Mechanistic Investigation of the Androgen Receptor DNA-Binding Domain and Modulation via Direct Interactions with DNA Abasic Sites: Understanding the Mechanisms Involved in Castration-Resistant Prostate Cancer.

The androgen receptor (AR) is an important drug target in prostate cancer and a driver of castration-resistant prostate cancer (CRPC). A significant challenge in designing effective drugs lies in targeting constitutively active AR variants and, most importantly, nearly all AR variants lacking the ligand-binding domain (LBD). Recent findings show that an AR's constitutive activity may occur in the presence of somatic DNA mutations within non-coding regions, but the role of these mutations remains elusive. The discovery of new drugs targeting CRPC is hampered by the limited molecular understanding of how AR binds mutated DNA sequences, frequently observed in prostate cancer, and how mutations within the protein and DNA regulate AR-DNA interactions. Using atomistic molecular dynamics (MD) simulations and quantum mechanical calculations, we focused our efforts on (i) rationalising the role of several activating DBD mutations linked to prostate cancer, and (ii) DBD interactions in the presence of abasic DNA lesions, which frequently occur in CRPC. Our results elucidate the role of mutations within DBD through their modulation of the intrinsic dynamics of the DBD-DNA ternary complex. Furthermore, our results indicate that the DNA apurinic lesions occurring in the androgen-responsive element (ARE) enhance direct AR-DNA interactions and stabilise the DBD homodimerisation interface. Moreover, our results strongly suggest that those abasic lesions may form reversible covalent crosslinks between DNA and lysine residues of an AR via a Schiff base. In addition to providing an atomistic model explaining how protein mutations within the AR DNA-binding domain affect AR dimerisation and AR-DNA interactions, our findings provide insight into how somatic mutations occurring in DNA non-coding regions may activate ARs. These mutations are frequently observed in prostate cancer and may contribute to disease progression by enhancing direct AR-DNA interactions.

Synergy of 1-MCP and hypobaric treatments prevent fermented flavour and improve consumers' acceptability of 'Shughri' pear.

Development of fermented flavour during storage reduces acceptability of Shughri pear. Therefore, the current study was designed to investigate the combined effect of 1-Methylcyclopropene (1-MCP) and hypobaric treatment on stability of Shughri pear during 120 days of storage. Fruit were treated individually or combinedly with 25, 50, and 75 kilo pascal hypobaric treatments for 4 h and 1-MCP (0.3 µLL-1 and 0.6 µLL-1) for 24 h, whereas control received no treatment. The pears were stored for 120 days at (0 ± 1 °C, 85 ± 5% RH), and were evaluated after every 30 days. After cold storage, pears were shifted to simulated retail conditions (20 ± 3 °C, 65 ± 5% RH). The combination of 25 kPa + 0.6 µLL-1 1-MCP significantly (P ≤ 0.05) delayed fruit ripening, reduced Alcohol dehydrogenase (ADH), and Pyruvate decarboxylase (PDC) activities, maintained the quality, and led to higher consumers' acceptability of the pear followed by 50 kPa + 0.6 µLL-1 and 25 kPa + 0.3 µLL-1. The control fruit were marketable for a week after storage with relatively less acceptability due to fermented flavour compared to treated fruit, marketable for more than two weeks. Among all the treatments, the synergy of 1-MCP and hypobaric treatment 25 kPa + 0.6 µLL-1 1-MCP improved the postharvest storage life and quality parameters, preventing development of fermented flavour in the pears. The experiment was conducted on pilot scale, for commercial application, the results of this study should be validated on large scale.

Whole-genome characterization of chronological age-associated changes in methylome and circular RNAs in moso bamboo (Phyllostachys edulis) from vegetative to floral growth.

