Loss of fatty acid binding protein 3 ameliorates lipopolysaccharide-induced inflammation and endothelial dysfunction.

Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states.

Biophysical and structural characterization of tetramethrin serum protein complex and its toxicological implications.

Tetramethrin (TMT) is a commonly used insecticide and has a carcinogenic and neurodegenerative effect on humans. The binding mechanism and toxicological implications of TMT to human serum albumin (HSA) were examined in this study employing a combination of biophysical and computational methods indicating moderate binding affinity and potential hepato and renal toxicity. Fluorescence quenching experiments showed that TMT binds to HSA with a moderate affinity, and the binding process was spontaneous and predominantly enthalpy-driven. Circular dichroism spectroscopy revealed that TMT binding did not induce any significant conformational changes in HSA, resulting in no changes in its alpha-helix content. The binding site and modalities of TMT interactions with HSA as computed by molecular docking and molecular dynamics simulations revealed that it binds to Sudlow site II of HSA via hydrophobic interactions through its dimethylcyclopropane carboxylate methyl propanyl group. The structural dynamics of TMT induce proper fit into the binding site creating increased and stabilizing interactions. Additionally, molecular mechanics-Poisson Boltzmann surface area calculations also indicated that non-polar and van der Waals were found to be the major contributors to the high binding free energy of the complex. Quantum mechanics (QM) revealed the conformational energies of the binding confirmation and the degree of deviation from the global minimum energy conformation of TMT. The results of this study provide a comprehensive understanding of the binding mechanism of TMT with HSA, which is important for evaluating the toxicity of this insecticide in humans.

Dual role of an essential HtrA2/Omi protease in the human malaria parasite: Maintenance of mitochondrial homeostasis and induction of apoptosis-like cell death under cellular stress.

Members of the HtrA family of serine proteases are known to play roles in mitochondrial homeostasis as well as in programmed cell death. Mitochondrial homeostasis and metabolism are crucial for the survival and propagation of the malaria parasite within the host. Here we have functionally characterized a Plasmodium falciparum HtrA2 (PfHtrA2) protein, which harbours trypsin-like protease activity that can be inhibited by its specific inhibitor, ucf-101. A transgenic parasite line was generated, using the HA-glmS C-terminal tagging approach, for localization as well as for inducible knock-down of PfHtrA2. The PfHtrA2 was localized in the parasite mitochondrion during the asexual life cycle. Genetic ablation of PfHtrA2 caused significant parasite growth inhibition, decreased replication of mtDNA, increased mitochondrial ROS production, caused mitochondrial fission/fragmentation, and hindered parasite development. However, the ucf-101 treatment did not affect the parasite growth, suggesting the non-protease/chaperone role of PfHtrA2 in the parasite. Under cellular stress conditions, inhibition of PfHtrA2 by ucf-101 reduced activation of the caspase-like protease as well as parasite cell death, suggesting the involvement of protease activity of PfHtrA2 in apoptosis-like cell death in the parasite. Under these cellular stress conditions, the PfHtrA2 gets processed but remains localized in the mitochondrion, suggesting that it acts within the mitochondrion by cleaving intra-mitochondrial substrate(s). This was further supported by trans-expression of PfHtrA2 protease domain in the parasite cytosol, which was unable to induce any cell death in the parasite. Overall, we show the specific roles of PfHtrA2 in maintaining mitochondrial homeostasis as well as in regulating stress-induced cell death.

Biodecolorization and biodegradation of Reactive Green 12 textile industry dye and their post-degradation phytotoxicity-genotoxicity assessments.

