Prevalence of resistance-associated viral variants to the HIV-specific broadly neutralising antibody 10-1074 in a UK bNAb-naïve population.

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.

Robot-assisted Foley Tie Ureteric Tapering and Reimplantation.

Objective: This study aimed to introduce and evaluate the feasibility and outcomes of a novel surgical technique, robot-assisted Foley tie ureteric tapering (RAFUT) and reimplantation, specifically designed for intravesical ureteral tapering during pediatric robotic-assisted ureteric reimplantation. Materials and Methods: A retrospective analysis was conducted on pediatric patients diagnosed with primary vesicoureteric reflux (VUR), who underwent RAFUT between January 2019 and July 2021. Patient records were reviewed to assess preoperative characteristics, operative details, and postoperative outcomes. RAFUT involved meticulous patient positioning, precise port placement with a 6 mm separation, and bladder anchoring to maintain pneumovesicum. Ureteric tapering was performed with the Foley tie technique to enhance surgical precision. The primary outcome measures included operative time, complications, and postoperative VUR resolution. Results: All four patients underwent successful intravesical RAFUT without any intraoperative or postoperative complications. The age of the patients ranged from 3 to 12 years, with varying bladder capacities (range: 210-550 mL). The operating times ranged from 180 to 210 min, and the estimated blood loss was 35-50 mL. None of the patients required conversion to open surgery. Patients demonstrated resolution of VUR on postoperative imaging, and none experienced recurrent urinary tract infections during follow-up, which ranged from 1.5 to nearly 4 years. Conclusion: RAFUT represents a safe and effective surgical technique for intravesical ureteral tapering during pediatric robotic-assisted ureteric reimplantation. This innovative approach addresses the challenges posed by intravesical surgery for dilated ureters, maintains anatomical orientation, and offers precise excision and suturing capabilities.

Targeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus.

Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03-9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity.

Kenaf-based activated carbon: A sustainable solution for high-performance aqueous symmetric supercapacitors.

This study presents an innovative method for synthesizing activated carbon with an exceptionally high surface area (3359 m2 g-1) using kenaf fiber-based biochar through chemical activation. The achieved specific surface area surpasses activated carbon derived from other reported fiber-based precursors. The resulting activated carbon was investigated as electrodes for supercapacitors, revealing a remarkable maximum capacitance of 312 F g-1 at a current density of 0.5 A g-1. An aqueous symmetric supercapacitor employing these high-surface-area electrodes exhibited an outstanding energy density of 18.9 Wh kg-1 at a power density of 250 W kg-1. Notably, the supercapacitor retained exceptional capacitance, maintaining 93% of its initial capacitance even after 5000 charge-discharge cycles.

Blood-based microRNA profiling unveils complex molecular dynamics in breast cancer.

BACKGROUND: Breast cancer, a genetically intricate disease with diverse subtypes, exhibits heightened incidence globally. In this study, we aimed to investigate blood-based microRNAs (miRNAs) as potential biomarkers for breast cancer. The primary objectives were to explore the role of miRNAs in cancer-related processes, assess their differential expression between breast cancer patients and healthy individuals, and contribute to a deeper understanding of the molecular underpinnings of breast cancer. METHODS: MiRNA extraction was performed on 40 breast cancer patients and adjacent normal tissues using a commercial RNA isolation kit. Total RNA quantification and quality assessment were conducted with advanced technologies. MiRNA profiling involved reverse transcription, labeling, and hybridization on Agilent human miRNA arrays (V2). Bioinformatics analysis utilized the DIANA system for target gene prediction and the DIANA-mirPath tool for pathway enrichment analysis. Selected miRNAs underwent validation through quantitative real-time PCR. RESULTS: Principal component analysis revealed overlapping miRNA expression patterns in primary and malignant breast tumors, underscoring the genetic complexity involved. Statistical analysis identified 54 downregulated miRNAs in malignant tumors and 38 in primary tumors compared to controls. Bioinformatics analysis implicated several pathways, including Wnt, TGF-b, ErbB, and MAPK signaling. Validation through qRT-PCR confirmed altered expression of hsa-miR-130a, hsa-miR-21, hsa-miR-223, and hsa-let-7c key miRNAs, highlighting their significance in breast cancer. The results from microarray were further validated by qPCR and the expression of which are downregulated in breast cancer was detected. CONCLUSION: This study provides significant insights into distinct miRNA expression patterns in normal and malignant breast tissues. The overlapping miRNA profiles in primary and malignant tumors underscore the complexity of genetic regulation in breast cancer. The identification of deregulated miRNAs and affected pathways contributes to our understanding of breast cancer pathogenesis. The validated miRNAs hold potential as diagnostic and prognostic markers, offering avenues for further clinical exploration in breast cancer research.