In mammals, DNA methylation is associated with aging. However, age-related DNA methylation changes during phase transitions largely remain unstudied in plants. Moso bamboo (Phyllostachys edulis) requires a very long time to transition from the vegetative to the floral phase. To comprehensively investigate the association of DNA methylation with aging, we present here single-base-resolution DNA methylation profiles using both high-throughput bisulfite sequencing and single-molecule nanopore-based DNA sequencing, covering the long period of vegetative growth and transition to flowering in moso bamboo. We discovered that CHH methylation gradually accumulates from vegetative to reproductive growth in a time-dependent fashion. Differentially methylated regions, correlating with chronological aging, occurred preferentially at both transcription start sites and transcription termination sites. Genes with CG methylation changes showed an enrichment of Gene Ontology (GO) categories in 'vegetative to reproductive phase transition of meristem'. Combining methylation data with mRNA sequencing revealed that DNA methylation in promoters, introns and exons may have different roles in regulating gene expression. Finally, circular RNA (circRNA) sequencing revealed that the flanking introns of circRNAs are hypermethylated and enriched in long terminal repeat (LTR) retrotransposons. Together, the observations in this study provide insights into the dynamic DNA methylation and circRNA landscapes, correlating with chronological age, which paves the way to study further the impact of epigenetic factors on flowering in moso bamboo.

ipa1 improves rice drought tolerance at seedling stage mainly through activating abscisic acid pathway.

KEY MESSAGE: ipa1 enhances rice drought tolerance mainly through activating the ABA pathway. It endows rice seedlings with a more developed root system, smaller leaf stomata aperture, and enhanced carbon metabolism. Drought is a major abiotic stress to crop production. IPA1 (IDEAL PLANT ARCHITECTURE 1)/OsSPL14 encodes a transcription factor and has been reported to function in both rice ideal plant architecture and biotic resistance. Here, with a pair of IPA1 and ipa1-NILs (Near Iso-genic Lines), we found that ipa1 could significantly improve rice drought tolerance at seedling stage. The ipa1 plants had a better-developed root system and smaller leaf stomatal aperture. Analysis of carbon-nitrogen metabolism-associated enzyme activity, gene expression, and metabolic profile indicated that ipa1 could tip the carbon-nitrogen metabolism balance towards an increased carbon metabolism pattern. In both the control and PEG-treated conditions, ABA content in the ipa1 seedlings was significantly higher than that in the IPA1 seedlings. Expression of the ABA biosynthesis genes was detected to be up-regulated, whereas the expression of ABA catabolism genes was down-regulated in the ipa1 seedlings. In addition, based on yeast one-hybrid assay and dual-luciferase assay, IPA1 was found to directly activate the promoter activity of OsHOX12, a transcription factor promoting ABA biosynthesis, and OsNAC52, a positive regulator of the ABA pathway. The expression of OsHOX12 and OsNAC52 was significantly up-regulated in the ipa1 plants. Combined with the previous studies, our results suggested that ipa1 could improve rice seedling drought tolerance mainly through activating the ABA pathway and that regulation of the ipa1-mediated ABA pathway will be an important strategy for improving drought resistance of rice.

Proactive Caching in D2D Assisted Multitier Cellular Network.

Cache-enabled networks suffer hugely from the challenge of content caching and content delivery. In this regard, cache-enabled device-to-device (D2D) assisted multitier cellular networks are expected to relieve the network data pressure and effectively solve the problem of content placement and content delivery. Consequently, the user can have a better opportunity to get their favored contents from nearby cache-enabled transmitters (CETs) through reliable and good-quality links; however, as expected, designing an effective caching policy is a challenging task due to the limited cache memory of CETs and uncertainty in user preferences. In this article, we introduce a joint content placement and content delivery technique for D2D assisted multitier cellular networks (D2DMCN). A support vector machine (SVM) is employed to predict the content popularity to determine which content is to be cached and where it is to be cached, thereby increasing the overall cache hit ratio (CHR). The content request is satisfied either by the neighboring node through the D2D link or by the cache-enabled base stations (BSs) of the multitier cellular networks (MCNs). Similarly, to solve the problem of optimal content delivery, the Hungarian algorithm is employed aiming to improve the quality of satisfaction. The simulation results indicate that the proposed content placement strategy effectively optimizes the overall cache hit ratio of the system. Similarly, an effective content delivery approach reduces the request content delivery delay and power consumption.

