Miracle-dz/UniFAR-FTUs huggingface dataset:
Hair cell α9α10 nicotinic acetylcholine receptor functional expression regulated by ligand binding and deafness gene products

Significance Auditory hair cells receive olivocochlear efferent innervation, which improves sound discrimination and mitigates acoustic trauma. The olivocochlear synapse involves α9α10 nicotinic acetylcholine receptors (nAChRs), which do not express in recombinant cell lines. Here, genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. These single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and abnormally retain α9α10-mediated transmission through development. This study identifies unexpected functions for human deafness genes TMIE/TMEM132e and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders. Auditory hair cells receive olivocochlear efferent innervation, which refines tonotopic mapping, improves sound discrimination, and mitigates acoustic trauma. The olivocochlear synapse involves α9α10 nicotinic acetylcholine receptors (nAChRs), which assemble in hair cells only coincident with cholinergic innervation and do not express in recombinant mammalian cell lines. Here, genome-wide screening determined that assembly and surface expression of α9α10 require ligand binding. Ion channel function additionally demands an auxiliary subunit, which can be transmembrane inner ear (TMIE) or TMEM132e. Both of these single-pass transmembrane proteins are enriched in hair cells and underlie nonsyndromic human deafness. Inner hair cells from TMIE mutant mice show altered postsynaptic α9α10 function and retain α9α10-mediated transmission beyond the second postnatal week associated with abnormally persistent cholinergic innervation. Collectively, this study provides a mechanism to link cholinergic input with α9α10 assembly, identifies unexpected functions for human deafness genes TMIE/TMEM132e, and enables drug discovery for this elusive nAChR implicated in prevalent auditory disorders.
Plant flavone Chrysin as an emerging histone deacetylase inhibitor for prosperous epigenetic‐based anticancer therapy

Aberrations in epigenetic mechanisms provide a fertile platform for tumour initiation and progression. Thus, agents capable of modulating the epigenetic environment of neoplasms will be a valuable addition to the anticancer therapeutics. Flavones are emerging as befitting anticancer agents due to their inherent antioxidant activity and the ability to restrain epi‐targets namely histone deacetylases (HDACs). HDACs have broader implications in pathogenesis of various cancers. Chrysin, a flavone possessing the ability to inhibit HDACs could prove as a potential anticancer drug. Thus, in this article we focussed on Chrysin and its distinct antineoplastic effect against bellicose malignancies including lung, colorectal, cervical, gastric, melanoma, hepatocellular carcinoma and breast cancer. The underlying signalling cascades triggered by Chrysin for inducing cytotoxic effect in these cancer models are discussed. Importantly, approaches towards combinatorial treatments by Chrysin and commercial anticancer agents are taken into account. The downstream molecular mechanism aroused by combined therapy for abrogating onerous cancer chemoresistance is delineated as well. Moreover, the nano‐combinatorial approach involving co‐encapsulation of Chrysin with other herbal and non‐herbal agents for clinical excellence is elucidated.
Caffeine enhances BOLD responses to electrical whisker pad stimulation in rats during alpha‐chloralose anaesthesia

By reducing the cerebral blood flow and thereby increasing the resting deoxyhaemoglobin concentration, many human studies have shown that caffeine has a beneficial effect on enhancing the magnitude of blood‐oxygenation‐level‐dependent (BOLD) responses. However, the effect of caffeine on BOLD responses in animals under anaesthesia has not been demonstrated. In this study, we aimed to determine the effect of systemic caffeine administration on BOLD responses in rats under alpha‐chloralose. By applying electric whisker pad stimulation to male Sprague‐Dawley rats, we performed fMRI measurements before and after the caffeine injection (40 mg/kg, n = 7) or an equivalent volume of saline (n = 6) at 7T. To understand the potential perturbation of animal physiology during stimulation, arterial blood pressure was measured in a separate group of animals (n = 3) outside the scanner. Caffeine significantly decreased baseline BOLD signals (p = .05) due to the increased deoxyhaemoglobin level. Both BOLD responses and t‐values in the primary somatosensory cortex were significantly increased (both p < .05). The blood pressure changed insignificantly (p > .05). No significant differences in BOLD responses and t‐values were observed in the control condition of saline injection (both p > .05). These findings suggested that, although the cerebral activity was lower under alpha‐chloralose anaesthesia, the higher level of deoxygemoglobin at the baseline under the caffeinated condition can benefit the magnitude of BOLD responses in rats. These findings suggest that animal models might serve as potential platforms for further caffeine‐related fMRI research studies.
A Comparative Photophysical Study of Structural Modifications of Thioflavin T-Inspired Fluorophores.

