The intersection of frailty and metabolism.

On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.

Clinical diagnosis of viral hepatitis: Current status and future strategies.

Viral hepatitis (VH) is a significant public health issue with tremendous potential to aggravate into chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Recent decade has witnessed remarkable uprising in the drug development and effective treatment of VH. An upsurge is seen in identification of antiviral therapies with low rates of viral resistance, the improvement of Hepatitis B Virus (HBV) vaccination and the development of direct-acting antivirals for Hepatitis C Virus (HCV). But unfortunately, the "2030 worldwide eradication" objective of World Health Organization (WHO) is still unmet. It can be largely attributed to the deficit faced by the healthcare system concerning screening and diagnosis. A timely, accurate and comprehensive screening; encompassing maximum population coverage is essential to combat this disease. However, advancements in VH diagnostics remain inadequate and with a marginal use in routine practice. This paper deliberates upon the lacunae in traditional and prevailing diagnostic methodology of viral hepatitis, especially their inadequacy in meeting the unique situations prevailing low- and middle-income countries (LMIC).

Intracranial Interdural and Extradural Cerebellar Convexity Dermoid Cyst: A Case Report of Rare Tumor at the Rarest Location.

Intracranial dermoid cysts are rare dysembryonic tumors of benign nature. These are uncommon in adults. If present, they are usually located in the midline or along the lines of embryonic fusion. The posterior fossa region is an infrequent site. Extradural or interdural locations are even more rare. In this case report, the authors report a laterally located large posterior fossa right cerebellar convexity interdural and extradural dermoid cyst over the sigmoid sinus. It was managed by totally extradural maximum possible safe decompression with microneurosurgical technique. The authors share their experience of addressing this rare pathology at the rarest location with unusual imaging findings.

Recent Advances in Nanomechanical Measurements and Their Application for Pharmaceutical Crystals.

Mechanical behavior of pharmaceutical crystals directly impacts the formulation development and manufacturing of drug products. The understanding of crystal structure-mechanical behavior of pharmaceutical and molecular crystals has recently gained substantial attention among pharmaceutical and materials scientists with the advent of advanced nanomechanical testing instruments like nanoindentation. For the past few decades, instrumented nanoindentation was a popular technique for measuring the mechanical properties of thin films and small-length scale materials. More recently it is being implemented to investigate the mechanical properties of pharmaceutical crystals. Integration of correlative microscopy techniques and environmental control opened the door for advanced structure-property correlation under processing conditions. Preventing the degradation of active pharmaceutical ingredients from external factors such as humidity, temperature, or pressure is important during processing. This review deals with the recent developments in the synchronized nanomechanical measurements of pharmaceutical crystals toward the fast and effective development of high-quality pharmaceutical drug products. This review also summarizes some recent reports to intensify how one can design and control the nanomechanical properties of pharmaceutical solids. Measurement challenges and the scope for studying nanomechanical properties of pharmaceutical crystals using nanoindentation as a function of crystal structure and in turn to develop fundamental knowledge in the structure-property relationship with the implications for drug manufacturing and development are discussed in this review. This review further highlights recently developed capabilities in nanoindentation, for example, variable temperature nanoindentation testing, in situ imaging of the indented volume, and nanoindentation coupled Raman spectroscopy that can offer new quantitative details on nanomechanical behavior of crystals and will play a decisive role in the development of coherent theories for nanomechanical study of pharmaceutical crystal.

Survey data to evaluate consumer behaviour and consumption pattern of sustainable apparel: A study on consumer awareness level.

A consumer survey was conducted in Uttar Pradesh in five major cities Lucknow, Kanpur, Agra, Varanasi, and Meerut District, from 2022 to 2023 to understand consumer awareness and consumer behaviour towards Sustainable Apparel. The data were collected from 384 respondents via face-to-face interviews through field surveys in different colleges and universities. A paper-based questionnaire was analyzed using SPSS (version 22) using descriptive and, correlation, ANOVA, and regression statistical analysis.

