Serine hydroxymethyltransferase6 is involved in growth and resistance against pathogens via ethylene and lignin production in Arabidopsis.

Photorespiratory serine hydroxymethyltransferases (SHMTs) are important enzymes of cellular one-carbon metabolism. In this study, we investigated the potential role of SHMT6 in Arabidopsis thaliana. We found that SHMT6 is localized in the nucleus and expressed in different tissues during development. Interestingly SHMT6 is inducible in response to avirulent, virulent Pseudomonas syringae and to Fusarium oxysporum infection. Overexpression of SHMT6 leads to larger flowers, siliques, seeds, roots, and consequently an enhanced overall biomass. This enhanced growth was accompanied by increased stomatal conductance and photosynthetic capacity as well as ATP, protein, and chlorophyll levels. By contrast, a shmt6 knockout mutant displayed reduced growth. When challenged with Pseudomonas syringae pv tomato (Pst) DC3000 expressing AvrRpm1, SHMT6 overexpression lines displayed a clear hypersensitive response which was characterized by enhanced electrolyte leakage and reduced bacterial growth. In response to virulent Pst DC3000, the shmt6 mutant developed severe disease symptoms and becomes very susceptible, whereas SHMT6 overexpression lines showed enhanced resistance with increased expression of defense pathway associated genes. In response to Fusarium oxysporum, overexpression lines showed a reduction in symptoms. Moreover, SHMT6 overexpression lead to enhanced production of ethylene and lignin, which are important components of the defense response. Collectively, our data revealed that SHMT6 plays an important role in development and defense against pathogens.

Improving Access to Eye Care in Rural Communities: PocDoc's Web-Based Visual Acuity Screening Tool.

Objective: Visual acuity (VA) testing is crucial for early intervention in cases of visual impairment, especially in rural health care. This study aimed to determine the potential of a web-based VA test (PocDoc) in addressing the unique health care needs of rural areas through the comparison in its effectiveness against the conventional VA test in identifying visual impairment among an Indian rural population. Methods: Prospective comparative study conducted in December 2022 at a tertiary referral eye care center in central India. We evaluated all patients with the PocDoc VA tests using three device types, and the conventional VA test. Bland-Altman plot (BAP) compared PocDoc and conventional VA tests. Fisher's exact tests evaluated associations between categorical parameters. Kruskal-Wallis tests followed by post hoc Dunn's tests identified association between categorical parameters and numerical parameters. Results: We evaluated 428 patients (792 measurements of VA) with mean age 36.7 (±23.3) years. PocDoc resulted in slightly worse VA scores (mean logMAR: 0.345) than conventional (mean logMAR: 0.315). Correlation coefficient between the conventional and PocDoc logMAR VA values was rho = 0.845 and rho2 = 0.7133 (p = 6.617 × 10-215; adjusted p = 2.205 × 10-214). Most data points fell within the interchangeable range of ±0.32 on BAP. Difference between the two methods increased with higher logMAR values, indicating poorer agreement for worse VA scores. Conclusions: Identifying and addressing the unique health care needs of rural populations is critical, including access to appropriate and effective VA testing methods. Validating and improving VA testing methods can ensure early intervention and improve the quality of life for individuals with visual impairment.

Dissection of QTLs conferring drought tolerance in B. carinata derived B. juncea introgression lines.

