Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer

Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents. Description EGFR regulates GCH1/BH4 expression in neuropathic pain and cancer in mice. A shared target between cancer and pain Neuropathic pain is a chronic condition for which effective safe treatments are lacking. Polymorphisms in the GTP cyclohydrolase 1 (GCH1) gene have been associated with chronic pain severity; and modulation of the GCH1/BH4 pathway has been shown to affect neuropathic pain. Here, Cronin et al. screened over a thousand annotated and FDA-approved compounds and showed that the antipsychotic fluphenazine hydrochloride reduced GCH1 expression and had analgesic effects in a neuropathic pain model in rodents. Among the hits, EGFR/KRAS pathway modulators also affected GCH1 expression, and the authors identified a common signaling, downstream KRAS, involving GCH1, that affects chronic pain and lung cancer development in mice. The results suggest that targeting this signaling could alleviate neuropathic pain.
Results of a 2‐year lifestyle intervention for type 2 diabetes: the Reach Ahead for Lifestyle and Health‐Diabetes randomized controlled trial

The Reach Ahead for Lifestyle and Health (REAL HEALTH)‐Diabetes study assessed the comparative effectiveness of two Look AHEAD (Action for Health in Diabetes)‐adapted lifestyle intervention (LI) arms targeting weight loss in type 2 diabetes compared with medical nutrition therapy (MNT) referral. At 1 year, LI had greater weight loss than MNT. This study reports outcomes at 24 (end of LI) and 36 months.
Intelligent Auto-grading System

Teachers tend to set the free-text questions for testing the comprehensive ability of students. That leads to the increasing attention to the intelligent auto-grading system for easing the grading load on examiners. In this paper, we present a novel automatic essay scoring system based on Natural Language Processing and Deep Learning technologies. In particular, the proposed system encodes an essay as sequential embeddings and harnesses a bi-directional LSTM to catch the semantic information. Meanwhile, the system constructs the attention for each essay so that the network can learn to focus on the valid information correctly in an article, which can also provide the reasonable evidence of the predictive result. The dataset for training and testing is the public essay set available in the Automated Student Assessment Prize on Kaggle. The study shows that our system achieves state-of-the-art performance in grade prediction, and more importantly, our intelligent auto-grading system can focus on the critical words and sentences, analyze the logical semantic relationship of the context and predict the interpretable grades.
Relative to processed red meat, alternative protein sources are associated with a lower risk of hypertension and diabetes in a prospective cohort of French women

Abstract Many dietary guidelines recommend restricting the consumption of processed red meat (PRM) in favour of healthier foods such as fish, to reduce the risk of chronic conditions such as hypertension and diabetes. The objective of this study was to estimate the potential effect of replacing PRM for fatty fish, lean fish, red meat, eggs, pulses, or vegetables, on the risk of incident hypertension and diabetes. This was a prospective study of women in the E3N cohort study. Cases of diabetes and hypertension were based on self-report, specific questionnaires, and drug reimbursements. In the main analysis, information on regular dietary intake was assessed with a single food history questionaire, and food substitutions were modelled using cox proportional hazard models. 95 % confidence intervals were generated via bootstrapping. 71 081 women free of diabetes and 45 771 women free of hypertension were followed for an average of 18·7 and 18·3 years, respectively. 2681 incident cases of diabetes and 12 327 incident cases of hypertension were identified. Relative to PRM, fatty fish was associated with a 15 % lower risk of diabetes (HR = 0·85, 95 CI (0·73, 0·97)) and hypertension (HR = 0 85 (0·79, 0·91)). Between 3 and 10 % lower risk of hypertension or diabetes was also observed when comparing PRM with vegetables, unprocessed red meat or pulses. Relative to PRM, alternative protein sources such as fatty fish, unprocessed red meat, vegetables or pulses was associated with a lower risk of hypertension and diabetes.
Thalamocortical connectivity and its relationship with symptoms and cognition across the psychosis continuum

