Changes in antimicrobial resistance of Escherichia coli isolated from community-associated urinary tract infection before and during the COVID-19 pandemic in India.

PURPOSE: The impact of the COVID-19 pandemic on antimicrobial resistance (AMR) is largely studied in healthcare settings. There is a need to understand the fluctuations in AMR during pandemic at the community level. With urinary tract infection (UTI) being one of the most common infections in the community, the AMR profile of community-acquired UTI (CA-UTI) is considered representative AMR at the community level. METHODS: The study was taken in a cohort of patients with a clinical diagnosis of CA-UTI. The four study sites represented different community health centres in India. Escherichia coli isolates were analysed phenotypically and genotypically for AMR pre-COVID (October 2019-February 2020) and in the first (March 2020-February 2021) and second waves of COVID-19 (March 2021-December 2021). RESULTS: E. coli was the predominant uropathogen (229, 82%). Increased susceptibility to nitrofurantoin was observed during the pandemic. Reduced susceptibility to first-line oral antibiotics and carbapenems was seen during the second wave, and an increased minimum inhibitory concentration (MIC50) to beta-lactams and fluoroquinolones was seen during the pandemic. Genomic analysis of E. coli isolates showed some AMR genes (aacC1, aacC4, SHV, QepA) only during the second wave. CONCLUSION: One good outcome of the pandemic was increased susceptibility to nitrofurantoin, while drawback was a significant decrease in susceptibility to oral antibiotics during the second wave and increased MIC50 of some antibiotics. Decreased susceptibility to last-resort carbapenems and the occurrence of various AMR genes during the second wave of the pandemic are of great concern.

Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

Aminic Organoselenium Compounds as Glutathione Peroxidase Mimics and Inhibitors of Ferroptosis.

The synthesis of diarylamine-based organoselenium compounds via the nucleophilic substitution reactions has been described. Symmetrical monoselenides and diselenides were conveniently synthesized by the reduction of their corresponding selenocyanates using sodium borohydride. Selenocyanates were obtained from 2-chloro acetamides by the nucleophilic displacement with potassium selenocyanate. Selenides were synthesized by treating the 2-chloro acetamides with in situ generated sodium butyl selenolate as nucleophile. Further, the newly synthesized organoselenium compounds were evaluated for their glutathione peroxidase (GPx)-like activity in thiophenol assay. This study revealed that the methoxy-substituted organoselenium compounds showed significant effect on the GPx-like activity. The catalytic parameters for the most efficient catalysts were also determined. The anti-ferroptotic activity for all GPx-mimics evaluated in a 4-OH-tamoxifen (TAM) inducible GPx4 knockout cell line using liproxstatin as standard.

Novel Dihydrocoumarins Induced by Radiolysis as Potent Tyrosinase Inhibitors.

A representative naturally occurring coumarin, 4-methylumbelliferone (5), was exposed to 50 kGy of gamma ray, resulting in four newly generated dihydrocoumarin products 1-4 induced by the gamma irradiation. The structures of these new products were elucidated by interpretation of spectroscopic data (NMR, MS, [α]D, and UV). The unusual bisdihydrocoumarin 4 exhibited improved tyrosinase inhibitory capacity toward mushroom tyrosinase with IC50 values of 19.8 ± 0.5 µM as compared to the original 4-methylumbelliferone (5). A kinetic analysis also exhibited that the potent metabolite 4 had non-competitive modes of action. Linkage of the hydroxymethyl group in the C-3 and C-4 positions on the lactone ring probably enhances the tyrosinase inhibitory effect of 4-methylumbelliferone (5). Thus, the novel coumarin analog 4 is an interesting new class of tyrosinase inhibitory candidates that requires further examination.

A novel mitigation strategy for the prevention of transfusion-transmitted malaria.