BACKGROUND: Drought is one of the important abiotic stresses that can significantly reduce crop yields. In India, about 24% of Brassica juncea (Indian mustard) cultivation is taken up under rainfed conditions, leading to low yields due to moisture deficit stress. Hence, there is an urgent need to improve the productivity of mustard under drought conditions. In the present study, a set of 87 B. carinata-derived B. juncea introgression lines (ILs) was developed with the goal of creating drought-tolerant genotypes. METHOD: The experiment followed the augmented randomized complete block design with four blocks and three checks. ILs were evaluated for seed yield and its contributing traits under both rainfed and irrigated conditions in three different environments created by manipulating locations and years. To identify novel genes and alleles imparting drought tolerance, Quantitative Trait Loci (QTL) analysis was carried out. Genotyping-by-Sequencing (GBS) approach was used to construct the linkage map. RESULTS: The linkage map consisted of 5,165 SNP markers distributed across 18 chromosomes and spanning a distance of 1,671.87 cM. On average, there was a 3.09 cM gap between adjoining markers. A total of 29 additive QTLs were identified for drought tolerance; among these, 17 (58.6% of total QTLs detected) were contributed by B. carinata (BC 4), suggesting a greater contribution of B. carinata towards improving drought tolerance in the ILs. Out of 17 QTLs, 11 (64.7%) were located on the B genome, indicating more introgression segments on the B genome of B. juncea. Eight QTL hotspots, containing two or more QTLs, governing seed yield contributing traits, water use efficiency, and drought tolerance under moisture deficit stress conditions were identified. Seventeen candidate genes related to biotic and abiotic stresses, viz., SOS2, SOS2 like, NPR1, FAE1-KCS, HOT5, DNAJA1, NIA1, BRI1, RF21, ycf2, WRKY33, PAL, SAMS2, orf147, MAPK3, WRR1 and SUS, were reported in the genomic regions of identified QTLs. CONCLUSIONS: The significance of B. carinata in improving drought tolerance and WUE by introducing genomic segments in Indian mustard is well demonstrated. The findings also provide valuable insights into the genetic basis of drought tolerance in mustard and pave the way for the development of drought-tolerant varieties.

Comparative transcriptomic and metabolite profiling reveals genotype-specific responses to Fe starvation in chickpea.

Iron deficiency is a major nutritional stress that severely impacts crop productivity worldwide. However, molecular intricacies and subsequent physiological and metabolic changes in response to Fe starvation, especially in leguminous crops like chickpea, remain elusive. In the present study, we investigated physiological, transcriptional, and metabolic reprogramming in two chickpea genotypes (H6013 and L4958) with contrasting seed iron concentrations upon Fe deficiency. Our findings revealed that iron starvation affected growth and physiological parameters of both chickpea genotypes. Comparative transcriptome analysis led to the identification of differentially expressed genes between the genotypes related to strategy I uptake, metal ions transporters, reactive oxygen species-associated genes, transcription factors, and protein kinases that could mitigate Fe deficiency. Our gene correlation network discovered several putative candidate genes like CIPK25, CKX3, WRKY50, NAC29, MYB4, and PAP18, which could facilitate the investigation of the molecular rationale underlying Fe tolerance in chickpea. Furthermore, the metabolite analysis also illustrated the differential accumulation of organic acids, amino acids and other metabolites associated with Fe mobilization in chickpea genotypes. Overall, our study demonstrated the comparative transcriptional dynamics upon Fe starvation. The outcomes of the current endeavor will enable the development of Fe deficiency tolerant chickpea cultivars.

Raman Evidence of Multiple Adsorption Sites and Structural Transformation in ZIF-4.

The zeolitic imidazolate framework, ZIF-4, exhibits soft porosity and is known to show pore volume changes with temperatures, pressures, and guest adsorption. However, the mechanism and adsorption behavior of ZIF-4 are not completely understood. In this work, we report an open to narrow pore transition in ZIF-4 around T ∼ 253 K upon lowering the temperature under vacuum (10-6 Torr) conditions, facilitated by C-H···π interactions. In the gaseous environment of N2 and CO2 around the framework, characteristic Raman peaks of adsorbed gases were observed under ambient conditions of 293 K and 1 atm. A guest-induced transition at ∼153 K resulting in the opening of new adsorption sites was inferred from the Raman spectral changes in the C-H stretching modes and low-frequency modes (<200 cm-1). In contrast to a single vibrational mode generally reported for entrapped N2, we show three Raman modes of adsorbed N2 in ZIF-4. The adsorption is facilitated by dispersive and quadrupolar interactions. From our temperature-dependent Raman results and theoretical analysis based on the density functional tight-binding approach, we conclude that the C-Hs are the preferred adsorption sites on ZIF-4 in the following order: C4-H, C5-H > C2-H > center of the Im ring (interacting with C-H centers) > center of the cavity. We also show that with an increasing concentration of N2 adsorbed at low temperatures, the ZIF-4 structure undergoes shear distortion of the window formed by 4-imidazole rings and consequent volumetric expansion. Our results have immediate implications in the field of porous materials and could be vital in identifying subtle structural transformations that may favor or hinder guest adsorption.