Abstract Background Coordination between the thalamus and cortex is necessary for efficient processing of sensory information and appears disrupted in schizophrenia. The significance of this disrupted coordination (i.e. thalamocortical dysconnectivity) to the symptoms and cognitive deficits of schizophrenia is unclear. It is also unknown whether similar dysconnectivity is observed in other forms of psychotic psychopathology and associated with familial risk for psychosis. Here we examine the relevance of thalamocortical connectivity to the clinical symptoms and cognition of patients with psychotic psychopathology, their first-degree biological relatives, and a group of healthy controls. Method Patients with a schizophrenia-spectrum diagnosis (N = 100) or bipolar disorder with a history of psychosis (N = 33), their first-degree relatives (N = 73), and a group of healthy controls (N = 43) underwent resting functional MRI in addition to clinical and cognitive assessments as part of the Psychosis Human Connectome Project. A bilateral mediodorsal thalamus seed-based analysis was used to measure thalamocortical connectivity and test for group differences, as well as associations with symptomatology and cognition. Results Reduced connectivity from mediodorsal thalamus to insular, orbitofrontal, and cerebellar regions was seen in schizophrenia. Across groups, greater symptomatology was related to less thalamocortical connectivity to the left middle frontal gyrus, anterior cingulate, right insula, and cerebellum. Poorer cognition was related to less thalamocortical connectivity to bilateral insula. Analyses revealed similar patterns of dysconnectivity across patient groups and their relatives. Conclusions Reduced thalamo-prefrontal-cerebellar and thalamo-insular connectivity may contribute to clinical symptomatology and cognitive deficits in patients with psychosis as well as individuals with familial risk for psychotic psychopathology.
Crystallization of Beta-phase Poly (vinylidene fluoride) films using dimethyl sulfoxide (DMSO) solvent and at suitable annealing condition

In literature it has been reported that the gamma-phase PVDF film is formed from dimethyl sulfoxide (DMSO) solvents regardless of preparation temperature. In this report the crystallization of both alpha and gamma phase from DMSO solvent by varying preparation temperature has been described. This paper also describes the conversion of gamma-phase to beta- phase and alpha-phase at different annealing condition. When thin films were annealed at 90C for 5 hours, then maximum beta-phase content (greater than 95%) is present in PVDF thin film. The PVDF films completely converted to alpha-phase, when they were annealed at 160C for 5 hours. From (X-ray diffraction) XRD, Fourier Transform Infrared Spectrum (FTIR), (Differential thermal analysis) DTA and Raman studies, it is confirmed that the PVDF thin films, cast from DMSO solution and annealed at 90C for 5 hours, have maximum percentage of beta-phase(greater than 95%).
Model misspecification and bias for inverse probability weighting estimators of average causal effects

Commonly used semiparametric estimators of causal effects specify parametric models for the propensity score (PS) and the conditional outcome. An example is an augmented inverse probability weighting (IPW) estimator, frequently referred to as a doubly robust estimator, because it is consistent if at least one of the two models is correctly specified. However, in many observational studies, the role of the parametric models is often not to provide a representation of the data‐generating process but rather to facilitate the adjustment for confounding, making the assumption of at least one true model unlikely to hold. In this paper, we propose a crude analytical approach to study the large‐sample bias of estimators when the models are assumed to be approximations of the data‐generating process, namely, when all models are misspecified. We apply our approach to three prototypical estimators of the average causal effect, two IPW estimators, using a misspecified PS model, and an augmented IPW (AIPW) estimator, using misspecified models for the outcome regression (OR) and the PS. For the two IPW estimators, we show that normalization, in addition to having a smaller variance, also offers some protection against bias due to model misspecification. To analyze the question of when the use of two misspecified models is better than one we derive necessary and sufficient conditions for when the AIPW estimator has a smaller bias than a simple IPW estimator and when it has a smaller bias than an IPW estimator with normalized weights. If the misspecification of the outcome model is moderate, the comparisons of the biases of the IPW and AIPW estimators show that the AIPW estimator has a smaller bias than the IPW estimators. However, all biases include a scaling with the PS‐model error and we suggest caution in modeling the PS whenever such a model is involved. For numerical and finite sample illustrations, we include three simulation studies and corresponding approximations of the large‐sample biases. In a dataset from the National Health and Nutrition Examination Survey, we estimate the effect of smoking on blood lead levels.
Evidence‐based guidelines for automated conservation assessments of plant species

Assessing species’ extinction risk is vital to setting conservation priorities. However, assessment endeavors, such as those used to produce the IUCN Red List of Threatened Species, have significant gaps in taxonomic coverage. Automated assessment (AA) methods are gaining popularity to fill these gaps. Choices made in developing, using, and reporting results of AA methods could hinder their successful adoption or lead to poor allocation of conservation resources. We explored how choice of data cleaning type and level, taxonomic group, training sample, and automation method affect performance of threat status predictions for plant species. We used occurrences from the Global Biodiversity Information Facility (GBIF) to generate assessments for species in 3 taxonomic groups based on 6 different occurrence‐based AA methods. We measured each method's performance and coverage following increasingly stringent occurrence cleaning. Automatically cleaned data from GBIF performed comparably to occurrence records cleaned manually by experts. However, all types of data cleaning limited the coverage of AAs. Overall, machine‐learning‐based methods performed well across taxa, even with minimal data cleaning. Results suggest a machine‐learning‐based method applied to minimally cleaned data offers the best compromise between performance and species coverage. However, optimal data cleaning, training sample, and automation methods depend on the study group, intended applications, and expertise.
Interaction Effect Between Breast Density and Reproductive Factors on Breast Cancer Risk in Korean Population

