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Introduction Some of the well-established breast and ovarian cancer susceptibility genes, such as breast cancer 1 (BRCA1), BRCA2, and PALB2, encode proteins that play a key role in repairing double-strand [...], Loss of BRCA2 (breast cancer 2) is lethal for normal cells. Yet it remains poorly understood how, in BRCA2 mutation carriers, cells undergoing loss of heterozygosity overcome the lethality and undergo tissue-specific neoplastic transformation. Here, we identified mismatch repair gene mutL homolog 1 (MLH1) as a genetic interactor of BRCA2 whose overexpression supports the viability of Brca2-null cells. Mechanistically, we showed that MLH1 interacts with Flap endonuclease 1 (FEN1) and competes to process the RNA flaps of Okazaki fragments. Together, they restrained the DNA2 nuclease activity on the reversed forks of lagging strands, leading to replication fork (RF) stability in BRCA2-deficient cells. In these cells, MLH1 also attenuated R-loops, allowing the progression of stable RFs, which suppressed genomic instability and supported cell viability. We demonstrated the significance of their genetic interaction by the lethality of Brca2-mutant mice and inhibition of Brca2-deficient tumor growth in mice by Mlh1 loss. Furthermore, we described estrogen as inducing MLH1 expression through estrogen receptor [alpha] (ER[alpha]), which might explain why the majority of BRCA2 mutation carriers develop ER- positive breast cancer. Taken together, our findings reveal a role of MLH1 in relieving replicative stress and show how it may contribute to the establishment of BRCA2-deficient breast tumors. more...

We first prove that there always exists a maximal rectangularly dualizable graph for a given rectangularly dualizable graph and present an algorithm for its construction. Further, we show that a maximal rectangularly dualizable graph can always be transformed to an edge-irreducible rectangularly dualizable graph and present an algorithm that transforms a maximal rectangularly dualizable graph to an edge-irreducible rectangularly dualizable graph. more...

Abstract The present research work focused on predicting the electrical conductivity (EC) of surface water in the Upper Ganga basin using four machine learning algorithms: multilayer perceptron (MLP), co-adaptive neuro-fuzzy inference system (CANFIS), random forest (RF), and decision tree (DT). The study also utilized the gamma test for selecting appropriate input and output combinations. The results of the gamma test revealed that total hardness (TH), magnesium (Mg), and chloride (Cl) parameters were suitable input variables for EC prediction. The performance of the models was evaluated using statistical indices such as Percent Bias (PBIAS), correlation coefficient (R), Willmott’s index of agreement (WI), Index of Agreement (PI), root mean square error (RMSE) and Legate-McCabe Index (LMI). Comparing the results of the EC models using these statistical indices, it was observed that the RF model outperformed the other algorithms. During the training period, the RF algorithm has a small positive bias (PBIAS = 0.11) and achieves a high correlation with the observed values (R = 0.956). Additionally, it shows a low RMSE value (360.42), a relatively good coefficient of efficiency (CE = 0.932), PI (0.083), WI (0.908) and LMI (0.083). However, during the testing period, the algorithm’s performance shows a small negative bias (PBIAS = − 0.46) and a good correlation (R = 0.929). The RMSE value decreases significantly (26.57), indicating better accuracy, the coefficient of efficiency remains high (CE = 0.915), PI (0.033), WI (0.965) and LMI (− 0.028). Similarly, the performance of the RF algorithm during the training and testing periods in Prayagraj. During the training period, the RF algorithm shows a PBIAS of 0.50, indicating a small positive bias. It achieves an RMSE of 368.3, R of 0.909, CE of 0.872, PI of 0.015, WI of 0.921, and LMI of 0.083. During the testing period, the RF algorithm demonstrates a slight negative bias with a PBIAS of − 0.06. The RMSE reduces significantly to 24.1, indicating improved accuracy. The algorithm maintains a high correlation (R = 0.903) and a good coefficient of efficiency (CE = 0.878). The index of agreement (PI) increases to 0.035, suggesting a better fit. The WI is 0.960, indicating high accuracy compared to the mean value, while the LMI decreases slightly to − 0.038. Based on the comparative results of the machine learning algorithms, it was concluded that RF performed better than DT, CANFIS, and MLP. The study recommended using the current month’s total hardness (TH), magnesium (Mg), and chloride (Cl) parameters as input variables for multi-ahead forecasting of electrical conductivity (ECt+1, ECt+2, and ECt+3) in future studies in the Upper Ganga basin. The findings also indicated that RF and DT models had superior performance compared to MLP and CANFIS models. These models can be applied for multi-ahead forecasting of monthly electrical conductivity at both Varanasi and Prayagraj stations in the Upper Ganga basin. more...

