Computational Exploration of Limonin as a Potential Inhibitor of DapB in Klebsiella pneumoniae.

Klebsiella pneumoniae has emerged as a significant multidrug-resistant pathogen, classified as a critical priority by the World Health Organization. The rising rates of antibiotic resistance have led to increased therapeutic failures, diminishing the effectiveness of existing antibiotics. Consequently, there is an urgent need for alternative treatments to effectively inhibit the growth of K. pneumoniae and mitigate associated diseases. Phytochemicals have demonstrated potential advantages over traditional antibiotics, prompting their exploration as innovative therapeutic agents. This study aimed to identify phytochemicals that can inhibit dapB, a vital enzyme in the lysine biosynthesis pathway of K. pneumoniae, which is essential for protein synthesis and the cross-linking of the bacterial peptidoglycan cell wall. We screened 17,934 phytochemicals based on Lipinski's Rule of Five, along with their Absorption, Distribution, Metabolism, Excretion properties and toxicological parameters. Next, we conducted triplicate docking studies against dapB to evaluate the library further. The most promising molecules then underwent 100 ns Molecular Dynamics simulations in triplicate, followed by binding free energy calculations to identify potential dapB inhibitors. This in silico analysis highlighted limonin as a promising inhibitor of dapB in K. pneumoniae. Further experimental validation is crucial to enhance limonin's potential as a novel therapeutic agent against K. pneumoniae-associated diseases.

A Survey Among Psychiatrists to Assess the Need for Psychiatry Sub/Super-specialization Courses in India.

Background: India's landscape of sub/super-specialization courses is expanding rapidly. Numerous courses spanning various domains of psychiatry exist, and this trend is poised to continue its upward trajectory. We aimed to assess the need for sub/super-specialization courses in psychiatry in India and explore the structural components of the courses. Methods: This was a cross-sectional study. A total of 142 psychiatrists/psychiatry residents from India were surveyed using an online questionnaire after approval from the Institutional Ethics Committee. Results: "Good" and "intense" need for specialization courses was reported to be highest for child and adolescent psychiatry (68.3%), followed by addiction psychiatry (56.4%) and psychotherapy (55.6%). A 1-year post-doctoral fellowship was reported to be the most preferred course format. Practical examination was suggested to be the preferred summative assessment method for different course formats. Conclusion: The availability of sub/super-specialization courses presents an opportunity to enhance psychiatrists' training in specific areas of interest. Offering a variety of course options enables psychiatrists to select the most suitable program based on their individual requirements and career goals.

Different dietary branched-chain amino acid ratios, crude protein levels, and protein sources can affect the growth performance and meat yield in broilers.

Balanced ratios of branched-chain amino acids (BCAAs) can enhance chicken growth, immunity, and muscle synthesis. However, these ratios can be affected by changes in crude protein (CP) levels or the substitution of protein sources, leading to BCAA antagonism. This, in turn, can have a negative impact on chicken growth. In Experiment 1, a total of 960 0-d-old male Cobb 500 broilers were divided into 6 treatments with 8 replicates. Three different BCAA ratios were used in High or Low CP diets as follows: 1) Low Leu group (Low level of leucine with increased valine and isoleucine levels), 2) Med Leu group, and 3) High Leu group (High level of leucine with reduced valine and isoleucine levels) for a total of 6 diets. In Experiment 2, a total of 640 0-d-old male Cobb 500 broilers were divided into 4 treatments with 8 replicates. The four diets had either High or Low CP and one of two protein sources with the same medium levels of BCAAs: 1) the soybean meal (SBM) group, which had SBM as the main protein source (protein bound AA), and 2) the wheat middlings with non-bound AAs (WM+AA) group (non-bound AA), which had additional non-bound AAs to replace SBM. The High Leu diet had a negative effect on overall growth performance, carcass weight, breast muscle weight, and body mineral composition compared to the Low Leu and Med Leu groups, particularly in the High CP diet (P < 0.05). The SBM group showed increased growth performance, breast muscle weight, expression levels of genes promoting muscle growth, and improved bone mineral composition compared to the WM+AA group, and the High CP group intensified the negative effect of the WM+AA diet (P < 0.05). In summary, balanced BCAA ratios and SBM-based diets have positive effects on chicken growth and muscle accretion, whereas excessive leucine and non-bound AA levels in the diets may negatively affect growth performance and meat yield in chickens.