Hypobaric treatment augments the efficacy of 1-MCP in apple fruit.

This research aimed to extend the postharvest shelf life of Royal Gala apple during cold storage and maintain its market value in simulated retail conditions. Apples were treated with hypobaric pressure (50 kPa for 4 h) followed by 1-MCP (0.5 µL L-1, 0.7 µL L-1, and 1.0 µL L-1) treatment for 24 h individually and in combinations, stored at (1 ± 1 °C, 85 ± 3% RH) for 120 d and analyzed for different quality parameters (Peel color, firmness, weight loss, TSS, acidity, ethylene production rate, and respiration rate) at each 30 d interval, followed by a 20 d simulated retail condition at 20 ± 3 °C with 4 d interval. Results indicated that all 1-MCP concentrations were more effective in retaining quality compared to individual hypobaric treatment. However, a synergistic effect was observed by combining 1-MCP with hypobaric treatment. Among the combined treatments, 1.0 µL L-11-MCP + 50 kPa more effectively and significantly retained quality during cold storage. Furthermore, the apples were more juicy, tasty, and attractive in color than others in simulated conditions. Addition of hypobaric treatment to 1-MCP might reduce endogenous ethylene in fruit by outward diffusion and blocking further ethylene synthesis by the action of 1-MCP. However, in-depth study is required for further understanding the phenomena.

Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders.

Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5-7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer's diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein-protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aß42. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aß42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in 'Alzheimer's disease research.

Perceived stress score among doctors serving at various government and private hospitals in Faisalabad.

OBJECTIVE: To analyse the prevalence of stress among doctors serving at various public and private hospitals. METHODS: The cross-sectional study was conducted at four public and private hospitals in Faisalabad, Pakistan, from July to December 2019, and comprised doctors with at least one year of professional service. Data was collected using the Perceived Stress Scale Questionnaire and was analysed using SPSS 20. RESULTS: Of the 162 respondents, 87(53.7%) were males and 75(46.3%) were females. The females had significantly higher (p<0.05) perceived stress scores compared to the males. Age, number of years in job, and number of children had negative correlation with stress scores (p<0.05). Stress was significantly low in doctors who managed to usually get time-out for relaxation (p<0.01) and in those doing private practice (p<0.05). The effect of doctor's marital status, type of specialty and residence was not significant (p>0.05). CONCLUSIONS: Younger doctors, particularly females, in their early career were found to have higher perceived stress scores compared to their senior colleagues with more children and well-established private practice.

Adverse drug reaction prevalence and mechanisms of action of first-line anti-tubercular drugs.

PURPOSE: Understanding the appearance of anti-tubercular drug-related adverse drug reactions (ADRs) in patients receiving tuberculosis (TB) treatment is important, and may be related to morbidity and mortality if not recognized early. Here, we aimed to characterize the mechanisms underlying adverse drug reactions due to combination anti-tuberculosis therapy of the Revised National Tuberculosis Control Program (RNTCP). METHODS: This was a prospective observational study conducted in 9 DOTS centers of New Delhi, India. All enrolled TB patients receiving first-line tuberculosis treatment as per RNTCP guidelines were monitored for ADRs. All ADRs that appeared during the treatment were recorded and analyzed. RESULTS: The study included 1011 TB patients on anti-TB treatment under DOTS. According to Naranjo's probability scale, of a total 351 (34.72%) reported adverse events, 102 (10.09%) were definite, 59 (5.83%) probable, 123 (12.17%) possible, and 67 (6.63%) doubtful. On the Hartwig severity scale, of the 351 adverse drug events, 225 (22.26%) were mild, 105 (10.38%) were moderate, and 21 (2.08%) were severe. Out of 102 reported adverse drug reactions, 81 (79.41%) were moderate and 21 (20.59%), while 65.28% did not experience any ADRs. CONCLUSIONS: Directly Observed Treatment (DOT) is effective and safe compared to daily treatment regimens. Patients receiving DOTS therapy needed close monitoring for adverse events. Therefore, a pharmacovigilance program should be added at the National level to accesses the adverse event incidence.

