Discovery of novel dihydronaphthalene-imidazole ligands as potential inhibitors of Staphylococcus aureus multidrug resistant NorA efflux pump: A combination of experimental and in silico molecular docking studies.

Overexpression of the efflux pump is a predominant mechanism by which bacteria show antimicrobial resistance (AMR) and leads to the global emergence of multidrug resistance (MDR). In this work, the inhibitory potential of library of dihydronapthyl scaffold-based imidazole derivatives having structural resemblances with some known efflux pump inhibitors (EPI) were designed, synthesized and evaluated against efflux pump inhibitor against overexpressing bacterial strains to study the synergistic effect of compounds and antibiotics. Out of 15 compounds, four compounds (Dz-1, Dz-3, Dz-7, and Dz-8) were found to be highly active. DZ-3 modulated the MIC of ciprofloxacin, erythromycin, and tetracycline by 128-fold each against 1199B, XU212 and RN4220 strains of S. aureus respectively. DZ-3 also potentiated tetracycline by 64-fold in E. coli AG100 strain. DZ-7 modulated the MIC of both tetracycline and erythromycin 128-fold each in S. aureus XU212 and S. aureus RN4220 strains. DZ-1 and DZ-8 showed the moderate reduction in MIC of tetracycline in E. coli AG100 only by 16-fold and 8-fold, respectively. DZ-3 was found to be the potential inhibitor of NorA as determined by ethidium bromide efflux inhibition and accumulation studies employing NorA overexpressing strain SA-1199B. DZ-3 displayed EPI activity at non-cytotoxic concentration to human cells and did not possess any antibacterial activity. Furthermore, molecular docking studies of DZ-3 was carried out in order to understand the possible binding sites of DZ-3 with the active site of the protein. These studies indicate that dihydronaphthalene scaffolds could serve as valuable cores for the development of promising EPIs.

Novel lncRNAs LINC01221, RP11-472G21.2 and CRNDE are markers of differential expression in pediatric patients with T cell acute lymphoblastic leukemia.

INTRODUCTION: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) poses significant challenges due to its aggressive nature and resistance to standard treatments. Long non-coding RNAs (lncRNAs) have emerged as potential biomarkers and therapeutic targets in leukemia. This study aims to characterize the lncRNA landscape in pediatric T-ALL, identify specific lncRNAs signatures, and assess their clinical relevance. METHODS: RNA sequencing was performed on T-ALL patient and control samples. Differential expression analysis identified dysregulated lncRNAs and mRNAs. Functional enrichment analysis revealed potential roles of these lncRNAs in cancer pathogenesis. Validation of candidate lncRNAs was conducted using real-time PCR. Clinical correlations were assessed, including associations with patients' clinical characteristics and survival outcomes. RESULTS: Analysis identified 674 dysregulated lncRNAs in pediatric T-ALL, with LINC01221 and CRNDE showing the most interactions in cancer progression pathways. Functional enrichment indicated involvement in apoptosis, survival, proliferation, and metastasis. Top 10 lncRNAs based on adjusted p value < 0.05 and Fold Change > 2 were selected for validation. Seven lncRNAs LINC01221, PCAT18, LINC00977, RP11-620J15.3, RP11-472G21.2, CTD-2291D10.4, and CRNDE showed correlation with RNA sequencing data. RP11-472G21.2 and CTD-2291D10.4 were highly expressed in T-ALL patients, with RP11-620J15.3 correlating significantly with better overall survival (p = 0.0007) at a median follow up of 32 months. The identified lncRNAs were further analysed in B-ALL patients. Distinct lncRNAs signatures were noted, distinguishing T-ALL from B-ALL and healthy controls, with lineage-specific overexpression of LINC01221 (p < 0.0001), RP11-472G21.2 (p < 0.001) and CRNDE (p = 0.04) in T-ALL. CONCLUSION: This study provides insights into the lncRNA landscape of pediatric T-ALL, offering potential diagnostic and prognostic markers. RP11-620J15.3 emerges as a promising prognostic marker, and distinct lncRNAs signatures may aid in the differentiation of T-ALL subtypes. Further research with larger cohorts is warranted to validate these findings and advance personalized treatment strategies for pediatric T-ALL patients.

