Miracle-dz/UniFAR-FTUs huggingface dataset:
Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough

The vast majority of people with cystic fibrosis (CF) are now eligible for CF transmembrane regulator (CFTR) modulator therapy. The remaining individuals with CF harbor premature termination codons (PTCs) or rare CFTR variants with limited treatment options. Although the clinical modulator response can be reliably predicted using primary airway epithelial cells, primary cells carrying rare CFTR variants are scarce. To overcome this obstacle, cell lines can be created by overexpression of mouse Bmi-1 and human TERT (hTERT). Using this approach, we developed 2 non-CF and 6 CF airway epithelial cell lines, 3 of which were homozygous for the W1282X PTC variant. The Bmi-1/hTERT cell lines recapitulated primary cell morphology and ion transport function. The 2 F508del-CFTR cell lines responded robustly to CFTR modulators, which was mirrored in the parent primary cells and in the cell donors’ clinical response. Cereblon E3 ligase modulators targeting eukaryotic release factor 3a (eRF3a) rescued W1282X-CFTR function to approximately 20% of WT levels and, when paired with G418, rescued G542X-CFTR function to approximately 50% of WT levels. Intriguingly, eRF3a degraders also diminished epithelial sodium channel (ENaC) function. These studies demonstrate that Bmi-1/hTERT cell lines faithfully mirrored primary cell responses to CFTR modulators and illustrate a therapeutic approach to rescue CFTR nonsense mutations.
Promising Biomarkers in Head and Neck Cancer: The Most Clinically Important miRNAs

Head and neck cancers (HNCs) comprise a heterogeneous group of tumors that extend from the oral cavity to the upper gastrointestinal tract. The principal etiologic factors for oral tumors include tobacco smoking and alcohol consumption, while human papillomavirus (HPV) infections have been accused of a high incidence of pharyngeal tumors. Accordingly, HPV detection has been extensively used to categorize carcinomas of the head and neck. The diverse nature of HNC highlights the necessity for novel, sensitive, and precise biomarkers for the prompt diagnosis of the disease, its successful monitoring, and the timely prognosis of patient clinical outcomes. In this context, the identification of certain microRNAs (miRNAs) and/or the detection of alterations in their expression patterns, in a variety of somatic fluids and tissues, could serve as valuable biomarkers for precision oncology. In the present review, we summarize some of the most frequently studied miRNAs (including miR-21, -375, -99, -34a, -200, -31, -125a/b, -196a/b, -9, -181a, -155, -146a, -23a, -16, -29, and let-7), their role as biomarkers, and their implication in HNC pathogenesis. Moreover, we designate the potential of given miRNAs and miRNA signatures as novel diagnostic and prognostic tools for successful patient stratification. Finally, we discuss the currently ongoing clinical trials that aim to identify the diagnostic, prognostic, or therapeutic utility of miRNAs in HNC.
Overview and update on molecular testing in non‐small cell lung carcinoma utilizing endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) samples

Lung carcinoma remains one of the most frequent and aggressive human neoplasms. Fortunately, in the last decades, the increasing knowledge of the molecular mechanisms leading to cancer development has allowed the use of targeted therapies with improvement of prognosis in many patients. Clinical management has also changed after the introduction of endobronchialultrasonographic bronchoscopy that allows a conservative staging of lung tumors, avoiding the need of mediastinoscopy for lymph node staging. Lung pathologists and cytopathologists are facing the challenge of giving the more comprehensive prognostic and predictive information with ever smaller tissue or cytological samples. The aim of this review is to summarize the molecular testing for non‐small cell lung carcinoma and how pathologists can contribute to the patient's outcome with a conscious management of biological samples.
GSDMD drives canonical inflammasome‐induced neutrophil pyroptosis and is dispensable for NETosis

Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL‐1β secretion and neutrophil cell death remain unclear. Here, we show that neutrophil‐targeted expression of the disease‐associated gain‐of‐function Nlrp3A350V mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm the activity of the canonical NLRP3 and NLRC4 inflammasomes in neutrophils, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes also promote maturation and secretion of interleukin (IL)‐1β in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage in neutrophils, and canonical inflammasome‐induced pyroptosis and secretion of mature IL‐1β are blunted in GSDMD‐knockout neutrophils. In contrast, GSDMD is dispensable for PMA‐induced NETosis. We also show that Salmonella Typhimurium‐induced pyroptosis is markedly increased in Nox2/Gp91Phox‐deficient neutrophils that lack NADPH oxidase activity and are defective in PMA‐induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome‐induced neutrophil pyroptosis and mitogen‐induced NETosis, respectively.
Role of Src kinase in regulating protein kinase C mediated phosphorylation of TRPV1

Transient receptor potential vanilloid‐1 (TRPV1), activated by heat, acidic pH, endogenous vanilloids and capsaicin, is essential for thermal hyperalgesia. Under inflammatory conditions, phosphorylation of TRPV1 by protein kinase C (PKC) can sensitize the channel and decrease the activation threshold. Src kinase also phosphorylates TRPV1, promoting channel trafficking to the plasma membrane. These post‐translational modifications are important for several chronic pain conditions. This study presents a previously undescribed relationship between Src and PKC phosphorylation of TRPV1, influencing the thermal hypersensitivity associated with TRPV1 activation.
Role of somatostatin receptor SSRT5-AS1 in predicting biomarkers of primary androgen deprivation therapy on prostate cancer in Indonesian population.

INTRODUCTION Androgen deprivation therapy (ADT) has been the pivotal strategy for treating advanced prostate cancers. Despite the high efficacy of ADT in prohibiting tumor growth, >50% cases of prostate cancer will develop into an aggressive variant known as castration resistant prostate cancer (CRPC). This study aimed to evaluate the potential role SSRT5-AS1 expression as a biomarker for response to ADT in prostate cancer. MATERIALS AND METHODS In total, 36 patients diagnosed with prostate cancer at Dr. Sardjito General Hospital, Yogyakarta, Indonesia were enrolled from 2015 and 2019. The expression of SSRT5-AS1 in primary tumors was quantified using quantitative real-time polymerase chain reaction. RESULTS The mean age of patients enrolled in this study was 69.07 ± 8.7 years, and the mean of prostate-specific antigen in patients was 141.22 ±112.28 ng/ml. Compared with the median, a higher expression of SSTR5-AS1 had more significant prognostic value than the variable shorter time to CRPC (p= 0.043). CONCLUSION This study demonstrated that high expression of SSRT5-AS1 is a promising biomarker to predict response to ADT in patients with prostate cancer.
Volatility forecasts of stock index futures in China and the US–A hybrid LSTM approach

This paper is concerned with the unsolved issue of how to accurately predict the financial market volatility. We propose a novel volatility prediction method for stock index futures prediction based on LSTM, PCA, stock indices and relevant futures. Inspired by the recent advancement of deep learning methodology, six models that combine a variety of artificial intelligence techniques are compared, including ANN, ANN(PCA), ANN(AE), LSTM, LSTM(PCA), and LSTM(AE). That is, in the design and comparison of the proposed AI models, we consider the combination of two dimensionality reduction methods (PCA and AE) and two typical neural networks (ANN and LSTM) in processing time series data. Besides, to further assess the prediction performance of the proposed models, two widely-applied statistical models (i.e. AR and EGARCH) on volatility prediction are used as benchmarks. In the empirical study, we collect financial trading data in both China and the US, and compare the performances of different models in predicting 5 days and 10 days ahead volatilities of stock index futures. In all, our analysis supports the use of LSTM(PCA) model to tackle those irregular and complex datasets.
A global grounded theory exploration of investigators’ perspectives on male hormonal contraceptive development and acceptability