Arabidopsis protein arginine methyltransferase 3 is required for ribosome biogenesis by affecting precursor ribosomal RNA processing.

Ribosome biogenesis is a fundamental and tightly regulated cellular process, including synthesis, processing, and assembly of rRNAs with ribosomal proteins. Protein arginine methyltransferases (PRMTs) have been implicated in many important biological processes, such as ribosome biogenesis. Two alternative precursor rRNA (pre-rRNA) processing pathways coexist in yeast and mammals; however, how PRMT affects ribosome biogenesis remains largely unknown. Here we show that Arabidopsis PRMT3 (AtPRMT3) is required for ribosome biogenesis by affecting pre-rRNA processing. Disruption of AtPRMT3 results in pleiotropic developmental defects, imbalanced polyribosome profiles, and aberrant pre-rRNA processing. We further identify an alternative pre-rRNA processing pathway in Arabidopsis and demonstrate that AtPRMT3 is required for the balance of these two pathways to promote normal growth and development. Our work uncovers a previously unidentified function of PRMT in posttranscriptional regulation of rRNA, revealing an extra layer of complexity in the regulation of ribosome biogenesis.

Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.

Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Krüppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status.

CLINICAL FEATURES AND OUTCOME ANALYSIS OF INTRACRANIAL HYDATID CYSTS.

BACKGROUND: Hydatid cyst of the brain is serious zoonotic parasitic infections which have profound health consequences if left untreated. The surgical excisions of the cysts are rewarding for both the patient the neurosurgeon. METHODS: The study was conducted prospectively at Department of Neurosurgery Hayatabad Medical Complex Peshawar from January 2013 to December 2014. Patients with a diagnosis of intracranial hydatid cysts were included, clinical and radiological features recorded, intervention and postoperative outcome were analysed. RESULTS: Eleven patients with a male to female ratio of 1.7:1. Mean age was 12.4 (SD ± 6.5) years with median GCS on arrival of 10 (SD ± 2.5). Clinical features were headache (81.8%), vomiting (90.9%), seizures (36.4%), focal deficits (54.5%) and papilloedema (72.7%). The median GCS on discharge was 13 (SD ± 1.1) while GOS at 1 month follow up was 4 (SD ± 0.7). The bivariate analysis showed inverse correlation (R² = -0.68; p = 0.02) between duration of symptoms and outcome while GCS on admission was positively correlated (r(s) = 0.75; p = 0.007) with the outcome. There was no mortality. CONCLUSION: Despite its rarity the clinical features are non-specific while radiological features help in establishing diagnosis. Earlier diagnosis and prompt intervention is the key to favourable outcome.

Effect of parthenolide on growth and apoptosis regulatory genes of human cancer cell lines.

