The multifaceted role of intracellular glycosylation in cytoprotection and heart disease.

The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked ß-N-actylglucosamine (O-GlcNAc) is an essential posttranslational modification that is common in metozoans. O-GlcNAc is cycled on and off proteins in response to environmental and physiological stimuli impacting protein function, which, in turn, tunes pathways that include transcription, translation, proteostasis, signal transduction, and metabolism. One class of stimulus that induces rapid and dynamic changes to O-GlcNAc is cellular injury, resulting from environmental stress (for instance, heat shock), hypoxia/reoxygenation injury, ischemia reperfusion injury (heart attack, stroke, trauma hemorrhage), and sepsis. Acute elevation of O-GlcNAc before or after injury reduces apoptosis and necrosis, suggesting that injury-induced changes in O-GlcNAcylation regulate cell fate decisions. However, prolonged elevation or reduction in O-GlcNAc leads to a maladaptive response and is associated with pathologies such as hypertrophy and heart failure. In this review, we discuss the impact of O-GlcNAc in both acute and prolonged models of injury with a focus on the heart and biological mechanisms that underpin cell survival.

Differential Detection of O-GlcNAcylated proteins in the heart using antibodies.

Thousands of mammalian intracellular proteins are dynamically modified by O-linked ß-N-acetylglucosamine (O-GlcNAc). Global changes in O-GlcNAcylation have been associated with the development of cardiomyopathy, heart failure, hypertension, and neurodegenerative disease. Levels of O-GlcNAc in cells and tissues can be detected using numerous approaches; however, immunoblotting using GlcNAc-specific antibodies and lectins is commonplace. The goal of this study was to optimize the detection of O-GlcNAc in heart lysates by immunoblotting. Using a combination of tissue fractionation, immunoblotting, and galactosyltransferase labeling, as well as hearts from wild-type and O-GlcNAc transferase transgenic mice, we demonstrate that contractile proteins in the heart are differentially detected by two commercially available antibodies (CTD110.6 and RL2). As CTD110.6 displays poor reactivity toward contractile proteins, and as these proteins represent a major fraction of the heart proteome, a better assessment of cardiac O-GlcNAcylation is obtained in total tissue lysates with RL2. The data presented highlight tissue lysis approaches that should aid the assessment of the cardiac O-GlcNAcylation by immunoblotting.

Simultaneous monitoring and dietary risk assessment of 386 pesticides in market samples of black tea.

Black tea samples (390) collected from local markets situated in different locations of India were monitored for the residues of 386 pesticides using QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) based extraction and analysis by gas and liquid chromatography tandem mass spectrometry (GC-MS/MS and LC-MS/MS). Residues of seventeen pesticides were detected, of which propargite, cypermethrin, and novaluron showed the highest % positive detections. A comparison of the concentrations of the detected pesticide residues with the available national and international maximum residue limits (MRLs) showed that seven samples exceeded the Indian MRLs while no sample was found to exceed the CODEX MRLs. The risk due to the detected pesticide levels evaluated in terms of hazard quotient (HQ) and hazard index (HI) was found to be very low (<1), suggesting that the pesticide residues in the tea were safe for consumption by Indian adults and children.

Digital Intervention For The Management Of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive, multifactorial, chronic, neurodegenerative disease with high prevalence and limited therapeutic options, making it a global health crisis. Being the most common cause of dementia, AD erodes the cognitive, functional, and social abilities of the individual and causes escalating medical and psychosocial needs. As yet, this disorder has no cure and current treatment options are palliative in nature. There is an urgent need for novel therapy to address this pressing challenge. Digital therapeutics (Dtx) is one such novel therapy that is gaining popularity globally. Dtx provides evidence based therapeutic interventions driven by internet and software, employing tools such as mobile devices, computers, videogames, apps, sensors, virtual reality aiding in the prevention, management, and treatment of ailments like neurological abnormalities and chronic diseases. Dtx acts as a supportive tool for the optimization of patient care, individualized treatment and improved health outcomes. Dtx uses visual, sound and other non-invasive approaches for instance-consistent therapy, reminiscence therapy, computerised cognitive training, semantic and phonological assistance devices, wearables and computer-assisted rehabilitation environment to find applications in Alzheimer's disease for improving memory, cognition, functional abilities and managing motor symptom. A few of the Dtx-based tools employed in AD include "Memory Matters", "AlzSense", "Alzheimer Assistant", "smart robotic dog", "Immersive virtual reality (iVR)" and the most current gamma stimulation. The purpose of this review is to summarize the current trends in digital health in AD and explore the benefits, challenges, and impediments of using Dtx as an adjunctive therapy for the management of AD.