DDX3X dynamics, glioblastoma's genetic landscape, therapeutic advances, and autophagic interplay.

Glioblastoma is one of the most aggressive and deadly forms of cancer, posing significant challenges for the medical community. This review focuses on key aspects of Glioblastoma, including its genetic differences between primary and secondary types. Temozolomide is a major first-line treatment for Glioblastoma, and this article explores its development, how it works, and the issue of resistance that limits its effectiveness, prompting the need for new treatment strategies. Gene expression profiling has greatly advanced cancer research by revealing the molecular mechanisms of tumors, which is essential for creating targeted therapies for Glioblastoma. One important protein in this context is DDX3X, which plays various roles in cancer, sometimes promoting it or otherwise suppressing it. Additionally, autophagy, a process that maintains cellular balance, has complex implications in cancer treatment. Understanding autophagy helps to identify resistance mechanisms and potential treatments, with Chloroquine showing promise in treating Glioblastoma. This review covers the interplay between Glioblastoma, DDX3X, and autophagy, highlighting the challenges and potential strategies in treating this severe disease.

Unveiling frailty: comprehensive and sex-specific characterization in prematurely aging PolgA mice.

Frailty, a geriatric syndrome, is assessed using the frailty phenotype (FP) and frailty index (FI). While these approaches have been applied to aging mice, their effectiveness in prematurely aging mouse models such as PolgAD257A/D257A (PolgA) has not been completely explored. We demonstrated that frailty became evident in PolgA mice around 40 weeks, validated through body weight loss, reduced walking speed, decreased physical activity, and weaker grip strength. Moreover, we also identified sex differences in these mice with females exhibiting slightly more physical decline compared to males. Frailty prevalence in PolgA mice at 40 weeks parallels that observed in naturally aging mice at 27 months and aging humans at 65-70 years. These findings contribute to understanding frailty onset and sex-specific patterns in this prematurely aging mouse model, emphasizing the significance of the PolgA mouse model in investigating aging and related disorders.

Alternate Care Sites: A Novel Concept in Nepal During Disaster and Public Health Emergencies.

ABSTRACT: Nepal has a health care system that is complicated by access, affordability, and availability. The geographical difficulty makes the health care reach to public more difficult. Nepal being a disasterprone country, it makes very important to strengthen the disaster preparedness up to the mark before the disaster strikes. During disaster and public health emergencies, the healthcare system quickly becomes overwhelmed or structural damage makes it non-functional, which necessitate the prior identification of Alternate Care Site by health service providers. Incorporating the identification of Alternate Care Sites into the Hospital Disaster Preparedness Plan represents a crucial transition from theoretical discussion to practical implementation for strengthening healthcare facilities. . This paper discusses the concept of Alternate Care site and its implementation in Nepal's health emergency preparedness for disaster and public health emergencies.

Comparing the performance of multiple trigger tools in identifying medication-related hospital readmissions.

BACKGROUND: Multiple trigger tools have been developed to identify medication-related hospital (re)admissions (MRRs); however, the accuracy of these tools in real-world clinical practice is uncertain. The objective of this study was to compare the accuracy of four different trigger tools (OPERAM, STOPP/START criteria, ADR-tool, and QUADRAT) to identify MRRs compared with clinical adjudication. METHODS: We conducted a secondary analysis of patients readmitted within 30 days to seven departments of a teaching hospital. In the primary study, which involved a retrospective chart review of 1111 readmissions, MRRs and their potential preventability were clinically adjudicated by physicians and pharmacists. In the current study, four trigger tools were applied by a different physician and pharmacist panel. Patients of all ages were included. Trigger tools included both explicit items specifying the event and the associated medication and implicit items requiring clinical knowledge. The accuracy of each trigger tool was assessed by calculating the proportion of clinically adjudicated MRRs each tool identified overall as well as according to explicit and implicit triggers separately. The accuracy of each tool to identify potentially preventable MRRs was also calculated. RESULTS: Of 1111 readmissions, 181 were adjudicated as medication-related (mean age 69 years, 56% male); 72 (40%) MRRs were potentially preventable. The original OPERAM tool identified 166 (92%) MRRs (62% through explicit triggers). The STOPP/START criteria identified 23 (13%, 7% through explicit triggers), the ADR tool identified 51 (28%, all explicit triggers), and the QUADRAT tool identified 76 (42%; all explicit triggers) MRRs. Of the 72 potentially preventable MRRs, OPERAM identified 59 (82%), STOPP/START identified 18 (25%), ADR identified 20 (28%), and QUADRAT identified 21 (29%). CONCLUSION: The original OPERAM tool identified the highest proportion of (preventable) MRRs. However, this tool includes many implicit triggers requiring expert clinical knowledge. Future studies should assess the practicality of implementing this tool in daily practice.