ABSTRACT While best practices have been proposed on how to engage men in family planning (FP), the limited options of male hormonal contraceptives (MHC) are a barrier to reaching men as clients of FP programs. The lack of alternative MHC is preventing the global health community from providing holistic reproductive healthcare. A qualitative grounded theory study was conducted in 2020 to explore MHC experts’ perceptions around the development and theoretical acceptability of MHCs. Individual in-depth interviews were conducted with 15 key informants. The informants cited evidence that there is a demand for MHC. The inability to access this data by the pharmaceutical industry was acknowledged. Many informants expressed concern of the possibility for MHC to increase male power in a predominantly patriarchal world. To most informants, at least for the initial introduction of MHC, fertility sharing is something that will largely happen among couples alone rather than individually. There is proven demand among women and men for MHC, however industries may still be reluctant to invest. Effort is needed by the sexual and reproductive health and rights community to include male engagement in FP and to advocate for the development and use of MHC as a tool for women’s empowerment.
Social Fear Affects Limbic System Neuronal Activity and Gene Expression

Social anxiety disorder (SAD) is a highly prevalent and comorbid anxiety disorder with rather unclear underlying mechanisms. Here, we aimed to characterize neurobiological changes occurring in mice expressing symptoms of social fear and to identify possible therapeutic targets for SAD. Social fear was induced via social fear conditioning (SFC), a validated animal model of SAD. We assessed the expression levels of the immediate early genes (IEGs) cFos, Fosl2 and Arc as markers of neuronal activity and the expression levels of several genes of the GABAergic, serotoninergic, oxytocinergic, vasopressinergic and neuropeptide Y (NPY)-ergic systems in brain regions involved in social behavior or fear-related behavior in SFC+ and SFC− mice 2 h after exposure to a conspecific. SFC+ mice showed a decreased number and density of cFos-positive cells and decreased expression levels of IEGs in the dorsal hippocampus. SFC+ mice also showed alterations in the expression of NPY and serotonin system-related genes in the paraventricular nucleus of the hypothalamus, basolateral amygdala, septum and dorsal raphe nucleus, but not in the dorsal hippocampus. Our results describe neuronal alterations occurring during the expression of social fear and identify the NPY and serotonergic systems as possible targets in the treatment of SAD.
A survey for characterizing details of fall events experienced by lower limb prosthesis users

Despite their importance to fall prevention research, little is known about the details of real-world fall events experienced by lower limb prosthesis users. This gap can be attributed to the lack of a structured, population-specific fall survey to document these adverse health events. The objective of this project was to develop a survey capable of characterizing the circumstances and consequences of fall events in lower limb prosthesis users. Best practices in survey development, including focus groups and cognitive interviews with diverse samples of lower limb prosthesis users, were used to solicit input and feedback from target respondents, so survey content would be meaningful, clear, and applicable to lower limb prosthesis users. Focus group data were used to develop fall event definitions and construct a conceptual fall framework that guided the creation of potential survey questions and response options. Survey questions focused on the activity, surroundings, situation, mechanics, and consequences of fall events. Cognitive interviews revealed that with minor revisions, survey definitions, questions, and response options were clear, comprehensive, and applicable to the experiences of lower limb prosthesis users. Administration of the fall survey to a national sample of 235 lower limb prosthesis users in a cross-sectional preliminary validation study, found survey questions to function as intended. Revisions to the survey were made at each stage of development based on analysis of participant feedback and data. The structured, 37-question lower limb prosthesis user fall event survey developed in this study offers clinicians and researchers the means to document, monitor, and compare fall details that are meaningful and relevant to lower limb prosthesis users in a standardized and consistent manner. Data that can be collected with the developed survey are essential to establishing specific goals for fall prevention initiatives in lower limb prosthesis users.
Artificial selection of microbial communities can become effective after using evolution-informed strategies

5 Multi-species microbial communities often display “community functions” stemming from interactions of 6 member species. Interactions are often difficult to decipher, making it challenging to design communi7 ties with desired functions. Alternatively, similar to artificial selection for individuals in agriculture and 8 industry, one could repeatedly choose communities with the highest functions to reproduce by randomly 9 partitioning each into multiple “Newborn” communities for the next cycle. However, community selec10 tion is challenging since rapid changes in species and genotype compositions can limit the heritability 11 of community function. To understand how to enact community selection, we used an individual-based 12 model to simulate this process to improve a community function that requires two species and is costly 13 to one species. Improvement was stalled by non-heritable variations in community function, such as the 14 stochastic populating of Newborn communities or measurement errors of community function. Com15 munity function improved when these non-heritable variations were suppressed in experimentally feasible 16 manners. 17
The prevalence of depression and its association with sociodemographic factors in menopausal women in South Korea

