attack that triggers HR and results in constitutive activation of plant defences that are related to the signalling pathways of pathogen starvation. These findings provide a mechanistic basis for the trade-off between plant growth and immunity because decreased susceptibility against Xoo compromised plant growth and yield.

Amelioration of endothelial integrity by 3,5,4'-trihydroxy-trans-stilbene against high-fat-diet-induced obesity and -associated vasculopathy and myocardial infarction in rats, targeting TLR4/MyD88/NF-κB/iNOS signaling cascade.

Exacerbated expression of TLR4 protein (foremost pattern recognition receptor) during obesity could trigger NF-κB/iNOS signaling through linker protein (MyD88), predisposed to an indispensable inflammatory response. The induction of this detrimental cascade leads to myocardial and vascular abnormalities. Molecular docking was studied for protein-ligand interaction between these potential targets and resveratrol. The pre-treatment of resveratrol (20 mg/kg/p.o/per day for ten weeks) was given to investigate the therapeutic effect against HFD-induced obesity and associated vascular endothelial dysfunction (VED) and myocardial infarction (MI) in Wistar rats. In addition to accessing the levels of serum biomarkers for VED and MI, oxidative stress, inflammatory cytokines, and histopathology of these tissues were investigated. Lipopolysaccharide (for receptor activation) and protein expression analysis were introduced to explore the mechanistic involvement of TLR4/MyD88/NF-κB/iNOS signaling. Assessment of in-silico analysis showed significant interaction between protein and ligand. The involvement of this proposed signaling (TLR4/MyD88/NF-κB/iNOS) was further endorsed by the impact of lipopolysaccharide and protein expression analysis in obese and treated rats. Moreover, resveratrol pre-treated rats showed significantly lowered cardio and vascular damage measured by the distinct down expression of the TLR4/MyD88/NF-κB/iNOS pathway by resveratrol treatment endorses its ameliorative effect against VED and MI.

Erratum: Bicritical states in temperature-modulated Rayleigh-Bénard convection [Phys. Rev. E 92, 013005 (2015)].

This corrects the article DOI: 10.1103/PhysRevE.92.013005.

Xanthone Derivatives Enhance the Therapeutic Potential of Neomycin against Polymicrobial Gram-Negative Bacterial Infections.

Gram-negative bacterial infections are difficult to manage as many antibiotics are ineffective owing to the presence of impermeable bacterial membranes. Polymicrobial infections pose a serious threat due to the inadequate efficacy of available antibiotics, thereby necessitating the administration of antibiotics at higher doses. Antibiotic adjuvants have emerged as a boon as they can augment the therapeutic potential of available antibiotics. However, the toxicity profile of antibiotic adjuvants is a major hurdle in clinical translation. Here, we report the design, synthesis, and biological activities of xanthone-derived molecules as potential antibiotic adjuvants. Our SAR studies witnessed that the p-dimethylamino pyridine-derivative of xanthone (X8) enhances the efficacy of neomycin (NEO) against Escherichia coli and Pseudomonas aeruginosa and causes a synergistic antimicrobial effect without any toxicity against mammalian cells. Biochemical studies suggest that the combination of X8 and NEO, apart from inhibiting protein synthesis, enhances the membrane permeability by binding to lipopolysaccharide. Notably, the combination of X8 and NEO can disrupt the monomicrobial and polymicrobial biofilms and show promising therapeutic potential against a murine wound infection model. Collectively, our results unveil the combination of X8 and NEO as a suitable adjuvant therapy for the inhibition of the Gram-negative bacterial infections.

Real-Time Shear Wave Elastography for Determining the Ideal Site of Liver Biopsy in Diffuse Liver Disease.

Objectives The objective of the study was to identify accurate site of liver biopsy under ultrasound and elastography guidance and compare the shear wave elastography (SWE) and transient elastography (TE) diagnostic accuracy with histopathological correlation. Methods This was a prospective single-center study where patients scheduled for nonfocal liver biopsy were divided into two groups (group U: ultrasound; group E elastography) by sequential nonrandom selection of patients. Elastography was performed before the biopsy and biopsies from the maximum stiffness segment were taken. Results There was no significant difference of intersegmental liver stiffness with mean velocity; however, biopsy segment velocities show significant difference with mean liver stiffness suggestive of heterogenous distribution of fibrosis. The rho ( r ; Spearman's correlation) value between biopsy segments and mean velocities shows excellent correlation. The diagnostic performance of TE was good for fibrosis stages F2, F3, and F4, while SWE was fair for the diagnosis of fibrosis stages F1 and F2 and fairly equal for the diagnosis stages F2 and F3. Area under the curve (AUC) values in differentiating mild (F1) or no fibrosis from significant fibrosis (≥F2) were 95.5 with cutoff value of at least 1.94 m/s. Conclusions The diagnostic performance of SWE is comparable with TE in liver fibrosis staging and monitoring. Fibrosis is heterogeneously distributed in different segments of the right lobe liver. Therefore, elastography at the time of biopsy may help in defining the accurate site for biopsy and improve histopathological yield in detecting liver fibrosis in patients with chronic liver disease. Advances in Knowledge Elastography-guided biopsy is helpful to determine the ideal site of biopsy.