The benzothiazolium salt, Thioflavin T (ThT), has been widely adopted as the 'gold-standard' fluorescent reporter of amyloid in vitro. Its properties as a molecular rotor result in a large-scale (~1000-fold) fluorescence turn-on upon binding to β-sheets in amyloidogenic proteins. However, the complex photophysics of ThT combined with the intricate and varied nature of the amyloid binding motif means these interactions are poorly understood. To study this important class of fluorophore, we present a detailed photophysical characterisation and comparison of a novel library of twelve ThT-inspired fluorescent probes for amyloid protein (PAPs), where both the charge and donor capacity of the heterocyclic and aminobenzene components have been interrogated, respectively. This enables direct photophysical juxtaposition of two structural groups; Class 1 the neutral 'PAP' and Class 2 the charged 'mPAP' fluorophores. We quantify binding and optical properties at both the bulk and single-aggregate levels with some derivatives showing higher aggregate affinity and brightness than ThT. Finally, we demonstrate their abilities to perform super-resolution imaging of α-synuclein fibrils with localisation precisions of ~16 nm. The properties of the derivatives provide new insights into the relationship between chemical structure and function of benzothiazole probes.
The Alternative Splicing Factor, MBNL1, Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness

This study describes an unexpected mechanism by which RNA-binding protein MBNL1, activity is inhibited in hypoxia by a simple isoform switch to regulate glioma stem cell self-renewal, tumorigenicity, and progression. Muscleblind-like proteins (MBNL) belong to a family of tissue-specific regulators of RNA metabolism that control premessenger RNA splicing. Inactivation of MBNL causes an adult-to-fetal alternative splicing transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer, glioblastoma (GBM), maintains stem-like features (glioma stem cell, GSC) through hypoxia-induced responses. Accordingly, we hypothesize here that hypoxia-induced responses in GBM might also include MBNL-based alternative splicing to promote tumor progression. When cultured in hypoxia condition, GSCs rapidly exported muscleblind-like-1 (MBNL1) out of the nucleus, resulting in significant inhibition of MBNL1 activity. Notably, hypoxia-regulated inhibition of MBNL1 also resulted in evidence of adult-to-fetal alternative splicing transitions. Forced expression of a constitutively active isoform of MBNL1 inhibited GSC self-renewal and tumor initiation in orthotopic transplantation models. Induced expression of MBNL1 in established orthotopic tumors dramatically inhibited tumor progression, resulting in significantly prolonged survival. This study reveals that MBNL1 plays an essential role in GBM stemness and tumor progression, where hypoxic responses within the tumor inhibit MBNL1 activity, promoting stem-like phenotypes and tumor growth. Reversing these effects on MBNL1 may therefore, yield potent tumor suppressor activities, uncovering new therapeutic opportunities to counter this disease. Significance: This study describes an unexpected mechanism by which RNA-binding protein, MBNL1, activity is inhibited in hypoxia by a simple isoform switch to regulate glioma stem cell self-renewal, tumorigenicity, and progression.
Establishment and Optimization of ISSR Reaction System for Pea

The optimum ISSR-PCR system for peas is established using ISSR-PCR amplification with five factors(DNA template,primer,dNTPs,Taq DNA polymerase and annealing temperature). The optimum reaction system(20 μL) contains 15 ng DNA template,0.15 mmol·L-1 dNTP,0.5 μmol·L-1 ISSR primer,1U Taq DNA polymerase.The suitable annealing temperature of primer 842 is 50℃. This reaction system will provide a technological base for genetic diversity analysis of pea germplasm,genetic map construction and gene location.
‘I just rolled up my sleeves’: Mothers’ perspectives on raising girls on the autism spectrum