The employment of versatile bacterial strains for the efficient degradation of carcinogenic textile dyes is a sustainable technology of bioremediation for a neat, clean, and evergreen globe. The present study has explored the eco-friendly degradation of complex Reactive Green 12 azo dye to its non-toxic metabolites for safe disposal in an open environment. The bacterial degradation was performed with the variable concentrations (50, 100, 200, 400, and 500 mg/L) of Reactive Green 12 dye. The degradation and toxicity of the dye were validated by high-performance liquid chromatography, Fourier infrared spectroscopy analysis, and phytotoxicity and genotoxicity assay, respectively. The highest 97.8% decolorization was achieved within 12 h. Alternations in the peaks and retentions, thus, along with modifications in the functional groups and chemical bonds, confirmed the degradation of Reactive Green 12. The disappearance of a major peak at 1450 cm-1 corresponding to the -N=N- azo link validated the breaking of azo bonds and degradation of the parent dye. The 100% germination of Triticum aestivum seed and healthy growth of plants verified the lost toxicity of degraded dye. Moreover, the chromosomal aberration of Allium cepa root cell treatment also validated the removal of toxicity through bacterial degradation. Thereafter, for efficient degradation of textile dye, the bacterium is recommended for adaptation to the sustainable degradation of dye and wastewater for further application of degraded metabolites in crop irrigation for sustainable agriculture.

In vitro assessment of newer colistin-sparing antimicrobial agents for clinical isolates of carbapenem-resistant organisms.

OBJECTIVES: Carbapenem-resistant organisms (CROs) are a significant public health threat globally, particularly in countries like India with high antibiotic resistance rates. The current study investigates the prevalence of CROs, detects resistance mechanisms using phenotypic methods and assesses the efficacy of newer antibiotics against CROs. METHODS: A prospective study conducted at a tertiary care hospital in India during 2021-23. Clinical specimens were processed and bacterial identification was performed using MALDI-TOF mass spectrometry followed by antimicrobial susceptibility testing using CLSI guidelines against a plethora of newer antibiotics for CROs. Carbapenemase production was detected using phenotypic methods, and the presence of the mcr-1 gene was assessed by real-time PCR. RESULTS: During the study period, predominantly (70 %) Gram-negative bacteria were isolated; amongst which 5692 strains were carbapenem-resistant, wherein resistance to different carbapenems ranged from 34.1% to 79 %. Majority of the carbapenemase producers were metallo-ß-lactamases (MBL) producers (75 %). Colistin resistance was noted in 5.4 % of selected carbapenem-resistant isolates. Among newer antibiotics, cefiderocol demonstrated the lowest resistance rates (0-14 %), while resistance to newer ß-lactam/ß-lactamase inhibitor combinations was very high in carbapenem-resistant isolates. Fosfomycin, minocycline and tigecycline, each showing variable efficacy depending on the site of infection. Moreover, newer ß-lactam/ß-lactamase inhibitor combinations offer restricted benefits due to widespread prevalence of MBL in the region. CONCLUSION: The escalating prevalence of CROs in India underscores the urgency for alternative treatment options beyond colistin. Hence, highlighting the critical importance of developing effective strategies to combat carbapenem resistance.

Perspectives on life cycle analysis of solar technologies with emphasis on production in India.

The COVID-19 pandemic impacted the solar power industry, business, and supply chain for 2019-2021, and installations are falling behind the mission plan. However, Indian PV manufacturers see it as a chance to engage in solar manufacturing to establish a competitive, sustainable, and robust domestic solar industry instead of import-based installations. Given the country's current environmental concerns, green and sustainable local manufacturing is the only viable alternative. By conducting a life cycle assessment (LCA), this study compared the environmental impacts generated by the five most promising photovoltaic technologies-mono-silicon, polysilicon, copper indium gallium selenide (CIGS), cadmium telluride (CdTe), and passivated emitter and rear contact (PERC) solar modules considering manufacturing in India. The study utilizes the ReCiPe method supported by Ecoinvent 3 databases and Simapro V9.0 software, and the functional unit for the data collection is in 'per square meter', which is later converted to 'per kWh' standard for comparison with the existing studies. The system boundary selected is from cradle to gate. The results demonstrate that cadmium telluride (CdTe) is the best technology for Indian climatic conditions in terms of environmental impact, with a global warming potential of 0.015 kg CO2 eq/kWh, stratospheric ozone depletion of 5.41E-09 kg CFC11 eq/kWh, human carcinogenic and non-carcinogenic toxicity of 6.67E-04 kg 1,4-DCB/kWh and 1.48E-02 kg 1,4-DCB/kWh, respectively and fine particulate matter formation of 3.96E-05 kg PM 2.5 eq/kWh assuming a lifetime of 25 years for these modules. CIGS follows CdTe in almost every environmental impact category.

