Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered Nucleosome Positioning at the Transcription Start Site and Deficient Transcriptional Initiation in Friedreich Ataxia*

Background: Friedreich ataxia (FRDA) is caused by an expanded GAA triplet repeat (GAA-TR) mutation that results in FXN transcriptional deficiency. Results: Repressive chromatin spreads from the expanded GAA-TR mutation, switching off the FXN gene promoter. Conclusion: Reduced transcriptional initiation is the major cause of FXN transcriptional deficiency in FRDA. Significance: Reactivation of FXN transcriptional initiation is a potential therapeutic strategy in FRDA. Most individuals with Friedreich ataxia (FRDA) are homozygous for an expanded GAA triplet repeat (GAA-TR) mutation in intron 1 of the FXN gene, which results in deficiency of FXN transcript. Consistent with the expanded GAA-TR sequence as a cause of variegated gene silencing, evidence for heterochromatin has been detected in intron 1 in the immediate vicinity of the expanded GAA-TR mutation in FRDA. Transcriptional deficiency in FRDA is thought to result from deficient elongation through the expanded GAA-TR sequence because of repeat-proximal heterochromatin and abnormal DNA structures adopted by the expanded repeat. There is also evidence for deficient transcriptional initiation in FRDA, but its relationship to the expanded GAA-TR mutation remains unclear. We show that repressive chromatin extends from the expanded GAA-TR in intron 1 to the upstream regions of the FXN gene, involving the FXN transcriptional start site. Using a chromatin accessibility assay and a high-resolution nucleosome occupancy assay, we found that the major FXN transcriptional start site, which is normally in a nucleosome-depleted region, is rendered inaccessible by altered nucleosome positioning in FRDA. Consistent with the altered epigenetic landscape the FXN gene promoter, a typical CpG island promoter, was found to be in a transcriptionally non-permissive state in FRDA. Both metabolic labeling of nascent transcripts and an unbiased whole transcriptome analysis revealed a severe deficiency of transcriptional initiation in FRDA. Deficient transcriptional initiation, and not elongation, is the major cause of FXN transcriptional deficiency in FRDA, and it is related to the spread of repressive chromatin from the expanded GAA-TR mutation.
Incidence and origin of Clostridium difficile in neonates

The stools of 65 of 92 (71%) infants in a special care nursery yielded Clostridium difficile on culture. Ninety percent of stools collected after 6 to 35 days in the unit were positive, and 36% of these also contained toxin. When tested in vitro, 94% of the isolates produced toxin. Of 110 swabs collected from the environment of the unit, 9% were positive for C. difficile, but the stools of 12 nurses working on the unit were negative. Thirty-five vaginal swabs collected from mothers just before delivery were negative for C. difficile on culture, but 16 of their infants had C. difficile in their stools. It was concluded that there is a high carriage rate in the stools of neonates of C. difficile acquired progressively during the course of their stay in the special care unit. Infection is mainly from environmental sources rather than maternal transmission.
[Study on DNA methylation status of WT1 gene in its promoter region in hematologic malignancy cell lines].

OBJECTIVE To study the DNA methylation status of WT1 gene promoter region in hematologic malignancy cell lines and its correlation with WT1 gene expression. METHODS 1. RT-PCR and methylation-specific PCR were performed for detecting WT1 gene expression and DNA methylation status in its promoter region in 8226, HL-60, Jurkat, K562, KG-1, NB4, Raji, SHI-1, U266 and U937 cell lines. 2. Treatment of U937 cells with 5-aza-CdR, a demethylation inducing agent and the changes in WT1 gene expression level and its promoter region methylation status were determined. RESULTS 1. HL-60, K562, KG-1, NB4 and SHI-1 cells showed higher levels while 8226, Jurkat, Raji, U266 and U937 cells showed extremely low levels of WT1 expression. DNA hypermethylation in WT1 gene promoter region was identified in 8226, Jurkat, Raji, U266 and U937 cells. 2. The WT1 gene expression in U937 was enhanced after treatment with 5-aza-CdR accompanied with the decrease of methylated and the increase of unmethylated levels in its promoter region. CONCLUSION Modulation of the DNA methylation status in WT1 promoter region is one of the epigenetic mechanisms for regulating its expression.
Utility of Short-Term Evaluation of Presbyopic Contact Lens Performance