In this study, the impact of heat treatments on AlFeCuCrMgx (x = 0, 0.5, 1, and 1.7) alloys prepared by mechanical alloying and spark plasma sintering were examined. The behavior of these high-entropy alloys (HEAs) was thoroughly studied after they had been heated to 470, 600, and 820 °C in a natural atmosphere. X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were used to study the phase evolution of the heat-treated alloys. The XRD data of the AlFeCuCrMgx (x = 0 and 0.5) alloys heated at 470, 600, and 820 °C present the dispersion of FCC Cu particles at the grain boundaries of parental phases. By contrast, the AlFeCuCrMgx (x = 1 and 1.7) alloys do not exhibit this characteristic. The microstructures of these alloys have been correlated with these results. Their sub-micron structures indicate that the precipitates are unaffected up to 820 °C. The impact of elevated temperatures on the AlFeCuCrMgx alloys was thoroughly examined based on conventional theory. more...

Background: The Unani formulation Majun Brahmi (MB), a combination of herbs, is used in India as a brain tonic and memory enhancer. Aluminium deposition in the brain is associated with the development of neurodegenerative diseases. Aims and Objectives: The present study was designed to observe that the effects of MB have been evaluated on aluminium trichloride or aluminium chloride (AlCl3)-induced cognitive impairment in an experimental rat model. Materials and Methods: Twenty male Wistar albino rats were divided into four groups of five rats each. AlCl3 was administered orally for 30 days to induce cognitive impairment. Group I received saline, Group II-AlCl3 (100 mg/kg b.wt), Group III-MB (1027.77 mg/kg b.wt), and Group IV-AlCl3 + MB (100 mg/kg b.wt+1027.77 mg/kg b.wt). At the end of the experiment, rats were subjected to behavioral and biochemical assessments. Results: Animals treated with AlCl3 showed a significant increase in time to reach the platform in the Morris water maze test (MWM), prolonged transfer latency (TL) in the elevated plus maze, and decreased step-down latency in the passive avoidance test, as compared to controls (P more...

OBJECTIVES: Ongoing symptomatic coronavirus disease 2019 (OSC) is defined as persistent symptoms beyond 4 weeks of acute illness. OSC leads to prolonged hospitalization and oxygen dependence. We aimed to find the outcome of Janus kinase inhibitors (JAKi) as a steroid-sparing agent to treat OSC. METHODS: In this single-center case-controlled study comparing JAKi and corticosteroids in OSC cases, data of 41 cases out of 86 were included – 21 in the JAKi group and 20 in the corticosteroid group from 4 weeks of acute illness to the next 4 weeks. Clinical parameters and inflammatory markers were recorded. The primary outcome was to compare the proportion of patients who were able to maintain oxygen saturation ≥95% with any oxygen supplementation in the two groups. RESULTS: The baseline clinical and demographic characteristics were similar in the two groups. The age was 53.65 ± 9.8 years and 51.48 ± 14.0 years in the corticosteroid group and JAKi group, respectively. At the baseline, 85% of patients in the corticosteroid group and 85.8% in the JAKi group were on oxygen support. The most common symptom in both groups was breathlessness followed by cough. Twenty percent of patients in the JAKi group received baricitinib and the remaining were given tofacitinib. At the time of follow-up, the majority of cases had a significant reduction in C-reactive protein (CRP) and D-dimer; however, the change in CRP and D-dimer was similar in both groups. The number of patients off oxygen support at 4 weeks was higher in the JAKi group (85% in the corticosteroid group vs. 95.2% in the JAKi group, P = 0.269), and the median time to liberation from oxygen support was significantly lower in JAKi group (19 days in corticosteroid group vs. 9 days in JAKi group, P < 0.001). The frequency of any adverse event was also higher in the corticosteroid group (70% vs. 23.8%, P = 0.003). CONCLUSION: JAKi can be used as immunomodulatory drugs in hypoxic OSC cases having evidence of ongoing inflammation. more...