Identification of potential andrographolide-based drug candidate against Keap1-Nrf2 pathway through rigorous cheminformatics screening.

The Keap1-Nrf2 [Kelch-like ECH-associated protein-1-Nuclear factor erythroid-2-related factor-2] regulatory pathway plays a vital role in the protection of cells by regulating transcription of antioxidant and detoxification genes. Andrographolide (AGP) regulates the Keap1-Nrf2 pathway by inhibiting the Keap1 protein. To identify a more potent AGP analog as a therapeutic agent against Keap1 protein, in this work, cheminformatics analysis of 237 AGP analogs was carried out. Amongst these, five AGP analogs were screened through virtual screening followed by their molecular docking analysis against Keap1 protein, which revealed greater binding affinities (binding energy = - 4.15 to - 5.59 kcal/mol) for the shortlisted AGP analogs compared to AGP (binding energy = - 4.02 kcal/mol). Pharmacophore mapping indicated 14 spatial features, including 3 hydrogen bond acceptors and 11 hydrophobic, while ADME analysis established the potential of all five analogs as orally-active drug-like candidates based on Lipinski's rule of five. We also examined the chemical reactivity of AGP and the shortlisted AGP analogs using DFT analysis, which revealed that except for one analog (AGP_A2) all are more chemically reactive than AGP. Further, molecular dynamics simulation analysis and MM/GBSA evidenced that AGP_A1 (PubchemID-123361152), AGP_A3 (PubchemID-58209855) and AGP_A4 (PubchemID-101362374) are the best drug like candidates compared to AGP and have greater potential to activate the Keap1-Nrf2 pathway by inhibiting the Keap1 protein.

Vitamin B12 and folic acid alleviate symptoms of nutritional deficiency by antagonizing aryl hydrocarbon receptor.

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.

Impact of maternal body mass index on the accuracy of third trimester sonographic estimation of fetal weight.

OBJECTIVES: To Determine whether maternal body mass index (BMI) can affect the accuracy of sonographic estimation of fetal weight (EFW) in the third trimester when compared to neonatal birthweight (BW). METHODS: Secondary analysis from our original prospective cohort of pregnant women beyond 34 weeks, distributed in 4 groups according to their BMI: normal, overweight, obese and morbid obese. Fetal biometry and fluid measurements were obtained by two experienced sonographers, blinded for patient's clinical information and to each other's measurements. Average EFW and neonatal BW were converted into gestational-specific Z-scores. Interobserver correlation coefficient (ICC) and Cronbach's reliability coefficient (CRC) were calculated. Bland-Altman (BA) plots were constructed to assess the level of accuracy. RESULTS: 100 women were enrolled (800 measurements obtained by 17 sonographers): 17 had normal BMI (17%), 27 were overweight (27%), 29 were obese (29%) and 27 were morbidly obese (27%). There was no statistical difference for GA at delivery (p = 0.74), EFW (p = 0.05) or BW (p = 0.09) between groups (Table 1). Mean Z-score for EFW was - 0.17 (SD 0.81) and for neonatal BW was - 0.25 (SD 0.74). ICC was 0.69 (95% CI 0.57, 0.78) and CRC was 0.82. Mean Z-score difference was small (Table 2). When stratifying according to BMI categories, the ICC ranged from 0.49 to 0.76. Reliability indices ranged from 0.66 to 0.86. The Z-scores' differences were overall small with no statistical difference (Table 3). BA showed evenly distributed interobserver differences (Fig. 1). CONCLUSIONS: When performed by trained sonographers, fetal weight estimation in the third trimester is accurate when compared to neonatal birthweight at increasing BMI categories.

Natural history, spectrum and outcome of stage 3 AKI in patients with acute-on-chronic liver failure.