Correlation between serum galanin and neuron-specific enolase levels with EEG abnormalities in pediatric convulsive status epilepticus and the efficacy of triple drug therapy.

OBJECTIVE: This study aimed to investigate the association between serum galanin (GAL) and neuron-specific enolase (NSE) levels in children with convulsive status epilepticus (CSE) and their relationship with abnormal electroencephalogram (EEG) patterns. Additionally, the study assessed the effectiveness of a combination therapy involving midazolam, diazepam, and phenobarbital in treating CSE. PATIENTS AND METHODS: The research involved 100 children diagnosed with CSE and included a control group of 50 healthy children. Serum GAL and NSE levels were measured, and EEGs were analyzed for abnormalities in the CSE group. Comparisons were made between the healthy control group and the CSE group, particularly within the first 24 hours after persistent seizures. The severity of EEG abnormalities was correlated with GAL and NSE levels. The treatment consisted of an observation group that received the triple therapy of midazolam, diazepam, and phenobarbital, while a control group received diazepam and phenobarbital. Clinical efficacy, symptom improvement, Status Epilepticus Severity Score (STESS), and adverse reactions were evaluated. RESULTS: The results indicated elevated levels of GAL and NSE in the CSE group, with higher levels noted within 24 hours after persistent seizures. Furthermore, a positive correlation was observed between the severity of EEG abnormalities and GAL and NSE levels. The group receiving the triple therapy demonstrated superior efficacy, faster resolution of seizures and fever, reduced STESS scores, and fewer adverse reactions than the control group. In conclusion, this study highlights the positive correlation between serum GAL and NSE levels and the severity of EEG abnormalities in pediatric CSE. The triple therapy approach is effective in treating CSE, leading to improved clinical symptoms, reduced brain damage, and enhanced safety. CONCLUSIONS: The study concludes that serum GAL and NSE levels in children with convulsive status epilepticus are positively correlated with the degree of EEG abnormalities. The combination therapy involving midazolam, diazepam, and phenobarbital is effective in treating children with convulsive status epilepticus, significantly improving clinical symptoms, reducing brain damage, and ensuring safety.

Computational ensemble expert system classification for the recognition of bruxism using physiological signals.

This study aimed to develop an automatic diagnostic scheme for bruxism, a sleep-related disorder characterized by teeth grinding and clenching. The aim was to improve on existing methods, which have been proven to be inefficient and challenging. We utilized a novel hybrid machine learning classifier, facilitated by the Weka tool, to diagnose bruxism from biological signals. The study processed and examined these biological signals by calculating the power spectral density. Data were categorized into normal or bruxism categories based on the EEG channel (C4-A1), and the sleeping phases were classified into wake (w) and rapid eye movement (REM) stages using the ECG channel (ECG1-ECG2). The classification resulted in a maximum specificity of 93% and an accuracy of 95% for the EEG-based diagnosis. The ECG-based classification yielded a supreme specificity of 87% and an accuracy of 96%. Furthermore, combining these phases using the EMG channel (EMG1-EMG2) achieved the highest specificity of 95% and accuracy of 98%. The ensemble Weka tool combined all three physiological signals EMG, ECG, and EEG, to classify the sleep stages and subjects. This integration increased the specificity and accuracy to 97% and 99%, respectively. This indicates that a more precise bruxism diagnosis can be obtained by including all three biological signals. The proposed method significantly improves bruxism diagnosis accuracy, potentially enhancing automatic home monitoring systems for this disorder. Future studies may expand this work by applying it to patients for practical use.

Risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis and associated outcomes.