EZH2-mediated development of therapeutic resistance in cancer.

Enhancer of zeste homolog 2 (EZH2) regulates gene expression and plays a definite role in cell proliferation, apoptosis, and senescence. Overexpression of EZH2 has been found in various human malignancies, including prostate, breast, and ovarian cancers, and is associated with increased metastasis and poor prognosis. EZH2 catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) as a canonical role in a PRC2-dependent manner. This mechanism silences various tumor suppressor genes through EZH2-mediated histone lysine methyltransferase activity. As a non-canonical role, EZH2 partners with other signaling molecules to undergo post-translational modification to orchestrate its function as a co-activator playing a critical role in cancer progression. Dysregulation of EZH2 has also been associated with therapeutic resistance in cancer cells. Given the role of EZH2 in promoting carcinogenesis and therapy resistance, both canonical and non-canonical EZH2 inhibitors have been used to combat multiple cancer types. Moreover, combining EZH2 inhibitors with other therapeutic modalities have shown to enhance the therapeutic efficacy and overcome potential resistance mechanisms in these cancerous cells. Therefore, targeting EZH2 through canonical and non-canonical modes appears to be a promising therapeutic strategy to enhance efficacy and overcome resistance in multiple cancers.

Pattern Recognition of Common Multiple Congenital Malformation Syndromes with Underlying Chromatinopathy.

Chromatinopathy is an emerging category of multiple malformation syndromes caused by disruption in global transcriptional regulation with imbalances in the chromatin states (i.e., open or closed chromatin). These syndromes are caused by pathogenic variants in genes coding for the writers, erasers, readers, and remodelers of the epigenetic machinery. Majority of these disorders (93%) show neurological dysfunction in the form of intellectual disability. Other overlapping features are growth abnormalities, limb deformities, and immune dysfunction. In this study, we describe a series of children with six common chromatinopathy syndromes with an aim to develop pattern recognition of this emerging category of multiple malformation syndromes.

Case Studies of Two Classical Imprinting Growth Disorders: Silver-Russell and Beckwith-Wiedemann Syndromes.

The genetic influences on human growth are being increasingly deciphered. Silver-Russell and Beckwith-Wiedemann syndromes (SRS; BWS) are two relatively common genetic syndromes with under- and overgrowth-related issues being the reason for referral. Aberration in genomic imprinting is the underlying genetic pathomechanism behind these syndromes. Herein, we described a series of children with these two growth disorders and give an orientation to the reader of the concept of imprinting as well as the genetic testing strategy and counseling to be offered in these syndromes.

Comparison of surface adsorption efficacies of eco-sustainable agro/animal biomass-derived activated carbon for the removal of rhodamine B and hexavalent chromium.

Effective management and remediation strategies are crucial to minimize the impacts of both organic and inorganic contaminants on environmental quality and human health. This study investigates a novel approach utilizing cotton shell activated carbon (CSAC), rice husk activated carbon (RHAC), and wasp hive activated carbon (WHAC), produced through alkali treatment and carbonization under N2 atmosphere at 600 °C. The adsorption capacities of biomass-derived mesoporous activated carbons (CSAC, RHAC, WHAC) alongside macroporous commercial activated carbons (CAC) were evaluated for removing rhodamine B (Rh B) and hexavalent chromium (Cr6+). The CSAC exhibits remarkable adsorption efficiency (255.4 mg.g-1) for Cr(VI) removal, while RHAC demonstrates superior efficacy (174.2 mg.g-1) for Rh B adsorption. Investigating various optimal parameters including initial pH (pH 3 for Cr and pH 7 for Rh B), catalyst dosage (200 mg.L-1), and initial concentration (20 mg.L-1), the Redlich-Peterson isotherm model is applied to reveal a hybrid adsorption mechanism encompassing monolayer (chemisorption) and multilayer (van der Waals adsorption) processes. Kinetic analysis highlights the pseudo-second-order and Elovich models as the most suitable, suggesting physiochemisorption mechanisms. Thermodynamic analysis indicates the endothermic nature of the adsorption process, with increased randomness at the solid-solution interface. Isosteric heat investigations using Clausius-Clapeyron, Arrhenius, and Eyring equations reveal a heterogeneous surface nature across all activated carbons. Further confirmation of Rh B and Cr(VI) adsorption onto activated carbons is provided through FTIR, FESEM, and EDAX analysis. This study highlights the innovation and promise of utilizing biomass-derived activated carbons for effective pollutant removal.