Background This study was conducted to explore the effect of known risk factors, focusing on risk factors including age at menarche, age at menopause, number of children, family history of breast cancer, and age at first birth according to breast density, in consideration of interaction among East-Asian women. Methods Case-control study with 2,123 cases and 2,121 controls with mammographic density was conducted. Using the mammographic film, breast density was measured using Breast Imaging-Reporting and Data System. To identify the association of selected reproductive factors including age at menarche, age at menopause, number of children, family history of breast cancer, and age at first birth according to breast density, stratified analysis was conducted according to breast density groups and interaction effects was assessed. The results were presented with adjusted OR and 95% CIs. Results Significant interaction effect between age at first birth and breast density on breast cancer (P = 0.048) was observed. Women with age at first birth ≥ 28 years old showed increased breast cancer risk in extremely dense breast group (≥ 75%) (OR = 1.627, 95% CI = 1.190–2.226). However, women with fatty breast (< 50%) and heterogeneously dense breast (50%–75%) did not show an increased association. Age at menarche, age at menopause, number of children, and family history of breast cancer did not show significant interaction with breast cancer and similar risk patterns were observed. Conclusions Age at first birth showed significant interaction with breast density on breast cancer risk. Further studies considering biologically plausable model between exposure, intermediate outcomes and breast cancer risk with prospective design need to be undertaken in East Asian women.
Perceived Parental Undifferentiated Rejection and Children’s Personality Dispositions: A Meta-Analysis of Multicultural Studies

Abstract Prior multicultural meta-analyses have shown that three of the four individual expressions of parental rejection (viz., coldness/lack of affection, hostility/aggression, and indifference/neglect) tend to be significantly associated with all seven of the personality dispositions most central to interpersonal acceptance-rejection theory (IPARTheory). These dispositions include hostility/aggression, dependence, negative self-esteem, negative self-adequacy, emotional instability, emotional unresponsiveness, and negative worldview. However, it was unknown whether the fourth expression of rejection (i.e. undifferentiated rejection) tends to be associated transculturally, as predicted by the theory, with this cluster of dispositions among children. Thus, this meta-analysis investigated 1) the extent to which children’s perceptions of maternal and paternal undifferentiated rejection were related to these personality dispositions, and 2) the extent to which these relations varied by gender of parent. To address these questions, we performed a meta-analysis on 16 studies involving 12,538 children in 14 countries. Results showed significant associations between all seven personality dispositions and both maternal and paternal undifferentiated rejection. The results also showed significantly stronger relations between maternal than paternal undifferentiated rejection on five of the seven indices of children’s personality.
Glycemic index, glycemic load, and lung cancer risk: A meta-analysis of cohort and case-control studies

Objective Glycemic index (GI) or glycemic load (GL) has been investigated in the field of cancer research for several years. However, the relationship between GI or GL and lung cancer risk remains inconsistent. Therefore, this study aimed to summarize previous findings on this relationship. Methods PubMed, Embase, Scopus, Web of Science databases, and Cochrane Library were searched by July 2021. This review was conducted in accordance with the PRISMA guidelines. A fixed or random-effects model was adopted for meta-analysis to compute the pooled relative risks (RR) and their corresponding 95% confidence intervals (CIs). Subgroup analyses, sensitivity analyses, and publication bias analyses were also performed. Results In total, nine articles were included, with four case-control studies and five cohort studies, including 17,019 cases and 786,479 controls. After merging the studies, pooled multivariable RRs of lung cancer based on the highest versus the lowest intake were 1.14 (95%CI: 1.03–1.26) and 0.93 (95%CI: 0.84–1.02) for GI and GL. Results persisted in most stratifications after stratifying by potential confounders in the relationship between GI and lung cancer risk. There was a non-linear dose response relation for GI with lung caner risk. Conclusion GI typically has a positive relationship with lung cancer risk. However, no associations between GL and lung cancer risk were observed based on current evidence, suggesting that this issue should be studied and verified further to substantiate these findings.
Analyses on the influence of normal nasal morphological variations on odorant transport to the olfactory cleft