Chronic testosterone deficiency increases late inward sodium current and promotes triggered activity in ventricular myocytes from aging male mice.

Clinical studies suggest low testosterone levels are associated with cardiac arrhythmias, especially in later life. We investigated whether chronic exposure to low circulating testosterone promoted maladaptive electrical remodeling in ventricular myocytes from aging male mice and determined the role of late inward sodium current (INa,L) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1 mo) and were aged to 22-28 mo. Ventricular myocytes were isolated; transmembrane voltage and currents were recorded (37°C). Action potential duration at 70 and 90% repolarization (APD70 and APD90) was prolonged in GDX compared with sham myocytes (APD90, 96.9 ± 3.2 vs. 55.4 ± 2.0 ms; P < 0.001). INa,L was also larger in GDX than sham (-2.4 ± 0.4 vs. -1.2 ± 0.2 pA/pF; P = 0.002). When cells were exposed to the INa,L antagonist ranolazine (10 µM), INa,L declined in GDX cells (-1.9 ± 0.5 vs. -0.4 ± 0.2 pA/pF; P < 0.001) and APD90 was reduced (96.3 ± 14.8 vs. 49.2 ± 9.4 ms; P = 0.001). GDX cells had more triggered activity (early/delayed afterdepolarizations, EADs/DADs) and spontaneous activity than sham. EADs were inhibited by ranolazine in GDX cells. The selective NaV1.8 blocker A-803467 (30 nM) also reduced INa,L, decreased APD and abolished triggered activity in GDX cells. Scn5a (NaV1.5) and Scn10a (NaV1.8) mRNA was increased in GDX ventricles, but only NaV1.8 protein abundance was increased in GDX compared with sham. In vivo studies showed QT prolongation and more arrhythmias in GDX mice. Thus, triggered activity in ventricular myocytes from aging male mice with long-term testosterone deficiency arises from APD prolongation mediated by larger NaV1.8- and NaV1.5-associated currents, which may explain the increase in arrhythmias.NEW & NOTEWORTHY Older men with low testosterone levels are at increased risk of developing cardiac arrhythmias. We found aged mice chronically exposed to low testosterone had more arrhythmias and ventricular myocytes had prolonged repolarization, abnormal electrical activity, larger late sodium currents, and increased expression of NaV1.8 sodium channels. Drugs that inhibit late sodium current or NaV1.8 channels abolished abnormal electrical activity and shortened repolarization. This suggests the late sodium current may be a novel target to treat arrhythmias in older testosterone-deficient men.

Countrywide monitoring of absorbed dose rate in air due to outdoor natural gamma radiation in India.

The Indian Environmental Radiation Monitoring Network continuously monitors, throughout India, the absorbed dose rate in air due to outdoor natural gamma radiation, by using Geiger-Mueller detector-based standalone environmental radiation monitors. The network consists of 546 monitors spread across 91 monitoring locations distributed all over the country. In this paper, the countrywide long-term monitoring results are summarised. The measured mean dose rate of the monitoring locations followed a log-normal distribution and ranged from 50 to 535 nGy.h-1 with a median value of 91 nGy.h-1. Due to outdoor natural gamma radiation, the average annual effective dose was estimated to be 0.11 mSv.y-1.

TIM-3 increases the abundance of type-2 dendritic cells during Leishmania donovani infection by enhancing IL-10 production via STAT3.