Little previous research has elucidated the everyday experiences of autistic girls or their families. This study used qualitative in-depth interviews to explore mothers’ experiences of the diagnosis, presentation and impact of caring for a daughter with autism. Nineteen women with autistic daughters (aged between 7 and 18) participated in the research, which took place in Ireland. Thematic analysis identified six themes: What’s Going On? ; Road to Acceptance; Beyond the Stigma of Autism; Autism: Like a Girl; Mothers Holding It All Together; and Mothers Roll Up Their Sleeves. The analysis suggests that the path of autism in girls in Ireland is marked by diagnostic delays, social stigma, interpersonal difficulties, mental health comorbidities and parental stress. However, these challenges were offset by the resilience of mothers, buttressed by pride in their daughters and support from other women. Results will inform the development of policy and practice that is sensitive to the lived realities of autistic girls and their families. Lay abstract Autism in boys has been well researched but very little is known about the everyday experiences of autistic girls or their families. Mothers’ views and insights can be very helpful in increasing knowledge around the unique demands of raising a daughter with autism. This study conducted interviews with Irish mothers to examine their own experiences regarding (a) getting an autism diagnosis for their daughter, (b) their daughters’ personal characteristics and (c) the impact of caring for a daughter with autism. The study suggests that the route to an autism diagnosis for girls in Ireland is made more difficult by delays and missed diagnoses, and often followed by inadequate supports. Mothers described autistic girls as presenting with social challenges and mental health difficulties. Many mothers experienced judgement from other parents and family members, acute stress and mental health struggles. However, these challenges were offset by mothers’ resilience, pride in their daughters and support from other women. The findings of this study highlight the importance of specific support for autistic girls and their families.
Physical Activity Changes and Its Risk Factors among Community-Dwelling Japanese Older Adults during the COVID-19 Epidemic: Associations with Subjective Well-Being and Health-Related Quality of Life

Psychological distress caused by decreased physical activity (PA) is a growing concern among the elderly due to public health measures since the coronavirus disease (COVID-19). We aimed to (1) assess how public health restrictions impact PA, subjective well-being (SWB), and health-related quality of life (HRQoL) of community-dwelling elderly, and (2) investigate risk factors that lead to a decline in PA. Self-administered questionnaires assessed the changes in PA, SWB, HRQoL. Multivariate logistic regression analysis was performed to identify significant associated risk factors for decreased PA. Of 165 participants (valid response rate, 41.3%; mean age, 78.5 ± 8.0 years), 47.3% became less active, 23.0% became more active, and 29.7% maintained PA levels. There was a significant decrease in SWB at baseline and follow-up after COVID-19 restrictions in the less active group (p < 0.01). Higher levels of moderate or strenuous exercise/sports activity at baseline (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.01–1.24), and lower mental component HRQoL scores at baseline (OR, 0.96; 95% CI, 0.93–0.99) were associated with an increased risk of decreased PA. Public health restrictions impact the PA of the elderly, especially those who had higher levels of exercise/sports activity and lower HRQoL before COVID-19. Decreased PA was strongly associated with lower SWB.
Evaluation of the association between biochemical and immunohistochemical score of caspase-9 and TNFα, and the grading of lumbar disc herniation