BACKGROUND AND AIM: There is limited data on natural course and interventions in stage-3 acute kidney injury (AKI-3) in patients with acute-on-chronic liver failure (ACLF). We studied the factors of AKI-3 reversal and outcomes of dialysis in ACLF patients. METHODS: Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed. RESULTS: At 1 month, 337 (33%) patients had AKI-3, of which, 131 had AKI-3 at enrolment and 206 developed AKI-3 during hospital stay. Of patients with AKI-3 at enrolment, 18% showed terlipressin response, 21% had AKI resolution and 59% required dialysis. High MELD (≥35) (model 1), serum bilirubin (≥23 mg/dL) (model 2) and AARC score (≥11) (model 3) were independent risk factors for dialysis. Dialysis was associated with worse survival in all AKI patients but improved outcomes in patients with AKI-3 (p = .022, HR 0.69 [0.50-0.95]). Post-mortem kidney biopsies (n = 61) revealed cholemic nephropathy (CN) in 54%, acute tubular necrosis (ATN) in 31%, and a combination (CN and ATN) in 15%. Serum bilirubin was significantly higher in patients with CN, CN and ATN compared with ATN respectively ([30.8 ± 12.2] vs. [26.7 ± 12.0] vs. [18.5 ± 9.8]; p = .002). CONCLUSION: AKI-3 rapidly increases from 13% to 33% within 30 days in ACLF patients. Histopathological data suggested cholemic nephropathy as the predominant cause which correlated with high bilirubin levels. AKI-3 resolves in only one in five patients. Patients with AARC grade 3 and MELD >35 demand need for early dialysis in AKI-3 for improved outcomes.

Identification and analysis of miRNAs-lncRNAs-mRNAs modules involved in stem-elongation of deepwater rice (Oryza sativa L.).

Deepwater is an abiotic stress that limits rice cultivation worldwide due to recurrent floods. The miRNAs and lncRNAs are two non-coding RNAs emerging as major regulators of gene expressions under different abiotic stresses. However, the regulation of these two non-coding RNAs under deepwater stress in rice is still unexplored. In this study, small RNA-seq and RNA-seq from internode and node tissues were analyzed to predict deepwater stress responsive miRNAs and lncRNAs, respectively. Additionally, a competitive endogenous RNA (ceRNA) study revealed about 69 and 25 lncRNAs acting as endogenous target mimics (eTM) with the internode and node miRNAs, respectively. In ceRNA analyses, some of the key miRNAs such as miR1850.1, miR1848, and IN-nov-miR145 were upregulated while miR159e was downregulated, and their respective eTM lncRNAs and targets were found to have opposite expressions. Moreover, we have transiently expressed one module (IN-nov-miR145-Cc-TCONS_00011544-Os11g36430.3) in tobacco leaves. The integrated analysis has identified differentially expressed (DE) miRNAs, lncRNAs and their target genes, and the complex regulatory network, which might lead to stem elongation under deepwater stress. In this novel attempt to identify and characterize miRNAs and lncRNAs under deepwater stress in rice, we have provided, probably for the first time, a reference platform to study the interactions of these two non-coding RNAs with respective target genes through transient expression analyses.

Bioconjugate-loaded solid lipid nanoparticles for enhanced anticancer drug delivery to brain cancer cells: An in vitro evaluation.

Background & objectives: The treatment of brain cancer is still challenging for an oncologist due to the presence of the blood-brain barrier (BBB) which inhibits the entry of more than 98 per cent of drugs used during the treatment of brain disease. The cytotoxic drugs used in chemotherapy for brain cancer treatment also affect the normal cells due to lack of targeting. Therefore, the objective of the study was to develop tween 80-coated solid lipid nanoparticles (SLNs) loaded with folic acid-doxorubicin (FAD) conjugate for site-specific drug delivery to brain cancer cells. Methods: The FAD conjugate was synthesized by the conjugation of folic acid with doxorubicin and characterized by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. SLNs loaded with FAD were prepared by the solvent injection method. The SLNs were characterized by the particle size, zeta potential, surface morphology, entrapment efficiency, etc. Results: The average particle size of FAD conjugate-loaded SLNs (SLN-C) was found to be 220.4±2.2 nm, with 36.2±0.6 per cent entrapment efficiency. The cytotoxicity and cellular uptake were determined on U87 MG cell lines. Half maximal inhibitory concentration value of the SLN-C was found to be 2.5 µg/ml, which confirmed the high antitumour activity against brain cancer cells. Interpretation & conclusions: The cell line studies confirmed the cytotoxicity and internalization of SLN-C in U87 MG brain cancer cells. The results confirmed that tween 80-coated SLNs have the potential to deliver the doxorubicin selectively in the brain cancer cells.