The outcome of the disease visceral leishmaniasis (VL), caused by Leishmania donovani (LD), largely relies on the relative dominance of host-protective type-1 T helper (Th1) cell response versus disease-promoting type-2 T helper (Th2) cell response. The Th1 and Th2 responses, in turn, are believed to be elicited by type-1 conventional dendritic cells (cDC1) and type-2 conventional DCs (cDC2), respectively. However, it is still unknown which DC subtype (cDC1 or cDC2) predominates during chronic LD infection and the molecular mechanism governing such occurrence. Here we report that in chronically infected mice, the splenic cDC1-cDC2 balance shifted toward the cDC2 subtype and that the receptor T cell immunoglobulin and mucin protein-3 (TIM-3) expressed by DCs played a key role in mediating this effect. Transfer of TIM-3-silenced DCs in fact prevented the predominance of the cDC2 subtype in mice with chronic LD infection. We also found that LD actually upregulated TIM-3 expression on DCs by triggering a TIM-3-mediated signaling pathway STAT3 (signal transducer and activator of transcription 3)→interleukin (IL)-10→c-Src→transcription factors Ets1, Ets2, USF1, and USF2. Notably, TIM-3 promoted STAT3 activation via a non-receptor tyrosine kinase Btk. Adoptive transfer experiments further demonstrated a critical role for STAT3-driven TIM-3 upregulation on DCs in increasing cDC2 abundance in chronically infected mice, which ultimately aided disease pathogenesis by augmenting Th2 responses. These findings document a new immunoregulatory mechanism contributing to disease pathology during LD infection and define TIM-3 as a key mediator of this process.

Leishmania donovani Attenuates Dendritic Cell Trafficking to Lymph Nodes by Inhibiting C-Type Lectin Receptor 2 Expression via Transforming Growth Factor-ß.

To initiate an antileishmanial adaptive immune response, dendritic cells (DCs) must carry Leishmania antigens from peripheral tissues to local draining lymph nodes. However, the migratory capacity of DCs is largely compromised during Leishmania donovani infection. The molecular mechanism underlying this defective DC migration is not yet fully understood. Here, we demonstrate that L. donovani infection impaired the lymph node homing ability of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression. L. donovani exerted this inhibitory effect by inducing transforming growth factor-ß (TGF-ß) secretion from DCs. Indeed, TGF-ß produced in this manner inhibited nuclear factor-κB (NF-κB)-mediated CLEC-2 expression on DCs by activating c-Src. Notably, suppression of c-Src expression significantly improved the arrival of DCs in draining lymph nodes by preventing L. donovani-induced CLEC-2 downregulation on DCs. These findings reveal a unique mechanism by which L. donovani inhibits DC migration to lymph nodes and suggest a key role for TGF-ß, c-Src, and CLEC-2 in regulating this process. IMPORTANCE Dendritic cells (DCs) play a key role in initiating T cell-mediated protective immunity against visceral leishmaniasis (VL), the second most lethal parasitic disease in the world. However, the T cell-inducing ability of DCs critically depends on the extent of DC migration to regional lymph nodes. Notably, the migration of DCs is reported to be impaired during VL. The cause of this impaired DC migration, however, remains ill-defined. Here, we provide the first evidence that L. donovani, the causative agent of VL, attenuates the lymph node homing capacity of DCs by decreasing C-type lectin receptor 2 (CLEC-2) expression on DCs. Additionally, we have demonstrated how L. donovani mediates this inhibitory effect. Overall, our work has revealed a unique mechanism underlying L. donovani-induced impairment of DC migration and suggests a potential strategy to improve antileishmanial T cell activity by increasing DC arrival in lymph nodes.

The repertoire of mutational signatures in tobacco- and non-tobacco-induced oral cancer.

The use of tobacco products is one of the established contributors toward the development and spread of oral cancer. Additionally, recent research has indicated oral microbiome, infections with Human papilloma virus (HPV), Epstein-Barr virus (EBV), Candida as significant contributing factors to this disease along with lifestyle habits. Deregulation of cellular pathways envisaging metabolism, transcription, translation, and epigenetics caused by these risk factors either individually or in unison is manifold, resulting in the increased risk of oral cancer. Globally, this cancer continues to exist as one of the major causes of cancer-related mortalities; the numbers in the developing South Asian countries clearly indicate yearly escalation. This review encompasses the variety of genetic modifications, including adduct formation, mutation (duplication, deletion, and translocation), and epigenetic changes evident in oral squamous cell carcinoma (OSCC). In addition, it highlights the interference caused by tobacco products in Wnt signaling, PI3K/Akt/mTOR, JAK-STAT, and other important pathways. The information provided also ensures a comprehensive and critical revisit to non-tobacco-induced OSCC. Extensive literature survey and analysis has been conducted to generate the chromosome maps specifically highlighting OSCC-related mutations with the potential to act as spectacles for the early diagnosis and targeted treatment of this disease cancer.