BACKGROUND: Malaria is caused by protozoa of the genus Plasmodium and transmitted by Anopheles mosquitos. In the US, blood donors are assessed for malaria risk, including donor travel or previous residence in endemic areas and history of malaria by questionnaire and deferred for three months or three years, respectively. METHODS: The Procleix Plasmodium Assay is a qualitative nucleic acid test based on transcription-mediated amplification (TMA) for the detection of 18S ribosomal RNA of P. falciparum, P. ovale, P. vivax, P. malariae, and P. knowlesi for use on the Procleix Panther system. Analytical sensitivity was evaluated with in vitro transcripts and infected red blood cells. For clinical specificity, 12,800 individual donations and 283 pools of 16 samples from routine US donors were screened. Malaria risk was evaluated by testing 862 donors deferred for 3 years. Reactive results were confirmed with in-house real-time TMA assay and serology. RESULTS: Assay sensitivity was 8.47-11.89 RNA copies/mL and 2.10-6.82 infected red cells/mL. Specificity was 99.99% in 12,800 individual donations and 100% in 283 pools of 16. Of 862 tested deferred donor samples, one donor (0.12%) confirmed positive individually and in pools; he remained confirmed positive for 13 months. The infected donor was a prior resident of a malaria-endemic area in West Africa. CONCLUSIONS: The Procleix Plasmodium Assay showed high sensitivity and specificity and detected Plasmodium RNA in an asymptomatic presenting donor. This assay may prove helpful as a screening test versus the use of risk questions to reduce the number of donors deferred for malaria risk.

Comprehensive and evolutionary analysis of Spodoptera litura-inducible Cytochrome P450 monooxygenase gene family in Glycine max elucidate their role in defense.

Plants being sessile organisms and lacking both circulating phagocytic cells and somatic adaptive immune response, have thrived on various defense mechanisms to fend off insect pests and invasion of pathogens. CYP450s are the versatile enzymes, which thwart plants against insect pests by ubiquitous biosynthesis of phytohormones, antioxidants, and secondary metabolites, utilizing them as feeding deterrents and direct toxins. Therefore, a comprehensive analysis of biotic stress-responsive CYPs from Glycine max was performed to ascertain their function against S. litura-infestation. Phylogenetic analysis and evolutionary studies on conserved domains and motifs disclosed the evolutionary correspondence of these GmCYPs with already characterized members of the CYP450 superfamily and close relatedness to Medicago truncatula. These GmCYPs were mapped on 13 chromosomes; they possess 1-8 exons; they have evolved due to duplication and are localized in endoplasmic reticulumn. Further, identification of methyl-jasmonate, salicylic acid, defense responsive and flavonoid biosynthesis regulating cis-acting elements, their interaction with biotic stress regulating proteins and their differential expression in diverse types of tissues, and during herbivory, depicted their responsiveness to biotic stress. Three-dimensional homology modelling of GmCYPs, docking with heme cofactor required for their catalytic activity and enzyme-substrate interactions were performed to understand the functional mechanism of their action. Moreover, to gain insight into their involvement in plant defense, gene expression analysis was evaluated, which revealed differential expression of 11 GmCYPs upon S. litura-infestation, 12 GmCYPs on wounding while foliar spray of ethylene, methyl-jasmonate and salicylic acid differentially regulated 11 GmCYPs, 6 GmCYPs, and 10 GmCYPs respectively. Our study comprehensively analysed the underlying mechanism of GmCYPs function during S. litura-infestation, which can be further utilized for functional characterization to develop new strategies for enhancing soybean resistance to insect pests.

Glutathione Peroxidase-like Antioxidant Activity of 1,3-Benzoselenazoles: Synthesis and In Silico Molecular Docking Studies as Pancreatic Lipase Inhibitors.