Morphology, aspect ratio, and surface elemental composition of primary aerosol particles at urban region of India.

The PM2.5 and PM10 particles were characterized in terms of morphology (size and shape) and surface elemental composition at two different (traffic and industrial) locations in urban region of India and further linked to different morphological defining parameters. The overall PM2.5 and PM10 showed significant daily variability indicating higher PM10 as compared to PM2.5. PM2.5/PM10 ratio was found to be 0.58 ± 0.10 indicating the abundance of PM2.5. Soot aggregates, aluminosilicates, and brochosomes particles were classified based on morphology, aspect ratio (AR), and surface elemental composition of single particles. The linear regression analysis indicates the significant correlation between area equivalent (Daeq) and feret diameter (Dfd) (R2 0.86-0.98). Higher aspect ratio (1.48 ± 0.87-1.43 ± 0.50) was noted at traffic site as compared to industrial site (1.33 ± 0.58-1.29 ± 0.30), while circularity showed the opposite trend. Fractal dimension (Df) of soot aggregates estimated by the soot parameters method (SPM) were found to be 1.70, 1.72, and 1.88, mainly attributed to vehicular emissions, biomass, and industrial emission/coal burning, respectively. This further inferred that freshly emitted soot particles exhibited lacey in nature with spherical shape (Df 1.70) at traffic site, while at industrial location, they were different with compact shapes (Df 1.88) due to particle aging processes. This study inferred the synoptic changes in mass, chemical characteristics, and morphology of aerosol particles which provide the new insights into individual atmospheric particle and their dynamic nature.

Mitigation of haemato-genotoxic and stress response effects in Cyprinus carpio via silymarin dietary supplementation following deltamethrin exposure.

The study examined the potential of Silymarin, a blend of bioactive flavonolignans extracted from the milk thistle Silybum marianum, to mitigate Deltamethrin-induced toxicity in the blood of Cyprinus carpio. Fish were exposed to Deltamethrin (0.66 µg/L), the plant extract, or a combination of both for a duration of thirty days. Various parameters, including serum biochemical markers, erythrocytic abnormalities, and genotoxicity endpoints, were assessed. Results indicated a significant (p < 0.05) increase in the levels of AST, ALT, ALP, blood urea nitrogen, creatinine, glucose, cholesterol, and TLC in the fish exposed to the pesticide. Conversely, total protein, TEC, and Hb showed a notable decrease. There was also a notable rise in micronuclei and erythrocytic abnormalities such as acanthocytes, microcytes, and notched cells. Under ultrastructural examination, phenotypic deformities like spherocytosis, discocytes, and clumped erythrocytes were observed. However, dietary supplementation of silymarin (1 g/kg) significantly restored the biochemical, genetic, and cellular parameters, resembling those of the control group. This suggests the potential of this plant extract in protecting the common carp, Cyprinus carpio, from Deltamethrin-induced damage by scavenging free radicals and reducing DNA oxidative stress.

Distribution of pyrethroid insecticides in urban storm drain structures: Catch basins, open channels, and outfalls.

Surface water runoff can transport contaminants offsite to downstream aquatic ecosystems. The prevalence of impervious surfaces in urban areas enhances surface runoff and contributes to contamination of urban surface streams. Urban areas have complex drainage systems for the conveyance of drainage water, however, there is a dearth of information on the distribution of contaminants within storm drain system structures. Pyrethroid insecticides are among the most used insecticides in urban areas, and trace levels of pyrethroids are known to exert toxicity to aquatic invertebrates. To investigate pyrethroid occurrence and distribution throughout an urban drainage system, samples of water, sediment, algae, and biofilm were collected from catch basins, open channels, and outfalls in Los Angeles County, California, during the dry season. From 3 catch basins, 7 open channels, and 7 outfalls, a total of 28 water samples, 4 sediment samples, 8 algae samples, and 4 biofilm samples were collected and analyzed. Pyrethroid concentrations above the reporting limit were detected in 89% of water samples and all sediment, algae, and biofilm samples, with bifenthrin and cyfluthrin being the most frequently detected compounds. The median total pyrethroid concentrations in water, sediments, algae, and biofilms were 27 ng/L, 88 ng/g, 356 ng/g, and 3556 ng/g, respectively. Bifenthrin concentrations in catch basins were found to be significantly higher than those in open channels or outfalls. Significant correlations were found for various metrics, including between pyrethroid partitioning in water samples and total suspended solids. These findings highlight the role of underground catch basins as a sink as well as a secondary source for contaminants such as pyrethroid insecticides. Prevention of the input of these urban originated contaminants to catch basins is crucial for protecting the water quality of urban surface waters.