Generation of map on natural environmental background absorbed dose rate in India.

A systematic mapping of natural absorbed dose rate was carried out to assess the existing exposure situation in India. The mammoth nationwide survey covered the entire terrestrial region of the country comprising of 45127 sampling grids (grid size 36 km2) with more than 100,000 data points. The data was processed using Geographic Information System. This study is based on established national and international approaches to provide linkage with conventional geochemical mapping of soil. Majority (93%) of the absorbed dose rate data was collected using handheld radiation survey meters and remaining were measured using environmental Thermo Luminescent Dosimeters. The mean absorbed dose rate of the entire country including several mineralized regions, was found to be 96 ± 21 nGy/h. The median, Geometric Mean and Geometric Standard Deviation values of absorbed dose rate were 94, 94 and 1.2 nGy/h, respectively. Among the High Background Radiation Areas of the country, absorbed dose rate varied from 700 to 9562 nGy/h in Karunagappally area of Kollam district, Kerala. The absorbed dose rate in the present nationwide study is comparable with the global database.

Genic-intergenic polymorphisms of CYP1A genes and their clinical impact.

The humancytochrome P450 1A (CYP1A) subfamily genes, CYP1A1 and CYP1A2, encoding monooxygenases are critically involved in biotransformation of key endogenous substrates (estradiol, arachidonic acid, cholesterol) and exogenous compounds (smoke constituents, carcinogens, caffeine, therapeutic drugs). This suggests their significant involvement in multiple biological pathways with a primary role of maintaining endogenous homeostasis and xenobiotic detoxification. Large interindividual variability exist in CYP1A gene expression and/or catalytic activity of the enzyme, which is primarily due to the existence of polymorphic alleles which encode them. These polymorphisms (mainly single nucleotide polymorphisms, SNPs) have been extensively studied as susceptibility factors in a spectrum of clinical phenotypes. An in-depth understanding of the effects of polymorphic CYP1A genes on the differential metabolic activity and the resulting biological pathways is needed to explain the clinical implications of CYP1A polymorphisms. The present review is intended to provide an integrated understanding of CYP1A metabolic activity with unique substrate specificity and their involvement in physiological and pathophysiological roles. The article further emphasizes on the impact of widely studied CYP1A1 and CYP1A2 SNPs and their complex interaction with non-genetic factors like smoking and caffeine intake on multiple clinical phenotypes. Finally, we attempted to discuss the alterations in metabolism/physiology concerning the polymorphic CYP1A genes, which may underlie the reported clinical associations. This knowledge may provide insights into the disease pathogenesis, risk stratification, response to therapy and potential drug targets for individuals with certain CYP1A genotypes.

Age, sex, and frailty modify the expression of common reference genes in skeletal muscle from ageing mice.

Changes in gene expression with age are typically normalised to constitutively expressed reference genes (RGs). However, RG expression may be affected by age or overall health and most studies use only male animals. We investigated whether expression of common RGs (Gapdh, Gusb, Rplp0, B2m, Tubb5, Rpl7l1, Hprt, Rer1) was affected by age, sex and/or overall health (frailty index) in skeletal muscle from young (4-mos) and aged (25-26-mos) mice. Standard RG selection programs recommended Gapdh (RefFinder/Genorm/NormFinder) or Rpl7l1 (BestKeeper) without considering age and sex. Analysis of raw Cq values showed only Rplp0 was stable in both sexes at both ages. When qPCR data were normalised to Rplp0, age affected RG expression, especially in females. For example, Hprt expression declined with age (Hprt=9.8 ×10-2 ± 4.7 ×10-2 vs. 6.5 ×10-3 ± 8.8 ×10-4; mean±SEM), while Gusb expression increased (6.0 ×10-4 ± 5.5 ×10-5 vs. 1.7 ×10-3 ± 3.1 ×10-4; n = 5/group; p < 0.05). These effects were not seen in males. Tubb5 and Gapdh were not affected by age or sex when normalised to Rplp0. Similar results were seen with normalisation by Gapdh or the Rplp0/Gapdh pair. Interestingly, RG expression was graded not only by age but by frailty. These data demonstrate that age, sex, and frailty of animals must be carefully considered when selecting RGs to normalise mRNA abundance data.