Abstract Objective The aim of our study is to investigate the influence of caspase-9 and tumour necrosis factor alpha (TNFα) in the grade of lumbar disc herniation. We determined the strength of different predictors such as age, gender, disc grading, caspase-9 and TNFα. Methods We retrospectively reviewed 84 patients who had discectomies. Histological and biochemical evaluations of disc specimens were performed. All patients were scanned by the magnetic resonance imaging (MRI) scanner before the operation. Masson’s trichrome stain, biochemical analysis and immunohistochemical staining were performed to measure the expression levels of caspase-9 and TNFα. The results were evaluated statistically. Results This study included 84 patients (mean age: 41.59 ± 12.21 years; range: 19–76): 60 men (age 40.47 ± 12.63 years) and 24 women (44.42 ± 10.81 years). No statistically significant age difference was found between the genders (p = 0.182). MRI scans showed 16 patients had protrusion, 44 had extrusion and 24 had sequestration of discs. There was a statistically significant negative correlation between the grading of lumbar disc herniations and age (p < 0.001, r = −0.509). Histological and biochemical analyses of disc materials were done. Inflammation, collagen fibre deterioration, apoptotic process, TNFα and caspase-9 were seen to increase with increasing disc grading (p < 0.01). Conclusions Biochemical and immunohistochemical score of caspase-9 and TNFα indicate the grading of lumbar disc herniation. As the grading of disc herniation increases, inflammation of cells and collagen fibre disruption increase and accelerate the apoptotic process. Apoptosis in disc nucleus pulposus cells may reduce disc herniation.
Demographic and Clinical Characteristics Associated With Adherence to Guideline-Based Polysomnography in Children With Down Syndrome

Objectives To compare the demographic and clinical characteristics of children with Down syndrome who did and did not receive polysomnography to evaluate for obstructive sleep apnea after publication of the American Academy of Pediatrics’ guidelines recommending universal screening by age 4 years. Study Design Retrospective cohort study. Setting Single tertiary pediatric hospital. Methods Review was conducted of children with Down syndrome born between 2007 and 2012. Children who obtained polysomnography were compared with children who did not, regarding demographic data, socioeconomic status, and comorbidities. Results We included 460 children with Down syndrome; 273 (59.3%) received at least 1 polysomnogram, with a median age of 3.6 years (range, 0.1-8.9 years). There was no difference in the distribution of sex, insurance status, or socioeconomic status between children who received polysomnography and those who did not. There was a significant difference in race distribution (P = .0004) and distance from home to the medical center (P < .0001) between groups. Among multiple medical comorbidities, only children with a history of hypothyroidism (P = .003) or pulmonary aspiration (P = .01) were significantly more likely to have obtained polysomnography. Conclusions Overall, 60% of children with Down syndrome obtained a polysomnogram. There was no difference between groups by payer status or socioeconomic status. A significant difference in race distribution was noted. Proximity to the medical center and increased medical need appear to be associated with increased likelihood of obtaining a polysomnogram. This study illustrates the need for improvement initiatives to increase the proportion of patients receiving guideline-based screening.
PCNA promotes context-specific sister chromatid cohesion establishment separate from that of chromatin condensation

ABSTRACT Cellular genomes undergo various structural changes that include cis tethering (the tethering together of two loci within a single DNA molecule), which promotes chromosome condensation and transcriptional activation, and trans tethering (the tethering together of two DNA molecules), which promotes sister chromatid cohesion and DNA repair. The protein complex termed cohesin promotes both cis and trans forms of DNA tethering, but the extent to which these cohesin functions occur in temporally or spatially defined contexts remains largely unknown. Prior studies indicate that DNA polymerase sliding clamp PCNA recruits cohesin acetyltransferase Eco1, suggesting that sister chromatid cohesion is established in the context of the DNA replication fork. In support of this model, elevated levels of PCNA rescue the temperature growth and cohesion defects exhibited by eco1 mutant cells. Here, we test whether Eco1-dependent chromatin condensation is also promoted in the context of this DNA replication fork component. Our results reveal that overexpressed PCNA does not promote DNA condensation in eco1 mutant cells, even though Smc3 acetylation levels are increased. We further provide evidence that replication fork-associated E3 ligase impacts on Eco1 are more complex that previously described. In combination, the data suggests that Eco1 acetylates Smc3 and thus promotes sister chromatid cohesion in context of the DNA replication fork, whereas a distinct cohesin population participates in chromatin condensation outside the context of the DNA replication fork.
An Integrative Review of the Symptom Perception Process in Heart Failure