Alternating water sources to minimize contaminant accumulation in food plants from treated wastewater irrigation.

The use of treated wastewater (TWW) for agricultural irrigation is a critical measure in advancing sustainable water management and agricultural production. However, TWW irrigation in agriculture serves as a conduit to introduce many contaminants of emerging concern (CECs) into the soil-plant-food continuum, posing potential environmental and human health risks. Currently, there are few practical options to mitigate the potential risk while promoting the safe reuse of TWW. In this greenhouse study, the accumulation of 11 commonly occurring CECs was evaluated in three vegetables (radish, lettuce, and tomato) subjected to two different irrigation schemes: whole-season irrigation with CEC-spiked water (FULL), and half-season irrigation with CEC-spiked water, followed by irrigation with clean water for the remaining season (HALF). Significant decreases (57.0-99.8 %, p < 0.05) in the accumulation of meprobamate, carbamazepine, PFBS, PFBA, and PFHxA in edible tissues were found for the HALF treatment with the alternating irrigation scheme. The CEC accumulation reduction was attributed to reduced chemical input, soil degradation, plant metabolism, and plant growth dilution. The structural equation modeling showed that this mitigation strategy was particularly effective for CECs with a high bioaccumulation potential and short half-life in soil, while less effective for those that are more persistent. The study findings demonstrate the effectiveness of this simple and on-farm applicable management strategy that can be used to minimize the potential contamination of food crops from the use of TWW and other marginal water sources in agriculture, while promoting safe reuse and contributing to environmental sustainability.

Neurofibromatosis type 1: Clinical characteristics and mutation spectrum in a North Indian cohort.

Background: Neurofibromatosis type 1 (NF1) is a unique, highly penetrant neuro-cutaneous disorder with a wide range of manifestations. Though the clinical diagnosis of NF1 is straight forward, there can be other disorders which mimic NF1, especially its cutaneous features. Here we describe the clinical and mutation spectrum of a series of individuals whose primary diagnosis was NF1 or NF1 related disorders. Methods: We have screened 29 unrelated individuals who fulfilled the clinical criteria of NF1. Whole exome sequencing (WES) was done in all individuals except one with suspected microdeletion syndrome with NF1 in whom Cytogenetic microarray (CMA) was done. Results: Out of 29 suspected patients, 25 had germline pathogenic/likely pathogenic variants involving NF1 gene. Five novel and 20 known variants in coding and non-coding regions were identified, among them 7 variants were deletions (28%), 7 nonsense (28%), 3 splice-site (12%), 4 missense (16%), 2 duplications (8%) and 2 (8%) were contiguous deletions. In those where NF1 variants were not detected, 3 had neurofibromatosis type 2 (NF2) and 1 rare autosomal recessive form of Elher Danlos syndrome. Conclusion: We hereby present the wide range of manifestations in different age groups and the mutation spectrum ranging from small scale variants to contiguous gene deletion syndromes involving NF1 gene. We highlight the usefulness of molecular testing and its importance in tumor surveillance and genetic counseling in this disorder.

Severity Scoring Cutoff for MLPA and Its Diagnostic Yield in 332 North Indian Children with Developmental Delay.