CONTEXT: Parthenolide (a sesquiterpene lactone), a bioactive compound of Tanacetum parthenium (L.) Schultz Bip. (Asteraceae) herb, has been reported for antioxidant and anticancer activities. OBJECTIVE: The present study evaluated the effect of parthenolide on growth and apoptosis-regulatory genes of human cervical cancer (SiHa) and breast cancer (MCF-7) cell lines. MATERIALS AND METHODS: The cytotoxic activity of parthenolide (3.5-21 µM) was examined by MTT and LDH assays at 24 and 48 h time intervals. Apoptotic activity was evaluated by expression analysis of multiple apoptosis-regulatory genes (i.e., p53, Bcl-2, Bax, caspase-3, -6, and -9) by reverse transcriptase-PCR and DNA fragmentation assay. RESULTS: Parthenolide inhibited the growth of SiHa and MCF-7 cell lines in a concentration-dependent manner at 24 and 48 h time intervals (p < 0.001). The IC50 value of parthenolide against SiHa and MCF-7 cells were 8.42 ± 0.76 and 9.54 ± 0.82 µM, respectively. Parthenolide-treated cells showed up-regulation of p53, Bax, caspase-3, -6, and -3 genes and down-regulation of Bcl-2 gene (p ≤ 0.008). At IC50, the p53 gene was up-regulated by 9.67- and 3.15-fold in SiHa and MCF-7 cells, respectively. The Bax to Bcl-2 ratio was 3.4 and 2.3 for SiHa and MCF-7 cells, respectively. Also, the fragmented genomic DNA in parthenolide-treated cells showed the signs of apoptosis. CONCLUSION: Our study endorsed the biological activity of parthenolide and demonstrated the parthenolide-induced growth inhibition and apoptosis in SiHa and MCF-7 cells by modulating the expression of apoptosis-regulatory genes.

Wearable sensors based on artificial intelligence models for human activity recognition.

Human motion detection technology holds significant potential in medicine, health care, and physical exercise. This study introduces a novel approach to human activity recognition (HAR) using convolutional neural networks (CNNs) designed for individual sensor types to enhance the accuracy and address the challenge of diverse data shapes from accelerometers, gyroscopes, and barometers. Specific CNN models are constructed for each sensor type, enabling them to capture the characteristics of their respective sensors. These adapted CNNs are designed to effectively process varying data shapes and sensor-specific characteristics to accurately classify a wide range of human activities. The late-fusion technique is employed to combine predictions from various models to obtain comprehensive estimates of human activity. The proposed CNN-based approach is compared to a standard support vector machine (SVM) classifier using the one-vs-rest methodology. The late-fusion CNN model showed significantly improved performance, with validation and final test accuracies of 99.35 and 94.83% compared to the conventional SVM classifier at 87.07 and 83.10%, respectively. These findings provide strong evidence that combining multiple sensors and a barometer and utilizing an additional filter algorithm greatly improves the accuracy of identifying different human movement patterns.

Anti-Oxidative and Anti-Apoptotic Oligosaccharides from Pichia pastoris-Fermented Cress Polysaccharides Ameliorate Chromium-Induced Liver Toxicity.

Oxidative stress impairs the structure and function of the cell, leading to serious chronic diseases. Antioxidant-based therapeutic and nutritional interventions are usually employed for combating oxidative stress-related disorders, including apoptosis. Here, we investigated the hepatoprotective effect of oligosaccharides, produced through Pichia pastoris-mediated fermentation of water-soluble polysaccharides isolated from Lepidium sativum (cress) seed mucilage, on chromium(VI)-induced oxidative stress and apoptosis in mice. Gel permeation chromatography (GPC), using Bio-Gel P-10 column, of the oligosaccharides product of fermentation revealed that P. pastoris effectively fermented polysaccharides as no long chain polysaccharides were observed. At 200 µg/mL, fractions DF73, DF53, DF72, and DF62 exhibited DPPH radical scavenging activity of 92.22 ± 2.69%, 90.35 ± 0.43%, 88.83 ± 3.36%, and 88.83 ± 3.36%, respectively. The antioxidant potential of the fermentation product was further confirmed through in vitro H2O2 radical scavenging assay. Among the screened samples, the highest H2O2 radical scavenging activity was displayed by DF73, which stabilized the free radicals by 88.83 ± 0.38%, followed by DF53 (86.48 ± 0.83%), DF62 (85.21 ± 6.66%), DF72 (79.9 4± 1.21%), and EPP (77.76 ± 0.53%). The oligosaccharide treatment significantly alleviated chromium-induced liver damage, as evident from the increase in weight gain, improved liver functions, and reduced histopathological alterations in the albino mice. A distinctly increased level of lipid peroxide (LPO) free radicals along with the endogenous hepatic enzymes were evident in chromium induced hepatotoxicity in mice. However, oligosaccharides treatment mitigated these effects by reducing the LPO production and increasing ALT, ALP, and AST levels, probably due to relieving the oxidative stress. DNA fragmentation assays illustrated that Cr(VI) exposure induced massive apoptosis in liver by damaging the DNA which was then remediated by oligosaccharides supplementation. Histopathological observations confirmed that the oligosaccharide treatment reverses the architectural changes in liver induced by chromium. These results suggest that oligosaccharides obtained from cress seed mucilage polysaccharides through P. pastoris fermentation ameliorate the oxidative stress and apoptosis and act as hepatoprotective agent against chromium-induced liver injury.