The synthesis of 1,3-benzoselenazoles was achieved by the reaction of corresponding bis[3-amino-N-(p-tolyl)benzamide-2-yl] diselenide, bis[3-amino-N-(4-methoxyphenyl)benzamide-2-yl] diselenide, and bis[3-amino-N-(4-(dimethylamino)phenyl) benzamide-2-yl] diselenide with aryl aldehydes. The 1,3-benzoselenazoles continued to exist as planar molecules due to the presence of secondary Se···O interactions as revealed by the single-crystal X-ray analysis. The presence of secondary Se···O interactions in 1,3-benzoselenazoles was confirmed using natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Nucleus-independent chemical shift (NICS) values suggested the presence of aromatic character in a five-membered benzoselenazole heterocyclic ring. The glutathione peroxidase (GPx)-like antioxidant activity of all 1,3-benzoselenazoles was assessed using a thiophenol assay, exhibiting greater antioxidant activity than Ph2Se2 used as a reference. The most active catalyst carrying a strong electron-donating group (-NMe2) at the ortho-position to the benzoselenazole ring was further investigated at different concentrations of thiophenol, H2O2, and 1,3-benzoselenazoles as catalyst for determining their catalytic parameters. Moreover, the potential applications of all 1,3-benzoselenazoles against pancreatic lipase (PL) have been identified using in silico interactions between the active sites of the 1LPB protein as evaluated using a molecular docking study.

Single-molecule analysis of osmolyte-mediated nanomechanical unfolding behavior of a protein domain.

The small organic molecules, known as osmolytes being ubiquitously present in different cell types, affect protein folding, stability and aggregation. However, it is unknown how the osmolytes affect the nanomechanical unfolding behavior of protein domain. Here, we show the osmolyte-dependent mechanical unfolding properties of protein titin immunoglobulin-27 (I27) domain using an atomic force microscopy (AFM)-based single-molecule force spectroscopy. We found that amines and methylamines improved the mechanical stability of I27 domain, whereas polyols had no effect. Interestingly, glycine betaine (GB) or trimethylamine-N-oxide (TMAO) increased the average unfolding force of the protein domain. The kinetic parameters analyzed at single-molecule level reveal that stabilizing effect of osmolytes is due to a decrease in the unfolding rate constant of I27, which was confirmed by molecular dynamics simulations. Our study reveals different effects that diverse osmolytes have on the mechanical properties of the protein, and suggests the potential use of osmolytes in modulating the mechanical stability of proteins required for various nano-biotechnological applications.

Nucleic acid testing for monkeypox in United States blood donor specimens.

BACKGROUND: The 2022 multi-country outbreak of monkeypox (mpox) resulted in blood collection and public health agencies closely monitoring for changes in transmission dynamics that could pose a threat to the blood supply. While mpox virus (MPXV) is not known to be transfusion transmissible, there have been several studies demonstrating the detection of MPXV in blood. We evaluated the performance characteristics of a research use only (RUO) nucleic acid amplification test for MPXV. The assay was developed to detect MPXV DNA in plasma and serum specimens from human blood donors. METHODS AND MATERIALS: The sensitivity of the RUO MPXV Assay was determined using a synthetic DNA sequence, purified full-length genomic DNA, and a chemically inactivated virus. Specificity was determined using fresh plasma samples collected from blood donors during the outbreak. Plasma samples collected from donors considered at increased risk for exposure to mpox were also tested. RESULTS: For sensitivity, the 95% limit of detection (LOD) ranged from 0.26 copies/mL (inactivated virus) to 31.65 copies/mL (synthetic DNA) to 166.61 copies/mL (for full-length DNA). All donor samples tested with the RUO MPXV Assay were nonreactive, resulting in a specificity of 100% (95% CI, 99.93%-100.00%). DISCUSSION: The RUO MPXV Assay was developed as a potential blood donation screening assay in response to the outbreak. While not directly comparable, the 95% LOD fiducial limits obtained from partial- and full-length DNA analysis were similar to other manufacturers' MPXV assays. Additionally, this assay demonstrated high specificity for screening blood donors.

Factors associated with late gestational age of diagnosis and/or delayed referral of fetuses with major structural malformations: A study in a tertiary care hospital in South India.