Abstract This study examined factors that may be associated with depression among middle-aged women in South Korea using data from the 2018 (7th) wave of the Korean Longitudinal Survey of Women and Families. A sample of 6,399 women aged 35–64 years was included. Multivariate logistic regression was performed to identify factors associated with depressive symptoms, as measured by the CES-D-10 scale (Center for Epidemiological Studies Depression), in pre- and post-menopausal women. Results indicated that being single, having poorer self-rated health, and having a lower economic background were associated with an increased risk of depression in both groups. Being unemployed also increased the risk of depressed mood in pre-menopausal women, while factors significantly associated with an increased risk of depressive symptoms in post-menopausal women included having a lower level of education, musculoskeletal pain, and having pain or discomfort. Thus, these factors should be considered when developing interventions to improve the mood and quality of life of middle-aged women. Interventions in the local community may include health services (hormone therapy), educational learning programs, counselling, and improved access to leisure activities.
Health inequities as measured by the EQ-5D-5L during COVID-19: Results from New York in healthy and diseased persons

Introduction The effects of the COVID-19 pandemic caused considerable psychological and physical effects in healthy and diseased New Yorkers aside from the effects in those who were infected. We investigated the relationship between known risk-enhancing and health-promoting factors (social and medical), comorbidity indicators, and, as the primary outcome, health-related quality of life (HRQoL). Methods Between April 22 and May 5, 2020, a market research agency (Dynata) administered a digital survey including the EQ-5D-5L and items related to individual characteristics, social position, occupational and insurance status, living situation, exposures (smoking and COVID-19), detailed chronic conditions, and experienced access to care to an existing internet panel representative of New Yorkers. Results 2684 persons completed the questionnaire. The median age was 48 years old, and most respondents were non-Hispanic white (74%) and reported at least higher vocational training or a university education (83%). During COVID-19, mean HRQoL scores were 0.82 for the EQ-5D-5L index and 79.3 for the EQ VAS. Scores varied for healthy and diseased respondents differently by the above determinants. Lower age, impaired occupational status, loss of health insurance, and limited access to care exerted more influence on EQ-5D-5L scores of diseased persons compared to healthy persons. Among diseased persons, the number of chronic conditions and limited access to health care had the strongest association with EQ-5D-5L scores. While EQ-5D-5L scores improved with increasing age, gender had no noticeable effect. Deprivation factors showed moderate effects, which largely disappeared in (stratified) multivariable analysis, suggesting mediation through excess chronic morbidity and poor healthcare access. Generally, modifying effects were larger in the EQ-5D-5L as compared to the EQ VAS. Conclusions Almost all factors relating to a disadvantaged position showed a negative association with HRQoL. In diseased respondents, pre-existing chronic comorbidity and experienced access to health care are key factors.
Cross-sectional examination of ultra-processed food consumption and adverse mental health symptoms

Abstract Objective: To explore whether individuals who consume higher amounts of ultra-processed food (UPF) have more adverse mental health symptoms. Design: Using a cross-sectional design, we measured the consumption of UPF as a percentage of total energy intake in kilo-calories using the NOVA food classification system. We explored whether individuals who consume higher amounts of UPF were more likely to report mild depression, more mentally unhealthy days and more anxious days per month using multivariable analyses adjusting for potential confounding variables. Setting: Representative sample from the United States National Health and Nutrition Examination Survey between 2007 and 2012. Participants: 10 359 adults aged 18+ without a history of cocaine, methamphetamine or heroin use. Results: After adjusting for covariates, individuals with the highest level of UPF consumption were significantly more likely to report at least mild depression (OR: 1·81; 95 % CI1·09, 3·02), more mentally unhealthy (risk ratio (RR): 1·22; 95 % CI 1·18, 1·25) and more anxious days per month (RR: 1·19; 95 % CI 1·16, 1·23). They were also significantly less likely to report zero mentally unhealthy (OR: 0·60; 95 % CI 0·41, 0·88) or anxious days (OR: 0·65; 95 % CI 0·47, 0·90). Conclusions: Individuals reporting higher intakes of UPF were significantly more likely to report mild depression, more mentally unhealthy and more anxious days and less likely to report zero mentally unhealthy or anxious days. These data add important information to a growing body of evidence concerning the potential adverse effects of UPF consumption on mental health.
Liver cirrhosis prediction for patients with Wilson disease based on machine learning: a case–control study from southwest China