Chondroitin sulfate-based composites: a tour d'horizon of their biomedical applications.

Chondroitin sulfate (CS), a natural anionic mucopolysaccharide, belonging to the glycosaminoglycan family, acts as the primary element of the extracellular matrix (ECM) of diverse organisms. It comprises repeating units of disaccharides possessing ß-1,3-linked N-acetyl galactosamine (GalNAc), and ß-1,4-linked D-glucuronic acid (GlcA), and exhibits antitumor, anti-inflammatory, anti-coagulant, anti-oxidant, and anti-thrombogenic activities. It is a naturally acquired bio-macromolecule with beneficial properties, such as biocompatibility, biodegradability, and immensely low toxicity, making it the center of attention in developing biomaterials for various biomedical applications. The authors have discussed the structure, unique properties, and extraction source of CS in the initial section of this review. Further, the current investigations on applications of CS-based composites in various biomedical fields, focusing on delivering active pharmaceutical compounds, tissue engineering, and wound healing, are discussed critically. In addition, the manuscript throws light on preclinical and clinical studies associated with CS composites. A short section on Chondroitinase ABC has also been canvassed. Finally, this review emphasizes the current challenges and prospects of CS in various biomedical fields.

HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells.

HOXA5 is a transcription factor and tumor suppressor that promotes differentiation of breast epithelial cells and is frequently lost during malignant transformation. HOXA5 loss alone, however, does not confer tumorigenicity. To determine which molecular alterations combined with loss of HOXA5 expression can transform cells, we examined isogenic derivatives of a nonmalignant breast epithelial cell line containing knock-in or knockout mutations in key breast cancer genes. Knockdown (KD) of HOXA5 in cells harboring double knock-in (DKI) of mutated PIK3CA (E545K) and HER2 (V777L) induced epithelial-mesenchymal transition and migration and promoted invasive tumor outgrowth within mouse mammary ducts. The NF-κB pathway was significantly upregulated in DKI cells following HOXA5 KD. HOXA5 KD upregulated multiple NF-κB target genes, including IL6. IκBα protein, but not RNA, expression was reduced in HOXA5-KD cells. HOXA5 bound and stabilized IκBα, forming a nuclear HOXA5-IκBα complex. Chromatin immunoprecipitation sequencing database queries revealed that HOXA5 and IκBα are co-enriched at 528 genomic loci. In patients with breast cancer, high coexpression of HOXA5 and IκBα conferred a significantly better overall and progression-free survival. Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα. SIGNIFICANCE: Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.

PAAN/MIF nuclease inhibition prevents neurodegeneration in Parkinson's disease.

Parthanatos-associated apoptosis-inducing factor (AIF) nuclease (PAAN), also known as macrophage migration inhibitor factor (MIF), is a member of the PD-D/E(X)K nucleases that acts as a final executioner in parthanatos. PAAN's role in Parkinson's disease (PD) and whether it is amenable to chemical inhibition is not known. Here, we show that neurodegeneration induced by pathologic α-synuclein (α-syn) occurs via PAAN/MIF nuclease activity. Genetic depletion of PAAN/MIF and a mutant lacking nuclease activity prevent the loss of dopaminergic neurons and behavioral deficits in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Compound screening led to the identification of PAANIB-1, a brain-penetrant PAAN/MIF nuclease inhibitor that prevents neurodegeneration induced by α-syn PFF, AAV-α-syn overexpression, or MPTP intoxication in vivo. Our findings could have broad relevance in human pathologies where parthanatos plays a role in the development of cell death inhibitors targeting the druggable PAAN/MIF nuclease.

Recent advances in preventing neurodegenerative diseases.