Objectives To establish if evaluations of multifocal contact lens performance conducted at dispensing are representative of behavior after a moderate adaptation period. Methods Eighty-eight presbyopic subjects, across four clinical sites, wore each of four multifocal soft contact lenses (ACUVUE BIFOCAL, Focus Progressives, Proclear Multifocal, and SofLens Multifocal) for 4 days of daily wear. Comprehensive performance assessments were conducted at dispensing and after 4 days wear and included the following objective metrics: LogMAR acuity (contrast, 90% and 10%; illumination, 250 and 10 cd/m2; distance, 6 m, 100 cm, and 40 cm), stereopsis (RANDOT), reading critical print size and maximum speed and range of clear vision at near. Subjective assessments were made, with 100-point numerical rating scales, of comfort, ghosting (distance, near), visual quality (distance, intermediate, and near), and the appearance of haloes. At two sites, subjects (n = 39) also rated visual fluctuation (distance, intermediate, and near), facial recognition, and overall satisfaction. Results Among the objective variables, significant differences (paired t test, P<0.05) between dispensing and 4 days were found only for range of clear vision at near (2.9 ± 2.0 cm; mean difference ± standard deviation) and high contrast near acuity in low illumination (−0.013 ± 0.011 LogMAR). With the exception of insertion comfort, all subjective variables showed significant decrements over the same period. Overall satisfaction declined by an average of 10.9 ± 5.1 points. Conclusions Early assessment is relatively unrepresentative of performance later on during multifocal contact lens wear. Acuity based measures of vision remain substantially unchanged over the medium term, apparently because these metrics are insensitive indicators of performance compared with subjective alternatives.
Preparation of Apamarga Kshara and its role in surgical practice

Ayurveda depends mostly upon the medicinal plants for the remedy. In Rig-Veda and Atharvaveda, there are numerous of medicinal plants mentioned to be used as a drug. Kshara is the herbal extracts of plants like Apamarga (Achyranthes aspera Lin), Mulaka (Raphenus sativus Linn.), Snuhi (Euphorbia nerifolia Linn.), Aragwadha (Cassia fistula Linn.), Kutaja (Holarrhena antidysenterica Linn.), Vasa (Adhatoda vasica Linn.) and Arka (Calotropis gigantea Linn.). Kshara can be a compound or mixture of many herbs or may be from single herb. There is wide range of description available about Kshara as told by Acharya Sushruta and many other authoritative classics. This alkaline preparation has many therapeutic usages and even has replaced many surgical procedures and proved to be effective in treating many disorders like Dushta Vrana, Bhagandara, Arsha and Charmakeela. This paper deals with the most practical way of preparing Apamarga Kshara and its role in surgical practice.
Learning Local Dependence In Ordered Data

In many applications, data come with a natural ordering. This ordering can often induce local dependence among nearby variables. However, in complex data, the width of this dependence may vary, making simple assumptions such as a constant neighborhood size unrealistic. We propose a framework for learning this local dependence based on estimating the inverse of the Cholesky factor of the covariance matrix. Penalized maximum likelihood estimation of this matrix yields a simple regression interpretation for local dependence in which variables are predicted by their neighbors. Our proposed method involves solving a convex, penalized Gaussian likelihood problem with a hierarchical group lasso penalty. The problem decomposes into independent subproblems which can be solved efficiently in parallel using first-order methods. Our method yields a sparse, symmetric, positive definite estimator of the precision matrix, encoding a Gaussian graphical model. We derive theoretical results not found in existing methods attaining this structure. In particular, our conditions for signed support recovery and estimation consistency rates in multiple norms are as mild as those in a regression problem. Empirical results show our method performing favorably compared to existing methods. We apply our method to genomic data to flexibly model linkage disequilibrium. Our method is also applied to improve the performance of discriminant analysis in sound recording classification.
Effect of multivitamin versus multivitamin-mineral supplementation on metabolic profiles and biomarkers of oxidative stress in pregnant women: a double-blind randomized clinical trial