A biogenic hydrogel to recover Au(III) from electronic waste.

In the course of this investigation, we undertook the contemplation of a green chemistry paradigm with the express intent of procuring valuable metal, namely gold, from electronic waste (e-waste). In pursuit of this overarching objective, we conceived a procedural framework consisting of two pivotal stages. As an initial stage, we introduced a physical separation procedure relying on the utilization of the Eddy current separator, prior to embarking on the process of leaching from e-waste. Subsequent to the partitioning of metals from the non-metal constituents of waste printed circuit boards (PCB), we initiated an investigation into the hydrogel derived from basil seeds (Ocimum basilicum L.), utilizing it as a biogenic sorbent medium. The thorough characterization of hydrogel extracted from basil seeds involved the application of an array of analytical techniques, encompassing FTIR, XRD, SEM, and BET. The batch sorption experiments show more than 90% uptake in the pH range of 2-5. The sorption capacity of the hydrogel material was evaluated as 188.44 mg g-1 from the Langmuir Isotherm model. The potential interference stemming from a spectrum of other ions, encompassing Al, Cu, Ni, Zn, Co, Cr, Fe, Mn, and Pb was systematically examined. Notably, the sole instance of interference in the context of adsorption of gold ions was observed to be associated with the presence of lead. The application of the hydrogel demonstrated a commendable efficiency in the recovery of Au(III) from the leached solution derived from the waste PCB.

Media component bovine serum albumin facilitates the formation of mycobacterial biofilms in response to reductive stress.

BACKGROUND: Mycobacterium tuberculosis (Mtb) forms physiologically relevant biofilms harboring drug-tolerant bacteria. This observation has brought the study of mycobacterial biofilms to the forefront of tuberculosis research. We established earlier that dithiothreitol (DTT) mediated reductive stress induces cellulose-rich biofilm formation in Mtb cultures. The molecular events associated with the DTT-induced biofilm formation are not known. Furthermore, there are only limited tools for monitoring the presence of cellulose in biofilms. RESULTS: To decipher the molecular events associated with DTT-induced biofilm formation, we used Mtb and non-pathogenic, fast-growing Mycobacterium smegmatis (Msm). We observed that DTT induces biofilm formation in Msm cultures. We explored whether media components facilitate biofilm formation in mycobacteria upon exposure to DTT. We observed that media component bovine serum albumin promotes mycobacterial biofilm formation in response to DTT. Furthermore, we analyzed the composition of extracellular polymeric substances of Msm biofilms. We found that, like Mtb biofilms, Msm biofilms are also rich in polysaccharides and proteins. We also developed a novel protein-based molecular probe for imaging cellulose by utilizing the cellulose-binding domain of cellulase CenA from Cellulomonas fimi and fusing it to fluorescent reporter mCherry. Characterization of this new probe revealed that it has a high affinity for cellulose and could be used for visualizing cellulose biosynthesis during the development of Agrobacterium biofilms. Furthermore, we have demonstrated that biological macromolecule cellulose is present in the extracellular polymeric substances of Msm biofilms using this novel probe. CONCLUSIONS: This study indicates that DTT-mediated reduction of media component BSA leads to the formation of nucleating foci. These nucleating foci are critical for subsequent attachment of bacterial cells and induction of EPS production. Furthermore, this new tool, IMT-CBD-mC, could be used for monitoring cellulose incorporation in plant cells, understanding cellulose biosynthesis dynamics during biofilm formation, etc.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

BACKGROUND: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. METHODS: It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. RESULTS: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Whole and cortical kidney volume predict 5-year post-nephrectomy eGFR in Indian living kidney donors.