CO2 capture from ambient air via crystallization with tetraalkylammonium hydroxides.

Aqueous solutions of a series of short carbon chain tetra(n-alkyl)ammonium hydroxides, [Nnnnn][OH] with n = 2: n-ethyl, 3: n-propyl, 4: n-butyl, have been serendipitously found to be potential candidates for direct air carbon capture (DAC) when being used as reagents in more complicated reactions. Aqueous solutions of [N3333][OH], [N2222][OH], or [N3333][OH] with UO2SO4·3H2O and 1,4-diamidoximylbenzene, and [N4444][OH] with cytosine (HCyt) directly absorb CO2 from the atmosphere upon mild heating in the open atmosphere crystallizing in complexes reaching up to 2 : 1 CO2/[Nnnnn]OH ratio. [N2222][HCO3]·3H2O (1), [N2222]2[H(HCO3)3]·5H2O (2), [N3333][HCO3]·0.5H2O (3), [N3333][H(HCO3)2] (4), [N3333]2[(tpa)(H2CO3)2] (5; tpa = terephthalate), [N4444][H(Cyt)(HCO3)]·H2O (6) and [N4444][H2(Cyt)2(HCO3)]·H2O (7) have been isolated in crystalline form and structurally characterized by single crystal X-ray diffraction. The compounds are characterized by complex polyanionic formations from bicarbonate dimers ([(HCO3)2·(H2O)]24-) or chains ([H(HCO3)2]nn- or [H2(tpa)(HCO3)2]n2n-) to water-bicarbonate associates ([(HCO3)2·6H2O]2- and [(H2CO3·(HCO3)2)2·6H2O·2H2O]2-) and three-component anionic layers ([H(Cyt)(HCO3)·H2O]nn- and [H2(Cyt)2(HCO3)·H2O]nn-) frequently showing proton sharing. While some hydroxides themselves can maintain a high CO2/[Nnnnn][OH] ratio, particularly 2 and 4, the presence of secondary hydrogen bond donors/acceptors may increase the sorption efficiency through decreased solubility and enhanced crystallization.

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD.

Assessing Long Non-coding RNAs in Tobacco-associated Oral Cancer.

Cancer is one of the compelling and pegged diseases battled by clinicians and researchers worldwide. Among different types of cancer, oral cancer holds the sixth position globally. With an escalating prevalence in Asian countries, India, China, and Pakistan constitute a large proportion of total incidents of oral cancer patients in terms of new cases or deaths. This mounting prevalence is ascribed to poor oral hygiene and rampant use of substances earmarked as potential risk factors for the disease. Risk factors (dietary/lifestyle habits/occupational/environmental) trigger the activation of oncogenes, dysregulation of lncRNA and miRNA, and silence the tumor suppressor genes, which robustly contributes to the onset and progression of tumorigenesis in oral squamous cell carcinoma. Evidence suggests that specific carcinogens identified in tobacco and related products alter many cellular pathways predisposing to advanced stages of oral cancer. Long non-coding RNAs represent a broad group of heterogenous transcripts longer than 200 nucleotides which do not translate to form functional proteins. They regulate various cellular pathways by specifically interacting with other RNAs, DNA, and proteins. Their role in the pathogenesis of OSCC and other cancer is still being debated. In this review, we discuss the molecular insights of significant lncRNAs involved in some crucial deregulated pathways of tobacco-associated OSCC. The implications and challenges to harnessing the potential of lncRNAs as biomarkers in early diagnosis and targeted treatment have also been analyzed.