Abstract Objective: This study was designed to determine the favorable effects of received multivitamin versus multivitamin-mineral supplements on metabolic profiles and biomarkers of oxidative stress among Iranian pregnant women. Methods: This double-blind randomized-controlled clinical trial was conducted among 70 pregnant women, primigravida, aged 18–35 years old between 16 and 37 weeks gestation. Subjects were randomly assigned to receive either the multivitamin (n = 35) or multivitamin-mineral supplements (n = 35) for 20 weeks. Fasting blood samples were taken at baseline and after a 20-week intervention to measure lipid profiles and biomarkers of oxidative stress. Results: After 20 weeks of intervention, multivitamin-mineral supplementation resulted in a significant difference on serum triglycerides levels (changes from baseline in multivitamin-mineral group: +6.1 versus in multivitamin group: +45.9 mg/dl, p = 0.04) compared with the multivitamin group. In addition, increased concentrations of serum HDL-cholesterol (changes from baseline in multivitamin-mineral group: +0.1 versus in multivitamin group: −7.4 mg/dl, p = 0.02) and total glutathione (GSH) levels (changes from baseline in multivitamin-mineral group: +151.09 versus in multivitamin group: −116.21 µmol/l, p = 0.003) were also seen in the multivitamin-mineral group compared with the multivitamin group. Conclusion: Supplementation of multivitamin-mineral compared to multivitamin supplementation for 20 weeks during pregnancy had beneficial effects on triglycerides, HDL-cholesterol and GSH levels.
Effectiveness and cost-effectiveness of initial combination therapy with interferon/peginterferon plus ribavirin in patients with chronic hepatitis C in Germany: A health technology assessment commissioned by the German Federal Ministry of Health and Social Security

Objectives: The purpose of this health technology assessment (HTA), commissioned by the German Federal Ministry of Health and Social Security, was to systematically review the evidence for the effectiveness and cost-effectiveness of antiviral treatment (AVT) with interferon (INF) or peginterferon (PegIFN) in combination with ribavirin (RBV) in treatment-naïve patients with chronic hepatitis C (CHC) and to apply these data in the context of the German health-care system. Methods: We performed a systematic literature search on effectiveness and cost-effectiveness of AVT and summarized results using meta-analysis and evidence tables. We applied the German Hepatitis C Model (GEHMO), a decision-analytic Markov model, to determine long-term clinical effectiveness, costs, and incremental cost-effectiveness ratios (ICER) of the examined treatment strategies. Model parameters were derived from German databases, published international randomized clinical trials (RCT), and a Cochrane Review. Results: Overall, nine RCTs, two HTA reports, one Cochrane review, two meta-analyses, and seven economic evaluations met the inclusion criteria. These studies indicate that PegIFN+RBV achieved the highest sustained virological response rates (SVR) (54–61 percent), followed by IFN+RBV (38–54 percent) and IFN monotherapy (11–21 percent). Based on our meta-analysis, PegIFN+RBV reduced cases without SVR by 17 percent compared with INF+RBV. International cost-effectiveness studies indicate that INF+RBV is cost-effective when compared with INF monotherapy. For PegIFN+RBV, our decision analysis yielded an ICER of €9,800 per quality-adjusted life-year gained. Conclusions: This HTA suggests that initial combination therapy prolongs life, improves quality of life, and is cost-effective in patients with CHC. Peginterferon plus ribavirin is the most effective and efficient treatment among the examined options. However, because not all chronic hepatitis C patients will develop progressive liver disease, a thorough assessment of the eligibility and appropriateness of treatment with combination therapy must be performed in each individual patient.
Freud's ‘On narcissism: an introduction’

The author reviews Freud's (1914) seminal paper ‘On narcissism: an introduction’. Freud's paper is briefly set in the historical context of the evolution of psychoanalysis and psychoanalytic theories, and Freud's metapsychology up to the publication of his Narcissism paper is outlined. A detailed and comprehensive description of the content of the paper is given, accompanied by commentary on, and critical analysis of, Freud's ideas. Freud's applications of his ideas about narcissism in relation to homosexuality, hypochondria and psychosis are elucidated and discussed. The author concludes by considering some of the influences of Freud's ideas about narcissism on Kleinian and post-Kleinian developments in psychoanalytic theory.
Dementia knowledge among general practitioners: first results and psychometric properties of a new instrument