The Cost of Patient Education Materials Development: Opportunities to Identify Value and Priorities.

The study aim was to evaluate the costs associated with developing and reviewing patient education materials (pamphlets) across Ontario cancer centers. While patient education often produces a positive return on investment, limited efforts have been dedicated to optimizing the personnel, time, and capital dedicated to this feat across healthcare systems. Patient education leaders at 14 cancer centers completed a survey measure, estimating the number of hours spent developing and reviewing pamphlets and identifying the personnel involved in each procedural step. The time expended per center in each step was then combined with average salary data for the identified personnel to derive total cost estimates. Cancer centers spend on average $5672 (SD = $3180) developing (M = $4560, SD = $2620) and reviewing (M = $1112, SD = $654) one pamphlet. This cumulates to an average per annum spending of $65,401 (SD = $75,494) for pamphlet development and $19,819 (SD = $28,524) for annual pamphlet review at each cancer center. The cost and number of hours spent developing and reviewing pamphlets varied substantially between cancer centers. While the security of budgets for patient education varies across cancer centers, opportunities to optimize human capital and monetary resources should be considered. Results of the study can be used to advocate for sustainable investment into cancer education programs, improve the coordination of educational materials production and review, and ensure that resource quality and access are consistent across the province.

RUNX Binding Sites Are Enriched in Herpesvirus Genomes, and RUNX1 Overexpression Leads to Herpes Simplex Virus 1 Suppression.

Herpes simplex virus 1 (HSV-1) and HSV-2 can efficiently establish lifelong, transcriptionally silent latency states in sensory neurons to escape host detection. While host factors have previously been associated with long-range insulators in the viral genome, it is still unknown whether host transcription factors can repress viral genes more proximately to promote latency in dorsal root ganglion (DRG) neurons. Here, we assessed whether RUNX (runt-related transcription factor) transcription factors, which are critical in the development of sensory neurons, could be binding HSV-1 genome directly to suppress viral gene expression and lytic infection. Using previously published transcriptome sequencing data, we confirmed that mouse DRG neurons highly express Runx1 mRNA. Through computational analysis of HSV-1 and HSV-2 genomes, we observed that putative RUNX consensus binding sites (CBSs) were more enriched and more closely located to viral gene transcription start sites than would be expected by chance. We further found that RUNX CBSs were significantly more enriched among genomes of herpesviruses compared to those of nonherpesviruses. Utilizing an in vitro model of HSV-1 infection, we found that overexpressed RUNX1 could bind putative binding sites in the HSV-1 genome, repress numerous viral genes spanning all three kinetic classes, and suppress productive infection. In contrast, knockdown of RUNX1 in neuroblastoma cells induced viral gene expression and increased HSV-1 infection in vitro In sum, these data support a novel role for RUNX1 in directly binding herpesvirus genome, silencing the transcription of numerous viral genes, and ultimately limiting overall infection.IMPORTANCE Infecting 90% of the global population, HSV-1 and HSV-2 represent some of the most prevalent viruses in the world. Much of their success can be attributed to their ability to establish lifelong latent infections in the dorsal root ganglia (DRG). It is still largely unknown, however, how host transcription factors are involved in establishing this latency. Here, we report that RUNX1, expressed highly in DRG, binds HSV-1 genome, represses transcription of numerous viral genes, and suppresses productive in vitro infection. Our computational work further suggests this strategy may be used by other herpesviruses to reinforce latency in a cell-specific manner.

Terlipressin Is Superior to Noradrenaline in the Management of Acute Kidney Injury in Acute on Chronic Liver Failure.

