Highlights • Neuronal nicotinic ACh receptor (nAChR) dysfunction is involved in the pathophysiology of many neurological disorders. • nAChRs are increasingly appreciated for their roles in ...neurodevelopment and sensory processing. • α4β2 and α7 nAChRs in the basal forebrain cholinergic system are important for cognitive performance.
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the α7 and ...α4β2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs.
Background
Vitiligo, an autoimmune disorder characterised by skin depigmentation, is associated with reduced quality of life (QoL). Vitiligo may be under‐reported, in part because of misconceptions ...that it is a cosmetic disease.
Objectives
This survey sought to characterise vitiligo prevalence and explore the relationship between sociodemographic and clinical characteristics with QoL in a population‐based, multinational study.
Methods
Participants aged ≥18 years were recruited via an online panel in Europe, Japan and the USA to answer questions regarding skin disorders they may have experienced. Those reporting vitiligo (diagnosed or undiagnosed) or vitiligo signs (experiencing loss of skin colour but unaware of vitiligo and not diagnosed) were included in the analyses of vitiligo prevalence. Participants who self‐reported physician‐diagnosed vitiligo were given a broader survey to characterise disease progression, management and QoL (as measured with the Vitiligo‐specific QoL VitiQoL instrument).
Results
The total estimated vitiligo prevalence among 35 694 survey participants (Europe, n = 18 785; USA, n = 8517; Japan, n = 8392) was 1.3% (diagnosed, 0.6%; undiagnosed, 0.4%; vitiligo signs, 0.3%). Among 219 patients formally diagnosed with vitiligo (Europe, n = 150; USA, n = 48; Japan, n = 21), total VitiQoL scores were associated with age (P = 0.00017), disease extent (P < 0.0001), disease progression (P < 0.0001), disease management (P < 0.0001) and time since diagnosis (P = 0.0015). Behaviour scores varied based on skin phototype (P = 0.024) and ethnicity (P = 0.048). Higher total VitiQoL scores were reported in patients with head lesions (P = 0.027) and those with head and hand and/or wrist lesions (P = 0.018). Substantial high concern (rated 8–10 on an 11‐point Likert scale) for lesions was found across all body areas and varied with geographical region.
Conclusions
The vitiligo prevalence rate may be higher than previously reported, with a substantial proportion attributed to people who have not received a formal diagnosis. Among formally diagnosed patients with vitiligo, QoL was most severely impacted by more progressive and higher extent of disease.
The flammability of conventional alkyl carbonate electrolytes hinders the integration of large-scale lithium-ion batteries in transportation and grid storage applications. In this study, we have ...prepared a unique nonflammable electrolyte composed of low molecular weight perfluoropolyethers and bis(trifluoromethane)sulfonimide lithium salt. These electrolytes exhibit thermal stability beyond 200 °C and a remarkably high transference number of at least 0.91 (more than double that of conventional electrolytes). Li/LiNi ₁/₃Co ₁/₃Mn ₁/₃O ₂ cells made with this electrolyte show good performance in galvanostatic cycling, confirming their potential as rechargeable lithium batteries with enhanced safety and longevity.
We aim to study the relationship between vitamin D level, risk and severity of Coronavirus disease of 2019 (COVID-19) infection in pediatric population through systematic review. We searched PubMed, ...CINAHL, EMBASE, Cochrane Library and Google Scholar from December 2019 to June 2021 for retrieving articles studying association between vitamin D deficiencies with COVID-19. Qualitative details were synthesized in evidence table and quantitative data was used for deriving pooled estimate through meta-analysis. After initial search of 2261 articles, eight eligible studies (two reviews) were included in the systematic review. Meta-analysis of the quantitative data (six studies) showed pooled prevalence of vitamin D deficiency as 45.91% (95% CI: 25.148-67.450). In infected pediatric patients, low levels of vitamin D increased the risk of severe disease (odds ratio-5.5; 95% CI: 1.560-19.515; P = 0.008). It was also found that children and adolescents having vitamin D deficiency had greater risk of COVID infection as compared to patients with normal vitamin D levels. Improvement in disease severity with vitamin D supplementation was also noted. The systematic review showed that almost half of the pediatric COVID patients suffer from vitamin D deficiency. It is also clear that the low level of vitamin D is associated with greater risk of infection and poorer outcome in pediatrics.