Dual functionality of pyrimidine and flavone in targeting genomic variants of EGFR and ER receptors to influence the differential survival rates in breast cancer patients.

Breast cancer ranks as one of the most prevalent forms of cancer and stands as the primary global cause of mortality among women. Overexpression of EGFR and ER receptors or their genomic alterations leads to malignant transformation, disease aggression and is linked to poor patient survival outcomes. The clinical breast cancer patient's genomic expression, survival analysis, and computational drug-targeting approaches were used to identify best-hit phytochemicals for therapeutic purposes. Breast cancer patients have genomic alterations in EGFR (4%, n = 5699) and ER (9%, n = 8461), with the highest proportion being missense mutations. No statistically significant difference was observed in the patient survival rates between the altered and unaltered ER groups, unlike EGFR, with the lowest survival rates in the altered group. Computational screening of natural compound libraries (7711) against each EGFR (3POZ) and ER (3ERT) receptor shortlists the best-hit 3 compounds with minimum docking score (ΔG = -7.9 to -10.8), MMGBSA (-40.16 to -51.91 kcal/mol), strong intermolecular H-bonding, drug-like properties with least kd, and ki. MD simulation studies display stable RMSD, RMSF, and good residual correlation of best-hit common compounds (PubChem ID: 5281672 and 5280863) targeting both EGFR and ER receptors. In vitro, studies revealed that these common drugs exhibited a high anti-proliferative effect on MCF-7 and MDA-MB-231 breast cancer cells, with effective IC50 values (15-40 µM) and lower free energy, kd, and ki (5281672 > 5280863 > 5330286) much affecting HEK-293 non-cancerous cells, indicating the safety profile. The experimental and computational correlation studies suggest that the highly expressed EGFR and ER receptors in breast cancer patients having poor survival rates can be effectively targeted with best-hit common potent drugs with a multi-target therapeutic approach. Insight Box: The findings of this study provide valuable insights into the genomic/proteomic data, breast cancer patient's survival analysis, and EGFR and ER receptor variants structural analysis. The genetic alterations analysis of EGFR and ER/ESR1 in breast cancer patients reveals the high frequency of mutation types, which affect patient's survival rate and targeted therapies. The common best-hit compounds affect the cell survival patterns with effective IC50, drug-like properties having lower equilibrium and dissociation constants demonstrating the anti-proliferative effects. This work integrates altered receptor structural analysis, molecular interaction-based simulations, and ADMET properties to illuminate the identified best hits phytochemicals potential efficacy targeting both EGFR and ER receptors, demonstrating a multi-target therapeutic approach.

An Atomic Level Investigation of Sodium Ions Regulating Agonist and Antagonist Binding in the Active Site of a Novel Target 5HT2BR Against Drug-Resistant Epilepsy.

The study investigates the movement of sodium ions inside the ligand-binding pocket of the class-A GPCR serotonin receptor (5HT2BR), a primary target for modern drugs. The available PDBs are mutant chimeras, so a 3D structure is modeled and validated by structural similarity (84.05%), Ramachandran favorable residues (93.01%), and clash score. Using MD simulations (500 ns), the ion active site is tracked in the presence and absence of ions and ligands. The ions enter the active site along helices III, VI, and VII, and the primary residue (ASP3.32) interacts with ions via H-bond (stronger- ~2.4 Å). The radial distribution function around ASP3.32 rises promptly at intermediate distances (2 Å < r < 4 Å), suggesting a higher probability of finding sodium ions at these distances. The ions stabilize the receptor at a better RMSD and promote stronger interactions (3-H-bonds, 1-π-bond~3.35 Å) with the agonist, and not the antagonist (no H-bond). Simulating unrestrained ligands further confirms this pattern, suggesting that ions might promote agonist binding but not be a prerequisite for antagonist action. The study highlights the mechanistic evaluation of sodium ions mobility in 5HT2BR modulation and ligand binding, showing potential in drug development.