Staphylococcus arlettae mediated defense mechanisms and metabolite modulation against arsenic stress in Helianthus annuus.

Introduction: Arsenate, a metalloid, acting as an analog to phosphate, has a tendency to accumulate more readily in plant species, leading to adverse effects. Methods: In the current study, sunflower seedlings were exposed to 25, 50 and 100 ppm of the arsenic. Results: Likewise, a notable reduction (p<0.05) was observed in the relative growth rate (RGR) by 4-folds and net assimilation rate (NAR) by 75% of Helianthus annuus when subjected to arsenic (As) stress. Nevertheless, the presence of Staphylococcus arlettae, a plant growth-promoting rhizobacterium with As tolerance, yielded an escalation in the growth of H. annuus within As-contaminated media. S. arlettae facilitated the conversion of As into a form accessible to plants, thereby, increasing its uptake and subsequent accumulation in plant tissues. S. arlettae encouraged the enzymatic antioxidant systems (Superoxide dismutase (SOD), peroxidase (POD), ascorbate peroxidase (APX) and catalase (CAT)) and non-enzymatic antioxidants (flavonoids, phenolics, and glutathione) in H. annuus seedlings following substantial As accumulation. The strain also induced the host plant to produce osmolytes like proline and sugars, mitigating water loss and maintaining cellular osmotic balance under As-induced stress. S. arlettae rectified imbalances in lignin content, reduced high malonaldehyde (MDA) levels, and minimized electrolyte leakage, thus counteracting the toxic impacts of the metal. Conclusion: The strain exhibited the capability to concurrently encourage plant growth and remediate Ascontaminated growth media through 2-folds rate of biotransformation and bio-mobilization.

Pichia pastoris Mediated Digestion of Water-Soluble Polysaccharides from Cress Seed Mucilage Produces Potent Antidiabetic Oligosaccharides.

Diabetes mellitus is a heterogeneous metabolic disorder that poses significant health and economic challenges across the globe. Polysaccharides, found abundantly in edible plants, hold promise for managing diabetes by reducing blood glucose levels (BGL) and insulin resistance. However, most of these polysaccharides cannot be digested or absorbed directly by the human body. Here we report the production of antidiabetic oligosaccharides from cress seed mucilage polysaccharides using yeast fermentation. The water-soluble polysaccharides extracted from cress seed mucilage were precipitated using 75% ethanol and fermented with Pichia pastoris for different time intervals. The digested saccharides were fractionated through gel permeation chromatography using a Bio Gel P-10 column. Structural analysis of the oligosaccharide fractions revealed the presence of galacturonic acid, rhamnose, glucuronic acid, glucose and arabinose. Oligosaccharide fractions exhibited the potential to inhibit α-amylase and α-glucosidase enzymes in a dose-dependent manner in vitro. The fraction DF73 exhibited strong inhibitory activity against α-amylase with IC50 values of 38.2 ± 1.12 µg/mL, compared to the positive control, acarbose, having an IC50 value of 29.18 ± 1.76 µg/mL. Similarly, DF72 and DF73 showed the highest inhibition of α-glucosidase, with IC50 values of 9.26 ± 2.68 and 50.47 ± 5.18 µg/mL, respectively. In in vivo assays in streptozotocin (STZ)-induced diabetic mice, these oligosaccharides significantly reduced BGL and improved lipid profiles compared to the reference drug metformin. Histopathological observations of mouse livers indicated the cytoprotective effects of these sugars. Taken together, our results suggest that oligosaccharides produced through microbial digestion of polysaccharides extracted from cress seed mucilage have the potential to reduce blood glucose levels, possibly through inhibition of carbohydrate-digesting enzymes and regulation of the various signaling pathways.