OBJECTIVES: To evaluate the factors related to delayed diagnosis or referral of women with major congenital malformations in a tertiary care hospital in South India, with a specific emphasis on the socioeconomic and psychosocial aspects. METHODS: A retrospective analysis was conducted on 107 pregnant women with confirmed fetal anomalies at Jawaharlal Institute of Postgraduate Medical Education and Research. Both qualitative and quantitative data were collected on factors related to the patient, physician, and healthcare system that could have contributed to the delay. RESULTS: In our study of 107 patients, 98.1% had at least one antenatal check-up before 20 weeks. Among them, 75.2% (79/107) were advised to undergo a mid-trimester anomaly scan, and 70.8% (56/79) actually underwent the scan. However, 62.5% (35/56) of those who had the scan performed at the appropriate time had undetected abnormalities. Retrospective analysis showed that 28.5% (10/35) of these anomalies could have been detected as early as 12-14 weeks of gestation. Additionally, 24.3% (26/107) of women were advised to undergo scans at or after 20 weeks and 4.7% (5/107) had anomalies detected during the scan but were unaware about the findings until subsequent visits. Inadequate healthcare professional training, busy schedules, lack of awareness, and communication gaps were identified as potential reasons for delayed diagnosis. Psychosocial factors such as denial, fear, emotional distress, and anxiety also influenced decision-making and contributed to delayed medical care. CONCLUSION: Addressing healthcare provider training, communication between the healthcare professionals and the patients, and psychosocial factors are essential to prevent delays and improve pregnancy management. Future interventions should focus on awareness, providing comprehensive information, and support for parents facing fetal anomalies.

Managing Multiple Schwannomatosis of Vagus and Hypoglossal Nerves: The Unanticipated Complications.

Schwannomas are rare benign tumours of the nerve sheath. Extracranial schwannomas are usually found solitary, in the absence of other features of neurofibromatosis. The non NF1/2 multiple schwannomas are collectively described as the clinical scenario called schwannomatosis. We present a rare case of two extracranial schwannomas involving vagus and hypoglossal nerves in a 22-year-old female along with an unusual surgical complication of CSF leak presenting as post-op neck mass and a review of previously reported similar cases. A thorough literature search using the MeSH terms-'schwannomatosis' or 'Multiple Schwannoma' and 'Vagal Schwannoma' and 'Hypoglossal Schwannoma', was conducted using online databases and augmentated by hand search. A total of 13 reported cases were found and reviewed. Of the 14 cases described from review of literature and our case, 50% had involvement of vagus nerve as one of the components. 12.5% had hypoglossal and cervical sympathetic plexus involvement each. All patients underwent surgical excision. Half of the patients suffered intraoperative nerve sacrifice with resultant severe functional deficits like vocal cord paralysis, Horners syndrome, hypoglossal palsy, facial palsy and eleventh nerve palsy. In our case, there was un-unusual complication of CSF leak presenting as a cervical neck mass. Multiple extracranial head and neck schwannomas are rare and their management is fraught with several complications. Decision to operate is often perplexing. However, early planned surgical excision and preservation of nerve of origin minimizes the impact on quality of life postoperatively.

Inflammatory responses during trichomoniasis: The role of Toll-like receptors and inflammasomes.

Toll-like receptors (TLRs) and inflammasomes belong to the pattern recognition receptors (PRRs) of innate immunity identifying conserved compounds produced by pathogens or discharged by injured cells. Different cell subsets in the human urogenital system, such as epithelial cells and infiltrating leukocytes, express different kinds of TLRs (such as TLR2, TLR3, TLR4, TLR5 and TLR9) as well as inflammasomes (such as NLRP3, NLRC4 and AIM2). Various types of the Trichomonas vaginalis-derived components such as glycosyl-phosphatidylinositol (GPI), T. vaginalis virus (TVV), Lipophosphoglycan (LPG) and flagellin can be recognized by TLR2, TLR3, TLR4 and TLR5, respectively, leading to the production of proinflammatory cytokines and chemokines in the cervicovaginal mucosa. The T. vaginalis-induced inflammasomes can lead to pyroptosis as well as the release of IL-1ß and IL-18 promoting innate and adaptive immune responses. The PRR-mediated responses to T. vaginalis may contribute to the induction of protective immune responses, local inflammation, promotion of co-infections, or even the development of malignancies, for example, prostate cancer. The protective or pathogenic roles of the TLRs and inflammasomes during trichomoniasis are highlighted in this review. A better understanding of PRR-mediated responses provides invaluable insights to develop effective immunotherapeutic strategies against T. vaginalis infection.