BACKGROUND: We aim to determine clinical risk factors for postoperative complications in preterm infants with surgical necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). METHODS: A retrospective cohort study of preterm infants with surgical NEC or SIP to compare clinical factors between those with and without postoperative complications. RESULTS: 78/109 (71.5%) infants had any complication following surgical NEC. Adhesions (20/35, 57.1%) and wound infection (6/35, 17.1%) were the most common single surgical complications. Patients with a single surgical complication (35/66, 53%) were significantly less likely to be exposed to antenatal steroids, more frequently had a jejunostomy, needed a central line longer, and had a longer length of stay than those without any surgical complication. Infants with > 1 surgical complication (43/71, 60.5%) included mainly females, and had AKI more frequently at NEC onset, lower weight z-scores and lower weight for length z- scores at 36 weeks PMA than those without any complications.On multinomial logistic regression, antenatal steroids exposure (OR 0.23 [CI 0.06, 0.84]; p = 0.027) was independently associated with lower risk and jejunostomy 4.81 (1.29, 17.9) was independently associated with higher risk of developing a single complication. AKI following disease onset (OR 5.33 (1.38, 20.6), P = 0.015) was independently associated with > 1 complication in surgical NEC/SIP infants. CONCLUSION: Infants with postoperative complications following surgical NEC were more likely to be female, have additional morbidities, and demonstrate growth failure at 36 weeks PMA than those without surgical complications. There was no difference in mortality between those with and without surgical complications.

HepFREEPak: protocol for a multi-centre, prospective observational study examining efficacy and impact of current therapies for the treatment of hepatitis C in Pakistan and reporting resistance to antiviral drugs: study protocol.

BACKGROUND: Pakistan has one of the highest burdens of Hepatitis C virus (HCV) infection globally. To achieve the World Health Organization's goals for HCV elimination, there is a need for substantial scale-up in testing, treatment, and a reduction in new infections. Data on the population impact of scaling up treatment is not available in Pakistan, nor is there reliable data on the incidence of infection/reinfection. This project will fill this gap by providing important empirical data on the incidence of infection (primary and reinfection) in Pakistan. Then, by using this data in epidemic models, the study will determine whether response rates achieved with affordable therapies (sofosbuvir plus daclatasvir) will be sufficient to eliminate HCV in Pakistan. METHODS: This prospective multi-centre cohort study will screen 25,000 individuals for HCV antibody (Ab) and RNA (if Ab-positive) at various centers in Pakistan- Karachi (Sindh) and Punjab, providing estimates of the disease prevalence. HCV positive patients will be treated with sofosbuvir and daclatasvir for 12-weeks, (extended to 24-weeks in those with cirrhosis) and the proportion responding to this first-line treatment estimated. Patients who test HCV Ab negative will be recalled 12 months later to test for new HCV infections, providing estimates of the incidence rate. Patients diagnosed with HCV (~ 4,000) will be treated and tested for Sustained Virological Response (SVR). Questionnaires to assess risk factors, productivity, health care usage and quality of life will be completed at both the initial screening and at 12-month follow-up, allowing mathematical modelling and economic analysis to assess the current treatment strategies. Viral resistance will be analysed and patients who have successfully completed treatment will be retested 12 months later to estimate the rate of re-infection. CONCLUSION: The HepFREEPak study will provide evidence on the efficacy of available and widely used treatment options in Pakistan. It will also provide data on the incidence rate of primary infections and re-infections. Data on incidence risk factors will allow us to model and incorporate heterogeneity of risk and how that affects screening and treatment strategies. These data will identify any gaps in current test-and-treat programs to achieve HCV elimination in Pakistan. STUDY REGISTRATION: This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.

Phylogenetic Analysis of Hepatitis C Virus Infections in a Large Belgian Cohort Using Next-Generation Sequencing of Full-Length Genomes.