Chromosomal aberrations/rearrangements are the most common cause of intellectual disability (ID), developmental delay (DD), and congenital malformations. Traditionally, karyotyping has been the investigation of choice in such cases, with the advantage of being cheap and easily accessible, but with the caveat of the inability to detect copy number variations of sizes less than 5 Mb. Chromosomal microarray can solve this problem, but again the problems of expense and poor availability are major challenges in developing countries. The purpose of this study is to find the utility of multiplex ligation-dependent probe amplification (MLPA) as a middle ground, in a resource-limited setting. We also attempted to establish an optimum cutoff for the de Vries score, to enable physicians to decide between these tests on a case-to-case basis, using only clinical data. A total of 332 children with DD/ID with or without facial dysmorphism and congenital malformations were studied by MLPA probe sets P245. Assessment of clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history was done. We also scored the de Vries scoring for all the patients to find a suitable cutoff for MLPA screening. In our study, the overall detection rate of MLPA was 13.5% (45/332). The majority of patients were DiGeorge's syndrome with probe deletion in 22q11.21 in 3.3% (11/332) followed by 15q11.2 del in 3.6% (12/332, split between Angelman's and Prader-Willi's syndromes). Also, 3.0% (10/332) of patients were positive for Williams-Beuren's syndrome 7q11.23, 1.8% (6/332) for Wolf--Hirschhorn's syndrome 4p16.3, 1.2% (4/332) for 1p36 deletion, and 1% for each trichorhinophalangeal syndrome type I 8q23.3 duplication syndrome and cri du chat syndrome. The optimum cutoff of de Vries score for MLPA testing in children with ID and/or dysmorphism came out to be 2.5 (rounded off to 3) with a sensitivity of 82.2% and specificity of 66.7%. This is the largest study from India for the detection of chromosomal aberrations using MLPA common microdeletion kit P245. Our study suggests that de Vries score with a cutoff of 3 or more can be used to offer MLPA as the first tier test for patients with unexplained ID, with or without facial dysmorphism and congenital malformations.

Removal of food dyes using biological materials via adsorption: A review.

It is alarming that synthetic food dyes (FD) are widely used in various industries and that these facilities discharge their wastewater into the environment without treating it. FDs mixed into industrial wastewater pose a threat to the environment and human health. Therefore, removing FDs from wastewater is very important. This review explores the burgeoning field of FD removal from wastewater through adsorption using biological materials (BMs). By synthesizing a wealth of research findings, this comprehensive review elucidates the diverse array of BMs employed, ranging from algae and fungi to agricultural residues and microbial biomass. Furthermore, this review investigates challenges in practical applications, such as process optimization and scalability, offering insights into bridging the gap between laboratory successes and real-world implementations. Harnessing the remarkable adsorptive potential of BMs, this review presents a roadmap toward transformative solutions for FD removal, promising cleaner and safer production practices in the food and beverage industry.

Exploring the Prevalence, Predictors, and Impact of Bacterial Infections to Guide Empiric Antimicrobial Decisions in Cirrhosis (EPIC-AD).

Background/Aims: This study delved into cirrhosis-related infections to unveil their epidemiology, risk factors, and implications for antimicrobial decisions. Methods: We analyzed acutely decompensated cirrhosis patients (n = 971) from North India between 2013-2023 at a tertiary center. Microbiological and clinical features based on infection sites (EASL criteria) and patient outcomes were assessed. Results: Median age was 45 years; 87% were males with 47% having alcoholic hepatitis. Of these, 675 (69.5%) had infections; 305 (45%) were culture-confirmed. Notably, 71% of confirmed cases were multi-drug resistant organisms (MDRO)-related, chiefly carbapenem-resistant (48%). MDRO prevalence was highest in pulmonary (80.5%) and skin-soft-tissue infections (76.5%). Site-specific distribution and antimicrobials were suggested. Predictive models identified prior hospitalization [OR:2.23 (CI:1.58-3.14)], norfloxacin prophylaxis [OR:2.26 (CI:1.44-3.55)], prior broad-spectrum antibiotic exposure [OR:1.61 (CI:1.12-2.30)], presence of systemic inflammatory response-SIRS [OR:1.75 (CI: 1.23-2.47)], procalcitonin [OR:4.64 (CI:3.36-6.40)], and HE grade [OR:1.41 (CI:1.04-1.90)], with an area under curve; AUC of 0.891 for infection prediction. For MDRO infection prediction, second infection [OR: 7.19 (CI: 4.11-12.56)], norfloxacin prophylaxis [OR: 2.76 (CI: 1.84-4.13)], CLIF-C OF [OR: 1.10 (CI: 1.01-1.20)], prior broad-spectrum antibiotic exposure [OR: 1.66 (CI: 1.07-2.55)], rifaximin [OR: 040 (0.22-0.74)] multisite [OR: 3.67 (CI: 1.07-12.56)], and polymicrobial infection [OR: 4.55 (CI: 1.45-14.17)] yielded an AUC of 0.779 and 93% specificity. Norfloxacin prophylaxis, multisite infection, mechanical ventilation, prior broad-spectrum antibiotic exposure, and infection as acute precipitant predicted carbapenem-resistant infection (AUC: 0.821). Infections (culture-proven or probable), MDROs, carbapenem/pan-drug resistance, and second infections independently linked with mortality (P < 0.001), adjusted for age, leucocytosis, and organ failures. A model incorporating age [HR:1.02 (CI: 1.01-1.03), infection [HR:1.52 (CI: 1.05-2.20)], prior hospitalization [HR:5.33 (CI: 3.75-7.57)], norfloxacin [HR:1.29 (CI: 1.01-1.65)], multisite infection [HR:1.47 (CI:1.06-2.04)], and chronic liver failure consortium-organ failure score; CLIF-C OF [HR:1.17 (CI: 1.11-1.23)] predicted mortality with C-statistics of 0.782 (P < 0.05). Conclusion: High MDRO burden, especially carbapenem-resistant, necessitates urgent control measures in cirrhosis. Site-specific epidemiology and risk models can guide empirical antimicrobial choices in cirrhosis management.