Drought priming induced thermotolerance in wheat (Triticum aestivum L.) during reproductive stage; a multifaceted tolerance approach against terminal heat stress.

In wheat (Triticum aestivum L.), terminal heat stress obstructs reproductive functioning eventually leading to yield loss. Drought priming during the vegetative stage can trigger a quicker and effective defense response against impending high temperature stress and improve crop production. In the present study, two contrasting wheat cultivars (PBW670 and C306) were subjected to moderate drought stress of 50-55% field capacity for eight days during the jointing stage to generate drought priming (DP) response. Fifteen days after anthesis heat stress (36 °C) was imposed for three days and physiological response of primed, and non-primed plants was assessed by analyzing membrane damage, water status and antioxidative enzymes. Heat shock transcription factors (14 TaHSFs), calmodulin (TaCaM5), antioxidative genes (TaSOD, TaPOX), polyamine biosynthesis genes and glutathione biosynthesis genes were analyzed. GC-MS based untargeted metabolite profiling was carried out to underpin the associated metabolic changes. Yield related parameters were recorded at maturity to finally assess the priming response. Heat stress response was visible from day one of exposure in terms of membrane damage and elevated antioxidative enzymes activity. DP reduced the impact of heat stress by lowering the membrane damage (ELI, MDA & LOX) and enhancing antioxidative enzyme activity except APX in both the cultivars. Drought priming upregulated the expression of HSFs, calmodulin, antioxidative genes, polyamines, and the glutathione biosynthesis genes. Drought priming altered key amino acids, carbohydrate, and fatty acid metabolism in PBW670 but also promoted thermotolerance in C306. Overall, DP provided a multifaceted approach against heat stress and positive association with yield.

TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3.

The outcome of the disease visceral leishmaniasis (VL), caused by Leishmania donovani (LD), largely relies on the relative dominance of host-protective type-1 T helper (Th1) cell response versus disease-promoting type-2 T helper (Th2) cell response. The Th1 and Th2 responses, in turn, are believed to be elicited by type-1 conventional dendritic cells (cDC1) and type-2 conventional DCs (cDC2), respectively. However, it is still unknown which DC subtype (cDC1 or cDC2) predominates during chronic LD infection and the molecular mechanism governing such occurrence. Here we report that in chronically infected mice, the splenic cDC1-cDC2 balance shifted toward the cDC2 subtype and that the receptor T cell immunoglobulin and mucin protein-3 (TIM-3) expressed by DCs played a key role in mediating this effect. Transfer of TIM-3-silenced DCs in fact prevented the predominance of the cDC2 subtype in mice with chronic LD infection. We also found that LD actually upregulated TIM-3 expression on DCs by triggering a TIM-3-mediated signaling pathway STAT3 (signal transducer and activator of transcription 3)→interleukin (IL)-10→c-Src→transcription factors Ets1, Ets2, USF1, and USF2. Notably, TIM-3 promoted STAT3 activation via a non-receptor tyrosine kinase Btk. Adoptive transfer experiments further demonstrated a critical role for STAT3-driven TIM-3 upregulation on DCs in increasing cDC2 abundance in chronically infected mice, which ultimately aided disease pathogenesis by augmenting Th2 responses. These findings document a new immunoregulatory mechanism contributing to disease pathology during LD infection and define TIM-3 as a key mediator of this process.

Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-ß.

To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood. Here, we demonstrate that L. donovani infection impaired the lymph node homing ability of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression. L. donovani exerted this inhibitory effect by inducing transforming growth factor-ß (TGF-ß) secretion from DCs. Indeed, TGF-ß produced in this manner inhibited nuclear factor-κB (NF-κB)-mediated CLEC-2 expression on DCs by activating c-Src. Notably, suppression of c-Src expression significantly improved the arrival of DCs in draining lymph nodes by preventing L. donovani-induced CLEC-2 downregulation on DCs. These findings reveal a unique mechanism by which L. donovani inhibits DC migration to lymph nodes and suggest a key role for TGF-ß, c-Src, and CLEC-2 in regulating this process. IMPORTANCE Dendritic cells (DCs) play a key role in initiating T cell-mediated protective immunity against visceral leishmaniasis (VL), the second most lethal parasitic disease in the world. However, the T cell-inducing ability of DCs critically depends on the extent of DC migration to regional lymph nodes. Notably, the migration of DCs is reported to be impaired during VL. The cause of this impaired DC migration, however, remains ill-defined. Here, we provide the first evidence that L. donovani, the causative agent of VL, attenuates the lymph node homing capacity of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression on DCs. Additionally, we have demonstrated how L. donovani mediates this inhibitory effect. Overall, our work has revealed a unique mechanism underlying L. donovani-induced impairment of DC migration and suggests a potential strategy to improve antileishmanial T cell activity by increasing DC arrival in lymph nodes.