ABSTRACT Background: General practitioners (GPs) play an important role in dementia care. Sufficient knowledge is one of the prerequisites for adequate dementia management, and educational activities do include knowledge transfer. There is no up-to-date measure of GPs' knowledge of dementia, resulting in the use of unreliable ad hoc questionnaires in recent studies, thus increasing the risk of biased results. Methods: In a cross-sectional, observational questionnaire study, 292 German GPs answered 37 questions regarding factual dementia knowledge. For the purpose of cross-validation, the psychometric properties of the test and its associations with GP characteristics were analyzed in independent samples with item and regression analyses. Results: Twenty questions constituted a reliable questionnaire (Cohen's α = 0.733) with a normal distribution of test scores. Linear regression analysis revealed significant associations of the knowledge test score with the GPs' age and their attitudes towards dementia. Conclusions: The newly developed dementia-knowledge test for GPs can be used in observational studies, in which a rough and easy to use instrument is required.
Full-Length Hepatitis B Virus Core Protein Packages Viral and Heterologous RNA with Similarly High Levels of Cooperativity

ABSTRACT A critical feature of a viral life cycle is the ability to selectively package the viral genome. In vivo, phosphorylated hepatitis B virus (HBV) core protein specifically encapsidates a complex of pregenomic RNA (pgRNA) and viral polymerase; it has been suggested that packaging is specific for the complex. Here, we test the hypothesis that core protein has intrinsic specificity for pgRNA, independent of the polymerase. For these studies, we also evaluated the effect of core protein phosphorylation on assembly and RNA binding, using phosphorylated core protein and a phosphorylation mimic in which S155, S162, and S170 were mutated to glutamic acid. We have developed an in vitro system where capsids are disassembled and assembly-active core protein dimer is purified. With this protein, we have reassembled empty capsids and RNA-filled capsids. We found that core protein dimer bound and encapsidated both the HBV pregenomic RNA and heterologous RNA with high levels of cooperativity, irrespective of phosphorylation. In direct competition assays, no specificity for pregenomic RNA was observed. This suggests that another factor, such as the viral polymerase, is required for specific packaging. These results also beg the question of what prevents HBV core protein from assembling on nonviral RNA, preserving the protein for virus production.
Cancer in patients with schizophrenia: What is the next step?

People with schizophrenia, who constitute approximately 0.3–1% of the general population, have a nearly 20% shorter life expectancy than the general population. The incidence of varied types of cancers in patients with schizophrenia is controversial. The majority of previous research has demonstrated that patients who have schizophrenia and cancer have early mortality compared to the general population with cancer. The causes of early mortality in patients with schizophrenia and cancer might be attributed to a lower cancer screening rate and lack of effective treatment, including: (i) patient factors, such as poor lifestyle, passive attitude toward treatment, or comorbidity; (ii) physician factors, such as physician bias, which may decrease the delivery of care for individuals with mental disorders; and (iii) hospital administration factors, such as stigma and discrimination. Additional studies on patients with schizophrenia and cancer are warranted and should include the following: a comprehensive review of previous studies; a focus on differentiating the specific types of cancer; and methods for improvement. To decrease the early mortality of patients with schizophrenia, the following measures are proposed: (i) enhance early detection and early treatment, such as increasing the cancer screening rate for patients with schizophrenia; (ii) provide effective, timely treatment and rehabilitation; (iii) improve patients’ psychiatric symptoms and cognitive impairment; (iv) promote healthy behavior in the general population and emphasize healthy lifestyles in vulnerable populations; and (v) remove the stigma of schizophrenia. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this group of patients.
The TMEM106B risk allele is associated with lower cortical volumes in a clinically diagnosed frontotemporal dementia cohort