Hepatorenal syndrome (HRS) carries a high short-term mortality in patients with cirrhosis and acute on chronic liver failure (ACLF). Terlipressin and noradrenaline are routinely used in cirrhosis with HRS and have been found to be equally effective. There are no data comparing the efficacy of terlipressin with noradrenaline in ACLF patients with HRS. In an open-label, randomized controlled trial (RCT), consecutive patients with ACLF diagnosed with HRS acute kidney injury (AKI) were randomized to albumin with infusion of terlipressin (2-12 mg/day; n = 60) or noradrenaline (0.5-3.0 mg/h; n = 60). Response to treatment, course of AKI, and outcome were studied. Baseline characteristics, including AKI stage and sepsis-related HRS-AKI, were comparable between groups. Compared to noradrenaline, terlipressin achieved greater day 4 (26.1% vs. 11.7%; P = 0.03) and day 7 (41.7% vs. 20%; P = 0.01) response. Reversal of HRS was also better with terlipressin (40% vs. 16.7%; P = 0.004), with a significant reduction in the requirement of renal replacement therapy (RRT; 56.6% vs. 80%; P = 0.006) and improved 28-day survival (48.3% vs. 20%; P = 0.001). Adverse events limiting use of drugs were higher with terlipressin than noradrenaline (23.3% vs. 8.3%; P = 0.02), but were reversible. On multivariate analysis, high Model for End-Stage Liver Disease (MELD; odds ratio [OR], 1.10; confidence interval [CI] = 1.009-1.20; P = 0.03) and noradrenaline compared to terlipressin (OR, 3.05; CI = 1.27-7.33; P = 0.01) predicted nonresponse to therapy. Use of noradrenaline compared to terlipressin was also predictive of higher mortality (hazard ratio [HR], 2.08; CI = 1.32-3.30; P = 0.002). Conclusion: AKI in ACLF carries a high mortality. Infusion of terlipressin gives earlier and higher response than noradrenaline, with improved survival in ACLF patients with HRS-AKI.

Paracentesis-Induced Circulatory Dysfunction With Modest-Volume Paracentesis Is Partly Ameliorated by Albumin Infusion in Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Paracentesis-induced circulatory dysfunction (PICD) is a serious complication of large-volume (>5 L) paracentesis in cirrhosis and is reduced with albumin infusion. There is a lack of data on PICD in acute-on-chronic liver failure (ACLF). Because ACLF patients have greater hemodynamic derangements than patients with decompensated cirrhosis, we investigated whether PICD could develop with modest-volume paracentesis (MVP) and the role of albumin infusion. APPROACH AND RESULTS: A total of 80 ACLF patients undergoing <5 L paracentesis were randomized to receive albumin (8 g/dL of ascitic fluid; n = 40) or no albumin (n = 40) and serially followed to detect PICD. Baseline characteristics were comparable between groups, including volume of ascitic tap (4.16 ± 0.23 versus 4.14 ± 0.27 L; P = 0.72) and plasma renin activity (PRA; 20.5 ± 7.03 versus 23.2 ± 8.24 ng/mL/hour; P = 0.12). PICD was more frequent in the no-albumin group than the albumin group (70% versus 30%; P = 0.001), with higher incidence of hepatic encephalopathy (50% versus 27.5%; P = 0.04), hyponatremia (67.5% versus 22.5%; P < 0.001), acute kidney injury (62.5% versus 30%; P = 0.001), and in-house mortality (62.5% versus 27.5%; P = 0.003). PRA of 25.15 ng/mL at day 3 had sensitivity and specificity of 71% and 68%, respectively, for development of PICD at day 6. Albumin infusion decreased the incidence of PICD at day 6 (odds ratio, 0.068; 95% confidence interval, 0.011-0.43; P = 0.005). CONCLUSIONS: PICD is common and develops even with MVP in ACLF patients. Albumin infusion decreases the incidence of PICD and mortality in patients with ACLF. Clinical trial identifier: NCT02467348.

Incidence, Risk Factors, and Outcomes of Transition of Acute Kidney Injury to Chronic Kidney Disease in Cirrhosis: A Prospective Cohort Study.