Biomolecular map of albumin identifies signatures of severity and early mortality in acute liver failure.

BACKGROUND & AIMS: Acute liver failure (ALF) is associated with high mortality. Alterations in albumin structure and function have been shown to correlate with outcomes in cirrhosis. We undertook a biomolecular analysis of albumin to determine its correlation with hepatocellular injury and early mortality in ALF. METHODS: Altogether, 225 participants (200 patients with ALF and 25 healthy controls [HC]) were enrolled. Albumin was purified from the baseline plasma of the training cohort (ALF, n = 40; survivors, n = 8; non-survivors, n = 32; and HC, n = 5); analysed for modifications, functionality, and bound multi-omics signatures; and validated in a test cohort (ALF, n = 160; survivors, n = 53; non-survivors, n = 107; and HC, n = 20). RESULTS: In patients with ALF, albumin is more oxidised and glycosylated with a distinct multi-omics profile than that in HC, more so in non-survivors (p <0.05). In non-survivors, albumin was more often bound (p <0.05, false discovery rate <0.01) to proteins associated with inflammation, advanced glycation end product, metabolites linked to arginine, proline metabolism, bile acid, and mitochondrial breakdown products. Increased bacterial taxa (Listeria, Clostridium, etc.) correlated with lipids (triglycerides [4:0/12:0/12:0] and phosphatidylserine [39:0]) and metabolites (porphobilinogen and nicotinic acid) in non-survivors (r2 >0.7). Multi-omics signature-based probability of detection for non-survival was >90% and showed direct correlation with albumin functionality and clinical parameters (r2 >0.85). Probability-of-detection metabolites built on the top five metabolites, namely, nicotinic acid, l-acetyl carnitine, l-carnitine, pregnenolone sulfate, and N-(3-hydroxybutanoyl)-l-homoserine lactone, showed diagnostic accuracy of 98% (AUC 0.98, 95% CI 0.95-1.0) and distinguish patients with ALF predisposed to early mortality (log-rank <0.05). On validation using high-resolution mass spectrometry and five machine learning algorithms in test cohort 1 (plasma and paired one-drop blood), the metabolome panel showed >92% accuracy/sensitivity and specificity for prediction of mortality. CONCLUSIONS: In ALF, albumin is hyperoxidised and substantially dysfunctional. Our study outlines distinct 'albuminome' signatures capable of distinguishing patients with ALF predisposed to early mortality or requiring emergency liver transplantation. IMPACTS AND IMPLICATIONS: Here, we report that the biomolecular map of albumin is distinct and linked to severity and outcome in patients with acute liver failure (ALF). Detailed structural, functional, and albumin-omics analysis in patients with ALF led to the identification and classification of albumin-bound biomolecules, which could segregate patients with ALF predisposed to early mortality. More importantly, we found albumin-bound metabolites indicative of mitochondrial damage and hyperinflammation as a putative indicator of <30-day mortality in patients with ALF. This preclinical study validates the utility of albuminome analysis for understanding the pathophysiology and development of poor outcome indicators in patients with ALF.

LppDB - a Comprehensive Database for Lipopeptide based drugs: Exploring potential drug discovery aspects.