Designing the 5HT2BR structure and its modulation as a therapeutic target for repurposing approach in drug-resistant epilepsy.

The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (-53.44 kcal/mol) and Methylergonovine (-40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10-8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10-8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207-214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (-89.21 kcal/mol) than Methylergonovine (-63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy.

De novo transcriptome analysis and identification of defensive genes in garlic (Allium sativum L.) using high-throughput sequencing.

BACKGROUND: Garlic (Allium sativum L.) is the second most widely cultivated Allium which is mainly grown in temperate regions and used as a flavoring agent in a wide variety of foods. Garlic contains various bioactive compounds whose metabolic pathways, plant-pathogen interactions, defensive genes, identify interaction networks, and functional genomics were not previously predicted in the garlic at the genomic level. To address this issue, we constructed two garlic Illumina 2000 libraries from tissues of garlic clove and leaf. RESULTS: Approximately 43 million 125 bp paired-end reads were obtained in the two libraries. A total of 239,973 contigs were generated by de novo assembly of both samples and were compared with the sequences in the NCBI non-redundant protein database (Nr). In total, 42% of contigs were matched to known proteins in public databases including Nr, Gene Ontology (GO), and Cluster Orthologous Gene Database (COG), and then, contigs were mapped to 138 via functional annotation against the Kyoto Encyclopedia of Genes and Genomes pathway database (KEGG). In addition, a number of regulatory genes including the CCHC (Zn) family, followed by WD40, bromodomain, bZIP, AP2-EREBP, BED-type (Zn) proteins, and defense response proteins related to different conserved domains, such as RGA3, NBS-LRR, TIR-NBS-LRR, LRR, NBS-ARC, and CC-NBS-LRR were discovered based on the transcriptome dataset. We compared the ortholog gene family of the A. sativum transcriptome to A. thaliana, O. sativa, and Z. mays and found that 12,077 orthologous gene families are specific to A. sativum L. Furthermore, we identified genes involved in plant defense mechanisms, their protein-protein interaction network, and plant-pathogen interaction pathways. CONCLUSIONS: Our study contains an extensive sequencing and functional gene-annotation analysis of A. sativum L. The findings provide insights into the molecular basis of TFs, defensive genes, and a reference for future studies on the genetics and breeding of A. sativum L.

Longitudinal and transverse modes of temperature-modulated inclined layer convection.

A parametric instability of an incompressible, viscous, and Boussinesq fluid layer bounded between two parallel planes is investigated numerically. The layer is assumed to be inclined at an angle with the horizontal. The planes bounding the layer are subjected to a time-periodic heating. Above a threshold value, the temperature gradient across the layer leads to an instability of an initially quiescent state or a parallel flow, depending upon the angle of inclination. Floquet analysis of the underlying system reveals that under modulation, the instability sets in as a convective-roll pattern executing harmonic or subharmonic temporal oscillations, depending upon the modulation, the angle of inclination, and the Prandtl number of the fluid. Under modulation, the onset of the instability is in the form of one of two spatial modes: the longitudinal mode and the transverse mode. The value of the angle of inclination for the codimension-2 point is found to be a function of the amplitude and the frequency of modulation. Furthermore, the temporal response is harmonic, or subharmonic, or bicritical depending upon the modulation. The temperature modulation offers good control of time-periodic heat and mass transfer in the inclined layer convection.

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes.

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase involved in the homeostasis of cellular energy. AMPK has developed as an appealing clinical target for the diagnosis of multiple metabolic diseases such as diabetes mellitus, obesity, inflammation, and cancer. Genetic and pharmacological studies indicate that AMPK is needed in response to glucose deficiency, dietary restriction, and increased physical activity for preserving glucose homeostasis. After activation, AMPK influences metabolic mechanisms contributing to enhanced ATP production, thus growing processes that absorb ATP simultaneously. In this review, several natural products have been discussed which enhance the sensitivity of AMPK and alleviate sub complications or different pathways by which such AMPK triggers can be addressed. AMPK Natural products as potential AMPK activators can be developed as alternate pharmacological intervention to reverse metabolic disorders including type 2 diabetes.

Is Ultrasound-guided Bedside Percutaneous Transhepatic Biliary Drainage Safe and Feasible in Critically Ill Patients with Severe Cholangitis? A Preliminary Single-center Experience.