Frontotemporal dementia (FTD) is a neurodegenerative disease associated with impaired behaviour, language and motor function. Around a third of FTD is familial, with mutations in microtubule-associated protein tau ( MAPT ), progranulin ( GRN ) and chromosome 9 open reading frame 72 ( C9orf72 ) being the most common genetic causes. No other risk factors for FTD had been identified until a genome-wide association study of patients with the most common pathological form of FTD, frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), showed an association with single nucleotide polymorphisms (SNPs) in a region encoding transmembrane protein 106b (TMEM106b). 1 For the rs1990622 SNP the minor G allele was found to be less common in patients with FTLD-TDP than in a healthy control population, that is, those expressing this allele were less likely to develop disease, and this effect was greatest in those with GRN mutations (who have FTLD-TDP pathology). 1 Further studies of FTD cohorts have replicated the finding in other GRN cohorts, in those with C9orf72 expansions (who also have FTLD-TDP pathology) and in one undifferentiated clinical FTD cohort.2 3 Furthermore, neuroimaging studies have shown reduced left hemispheric grey matter volume in those carrying the major (risk) A allele within a healthy population cohort,4 and reduced functional connectivity in those homozygous for the risk allele in a GRN cohort.5 In this study we investigate the association of the rs1990622 SNP with cortical volumes in a clinically diagnosed FTD cohort and a subset of cases with likely FTLD-TDP. The UCL FTD DNA cohort database was searched for those with volumetric MRI. Data were available from 198 patients with an FTD spectrum disorder: 87 with behavioural variant FTD (bvFTD), 46 with non-fluent variant primary progressive aphasia …
Clinical trial of indomethacin in Alzheimer's disease

In a 6-month, double-blind, placebo-controlled study, 1100 to 150 mg/d indomethacin appeared to protect mild to moderately impaired Alzheimer's disease patients from the degree of cognitive decline exhibited by a well-matched, placebo-treated group. Over a battery of cognitive tests, indomethacin patients improved 1.3% (±1.8%), whereas placebo patients declined 8.4% (±2.3%)—a significant difference (p < 0.003). Caveats include adverse reactions to indomethacin and the limited scale of the trial.
Epidermal ‘alarm substance’ cells of fishes maintained by non-alarm functions: possible defence against pathogens, parasites and UVB radiation

Many fishes possess specialized epidermal cells that are ruptured by the teeth of predators, thus reliably indicating the presence of an actively foraging predator. Understanding the evolution of these cells has intrigued evolutionary ecologists because the release of these alarm chemicals is not voluntary. Here, we show that predation pressure does not influence alarm cell production in fishes. Alarm cell production is stimulated by exposure to skin-penetrating pathogens (water moulds: Saprolegnia ferax and Saprolegnia parasitica), skin-penetrating parasites (larval trematodes: Teleorchis sp. and Uvulifer sp.) and correlated with exposure to UV radiation. Suppression of the immune system with environmentally relevant levels of Cd inhibits alarm cell production of fishes challenged with Saprolegnia. These data are the first evidence that alarm substance cells have an immune function against ubiquitous environmental challenges to epidermal integrity. Our results indicate that these specialized cells arose and are maintained by natural selection owing to selfish benefits unrelated to predator–prey interactions. Cell contents released when these cells are damaged in predator attacks have secondarily acquired an ecological role as alarm cues because selection favours receivers to detect and respond adaptively to public information about predation.
The Maudsley Bipolar Disorder Project: insights into the role of the prefrontal cortex in bipolar disorder I

Purpose: The Maudsley Bipolar Disorder Project was set up in order to investigate the cognitive and structural/functional brain characteristics of Bipolar Disorder I (BDI). Methods: Participating patients with BDI (n = 43) were recruited from a secondary care setting, while in remission. They were matched to healthy controls for age, gender, race and years of education. Each participant underwent extensive clinical review, cognitive assessment, and Magnetic Resonance Imaging (MRI) in order to obtain brain structural and functional data. Results: When compared to controls, patients demonstrated subtle widespread impairment with executive function being more markedly reduced. Patients also displayed volume decrements in the ventral prefrontal cortex (VPFC) bilaterally and in the dorsal PFC (DPFC) on the left. The volume of the amygdala was bilaterally enlarged. Functional MRI of patients showed subtle