Improving Prefrontal Oxygenation and Cardiac Autonomic Activity Following Meditation: A Functional Near-Infrared Spectroscopy (fNIRS) Study.

OBJECTIVE: The empirical evidence explicitly demonstrates that meditation practice enhances both brain functions and mental well-being. A meditative relaxation approach called the mind sound resonance technique (MSRT) has shown promising effects on children, adolescents, and people with psychological illnesses. This study aimed to investigate the effects of MSRT practice on brain hemodynamics, heart rate variability (HRV), mindfulness, and anxiety levels in college students. METHODS: Fifty volunteers in all genders (females, n = 30; males, n = 20) aged between 19 and 30 years were chosen from an educational institute and allocated into two groups, i.e., MSRT (n = 25) and supine rest (SR; n = 25). Enrolled participants were measured cerebral hemodynamics and HRV before, during, and after the MSRT or SR practice. The self-reported assessments including state anxiety and mindfulness were assessed before and after the intervention. RESULTS: The results demonstrated that practicing MSRT significantly improved oxygenation (p < 0.05) in the right prefrontal cortex (PFC) and increased low-frequency (LF) (p < 0.05) and decreased high-frequency (HF) (p < 0.05) component of HRV when compared to the baseline. The between-group analysis showed a significant difference between MSRT and SR in the standard deviation of the normal-to-normal (SDNN) (p < 0.05) component of HRV. CONCLUSION: These crumbs of evidence imply that MSRT sessions may foster the development of anxiety-related coping skills by elevating mindfulness, promoting PFC oxygenation, and modulating HRV in MSRT practitioners.

Seasonal variations in soil characteristics control microbial respiration and carbon use under tree plantations in the middle gangetic region.

Seasonal variations directly impact the biochemical and microbial properties of the soil, influence carbon and nutrient cycling within the soil system. Soils under tree plantation (TP) are rich in organic matter and microbial population, making them more susceptible to seasonal variation. We studied the effect of seasonal variations in soil chemical properties (pH, electrical conductivity (EC), total organic carbon (TOC), total nitrogen (TN), C/N ratio etc) and microclimate (moisture and temperature) on microbial respiration (SR), biomass, and carbon (C) utilization efficiency under 13 years old Kadamb (Anthocephalus cadamba Miq.), Simaraubha (Simarouba glauca DC), and Litchi (Litchi chinensis Sonn.) based TPs in middle Gangetic region. In contrast to higher SR and metabolic quotient (qCO2) in winter, the microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) in fall > summer > spring > winter, irrespective of TPs. The positive relationship between qCO2 and C/N ratios strongly supports the dependence of microbes on soil carbon for respiration. qCO2 had a significantly positive relationship with soil moisture (MC) and Electrical conductivity (EC), but a significantly negative relationship with temperature and pH. Higher MBN/TN and MBC/TOC ratios fall under simaraubha, and litchi-based TPs indicated more nitrogen (N) and carbon accumulation into microbial biomass. The seasonal variation of MBC/MBN ratios signifies the changes in microbial communities and fungi dominate over bacteria during winter, as bacteria have a lower C/N ratio than fungi. Stepwise regression analysis suggested that soil properties and micro-climate regulated microbial biomass and SR differ with TPs. Thus, the study indicates that microbial activities and biomass production can significantly influence by soil properties and seasonal variations under TPs.

Comparative Evaluation of Serum Levels of Vitamin B12, Folic Acid, and ESR in Chronic Periodontitis Among Smokers, Gutkha Chewers, and Type 2 Diabetic Patients: A Cross-Sectional Study.