AIM: To study the additional utility of pre-nephrectomy whole and cortical kidney volumes (WKV, CKV) in predicting long-term post-nephrectomy kidney function in Indian living kidney donors (LKDs). METHODS: This retrospective cohort study included all LKDs who underwent nephrectomy between 1 January 2006 and 31 December 2015 at our centre, had pre-nephrectomy height, weight and computed tomography (CT) angiography with arterial and nephrographic phase documented, and 5-year post-nephrectomy creatinine values measured. Correlation between body surface area (BSA) adjusted pre-nephrectomy total CKV, WKV and pre-nephrectomy CKD EPI eGFR; BSA-adjusted remnant pre-nephrectomy CKV (rCKV), WKV (rWKV) and 5-year post-nephrectomy CKD EPI creatinine eGFR (5yeGFRCr ); predictors of 5yeGFRCr < 70% of pre-nephrectomy CKD EPI creatinine eGFR (pre-eGFRCr ), and an equation to predict 5yeGFRCr from pre-nephrectomy variables were calculated. RESULTS: A total of 196 LKDs (74% female, mean age 41.7 ± 11.0 years) were included in the study. Total WKV showed higher correlation with pre-nephrectomy eGFR than CKV, the highest with CKD EPI cystatin eGFR. Remnant WKV showed higher correlation than rCKV with post-nephrectomy eGFRCr and this increased over time. Older age, lower rWKV or rCKV, higher BSA, and higher pre-eGFRCr identified LKDs with 5yeGFRCr < 70% of pre-eGFRCr , with rCKV identifying a higher proportion (4.5%) of such LKDs. A model including rWKV or rCKV predicted 5yeGFRCr better than one including age, gender, BSA and pre-eGFRCr alone. CONCLUSION: Inclusion of pre-nephrectomy remnant CKV and WKV into models for 5yeGFRCr and sub-optimal post-nephrectomy adaptation in Indian LKDs improves their accuracy. CKD EPI cystatin eGFR correlates better with functional renal mass.

Homeopathy as an Adjuvant to Standard Care in Moderate and Severe Cases of COVID-19: A Single-Blind, Randomized, Placebo-Controlled Study.

OBJECTIVES: This study aimed to evaluate whether individualized homeopathic medicines have a greater adjunctive effect than adjunctive placebos in the treatment of moderate and severe cases of coronavirus disease 2019 (COVID-19). METHODS: The study was a randomized, single-blind, prospective, placebo-controlled clinical trial set in the clinical context of standard care. INTERVENTION: Patients of either sex, admitted in a tertiary care hospital, suffering from moderate or severe COVID-19 and above 18 years of age were included. In total, 150 patients were recruited and then randomly divided into two groups to receive either individualized homeopathic medicines or placebos, in addition to the standard treatment of COVID-19. OUTCOME MEASURES: The primary outcome was time taken to achieve RT-PCR-confirmed virus clearance for COVID-19. Secondary outcomes were changes in the Clinical Ordinal Outcomes Scale (COOS) of the World Health Organization, the patient-reported MYMOP2 scale, and several biochemical parameters. Parametric data were analyzed using unpaired t-test. Non-parametric data were analyzed using the Wilcoxon signed rank test. Categorical data were analyzed using Chi-square test. RESULTS: In total, 72 participants of the add-on homeopathy (AoH) group showed conversion of RT-PCR status to negative, in an average time of 7.53 ± 4.76 days (mean ± SD), as compared with 11.65 ± 9.54 days in the add-on placebo (AoP) group (p = 0.001). The mean COOS score decreased from 4.26 ± 0.44 to 3.64 ± 1.50 and from 4.3 ± 0.46 to 4.07 ± 1.8 in the AoH and AoP groups respectively (p = 0.130). The mortality rate for the AoH group was 9.7% compared with 17.3% in the AoP group. The MYMOP2 scores between the two groups differed significantly (p = 0.001), in favor of AoH. Inter-group differences in the pre- and post- mean values of C-reactive protein, fibrinogen, total leukocyte count, platelet count and alkaline phosphatase were each found to be statistically significant (p <0.05), favoring AoH; six other biochemical parameters showed no statistically significant differences. CONCLUSION: The study suggests homeopathy may be an effective adjunct to standard care for treating moderate and severe COVID-19 patients. More rigorous, including double-blinded, studies should be performed to confirm or refute these initial findings.