Myokines are associated with progression, course and mortality in alcohol-associated liver disease.

BACKGROUND AND AIMS: Myokines are the muscle-derived hormones orchestrating muscle and systemic health. Their role in the progression of alcohol-associated liver disease (ALD) remains elusive. METHODS: Three-hundred-one patients across the spectrum of ALD including fatty liver (FL, N = 13), compensated cirrhosis (CC, N = 17), non-acute decompensation (NAD, N = 95), acute decompensation (AD, N = 51) and acute-on-chronic liver failure (ACLF, N = 125) were recruited between 2021 and 2023. Plasma myostatin, decorin levels, nutritional status, handgrip strength (HGS), systemic inflammation, infection, ammonia, disease course and 30-day mortality were recorded. RESULTS: Patients aged 48 years (IQR: 38-52) and 97.7% of males were enrolled. Myostatin was elevated while decorin was reduced in cirrhosis compared to without cirrhosis, and further in DC compared to CC (p < 0.001). A step-wise increase in myostatin and reduction in decorin was observed transitioning from NAD to AD to ACLF (p < 0.001). Myostatin was further increased and decorin was reduced along with the grades and organ failures in AD and ACLF (p < 0.001, each). Baseline decorin (AUC: 0.797) and its combination with MELD (AUC: 0.814) predicted disease resolution in AD and ACLF. Although, both myostatin (aOR: 18.96) and decorin (aOR: 0.02) could predict mortality, decorin was independent (aOR: 0.04) and additive to MELD (AUC of MELD+logDecorin + logTLC + HE-grade:0.815); p < 0.05 each. Myostatin increased and decorin reduced with inflammation, hyperammonaemia, malnutrition and HGS in AD and ACLF (p < 0.05, each). CONCLUSION: Myokines are linked with malnutrition, fibrosis, systemic inflammation, organ failures, disease course and mortality in ALD. Decorin enhances the risk estimation of mortality of MELD in AD and ACLF. Therapeutic modulation of myokines is a potentially disease-modifying target in ALD.

Chromosome 1p36 Deletion Syndrome: Four Patients with Variable Presentations.

Chromosome 1p36 deletion accounts for around 1% of cases of intellectual disability. The pattern of clinical features includes developmental delay, hypotonia, seizures, short stature, intellectual disability, vision and hearing deficits, congenital heart disease, and renal abnormalities. The size of deletion can be variable. We report four cases of 1p36 deletion syndrome detected in the past 3 years in a genetic clinic. One patient was detected by next-generation sequencing, another by chromosomal microarray, and the remaining two by multiplex ligation-dependent probe amplification. We discuss the variable presentations in the four children. Early diagnosis enables better prognostication and further reproductive planning.