The hepatitis C virus (HCV) epidemic in Western countries is primarily perpetuated by the sub-populations of men who have sex with men (MSM) and people who inject drugs (PWID). Understanding the dynamics of transmission in these communities is crucial for removing the remaining hurdles towards HCV elimination. We sequenced 269 annotated HCV plasma samples using probe enrichment and next-generation sequencing, obtaining 224 open reading frames of HCV (OR497849-OR498072). Maximum likelihood phylogenies were generated on the four most prevalent subtypes in this study (HCV1a, 1b, 3a, 4d) with a subsequent transmission cluster analysis. The highest rate of clustering was observed for HCV4d samples (13/17 (76.47%)). The second highest rate of clustering was observed in HCV1a samples (42/78 (53.85%)) with significant association with HIV-positive MSM. HCV1b and HCV3a had very low rates of clustering (2/83 (2.41%) and (0/29)). The spread of the prevalent subtype HCV1b appears to have been largely curtailed, and we demonstrate the onwards transmission of HCV1a and HCV4d in the HIV-positive MSM population across municipal borders. More systematic data collection and sequencing is needed to allow a better understanding of the HCV transmission among the community of PWID and overcome the remaining barriers for HCV elimination in Belgium.

Clinical determinants of intestinal failure and death in preterm infants with surgical necrotizing enterocolitis.

OBJECTIVE: We sought to investigate the clinical determinants of intestinal failure and death in preterm infants with surgical NEC. METHODS: Retrospective comparison of clinical information between Group A = intestinal failure (Parenteral nutrition (PN) >90 days) and death and Group B = survivors and with PN dependence < 90 days in preterm infants with surgical NEC. RESULTS: Group A (n = 99/143) had a lower mean gestational age (26.4 weeks [SD3.5] vs. 29.4 [SD 3.5]; p = 0.013), lower birth weight (873 gm [SD 427g] vs. 1425 gm [894g]; p = <0.001), later age of NEC onset (22 days [SD20] vs. 16 days [SD 17]; p = 0.128), received surgery later (276 hours [SD 544] vs. 117 hours [SD 267]; p = 0.032), had cholestasis, received dopamine (80.6% vs. 58.5%; p = 0.010) more frequently and had longer postoperative ileus time (19.8 days [SD 15.4] vs. 11.8 days [SD 6.5]; p = <0.001) and reached full feeds later (93 days [SD 45] vs. 44 [SD 22]; p = <0.001) than Group B.On multivariate logistic regression, higher birth weight was associated with lower risk (OR 0.35, 95% CI 0.15-0.82; p = 0.016) of TPN > 90 days or death. Longer length of bowel resected (OR 1.76, 95% CI 1.02-3.02; p = 0.039) and longer postoperative ileus (OR 2.87, 95% CI 1.26-6.53; p = 0.011) were also independently associated with TPN >90days or death adjusted for gestational age and antenatal steroid treatment. CONCLUSION: In preterm infants with surgical NEC, clinical factors such as lower birth weight, longer bowel loss, and postoperative ileus days were significantly and independently associated with TPN >90 days or death.

Clear cell sarcoma of kidney: A mimicker of Wilms' tumor.

The differential diagnosis for an abdominal mass in a 2-year-old child is broad and includes lesions of renal, hepatic, gastrointestinal, adrenal, and lymphatic origins. Of these, Wilms' tumor and neuroblastoma are the most common tumors, where Wilms' tumor represents about 92% of renal masses in children. Non-Wilms' renal tumors, rhabdoid tumors, and clear cell sarcoma of the kidney (CCSK) are uncommon. CCSK constitutes approximately 3% of all malignant renal tumors in childhood. In this report, we present a child presenting with a huge renal mass consistent with Wilms' tumor on computed tomography and initial biopsy. However, the final pathologic diagnosis after resection revealed CCSK.

Constant current pulsed power supply for long pulse arc discharge positive hydrogen ion source.

The simplest way to produce high density hydrogen plasmas is to form an arc between the arcing electrode and the plasma chamber (cathode). For arc-based hydrogen plasma generation, a pulsed power supply that delivers 2 ms-long constant current pulse has been developed. This pulsed power supply employs a high frequency buck converter topology with a nonlinear filter inductor. This paper describes the development and testing of a constant current pulsed power supply that operates at 50 A and 550 V with a pulse width of 2 ms and a pulse repetition rate of 2 Hz. By changing the arc current, the arc impedance and the positive hydrogen ion current were also measured. The extraction of positive hydrogen ions was carried out using a three-electrode extraction design, which results in a current of 80 mA of positive hydrogen ions at an energy of 50 keV.

Mini-versus standard percutaneous nephrolithotomy in pediatric population: A randomized controlled trial.