Survival after Trastuzumab Therapy in Patients with Locally Advanced or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of Randomized Controlled Trials.

Background: In the Trastuzumab for Gastric Cancer study, it was found that trastuzumab combined with doublet chemotherapy (fluoropyrimidine and platinum) was the gold-standard treatment for gastroesophageal adenocarcinoma (GEA) that was locally advanced, unresectable, or metastatic (HER2+). Materials and Methods: We performed a meta-analysis of randomized phase II/III studies testing trastuzumab in combination or alone. Results: This meta-analysis's findings involved 2048 patients in total. The treatment arm and hormone receptor status were used to stratify the combined HR. Overall, the PFS (Random model) HR [0.80] and 95% confidence intervals (CI) [0.68-0.95] were significantly higher for regimens containing trastuzumab, fluoropyrimidine, and platinum compared to regimens containing fluoropyrimidine and platinum. Conclusions: The results of this meta-analysis provide additional support for trastuzumab's use in treating HER2-positive GEA, particularly in cases where the disease lacks a HER2+ receptor.

Identification of Small Inhibitors for Human Metadherin, an Oncoprotein, through in silico Approach.

AIMS: Cancer is a disease that takes lives of thousands of people each year. There are more than 100 different types of cancers known to man. This fatal disease is one of the leading causes of death today. BACKGROUND: Astrocyte elevated gene-1(AEG-1)/Metadherin (MTDH) activates multiple oncogenic signaling pathways and leads to different types of cancers. MTDH interacting with staphylococcal nuclease domain containing 1(SND1) supports the survival and growth of mammary epithelial cells under oncogenic conditions. OBJECTIVE: Silencing MTDH or SND1 individually or disrupting their interaction compromises the tumorigenic potential of tumor-initiating cells. The aim of our present study was to investigate novel interactions of staphylococcal nuclease domain containing 1 (SND1) binding domain of AEG-1/MTDH with different lead compounds through molecular docking approach using MOE software. METHODS: Molecular docking was done by docking the ChemBridge database against important residues of MTDH involved in interaction with SND1. After docking the whole ChemBridge database, the top 200 interactive compounds were selected based on docking scores. After applying Lipinski's rule, all the remaining chosen compounds were studied on the basis of binding affinity, binding energy, docking score and protein-ligand interactions. Finally, 10 compounds showing multiple interactions with different amino acid residues were selected as the top interacting compounds. RESULTS: Three compounds were selected for simulation studies after testing these compounds using topkat toxicity and ADMET studies. The simulation study indicated that compound 32538601 is a lead compound for inhibiting MTDH-SND1 complex formation. CONCLUSION: These novels, potent inhibitors of MTDH-SND1 complex can ultimately help us in controlling cancer up to some extent.

Isolation of multiple electrocardiogram artifacts using independent vector analysis.

Electrocardiogram (ECG) signals are normally contaminated by various physiological and nonphysiological artifacts. Among these artifacts baseline wandering, electrode movement and muscle artifacts are particularly difficult to remove. Independent component analysis (ICA) is a well-known technique of blind source separation (BSS) and is extensively used in literature for ECG artifact elimination. In this article, the independent vector analysis (IVA) is used for artifact removal in the ECG data. This technique takes advantage of both the canonical correlation analysis (CCA) and the ICA due to the utilization of second-order and high order statistics for un-mixing of the recorded mixed data. The utilization of recorded signals along with their delayed versions makes the IVA-based technique more practical. The proposed technique is evaluated on real and simulated ECG signals and it shows that the proposed technique outperforms the CCA and ICA because it removes the artifacts while altering the ECG signals minimally.