Thermodynamic and structural profiles of multi-target binding of vinblastine in solution.

Structural information about drug-receptor interactions is paramount in drug discovery and subsequent optimization processes. Drugs can bind to multiple potential targets as they contain common chemical entities in their structures. Understanding the details of such interactions offer possibilities for repurposing and developing potent inhibitors of disease pathways. Vinblastine (VLB) is a potent anticancer molecule showing multiple receptor interactions with different affinities and degrees of structural perturbations. We have investigated the multi-target binding profile of VLB with DNA and human serum albumin (HSA) in a dynamic physiological environment using spectroscopic, molecular dynamics simulations, and quantum mechanical calculations to evaluate the structural features, mode, ligand and receptor flexibility, and energetics of complexation. These results confirm that VLB prefers to bind in the major groove of DNA with some inclination toward Thymidine residue and the TR-5 binding site in HSA with its catharanthine half making important contacts with both the receptors. Spectroscopic investigation at multiple temperatures has also proved that VLB binding is entropy driven indicating the major groove and TR-5 binding site of interaction. Finally, the overall binding is facilitated by van der Waals contacts and a few conventional H-bonds. VLB portrays reasonable conformational diversity on binding with multiple receptors.

Monogalactosyl diacylglycerol synthase 3 affects phosphate utilization and acquisition in rice.

Galactolipids are essential to compensate for the loss of phospholipids by 'membrane lipid remodelling' in plants under phosphorus (P) deficiency conditions. Monogalactosyl diacylglycerol (MGDG) synthases catalyse the synthesis of MGDG which is further converted into digalactosyl diacylglycerol (DGDG), later replacing phospholipids in the extraplastidial membranes. However, the roles of these enzymes are not well explored in rice. In this study, the rice MGDG synthase 3 gene (OsMGD3) was identified and functionally characterized. We showed that the plant phosphate (Pi) status and the transcription factor PHOSPHATE STARVATION RESPONSE 2 (OsPHR2) are involved in the transcriptional regulation of OsMGD3. CRISPR/Cas9 knockout and overexpression lines of OsMGD3 were generated to explore its potential role in rice adaptation to Pi deficiency. Compared with the wild type, OsMGD3 knockout lines displayed a reduced Pi acquisition and utilization while overexpression lines showed an enhancement of the same. Further, OsMGD3 showed a predominant role in roots, altering lateral root growth. Our comprehensive lipidomic analysis revealed a role of OsMGD3 in membrane lipid remodelling, in addition to a role in regulating diacylglycerol and phosphatidic acid contents that affected the expression of Pi transporters. Our study highlights the role of OsMGD3 in affecting both internal P utilization and P acquisition in rice.

Unique roles of aminophospholipid translocase Drs2p in governing efflux pump activity, ergosterol level, virulence traits, and host-pathogen interaction in Candida albicans.

Infections caused by Candida albicans are rising due to increment in drug resistance and a limited arsenal of conventional antifungal drugs. Thus, elucidating the novel antifungal targets still represent an alternative that could overcome the problem of multidrug resistance (MDR). In this study, we have uncovered the distinctive effect of aminophospholipid translocase (Drs2p) deletion on major MDR mechanisms of C. albicans. We determined that efflux activity was diminished in Δdrs2 mutant as revealed by extracellular rhodamine 6G (R6G) efflux and flow cytometry. Moreover, we further unveiled that Δdrs2 mutant displayed decreased ergosterol content and increased membrane fluidity. Furthermore, Drs2p deletion affects the virulence attributes and led to inhibited hyphal growth and reduced biofilm formation. Additionally, THP-1 cell lines' mediated host-pathogen interaction studies revealed that Δdrs2 mutant displayed enhanced phagocytosis and altered cytokine production leading to increased IL-6 and decreased IL-10 production. Taken together, the present study demonstrates the relevance of Drs2p in C. albicans and consequently disrupting pathways known for mediating drug resistance and immune recognition. Comprehensive studies are further required to authenticate Drs2p as a novel antifungal drug target.