INTRODUCTION: Mini PCNL has gained popularity in adult patients due to reduction in the complication rate with comparable stone free rate. There is paucity of level 1 evidence regarding the benefit of mini PCNL in the pediatric group. OBJECTIVE: We performed a randomised study to compare mini PCNL (mPCNL) with standard PCNL (sPCNL) for the management of renal calculi in patients less than 18 years of age in terms of safety, efficacy, and stone-free rate (SFR). MATERIALS AND METHODS: A randomised controlled trial was performed on 50 children who underwent PCNL from June 2015 to March 2021, who were divided into two groups. Group I had 25 patients managed with mPCNL (sheath size 16.5 Fr) and Group II had 25 patients who underwent sPCNL (sheath size 26 Fr). Primary outcomes including stone free rates (SFR) and hemoglobin drop and secondary outcomes like operative time, complications, pain score, need of analgesia, incidence of nephrostomy site leak, hospital stay in days were compared between the two groups. RESULTS: The mean age of patients in groups I and II was 9.4 ± 2.6 and 10.4 ± 2.26 years, respectively (p = 0.15). The mean stone sizes in both groups I and II were 18.6 ± 2.56 and 20.2 ± 3.58 mm, respectively (p > 0.05). The stone free rate for group I was 88% and for group II, 92% (p = 0.64). The average drop in hemoglobin was higher in group II compared to group I (1.1 ± 0.31 g/dl and 1.7 ± 0.23 g/dl respectively; p < 0.0001), however the mean blood transfusion rate was not significantly different in both groups. The operating time was shorter in group II compared to group I (p-value - 0.0030). The pain scores were lesser for the group I. Grade I complications were higher in group II as compared to group I (p-0.047); however, grade II complications were comparable in both groups. The mean hospital stay was not significantly different in both groups. DISCUSSION: This study confirms the role of mini PCNL in pediatric patients with renal stones. The stone clearance rate of mini PCNL is equivalent to standard PCNL, with lesser blood loss and postoperative complications, however with longer operative time during mPCNL. The small number of the participants in both arms is a limitation of this study and may also reflect fewer children with urolithiasis being treated surgically even in a tertiary care referral centre. CONCLUSIONS: Mini-PCNL offers equivalent stone free outcome with lower complications rate compared to the standard PCNL for all types of renal stones.

Ureterovesical Leak Following Renal Transplant and Effects of Acute Rejection and Antirejection Therapy: A Nested Case-Control Analysis and Outcome of 1102 Consecutive Renal Transplant Recipients.

OBJECTIVES: Studies on nontechnical risk factors for ureterovesical leak after renal transplant are scarce. This study aimed to report the possible pre- and postoperative risk factors and the role of acute rejection and antirejection therapies for urine leak after transplant and its effect on graft and patient survival. MATERIALS AND METHODS: We conducted a retrospective analysis of 13 patients (1.17%) with urine leak (case group) and 52 patients without leak (control group) (case-to-control ratio of 1:4) from 1102 living related (first degree) renal transplant recipients seen between January 2012 and December 2021. We analyzed demographic and clinical details and biochemical and outcome parameters using a nested case-control design. RESULTS: Cases were olderthan controls (P = .018), were more ABO incompatible (P = .009), and had more 6/6 HLA mismatch transplants (P = .047). Donors of cases were older than donors of controls (P = .049). The rate of postoperative hypoalbuminemia was greaterin the case group (P = .050). Rates of acute rejection (P = .012) and plasmapheresis (P = .003) were greaterin the case group than in the control group. On multivariate logistic regression analysis, recipient age, 6/6 HLA mismatch, and plasmapheresis were found to independently associated with urine leak. None ofthe patient required surgical repair, as all responded to conservative therapy. Urine leak did not affect graft outcomes (P = .324), but overall survival was less in cases than in controls. CONCLUSIONS: Nontechnical risk factors that cause posttransplant ureteric leak include older donor and recipient age and ABO incompatible and 6/6 HLA mismatch transplants. Acute rejection and plasmapheresis predispose leak, and an indwelling double J stent can allow adequate healing of the anastomosis. High index of suspicion and prompt management are imperative to preserve graft and patient outcome.

Genotyping and population characteristics of the China Kadoorie Biobank.