Transition to chronic kidney disease (CKD) after an episode of acute kidney injury (AKI) is known in patients without cirrhosis. We studied the incidence and risk factors for development of CKD in patients with cirrhosis. Competing risk analysis was performed to identify risk factors for CKD development. Of 818 patients with cirrhosis (age, 50.4 ± 11.8 years; 84% males; Model for End-Stage Liver Disease [MELD], 19.9 ± 9.9), 36% had AKI at enrollment, 27% had previous AKI, and 61% developed new episodes of AKI during the follow-up period. CKD developed in 269 (33%) patients. Serum cystatin C (CysC; subdistribution hazard ratio [SHR], 1.58; 1.07-2.33), episodes of previous AKI (SHR, 1.26; 1.02-1.56), and AKI stage at enrollment (no AKI [SHR, 1] vs. stage 1 [SHR, 3.28; 1.30-8.25] vs. stage 2 [SHR, 4.33; 1.76-10.66] vs. stage 3 [SHR, 4.5; 1.59-12.73]) were identified as baseline risk factors for CKD development. On time-varying competing risk analysis, MELD (SHR, 1.01; 1.00-1.03), number of AKI episodes (SHR, 1.25; 1.15-1.37), and CysC (SHR, 1.38; 1.01-1.89) predicted CKD development. Development of CKD was associated with higher risk of death. Reduction in glomerular filtration rate (GFR) not meeting CKD criteria was observed in 66% of patients with cirrhosis, more so in those with previous AKI episodes and a high CysC level and MELD score. Renal histology, available in 55 patients, showed tubulointerstitial injury in 86%, cholemic nephrosis in 29%, and glomerular changes in 38%. Conclusion: Almost two-thirds of patients with cirrhosis develop episodes of AKI and reduction in GFR; one-third progress to CKD, resulting in adverse outcomes. Higher MELD and CysC levels and number of AKI episodes predict development of CKD in patients with cirrhosis.

Co-orchestration of acute kidney injury and non-kidney organ failures in critically ill patients with cirrhosis.

BACKGROUND & AIMS: Little is known on the course of acute kidney injury (AKI) and its relation to non-kidney organ failures and mortality in critically ill patients with cirrhosis (CICs). METHODS: We conducted a large prospective, single-centre, observational study in which CICs were followed up daily, during the first 7 days of intensive care, collecting prespecified criteria for AKI, extrarenal extrahepatic organ failures (ERH-OFs) and systemic inflammatory response syndrome (SIRS). RESULTS: A total of 291 patients admitted to ICU were enrolled; 231 (79.4%) had at least one ERH-OFs, 168 (58%) had AKI at presentation, and 145 (49.8%) died by 28 days. At day seven relative to baseline, 151 (51.8%) patients had progressive or persistent AKI, while the rest remained free of AKI or had AKI improvement. The 28-day mortality rate was higher among patients with progressive/persistent AKI (74.2% vs 23.5%; P < .001) or maximum stage 3 of AKI in the first week. Two-level mixed logistic regression modelling identified independent baseline risk factors for progressive/persistent AKI, including 3 to 4 SIRS criteria, infections due to multidrug-resistant bacteria (MDR), elevated serum bilirubin, and number of ERH-OFs. Follow-up risk factors included increases in bilirubin and chloride levels, and new development of 2 or 3 ERH-OFs. CONCLUSIONS: Our results show that among CICs admitted to the ICU, the stage and course of AKI in the first week determines outcomes. Strategies combating MDR infections, multiorgan failure, liver failure and intense systemic inflammation could prevent AKI progression or persistence in CICs.

Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC.