Safety and feasibility of immediate tracheal extubation of small pediatric patients after living donor liver transplantation.

BACKGROUND: Immediate extubation is integral constituent of enhance recovery protocols. Purpose of this study was to examine success rates and safety of protocolized immediate extubation in pediatric living donor liver transplant recipients and to find out factors associated with non-immediate extubation in operation room. METHODS: We performed retrospective analysis for data of small (≤20 kg) pediatric patients transplanted between 2017 and 2019 (protocolized duration) and compared with data of transplants done between 2014 and 2016 (non-protocolized duration). Further, we compared data during each time duration between immediate extubation and non-immediate extubation group to find risk factors in that particular duration. RESULTS: Immediate extubation rates were significantly higher during protocolized duration compared with non-protocolized duration (85.52% vs. 48.29%, p < .001). Reintubation rates decreased during protocolized duration (10.9% vs. 4.6%). Hospital stays (20.47 ± 7.06 vs. 27.8 ± 6.2 days, p < .001) and mortality (13.2% vs. 28%, p = .04) were significantly decreased in protocolized duration. Higher age (OR: 2.85, 95% CI 1.22-6.67, p = .02), weight > 10 (OR: 4.37, 95% CI 1.16-16.46, p = .029) and high vasopressor support (OR: 32, 95% CI 6.4-160.13, p < .001) found as significant predictors of non-immediate extubation however only high vasopressor support found to be independent predictor during protocolized duration. CONCLUSIONS: Outcomes in pediatric transplants can be optimized by immediate extubation in majority of cases when protocolized as part of policy.

Moesin, an Ezrin/Radixin/Moesin Family Member, Regulates Hepatic Fibrosis.

BACKGROUND AND AIMS: Moesin, an ezrin/radixin/moesin family member, is involved in the regulation of cell adhesion, polarity, and migration by cross-linking between the actin cytoskeleton and plasma membrane. The primary effector cell in hepatic fibrosis is the hepatic stellate cell (HSC), which undergoes activation during liver injury leading to increased extracellular matrix production. APPROACH AND RESULTS: Here, we have hypothesized that moesin plays a critical role in linking the HSC cytoskeleton to the fibrogenic cascade during HSC activation. Moesin phosphorylation was up-regulated during HSC activation and fibrogenesis. Using moesin wild-type (WT) and mutant constructs (phosphomimicking T558D and nonphosphorylatable T558A), we found that cellular motility and contraction were increased in moesin WT-infected and T558D-infected cells, paralleled by an increase in smooth muscle α-actin and collagen 1 expression. In contrast, overexpression of nonphosphorylatable moesin and moesin knockout (KO) decreased cellular motility and contraction. Most importantly, moesin KO led to abrogation of liver fibrosis. The mechanism of moesin's effect was a reduction in myocardin-related transcription factor-A and serum-response factor (SRF)-mediated changes in the actin cytoskeleton, which in turn modulated the expression of matrix genes. CONCLUSIONS: Taken together, our findings suggest that the linkage between cytoskeletal dynamics and the correlated MRTF/SRF signaling pathway has a pivotal role in HSC activation and fibrogenesis.

Duration and determinants of delayed tuberculosis diagnosis and treatment in high-burden countries: a mixed-methods systematic review and meta-analysis.