Background and aim: Severe cholangitis secondary to biliary obstruction carries high mortality unless biliary drainage is performed urgently. Owing to various patient-related and logistical issues, bedside biliary drainage is considered a salvage therapeutic option. This study aims to evaluate the safety and efficacy of ultrasonography (USG)-guided biliary drainage at the bedside in patients with severe cholangitis admitted to the intensive care unit (ICU). Materials and methods: A total of 20 patients with severe cholangitis admitted to ICU who underwent bedside percutaneous transhepatic biliary drainage (PTBD) under USG guidance were retrospectively evaluated. Clinical outcomes, details about the PTBD procedure, and complications were recorded and analyzed. Results: Among 20 patients, 13 were male and 7 were female with a mean age of 50.5 years. The most common cause of biliary obstruction was gall bladder malignancy (45%, n = 9) followed by cholangiocarcinoma (25%, n = 5). Left- and right-sided PTBD was performed in 40% (n = 8) and 35% (n = 7) patients, respectively, while 25% (n = 5) of patients underwent bilateral PTBD. The technical success rate was 100%. A total of 65% (n = 13) of patients were discharged from ICU upon improvement while the remaining 35% (n = 7) died despite bedside PTBD. None of the patients had any major procedure-related complications. Conclusions: Ultrsound-guided bedside PTBD seems to be a safe and effective option in critically ill patients with severe cholangitis when shifting of patients is not feasible. How to cite this article: Singh J, Tripathy TP, Patel R, Chandel K. Is Ultrasound-guided Bedside Percutaneous Transhepatic Biliary Drainage Safe and Feasible in Critically Ill Patients with Severe Cholangitis? A Preliminary Single-center Experience. Indian J Crit Care Med 2023;27(1):16-21.

Allosteric modulation of conserved motifs and helices in 5HT2BR: Advances drug discovery and therapeutic approach towards drug resistant epilepsy.

The 5HT2BR, class-A GPCR is a new target, and its significance for seizure reduction in Dravet syndrome is just now gaining interest, suggesting its specific role in epileptic seizure management. Homology modeling of human 5HT2BR (P41595), was performed using a template 4IB4, the modeled structure was cross-validated (stereo chemical hindrance, Ramachandran plot, enrichment analysis) to mimic a closer native structure. Virtual screening (8532 compounds), drug-likeliness, mutagenicity, and carcinogenicity profiling prioritized six compounds for molecular dynamics (500 ns), Rgyr, DCCM. The receptor's C-alpha fluctuation upon bound agonist (6.91 Å), known antagonist (7.03 Å), and LAS 52115629 (5.83 Å) binding varies, leading to receptor stabilization. The residues C-alpha side-chain in active site strongly interacts (hydrogen bonds) with bound agonist (100% interaction: ASP135), known antagonist (95%:ASP135), and LAS 52115629 (100%:ASP135). The Rgyr for receptor-ligand complex, LAS 52115629 (25.68 Å), lies close to bound agonist-Ergotamine, and DCCM analysis also shows strong positive correlations for LAS 52115629 as compared to known drugs. LAS 52115629 is less likely to cause toxicity than known drugs. The structural parameters in the modeled receptor's conserved motifs (DRY, PIF, NPY) were altered for receptor activation upon ligand-binding, which otherwise was in the in-activated state. The ligand (LAS 52115629)-binding further alters the helices-III, V, VI (G-protein bound), and VII, which form potential interacting sites with the receptor and are proven necessary for activating the receptor. Therefore, LAS 52115629 can act as a potential 5HT2BR agonist, targeting drug-resistant epilepsy.Communicated by Ramaswamy H. Sarma.

Physiological implications of SWEETs in plants and their potential applications in improving source-sink relationships for enhanced yield.

The sugars will eventually be exported transporters (SWEET) family of transporters in plants is identified as a novel class of sugar carriers capable of transporting sugars, sugar alcohols and hormones. Functioning in intercellular sugar transport, SWEETs influence a wide range of physiologically important processes. SWEETs regulate the development of sink organs by providing nutritional support from source leaves, responses to abiotic stresses by maintaining intracellular sugar concentrations, and host-pathogen interactions through the modulation of apoplastic sugar levels. Many bacterial and fungal pathogens activate the expression of SWEET genes in species such as rice and Arabidopsis to gain access to the nutrients that support virulence. The genetic manipulation of SWEETs has led to the generation of bacterial blight (BB)-resistant rice varieties. Similarly, while the overexpression of the SWEETs involved in sucrose export from leaves and pathogenesis led to growth retardation and yield penalties, plants overexpressing SWEETs show improved disease resistance. Such findings demonstrate the complex functions of SWEETs in growth and stress tolerance. Here, we review the importance of SWEETs in plant-pathogen and source-sink interactions and abiotic stress resistance. We highlight the possible applications of SWEETs in crop improvement programmes aimed at improving sink and source strengths important for enhancing the sustainability of yield. We discuss how the adverse effects of the overexpression of SWEETs on plant growth may be overcome.