The worldwide health-care burden of neurodegenerative diseases is on the rise-a crisis created through a combination of increased caseload and lack of effective treatments. The limitations of pharmacotherapy in these disorders have led to an urgent shift toward research and clinical trials for the development of novel compounds, interventions, and methods that target shared features across the spectrum of neurodegenerative diseases. Research targets include neuronal cell death, mitochondrial dysfunction, protein aggregation, and neuroinflammation. In the past few years, there has been a growth in understanding of the pathophysiologic mechanisms of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. This increase in knowledge has led to the discovery of numerous novel neuroprotective therapeutic targets. In this context, we reviewed and summarized recent advancements in neuroprotective strategies in neurodegenerative diseases.

Virtual Dissection: An Interactive Anatomy Learning Tool.

The novelty of three-dimensional visualization technology (3DVT), such as virtual reality (VR), has captured the interest of many educational institutions. This study's objectives were to (1) assess how VR and physical models impact anatomy learning, (2) determine the effect of visuospatial ability on anatomy learning from VR and physical models, and (3) evaluate the impact of a VR familiarization phase on learning. This within-subjects, crossover study recruited 78 undergraduate students who studied anatomical structures at both physical and VR models and were tested on their knowledge immediately and 48 hours after learning. There were no significant differences in test scores between the two modalities on both testing days. After grouping participants on visuospatial ability, low visuospatial ability learners performed significantly worse on anatomy knowledge tests compared to their high visuospatial ability counterparts when learning from VR immediately (P = 0.001, d = 1.515) and over the long-term (P = 0.003, d = 1.279). In contrast, both low and high visuospatial ability groups performed similarly well when learning from the physical model and tested immediately after learning (P = 0.067) and over the long-term (P = 0.107). These results differ from current literature which indicates that learners with low visuospatial ability are aided by 3DVT. Familiarizing participants with VR before the learning phase had no impact on learning (P = 0.967). This study demonstrated that VR may be detrimental to low visuospatial ability students, whereas physical models may allow all students, regardless of their visuospatial abilities, to learn similarly well.

Nexus between light and culture media on morphogenesis in Bacopa monnieri and saponin yield thereof.

Bacopa monnieri, a well-documented nootropic plant of high commercial global demand had been explored for its effect in alleviating other diseases and symptoms. This is primarily attributed to different phytocompounds present in the plant. One of the major constituents among them are saponins. However, variation in agro-climatic conditions and choice of germplasm often affect the growth rate and yield of phytocompounds that significantly impact the efficacy of the plant and its extract. Tissue culture has been attempted to improve the yield of phytocompounds but is often restricted by higher cost and scalability. Current study explores the role of commercial hydroponic media 'Leafy 200' vis-à-vis Murashige and Skoog (MS) media, under different color and intensity of lights, on plant morphogenesis, biomass and saponin yield. Blue light induced more shoot differentiation than normal white light. Statistical studies performed using fractional factorial design showed no significant variations in the yield of saponins among the extracts. The study suggests that hydroponic culture to be a sustainable solution and possible substitute to tissue culture that may be exploited for scalable cultivation of the plant.

Early versus delayed extubation in extremely preterm neonates: a retrospective cohort study.

OBJECTIVE: To evaluate clinical outcomes associated with extubation timing among extremely preterm neonates. DESIGN/METHODS: Neonates <26 weeks' GA admitted to four tertiary neonatal centers were included if they met predetermined extubation criteria within first postnatal week and classified into early extubation (≤24 h; exposure group) and delayed extubation (>24 h; control group) after meeting extubation criteria. Patients with known severe IVH and/or significant PDA prior to meeting extubation criteria were excluded. RESULTS: Of 197 included infants, 75 were in exposure group. Survival without BPD (aOR 1.26; 95% CI 0.62-2.56; P = 0.52) and survival without severe IVH (aOR 1.98; 95% CI 0.93-4.23; P = 0.08) were not different, adjusted for GA, SNAP, number of surfactant doses and center. CONCLUSIONS: Extubation within 24 h of meeting extubation criteria in neonates <26 weeks' GA was not associated with survival without BPD or survival without severe IVH. However, confounding by indication cannot be ruled out without a prospective trial.