Objectives Wilson disease (WD) is a rare autosomal recessive disease caused by an ATP7B gene mutation. Liver cirrhosis is an important issue that affects the clinical management and prognosis of WD patients. Blood routine examination is a potential biomarker for predicting the occurrence of liver cirrhosis in WD. We aim to construct a predictive model for the occurrence of liver cirrhosis using general clinical information, blood routine examination, urine copper, and serum ceruloplasmin through a machine learning approach. Methods Case–control study of WD patients admitted to West China Fourth Hospital between 2005 and 2020. Patients with a score of at least four in scoring system of WD were enrolled. A machine learning model was constructed by EmpowerStats software according to the general clinical data, blood routine examination, 24 h urinary copper, and serum ceruloplasmin. Results This study analyzed 346 WD patients, of which 246 were without liver cirrhosis. And we found platelet large cell count (P-LCC), red cell distribution width CV (RDW-CV), serum ceruloplasmin, age at diagnosis, and mean corpuscular volume (MCV) were the top five important predictors. Moreover, the model was of high accuracy, with an area under the receiver operating characteristic curve of 0.9998 in the training set and 0.7873 in the testing set. Conclusions In conclusion, the predictive model for predicting liver cirrhosis in WD, constructed by machine learning, had a higher accuracy. And the most important indices in the predictive model were P-LCC, RDW-CV, serum ceruloplasmin, age at diagnosis, and MCV.
Bioactive Nitrosylated and Nitrated N-(2-hydroxyphenyl)acetamides and Derived Oligomers: An Alternative Pathway to 2-Amidophenol-Derived Phytotoxic Metabolites

Incubation of Aminobacter aminovorans, Paenibacillus polymyxa, and Arthrobacter MPI764 with the microbial 2-benzoxazolinone (BOA)-degradation-product 2-acetamido-phenol, produced from 2-aminophenol, led to the recently identified N-(2-hydroxy-5-nitrophenyl) acetamide, to the hitherto unknown N-(2-hydroxy-5-nitrosophenyl)acetamide, and to N-(2-hydroxy-3-nitrophenyl)acetamide. As an alternative to the formation of phenoxazinone derived from aminophenol, dimers- and trimers-transformation products have been found. Identification of the compounds was carried out by LC/HRMS and MS/MS and, for the new structure N-(2-hydroxy-5-nitrosophenyl)acetamide, additionally by 1D- and 2D-NMR. Incubation of microorganisms, such as the soil bacteria Pseudomonas laurentiana, Arthrobacter MPI763, the yeast Papiliotrema baii and Pantoea ananatis, and the plants Brassica oleracea var. gongylodes L. (kohlrabi) and Arabidopsis thaliana Col-0, with N-(2-hydroxy-5-nitrophenyl) acetamide, led to its glucoside derivative as a prominent detoxification product; in the case of Pantoea ananatis, this was together with the corresponding glucoside succinic acid ester. In contrast, Actinomucor elegans consortium synthesized 2-acetamido-4-nitrophenyl sulfate. 1 mM bioactive N-(2-hydroxy-5-nitrophenyl) acetamide elicits alterations in the Arabidopsis thaliana expression profile of several genes. The most responsive upregulated gene was pathogen-inducible terpene synthase TPS04. The bioactivity of the compound is rapidly annihilated by glucosylation.