Aim: The purpose of this research is to determine the relationship between periodontal disease severity, cigarette smoking, gutka chewing, and type 2 diabetes mellitus by estimating, correlating, and comparing blood levels of vitamin B12, folic acid, and erythrocyte sedimentation rate (ESR) in patients with chronic periodontitis. Methodology: A cross-sectional research study conducted at Rama Dental College Hospital and Research Centre in Kanpur involved 240 patients with chronic periodontitis, who also exhibited additional risk factors including smoking, gutkha chewing, and type-2 diabetes mellitus. Divided into four groups of 60 individuals each, the study aimed to estimate and correlate blood levels of vitamin B12, folic acid, and ESR. Group I served as the control with chronic periodontitis patients, while Group II comprised chronic periodontitis patients who were smokers, Group III included those who chewed gutkha, and Group IV consisted of patients with type-2 diabetes mellitus. Clinical parameters were assessed, and patients were followed up to track any changes or correlations. Result: This research confirmed that low levels of vitamin B12 and folic acid are linked to inflammatory diseases such chronic periodontitis. Conclusion: The study revealed that type-2 diabetic and gutka chewer groups exhibited statistically higher periodontal disease severity, vitamin B12, and folic acid deficiencies and elevated ESR compared to smokers and control groups.

The Impact of De-Roofing of Lateral Calcaneal wall in Open Reduction and Internal Fixation of Intra-Articular Fractures: Clinico-Radiological Outcomes of a Novel Technique and Review of Literature.

Background: Most displaced intra-articular calcaneus fractures need to be treated surgically but postoperative soft tissue complications limit to achieve of optimal functional outcomes. Certain mini-invasive techniques lead to better soft tissue healing but anatomical reduction gets compromised. Objectives: We aim to evaluate the results of lateral wall de-roofing of the calcaneum to achieve good anatomical reduction as well as to minimise soft tissue complications in the internal fixation of calcaneal fractures. Materials and Methods: Thirty-two patients (40 ft) with displaced intra-articular calcaneus fractures (10 were of Sanders type II, 16 were of type III, and 14 were of type IV) were treated between January 2018 and September 2021. All patients were managed surgically with open reduction and internal fixation using lateral extensile approach combined with de-roofing of the lateral wall. All patients were followed up for ≥1 year using functional parameters American Orthopaedic Foot and Ankle Score (AOFAS), visual analogue scale (VAS) and radiological parameters (Bohler angle, Gissane angle, height of the calcaneus, width of the calcaneus and pitch of calcaneus). Results: Out of 32 patients, one patient lost to follow-up. At 1 year follow-up, mean AOFAS hindfoot score was 86.2 ± 5 (Sanders type II: 91.2, Sanders type III: 87.6, and Sanders type III: 81.4), mean VAS score was 91.3 ± 2.1, mean Bohler angle (°) was 27.2 ± 4.7, mean Gissane angle (°) was 136.4 ± 5.2, mean calcaneus height was 46.2 ± 2.1 mm and mean calcaneus width was 45.1 ± 3.2 mm. Patients with decreased Bohler angle between postoperative images and follow-up had lower AOFAS hindfoot scores. Complications included persistent swelling (64.10%), stiffness (33.33%), superficial infections (5.12%), and wound dehiscence (10.25%). Conclusion: Lateral wall de-roofing is a useful technique which allows the lateral wall to get flattened reducing soft tissue complications and providing bone graft as well. This approach also adequately exposes fracture fragments, subtalar and calcaneocuboid joints for good anatomical reduction. Hence, it can act as a useful adjunct in the internal fixation of intra-articular calcaneus fractures. Level of Evidence: III.

Oral delivery of stabilized lipid nanoparticles for nucleic acid therapeutics.