AIM: Lipopeptides are amphiphilic compounds consisting of a cyclic peptide attached to a fatty acid side chain. These are found with various medicinal properties ranging from broad-spectrum antimicrobial to anticancer properties. INTRODUCTION: Elaborated studies on the therapeutic properties of peptides are hindered due to a lack of databases specifically dedicated to such classes of compounds where all the medicinal information of compounds is collectively studied in one place, which can accelerate the future scope of research on peptidolipidic compounds. METHOD: The chemical information was retrieved from the PubChem compound database, and their metabolism information was generated through Swiss ADME. The application information about their particular pathways was obtained from different kinds of literature. RESULTS: A python script was developed to extract the information about lipopeptides from a CSV file, and the information was stored in MySQL Database. The database contains information for 70 lipopeptides and their biochemical information, structure, chemical and physical properties, information on industrial and medicinal applications, functions and references for lipopeptides. CONCLUSION: The development of web-based database applications allows the data stored in the database to be accessed and viewed publicly.

Synthesis, Reactions, and Antioxidant Properties of Bis(3-amino-1-hydroxybenzyl)diselenide.

Bis(3-amino-1-hydroxybenzyl)diselenide containing two ortho groups was synthesized from 7-nitro-3H-2,1-benzoxaselenole and in situ generated sodium benzene tellurolate (PhTeNa). One-pot synthesis of 1,3-benzoselenazoles was achieved from bis(3-amino-1-hydroxybenzyl)diselenide and aryl aldehydes using acetic acid as a catalyst. The X-ray crystal structure of chloro-substituted benzoselenazole revealed a planar structure with T-shaped geometry around the Se atom. Both natural bond orbital and atoms in molecules calculations confirmed the presence of secondary Se···H interactions in bis(3-amino-1-hydroxybenzyl)diselenide and Se···O interactions in benzoselenazoles, respectively. The glutathione peroxidase (GPx)-like antioxidant activities of all compounds were evaluated using a thiophenol assay. Bis(3-amino-1-hydroxybenzyl)diselenide and benzoselenazoles showed better GPx-like activity compared to that of the diphenyl diselenide and ebselen, used as references, respectively. Based on 77Se{1H} NMR spectroscopy, a catalytic cycle for bis(3-amino-1-hydroxybenzyl)diselenide using thiophenol and hydrogen peroxide was proposed involving selenol, selenosulfide, and selenenic acid as intermediates. The potency of all GPx mimics was confirmed by their in vitro antibacterial properties against the biofilm formation of Bacillus subtilis and Pseudomonas aeruginosa. Additionally, molecular docking studies were used to evaluate the in silico interactions between the active sites of the TsaA and LasR-based proteins found in Bacillus subtilis and Pseudomonas aeruginosa.

Opportunistic Challenges of Computer-aided Drug Discovery of Lipopeptides: New Insights for Large Molecule Therapeutics.

Computer-aided drug designing is a promising approach to defeating the dry pipeline of drug discovery. It aims at reduced experimental efforts with cost-effectiveness. Naturally occurring large molecules with molecular weight higher than 500 Dalton such as cationic peptides, cyclic peptides, glycopeptides and lipopeptides are a few examples of large molecules which have successful applications as the broad spectrum antibacterial, anticancer, antiviral, antifungal and antithrombotic drugs. Utilization of microbial metabolites as potential drug candidates incur cost effectiveness through large scale production of such molecules rather than a synthetic approach. Computational studies on such compounds generate tremendous possibilities to develop novel leads with challenges to handle these complex molecules with available computational tools. The opportunities begin with the desired structural modifications in the parent drug molecule. Virtual modifications followed by molecular interaction studies at the target site through molecular modeling simulations and identification of structure-activity relationship models to develop more prominent and potential drug molecules. Lead optimization studies to develop novel compounds with increased specificity and reduced off targeting is a big challenge computationally for large molecules. Prediction of optimized pharmacokinetic properties facilitates development of a compound with lower toxicity as compared to the natural compounds. Generating the library of compounds and studies for target specificity and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) for large molecules are laborious and incur huge cost and chemical wastage through in-vitro methods. Hence, computational methods need to be explored to develop novel compounds from natural large molecules with higher specificity. This review article is focusing on possible challenges and opportunities in the pathway of computer-aided drug discovery of large molecule therapeutics.