Background: Automated hematology analyzers have become mainstream of complete blood count (CBC) during the past two decades; they are potential, more accurate to produce results of CBCs. However, often automated analyzers can give false results too, specially, falsely low platelet count due to platelets aggregates, which have to be confirmed on peripheral smears. Aims and Objectives: The aim and objective of the study was to diagnose thrombocytopenia (TCP) cases and differentiate them from pseudothrombocytopenia (PTCP) cases by analyzing platelet histogram and to determine the sensitivity and specificity of platelet histograms for diagnosing TCP and PTCP. Materials and Methods: The present study was conducted in the Department of Pathology at Shyam Shah Medical College, Rewa, M.P., after obtaining ethical clearance from the Institutional Ethics Committee. It was prospective study conducted for a period of 15 months from January 2021 to May 2022 on 1000 samples. Results: The sensitivity and specificity of platelet histogram flags and presence of multiple peaks to diagnose TCP and PTCP cases were calculated as 73.60% and 93.60%, respectively. The present study also interpret that mean platelet volume and platelet distribution width cannot use as indicator to differentiate between TCP and PTCP. Conclusion: The present study concludes that analysis and interpretation of histogram more specifically platelet histogram flagging provide clue for early detection of PTCP cases prior peripheral smear examination and also helpful in differentiating them from true TCP cases. These platelet histogram flagging can be used as a screening parameter for the detection of PTCP and these are helpful in preventing unnecessary stress for clinician, patients, and their relatives. However, the peripheral smear examination will remain the gold standard to differentiate TCP from, PTCP. more...

Abstract Background Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Clinical reports indicate that smoking is a significant risk factor for chronic kidney disease, and the tobacco epidemic exacerbates kidney damage in patients with DN. However, the underlying molecular mechanisms remain unclear. Method In the present study, we used a diabetic mouse model to investigate the molecular mechanisms for nicotine-exacerbated DN. Twelve-week-old female mice were injected with streptozotocin (STZ) to establish a hyperglycemic diabetic model. After four months, the control and hyperglycemic diabetic mice were further divided into four groups (control, nicotine, diabetic mellitus, nicotine + diabetic mellitus) by intraperitoneal injection of nicotine or PBS. After two months, urine and blood were collected for kidney injury assay, and renal tissues were harvested for further molecular assays using RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry. In vitro studies, we used siRNA to suppress Grem1 expression in human podocytes. Then we treated them with nicotine and high glucose to compare podocyte injury. Result Nicotine administration alone did not cause apparent kidney injury, but it significantly increased hyperglycemia-induced albuminuria, BUN, plasma creatinine, and the kidney tissue mRNA expression of KIM-1 and NGAL. Results from RNA-seq analysis, real-time PCR, Western blot, and immunohistochemistry analysis revealed that, compared to hyperglycemia or nicotine alone, the combination of nicotine treatment and hyperglycemia significantly increased the expression of Grem1 and worsened DN. In vitro experiments, suppression of Grem1 expression attenuated nicotine-exacerbated podocyte injury. Conclusion Grem1 plays a vital role in nicotine-exacerbated DN. Grem1 may be a potential therapeutic target for chronic smokers with DN. more...

The foundation of the upcoming generation of cutting-edge gadgets and digitally augmented technologies is expected to be smart soft materials. Because of their responsiveness and adaptability, liquid crystals (LCs) are promising smart soft materials. In the 20th century, LCs were crucial to changing the information display sector. However, several beyond-display uses for LCs have been proven at the turn of the twentieth century, neatly using their controlled stimuli-responsive and adaptable properties. New LC materials have been developed and engineered for such applications. The review comes close with a summary and viewpoints on the potential and problems facing LCs as smart soft materials. This review is expected to inspire a wide range of concepts for the application of nature's delicate phase of matter in the generation and beyond of smart and augmented devices. more...

Purpose: Breast cancer accounts for most cancer-related deaths in women with over 2.3 million new breast cancer cases diagnosed every year worldwide. Pim kinases are oncogenic proteins that play important role in various cancers. Pim-1 contains 1.7 kb promoter region without any transcriptional regulation, which is a characteristic feature of a housekeeping or constitutive promoter. This study was carried out to ascertain potential mutations in the promoter region of Pim-1 in breast cancer and also to comprehend the effect of mutations on c-Myc expression as well as on patients’ survival. Methods: Ninety-six Indian subjects with a first diagnosis of breast cancer who underwent surgery at our hospital were recruited in this study. Genomic DNA was isolated from whole blood, amplified and sequenced to identify potential mutations at the promoter region of Pim-1. FFPE sections were used to determine the c-Mycexpression in all the studied groups. Results: We observed a transversion (C>A at –502) and a deletion (–754Cdel) mutation in the promoter region with negligible association with tumor biology and c-Myc expression. Positive c-Myc expression was noted in almost 50% of the studied population with absolute nuclear staining or both cytoplasmic/nuclear staining. As per survival analysis, promoter region mutations did not modulate the patients’ survival, but patients with negative c-Myc expression had better disease-free survival compared with positive c-Myc expression. Conclusion: Our findings identified the presence of mutation in the promoter region of Pim-1 with negligible impact on c-Myc expression in patients with breast cancer more...