Supplemental digital content is available in the text. Background Accurate symptom perception is a fundamentally essential component of self-care for patients with heart failure (HF) so they can make appropriate decisions about their symptoms. Objective The purpose of this integrative review was to describe the pathways of the symptom perception process and its contributing factors in patients with HF. Methods A comprehensive literature search was conducted using PubMed, EMBASE, and PsycINFO databases to identify studies describing the symptom perception process (symptom detection, comprehension, and response) in adult patients with HF. Results Two pathways of the symptom perception process were identified from 42 articles: ideal and undesirable pathways. Patients in the ideal symptom perception pathway had a comprehensive understanding of HF and a firm belief in the importance of self-care, were vigilant, and possessed good decision-making skills. They also were able to successfully use their experiences for future care. However, patients in the undesirable symptom perception pathway had a limited understanding of HF with poor symptom monitoring skills and inaccurate judgments about symptoms. Diverse factors contributing to the symptom perception process were identified (eg, levels of understandings of HF and social support). Conclusion Our review indicated that symptom perception was likely to diversify the pathway of HF management. A variety of contributing factors to the symptom perception process were found to be intertwined. The findings of our review can inform the development of best patient education practice, although further research needs to be conducted to understand why and how patients can follow the most appropriate path from their past experiences.
Dehydroepiandrosterone for depressive symptoms: A systematic review and meta‐analysis of randomized controlled trials

Depression is a mental disorder that affects millions of people around the world. However, depressive symptoms can be seen in other psychiatric and medical conditions. Here, we investigate the effect of DHEA treatment on depressive symptoms in individuals with depression and/or other clinical conditions in which depressive symptoms are present. An electronic search was performed until October 2019, with no restrictions on language or year of publication in the following databases: Medline, EMBASE, LILACS, and Cochrane Library. Randomized controlled trials comparing DHEA versus placebo were included if the depressive symptoms were assessed. Fifteen studies with 853 female and male individuals were included in this review. To conduct the meta‐analysis, data were extracted from 14 studies. In comparison with placebo, DHEA improved depressive symptoms (standardized mean difference [SMD] −0.28, 95% (CI) −0.45 to −0.11, p =. 001, 12 studies, 742 individuals (375 in the experimental group and 367 in the placebo group), I2 = 24%), very low quality of evidence, 2 of 14 studies reporting this outcome were removed in a sensitivity analysis as they were strongly influencing heterogeneity between studies. No hormonal changes that indicated any risk to the participants' health were seen. Side effects observed were uncommon, mild, and transient, but commonly related to androgyny. In conclusion, DHEA was associated with a beneficial effect on depressive symptoms compared to placebo. However, these results should be viewed with caution, since the quality of evidence for this outcome was considered very low according to the GRADE criteria.
Loss-adjusting

Supplemental Digital Content is available in the text. Objectives: Complex Regional Pain Syndrome (CRPS) is a chronic pain condition that can present specific difficulties when occurring in adolescence. There is limited work exploring future narratives of healthy adolescents, and how these may differ for those who have chronic health conditions, but there is no research on the future narratives of adolescents who have CRPS. Materials and Methods: In this study, 50 adolescents (44 females, 5 males, 1 preferred not to say) aged 14 to 25 years (mean=19.8, SD=3.68), completed an online story completion task, with a further sample of 10 completing a follow-up telephone interview. Results: Story completion data were initially analyzed deductively based on the work of Morley and colleagues using hoped-for and feared-for future codes, revealing higher instances of hope (291 over 48 stories) than fear (99 over 27 stories). These codes were subsequently analyzed alongside the in-depth interview data using inductive thematic analysis, generating 2 themes that represent distinct, yet related, approaches of how adolescents incorporate CRPS into their future narratives: (1) the centrality of loss theme identifies the ways some adolescents described how CRPS brings loss, with narratives focused on how these adolescents imagine such losses continuing into the future, and (2) the adjusting to loss theme illustrates the ways other adolescents were able to imagine a future in which they were able to adjust to the losses which CRPS may bring. Discussion: CRPS may damage the future plans of adolescents. However, being or learning how to be flexible about these goals, may help them to build more positive future narratives.