Gastrointestinal disorders originate in the gastrointestinal tract (GIT), and the therapies can benefit from direct access to the GIT achievable through the oral route. RNA molecules show great promise therapeutically but are highly susceptible to degradation and often require a carrier for cytoplasmic access. Lipid nanoparticles (LNPs) are clinically proven drug-delivery agents, primarily administered parenterally. An ideal Orally Delivered (OrD) LNP formulation should overcome the diverse GI environment, successfully delivering the drug to the site of action. A versatile OrD LNP formulation has been developed to encapsulate and deliver siRNA and mRNA in this paper. The formulations were prepared by the systematic addition of cationic lipid to the base LNP formulation, keeping the total of cationic lipid and ionizable lipid to 50 mol%. Biorelevant media stability depicted increased resistance to bile salt mediated destabilization upon the addition of the cationic lipid, however the in vitro efficacy data underscored the importance of the ionizable lipid. Based on this, OrD LNP was selected comprising of 20% cationic lipid and 30% ionizable lipid. Further investigation revealed the enhanced efficacy of OrD LNP in vitro after incubation in different dilutions of fasted gastric, fasted intestinal media, and mucin. Confocal imaging and flow cytometry confirmed uptake while in vivo studies demonstrated efficacy with siRNA and mRNA as payloads. Taken together, this research introduces OrD LNP to deliver nucleic acid locally to the GIT.

Exploring mammalian heme peroxidases: A comprehensive review on the structure and function of myeloperoxidase, lactoperoxidase, eosinophil peroxidase, thyroid peroxidase and peroxidasin.

The peroxidase family of enzymes is a ubiquitous cluster of enzymes primarily responsible for the oxidation of organic and inorganic substrates. The mammalian heme peroxidase subfamily is characterized by a covalently linked heme prosthetic group which plays a key role in the oxidation of halides and psuedohalides into their respective hypohalous acid and hypothiocyanous acid under the influence of H2O2 as substrate. The members of the heme peroxidase family include Lactoperoxidase (LPO), Eosinophil peroxidase (EPO), Myeloperoxidase (MPO), Thyroid peroxidase (TPO) and Peroxidasin (PXDN). The biological activity of LPO, MPO and EPO pertains to antibacterial, antifungal and antiviral while TPO is involved in the biosynthesis of the thyroid hormone and PXDN helps maintain the ECM. While these enzymes play several immunomodulatory roles, aberrations in their activity have been implicated in diseases such as myocardial infarction, asthma and Alzheimer's amongst others. The sequence and structural similarities amongst the members of the family are strikingly high while the substrate specificities and subcellular locations vary. Hence, it becomes important to provide a consortium of information regarding the members to study their biochemical, pathological and clinical function.

Emerging lactic acid bacteria bacteriocins as anti-cancer and anti-tumor agents for human health.

Modern cancer diagnostics and treatment options have greatly improved survival rates; the illness remains a major cause of mortality worldwide. Current treatments for cancer, such as chemotherapy, are not cancer-specific and may cause harm to healthy cells; therefore, it is imperative that new drugs for cancer be developed that are both safe and effective. It has been found that lactic acid bacteria (LAB) have the potential to produce bacteriocins, which could potentially offer a promising alternative for cancer treatment. They have been shown in several studies to be effective against cancer cells while having no effect on healthy cells. More research is needed to fully understand the potential of LAB bacteriocins as anti-cancer medicines, to find the appropriate dose and delivery route, and to conduct clinical trials to evaluate the effectiveness and safety of the products in human patients, as is suggested by this work. Furthermore, LAB bacteriocins may evolve into a significant new class of anti-cancer drugs and food products. Patients with cancer may have a safe and effective alternative treatment option in the form of anti-cancer foods and drugs. Therefore, the aim of this study is to provide an in-depth analysis of the recent breakthroughs and potential future technical advancements of significant bacteriocins that are produced by LAB, how these bacteriocins function, and how these bacteriocins may be utilized as an anti-cancer agent. In addition, the current analysis emphasizes the significant constraints and boundaries that bacteriocins face when they are used as an anti-cancer factor.

Next-generation fertilizers: the impact of bionanofertilizers on sustainable agriculture.

Bionanofertilizers are promising eco-friendly alternative to chemical fertilizers, leveraging nanotechnology and biotechnology to enhance nutrient uptake by plants and improve soil health. They consist of nanoscale materials and beneficial microorganisms, offering benefits such as enhanced seed germination, improved soil quality, increased nutrient use efficiency, and pesticide residue degradation, ultimately leading to improved crop productivity. Bionanofertilizers are designed for targeted delivery of nutrients, controlled release, and minimizing environmental pollutants, making them a sustainable option for agriculture. These fertilizers also have the potential to enhance plant growth, provide disease resistance, and contribute to sustainable farming practices. The development of bionanofertilizers addresses the adverse environmental impact of chemical fertilizers, offering a safer and productive means of fertilization for agricultural practices. This review provides substantial evidence supporting the potential of bionanofertilizers in revolutionizing agricultural practices, offering eco-friendly and sustainable solutions for crop management and soil health.