BACKGROUND: Thirty countries with the highest tuberculosis (TB) burden bear 87% of the world's TB cases. Delayed diagnosis and treatment are detrimental to TB prognosis and sustain TB transmission in the community, making TB elimination a great challenge, especially in these countries. Our objective was to elucidate the duration and determinants of delayed diagnosis and treatment of pulmonary TB in high TB-burden countries. METHODS: We conducted a systematic review and meta-analysis of quantitative and qualitative studies by searching four databases for literature published between 2008 and 2018 following PRISMA guidelines. We performed a narrative synthesis of the covariates significantly associated with patient, health system, treatment, and total delays. The pooled median duration of delay and effect sizes of covariates were estimated using random-effects meta-analyses. We identified key qualitative themes using thematic analysis. RESULTS: This review included 124 articles from 14 low- and lower-middle-income countries (LIC and LMIC) and five upper-middle-income countries (UMIC). The pooled median duration of delays (in days) were-patient delay (LIC/LMIC: 28 (95% CI 20-30); UMIC: 10 (95% CI 10-20), health system delay (LIC/LMIC: 14 (95% CI 2-28); UMIC: 4 (95% CI 2-4), and treatment delay (LIC/LMIC: 14 (95% CI 3-84); UMIC: 0 (95% CI 0-1). There was consistent evidence that being female and rural residence was associated with longer patient delay. Patient delay was also associated with other individual, interpersonal, and community risk factors such as poor TB knowledge, long chains of care-seeking through private/multiple providers, perceived stigma, financial insecurities, and poor access to healthcare. Organizational and policy factors mediated health system and treatment delays. These factors included the lack of resources and complex administrative procedures and systems at the health facilities. We identified data gaps in 11 high-burden countries. CONCLUSIONS: This review presented the duration of delays and detailed the determinants of delayed TB diagnosis and treatment in high-burden countries. The gaps identified could be addressed through tailored approaches, education, and at a higher level, through health system strengthening and provision of universal health coverage to reduce delays and improve access to TB diagnosis and care. PROSPERO registration: CRD42018107237.

Living Donor Liver Transplant in patients with Hepatorenal Syndrome without the use of Intraoperative Renal Replacement Therapy, a single-center experience.

BACKGROUND: Continuous Renal Replacement Therapy (CRRT) is often used to support the intraoperative course during liver transplantation (LT) for patients with HRS. However, the use of intraoperative CRRT (IOCRRT) is not without its problems. Living donor liver transplantation (LDLT) is a planned operation and is possible without IOCRRT as the recipient can be optimized. AIM: To study the peritransplant outcomes of patients with CLD and HRS undergoing LT without IOCRRT. METHODS: Analysis of LT program database for perioperative outcomes in patients with HRS from Feb 2017 to Dec 2018. RESULTS: 87/363 (23.9%) adult LDLT patients had HRS, of whom 31 (35.6%) did not respond (NR) to standard medical therapy (SMT) prior to LT. Modified perioperative protocol enabled the NR patients (who were sicker and in persistent renal failure) to undergo LT without IOCRRT. Postoperative renal dysfunction was similar (2 in NR and 2 in R) at 1 year. Post-LT survival was also not different at one month (83.87% in NR and 87.5% in R [p = .640]) and at 1 year (77% in NR vs 80.4% in non-responders [p = .709]). CONCLUSION: IOCRRT can be avoided in HRS patients undergoing LDLT without compromising their outcomes (post-LT survival and RD), even in patients who have not responded to SMT, preoperatively.

Stitching Ynones with Nitromethanes: Domino Synthesis of Functionally Enriched Benzofurans and Benzothiophenes.

A convenient one-pot benzannulation of regioisomeric 2- or 3-substituted furan and thiophene ynones with a range of nitromethanes has been discovered to directly access densely and diversely functionalized benzofurans and benzothiophenes. In this protocol, the nitro group in nitromethanes functions as recursive carbanion activator to setup tandem Michael addition-6π-electrocyclization, and its eventual sacrificial elimination facilitates aromatization and overall benzannulation. This benzannulation was also explored with furan/thiophene based o-halo ynones wherein a Michael addition-SNAr process operates and nitromethanes leave their imprint to deliver nitro substituted benzo-furans and -thiophenes.

Diversification of α-ketoamides via transamidation reactions with alkyl and benzyl amines at room temperature.

A wide range of N-tosyl α-ketoamides underwent transamidation with various alkyl amines in the absence of a catalyst, base, or additive. On the other hand, transamidation in N-Boc α-ketoamides was achieved in the presence of Cs2CO3. The reactions proceeded at room temperature and provided good to excellent yields of transamidation products under the optimized conditions. Broad substrate scope, functional group tolerance and quick conversions are the important features of the developed methodology.