We present the calibration and background model for the Large Area X-ray Proportional Counter (LAXPC) detectors on board AstroSat. The LAXPC instrument has three nominally identical detectors to ...achieve a large collecting area. These detectors are independent of each other, and in the event analysis mode they record the arrival time and energy of each photon that is detected. The detectors have a time resolution of 10 s and a dead-time of about 42 s. This makes LAXPC ideal for timing studies. The energy resolution and peak channel-to-energy mapping were obtained from calibration on the ground using radioactive sources coupled with GEANT4 simulations of the detectors. The response matrix was further refined from observations of the Crab after launch. At around 20 keV the energy resolution of the detectors is 10%-15%, while the combined effective area of the three detectors is about 6000 cm2.
Abstract
Novel SARS-CoV-2, an etiological factor of Coronavirus disease 2019 (COVID-19), poses a great challenge to the public health care system. Among other druggable targets of SARS-Cov-2, the ...main protease (M
pro
) is regarded as a prominent enzyme target for drug developments owing to its crucial role in virus replication and transcription. We pursued a computational investigation to identify M
pro
inhibitors from a compiled library of natural compounds with proven antiviral activities using a hierarchical workflow of molecular docking, ADMET assessment, dynamic simulations and binding free-energy calculations. Five natural compounds, Withanosides V and VI, Racemosides A and B, and Shatavarin IX, obtained better binding affinity and attained stable interactions with M
pro
key pocket residues. These intermolecular key interactions were also retained profoundly in the simulation trajectory of 100 ns time scale indicating tight receptor binding. Free energy calculations prioritized Withanosides V and VI as the top candidates that can act as effective SARS-CoV-2 M
pro
inhibitors.
Nicotinic acetylcholine receptors are ligand-gated transmembrane ion channels that are present at the neuromuscular junction and in different locations in the nervous system. The different subtypes ...of neuronal nicotinic acetylcholine receptors that are found in the brain are thought to be involved in many neurological processes such as pain, cognitive function and depression, as well as in the pathophysiology of numerous neurological diseases and conditions. While the neurotransmitter acetylcholine is an endogenous agonist for all nicotinic receptors subtypes, many drugs that act as agonists and antagonists have also been identified or developed for these receptors. In addition, a novel class of compounds described as allosteric modulators have also been identified or developed for nicotinic acetylcholine receptors. Allosteric modulators are ligands that bind to nicotinic receptors at sites other than the orthosteric site where acetylcholine binds. One such allosteric modulator is desformylflustrabromine. Five chemical analogs along with desformylflustrabromine act as positive allosteric modulator for nAChRs that contain the beta2 subunit in their pentameric structure. Here the discovery and development, medicinal chemistry and pharmacological actions of desformylflustrabromine have been discussed. Desformylflustrabromine and its chemical analogs have the potential to develop into clinically used drugs for neurological diseases and conditions where nicotinic acetylcholine receptors are involved.
Several studies have shown that human induced pluripotent stem cell (iPSC)-derivatives are essentially fetal in terms of their maturational status. Inducing ageing in iPSC-motor neuron (MN) models of ...amyotrophic lateral sclerosis (ALS) has the potential to capture pathology with higher fidelity and consequently improve translational success. We show here that the telomerase inhibitor BIBR1532, hypothesised to recapitulate the telomere attrition hallmark of ageing in iPSC-MNs, was in fact cytotoxic to feeder-free iPSCs when used at doses previously shown to be effective in iPSCs grown on a layer of mouse embryonic fibroblasts. Toxicity in feeder-free cultures was not rescued by co-treatment with Rho Kinase (ROCK) inhibitor (Y-27632). Moreover, the highest concentration of BIBR1532 compatible with continued iPSC culture proved insufficient to induce detectable telomerase inhibition. Our data suggest that direct toxicity by BIBR1532 is the most likely cause of iPSC death observed, and that culture methods may influence enhanced toxicity. Therefore, recapitulation of ageing hallmarks in iPSC-MNs, which might reveal novel and relevant human disease targets in ALS, is not achievable in feeder-free culture through the use of this small molecule telomerase inhibitor.
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