The China Kadoorie Biobank (CKB) is a population-based prospective cohort of >512,000 adults recruited from 2004 to 2008 from 10 geographically diverse regions across China. Detailed data from questionnaires and physical measurements were collected at baseline, with additional measurements at three resurveys involving ∼5% of surviving participants. Analyses of genome-wide genotyping, for >100,000 participants using custom-designed Axiom arrays, reveal extensive relatedness, recent consanguinity, and signatures reflecting large-scale population movements from recent Chinese history. Systematic genome-wide association studies of incident disease, captured through electronic linkage to death and disease registries and to the national health insurance system, replicate established disease loci and identify 14 novel disease associations. Together with studies of candidate drug targets and disease risk factors and contributions to international genetics consortia, these demonstrate the breadth, depth, and quality of the CKB data. Ongoing high-throughput omics assays of collected biosamples and planned whole-genome sequencing will further enhance the scientific value of this biobank.

Genotypic Analysis of COL4A1 Gene in Diabetic Nephropathy and Type 2 Diabetes Mellitus Patients: A Comparative Genetic Study.

Diabetic nephropathy (DN) is specified by microalbuminuria, glomerular lesions, and renal fibrosis leading to end-stage renal disease. The pathophysiology of DN is multifactorial as a result of gene-environment interaction. Clinical studies suggested that gene mutations affect various pathways involved in DN, including extracellular matrix (ECM). During chronic hyperglycemia, collagen type-4-mediated ECM overproduction occurs, leading to renal fibrosis and DN development. In this study, COL4A1 gene variant rs605143 (G/A) was analyzed in diabetes and DN patients from the study population. We genotyped 386 study subjects, comprising 120 type 2 diabetes mellitus (T2DM) patients, 120 DN, and 146 healthy controls. All study subjects were analyzed for biochemical assays by commercially available kits and genotypic analysis by polymerase chain reaction-restriction fragment length polymorphism and confirmed by Sanger sequencing. Statistical analyses were done using SPSS and GraphPad. Anthroclinicopathological parameters showed a significant association between T2DM and DN. Genotype AA of COL4A1 gene variant rs605143 (G/A) showed a significant association with T2DM and DN compared with controls with 5.87- and 8.01-folds risk, respectively. Mutant allele A also significantly associated with T2DM and DN independently compared with healthy controls with 2.29- and 2.81-time risk in the study population. This study's findings suggested that COL4A1 gene variant rs605143 (G/A) can be used as predictive biomarkers for T2DM and DN independently. However, this gene variant needs to be analyzed in a large sample to explore the shared genetic association between T2DM and DN.

Hsp27 over expression protect against cadmium induced nephrotoxicity in Drosophila melanogaster.

Cadmium (Cd) exposure to the animals including humans is reported as nephrotoxic compounds i.e., disturbing redox status (increase oxidative stress), mitochondrial dysfunction, renal cell death and altered transporters in the renal system. Hsp27 (a small heat shock protein) has been shown as one of the modulators in the renal dysfunction and increased against the Cd induced toxicity. However, no studies are reported on the genetic modulation of stress protein against the Cd-induced nephrotoxicity. The current study aimed to examine the protective role of hsp27 overexpression against the Cd-induced nephrotoxicity using Drosophila melanogaster as an animal model. D. melanogaster renal system includes nephrocytes and Malpighian tubules (MTs) that show the functional similarity with mammalian kidney nephron. Overexpression of the hsp27 was found to reduce the Cd induced oxidative stress, rescue cell death in MTs of Cd exposed D. melanogaster larvae. The rescued GSH level, NADPH level and glucose 6 phosphate dehydrogenase (G6PD) activity were also observed in the MTs of the Cd exposed organism. Function (efflux activity and fluid secretion rate) of the MTs was restored in Cd exposed hsp27 overexpressed larvae. Further, results were confirmed by restored brush border microvilli density and reduced uric acid level. Tissue specific knockdown of hsp27 developed Cd like phenotypes in MTs and the phenotypes enhanced in Cd exposed condition. The present study clearly shows the role of hsp27 overexpression in restoration of the MTs function and protection against the Cd induced renal toxicity.

The small molecule Erk1/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL/J mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (Erk1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE animals injected with the Erk1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT2 Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between Erk1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising adjuvant therapeutic strategy.