Structure and dynamic simulation-based interactions of benzenoids, pyrroles and organooxygen compounds for effective targeting of GPX4 in ischemic stroke.

The discovery of a novel drug for ischemic stroke is plagued by expensive and unsuccessful outcomes. FDA-approved drugs could be a viable repurposing strategy for stroke therapy. Emerging evidence suggests the regulating role of Glutathione peroxidase (GPX4) in stroke and attracts as a potential target. To overcome limited therapeutic interventions, a drug repurposing in silico investigation of FDA-approved drugs is proposed for the GPX4 receptor in distinctive species (Homo sapiens and Mus musculus). The GPX4 UniProt wild type ids, that is, P36969 (Homo sapiens), P36970 (Rattus norvegicus) and O70325 (Mus musculus) are Swiss modelled, and resultant templates are 2OBI and 6HN3 for Homo sapiens, and 5L71 for Mus musculus with a sequence identity of ∼88%. Enrichment analysis reveals high sensitivity and ranked actives with ROC and AUC values of 0.59 and 0.61, respectively. Virtual screening at extra precision resulted hit Acarbosum, is similar between 2OBI and 6HN3, demonstrating a multiple-target specificity and Iopromide, targeting 2OBI. MD simulation at 100 ns following trajectory analysis provides RMSD (∼1.2-1.8Å), RMSF (∼1.6-2.7Å), Rgyr (∼15-15.6Å) depicting stabilisation of receptor-ligand complexes. Furthermore, average B-factor value of 2OBI, 6HN3 and 5L71 is 25Å, 24Å and 60Å with a defined resolution of 1.55Å, 1.01Å and 1.80Å, respectively, depicting the thermodynamic stability of the protein structures. The dynamic cross-correlation and principal component analysis of residual fluctuations reveal more positive correlation, high atomic displacements and greater residual clustering of residues from atomic coordinates. Therefore, Acarbosum, an FDA-approved drug, could act as a potential repurposing drug with a multi-target approach translating from preclinical to clinical stages.Communicated by Ramaswamy H. Sarma.

Terpenoid analogues as putative therapeutic agents towards glutathione peroxidase (GPX4) in neurodegenerative disorders: a dynamic computational approach.

Carvacrol, a monoterpenoid phenolic phytochemical, a potent antioxidant, and neuroprotective agent is an emerging neuroprotective agent for neurodegenerative diseases (NDDs). Considering scarce information on carvacrol analogues, we hypothesized an in silico investigation emphasizing their preferential binding towards glutathione peroxidase (GPX4) as a target across different species for evaluating through preclinical to clinical studies (2OBI and 6HN3 for Homo sapiens; 5L71 for Mus musculus). Enrichment analysis suggests that ROC (0.59) and AUC (0.61) values have higher sensitivity and significant number of ranked actives. Extra Precision (XP) of 59 compounds was conducted, followed by molecular dynamics and trajectory analysis. Top three hits were chosen for each target i.e., 101203408, 101419546, 59294 (2OBI); 101419546, 100938426, and 28092 (6HN3); and 12059, 52434, 335 (5L71) implying high docking score. 101419546 is common among 2OBI and 6HN3 targets, indicating a multi-target approach. Trajectory analysis of hits provides a permissible range of RMSD, RMSF, Rgyr (∼1.3-2 Å, ∼0.84-1.09 Å, ∼15.05-15.29 Å). Overlapped dynamically simulated 3D-structures of Apo and complexes display significant conformational changes in RMSD of the complexes (∼1.40-2.0 Å) in contrast to Apo (∼1.3-1.8 Å), suggesting structural stability and compactness of the complexes within 45-90 ns. DCCM and PCA analysis shows positive correlation and residual clustering among residues of complexes. The establishment of firm H-bonding, favorable aromaticity and ADMET profile makes them promising drugs across various GPX4 targets among the species. Studies considering the targets across different species aids in anticipating and discovering a common compound for future NDDs therapeutics from bench to bedside.Communicated by Ramaswamy H. Sarma.