BACKGROUND AND AIM: Plasma-exchange (PE) has improved survival in acute liver failure by ameliorating systemic inflammatory response syndrome (SIRS). We evaluated PE and compared it to Fractional Plasma Separation and Adsorption (FPSA) and standard medical treatment (SMT) in a large multinational cohort of ACLF patients. METHODS: Data were prospectively collected from the AARC database and analysed. Matching by propensity risk score (PRS) was performed. Competing risk survival analysis was done to identify deaths because of multiorgan failure (MOF). In a subset of 10 patients, we also evaluated the mechanistic basis of response to PE. RESULTS: ACLF patients (n = 1866, mean age 44.3 ± 12.3 yrs, 93% males, 65% alcoholics) received either artificial liver support (ALS) (n = 162); [PE (n = 131), FPSA (n = 31)] or were continued on standard medical therapy (SMT) (n = 1704). In the PRS-matched cohort (n = 208, [ALS-119; PE-94, FPSA-25)], SMT-89). ALS therapies were associated with a significantly higher resolution of SIRS (Odd's ratio 9.23,3.42-24.8), lower and delayed development of MOF (Hazard ratio 7.1, 4.5-11.1), and lower liver-failure-related deaths as compared to FPSA and SMT (P < .05). PE cleared inflammatory cytokines, damage-associated molecular patterns, and endotoxin in all patients. Responders improved monocyte phagocytic function and mitochondrial respiration and increased the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1RA) compared to non-responders. PE was associated with lesser adverse effects as compared to FPSA. CONCLUSIONS: PE improves systemic inflammation and lowers the development of MOF in patients with ACLF. Plasma-exchange provides significant survival benefit over FPSA and could be a preferred modality of liver support for ACLF patients.

Impact of metabolic risk factors on the severity and outcome of patients with alcohol-associated acute-on-chronic liver failure.

BACKGROUND: Metabolic risk factors may impact the severity and outcome of alcoholic liver disease. The present study evaluated this effect in patients with alcohol-associated acute-on-chronic liver failure (ACLF). METHODOLOGY: One thousand two hundred and sixteen prospectively enrolled patients with ACLF (males 98%, mean age 42.5 ± 9.4 years, mean CTP, MELD and AARC scores of 12 ± 1.4, 29.7 ± 7 and 9.8 ± 2 respectively) from the Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) database were analysed retrospectively. Patients with or without metabolic risk factors were compared for severity (CTP, MELD, AARC scores) and day 30 and 90 mortality. Information on overweight/obesity, type 2 diabetes mellitus (T2DM), hypertension and dyslipidaemia were available in 1028 (85%), 1019 (84%), 1017 (84%) and 965 (79%) patients respectively. RESULTS: Overall, 392 (32%) patients died at day 30 and 528 (43%) at day 90. Overweight/obesity, T2DM, hypertension and dyslipidaemia were present in 154 (15%), 142 (14%), 66 (7%) and 141 (15%) patients, respectively, with no risk factors in 809 (67%) patients. Patients with overweight/obesity had higher MELD scores (30.6 ± 7.1 vs 29.2 ± 6.9, P = .007) and those with dyslipidaemia had higher AARC scores (10.4 ± 1.2 vs 9.8 ± 2, P = .014). Overweight/obesity was associated with increased day 30 mortality (HR 1.54, 95% CI 1.06-2.24, P = .023). None of other metabolic risk factors, alone or in combination, had any impact on disease severity or mortality. On multivariate analysis, overweight or obesity was significantly associated with 30-day mortality (aHR 1.91, 95% CI 1.41-2.59, P < .001), independent of age, CTP, MELD and AARC scores. CONCLUSION: Overweight/obesity and dyslipidaemia increase the severity of alcohol-associated ACLF, and the former also increases the short-term mortality in these patients.

Role of transporters in plant disease resistance.

Plants being sessile have evolved numerous mechanisms to meet the changing environmental and growth conditions. Plant pathogens are responsible for devastating disease epidemics in many species. Transporter proteins are an integral part of plant growth and development, and several studies have documented their role in pathogen disease resistance. In this review, we analyze the studies on genome-wide identifications of plant transporters like sugars will eventually be exported transporters (SWEET), multidrug and toxic compound extrusion (MATE) transporters, ATP-binding cassette (ABC) transporters, natural resistance-associated macrophage proteins (NRAMP), and sugar transport proteins (STPs), all having a significant role in plant disease resistance. The mechanism of action of these transporters, their solute specificity, and the potential application of recent molecular biology approaches deploying these transporters for the development of disease-resistant plants are also discussed. The applications of genome editing tools, such as CRIPSR/Cas9, are also presented. Altogether the information included in this article gives a better understanding of the role of transporter proteins during plant-pathogen interaction.