The digital health dilemma: Exploring cyberchondria, well-being, and smartphone addiction in medical and non-medical undergraduates.

Background: The Internet is a popular source of health information, but too much research can cause anxiety (cyberchondria). Medical and non-medical personnel interpret information differently, leading to varying rates of cyberchondria. Smartphone addiction may also contribute to cyberchondria and impact mental health. Methods: The study was an epidemiological survey-based investigation with a cross-sectional design involving undergraduate students (aged 18 years or older) from Indian universities or colleges. The study utilized the Cyberchondria Severity Scale-Short Form (CSS-12), WHO-5 well-being index, and Smartphone Addiction Scale-Short Version (SAS-SV). Results: A total of 1033 participants (53.1% females and 46.4% males) were recruited in the survey. Of the participants, 58.5% were pursuing medical or paramedical courses, while the remaining 41.5% belonged to the non-medical group. High-severity cyberchondria was present in about 4.4% of the students. The medical cohort demonstrated a significantly lower cumulative CSS in comparison to the non-medical cohort (t = - 3.90; P < 0.01). Smartphone addiction was observed in 57.2% of individuals in the medical group and 55.9% of individuals in the non-medical group (P = 0.68). Medical students had a significantly lower mean well-being score compared to non-medical students (58.4 vs. 59.6; P < 0.01). There was a positive correlation between cyberchondria severity and smartphone addiction, which was consistent across both groups. Conclusion: Medical students have less cyberchondria than non-medical students. Cyberchondria severity is linked to smartphone addiction. Non-medical students with cyberchondria have higher subjective well-being.

Precision nutrition-based strategy for management of human diseases and healthy aging: current progress and challenges forward.

Currently, the treatment of various human ailments is based on different therapeutic approaches including traditional and modern medicine systems. Precision nutrition has come into existence as an emerging approach considering the diverse aspects such as age, sex, genetic and epigenetic makeup, apart from the pathophysiological conditions. The continuously and gradually evolving disciplines of genomics about nutrition have elucidated the importance of genetic variations, epigenetic information, and expression of myriads of genes in disease progression apart from the involvement in modulating therapeutic responses. Further, the investigations have presented the considerable role of gut microbiota comprising of commensal and symbionts performing innumerable activities such as release of bioactive molecules, defense against pathogenic microbes, and regulation of immunity. Noteworthy, the characteristics of the microbiome change depending on host attributes, environmental factors, and habitat, in addition to diet, and therefore can be employed as a biomarker to unravel the response to given food. The specific diet and the components thereof can be suggested for supporting the enrichment of the desired microbial community to some extent as an important part of precision nutrition to achieve not only the goal of human health but also of healthy aging.

Effective cerebral tuberculosis treatment via nose-to-brain transport of anti-TB drugs using mucoadhesive nano-aggregates.

Central nervous system tuberculosis (CNS-TB) is a severe form of extra-pulmonary tuberculosis with high mortality and morbidity rates. The standard treatment regimen for CNS-TB parallels that of pulmonary TB, despite the challenge posed by the blood-brain barrier (BBB), which limits the efficacy of first-line anti-TB drugs (ATDs). Nose-to-brain (N2B) drug delivery offers a promising solution for achieving high ATD concentrations directly at infection sites in the brain while bypassing the BBB. This study aimed to develop chitosan nanoparticles encapsulating ATDs, specifically isoniazid (INH) and rifampicin (RIF). These nanoparticles were further processed into micro-sized chitosan nano-aggregates (NA) via spray drying. Both INH-NA and RIF-NA showed strong mucoadhesion and significantly higher permeation rates across RPMI 2650 cells compared to free ATDs. Intranasal administration of these NAs to TB-infected mice for four weeks resulted in a significant reduction of mycobacterial load by approximately ∼2.86 Log 10 CFU compared to the untreated group. This preclinical data highlights the efficacy of intranasal chitosan nano-aggregates in treating CNS-TB, demonstrating high therapeutic potential, and addressing brain inflammation challenges. To our knowledge, this study is the first to show nasal delivery of ATD nano-formulations for CNS-TB management.