Abstract Objective Olfaction requires a combination of sensorineural components and conductive components, but conductive mechanisms have not typically received much attention. This study investigates the role of normal nasal vestibule morphological variations in ten healthy subjects on odorant flux in the olfactory cleft. Materials and methods Computed tomography images were used to create subject-specific nasal models. Each subject’s unilateral nasal cavity was classified according to its nasal vestibule shape as Standard or Notched. Inspiratory airflow simulations were performed at 15 L/min, simulating resting inspiration using computational fluid dynamics modeling. Odorant transport simulations for three odorants (limonene, 2,4-dinitrotoluene, and acetaldehyde) were then performed at concentrations of 200 ppm for limonene and acetaldehyde, and 0.2 ppm for dinitrotoluene. Olfactory cleft odorant flux was computed for each simulation. Results and discussion and conclusion Simulated results showed airflow in the olfactory cleft was greater in the Standard phenotype compared to the Notched phenotype. For Standard, median airflow was greatest in the anterior region (0.5006 L/min) and lowest in the posterior region (0.1009 L/min). Median airflow in Notched was greatest in the medial region (0.3267 L/min) and lowest in the posterior region (0.0756 L/min). Median olfactory odorant flux for acetaldehyde and limonene was greater in Standard (Acetaldehyde: Standard = 140.45 pg/cm2-s; Notched = 122.20 pg/cm2-s. Limonene: Standard = 0.67 pg/cm2-s; Notched = 0.65 pg/cm2-s). Median dinitrotoluene flux was greater in Notched (Standard = 2.86 × 10−4pg/cm2-s; Notched = 4.29 × 10−4 pg/cm2-s). The impact of nasal vestibule morphological variations on odorant flux at the olfactory cleft may have implications on individual differences in olfaction, which should be investigated further.
Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment

Cancer-related cognitive impairment (CRCI) is a major neurotoxicity affecting more than 50% of cancer survivors. The underpinning mechanisms are mostly unknown, and there are no FDA-approved interventions. Sphingolipidomic analysis of mouse prefrontal cortex and hippocampus, key sites of cognitive function, revealed that cisplatin increased levels of the potent signaling molecule sphingosine-1-phosphate (S1P) and led to cognitive impairment. At the biochemical level, S1P induced mitochondrial dysfunction, activation of NOD-, LRR-, and pyrin domain–containing protein 3 inflammasomes, and increased IL-1β formation. These events were attenuated by systemic administration of the functional S1P receptor 1 (S1PR1) antagonist FTY720, which also attenuated cognitive impairment without adversely affecting locomotor activity. Similar attenuation was observed with ozanimod, another FDA-approved functional S1PR1 antagonist. Mice with astrocyte-specific deletion of S1pr1 lost their ability to respond to FTY720, implicating involvement of astrocytic S1PR1. Remarkably, our pharmacological and genetic approaches, coupled with computational modeling studies, revealed that cisplatin increased S1P production by activating TLR4. Collectively, our results identify the molecular mechanisms engaged by the S1P/S1PR1 axis in CRCI and establish S1PR1 antagonism as an approach to target CRCI with therapeutics that have fast-track clinical application.
Expression and distribution patterns of VEGF, TGF‐β1 and HIF‐1α in the ovarian follicles of Tibetan sheep

Abstract Background Hypoxia‐inducible factor‐1α (HIF‐1α), vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF‐β1) are multifunctional growth factors that play an important role in follicular growth and development. However, its biological function in the follicular development of Tibetan sheep at different stages has not been described. Objectives The purpose of this study was to investigate the effect of VEGF, TGF‐β1 and HIF‐1α expression and distribution on the development of follicles of different sizes. Methods Immunohistochemistry (IHC), western blot (WB) and quantification real‐time polymerase chain reaction (qRT‐PCR) were used to detect the localisation and quantitative expression of VEGF, TGF‐β1 and HIF‐1α proteins and mRNA in small‐ (< 3 mm), medium‐ (3 mm < diameter < 5 mm)‐, and large‐ (> 5 mm) sized follicles. Results The results showed that the proteins VEGF, TGF‐β1 and HIF‐1α, as well as their mRNA, were expressed in follicles. However, the expression in medium‐sized follicles was significantly higher than that in large‐ and small‐sized follicles (p <0.05). IHC also showed that the proteins VEGF, TGF‐β1, and HIF‐1α were distributed in granulosa cells (GCs) in small‐, medium‐, and large‐sized follicles. Conclusions This study indicates that VEGF, TGF‐β1 and HIF‐1α, which operate in an autocrine or paracrine manner with the GCs, influence the follicular progressive growth, suggesting that these growth factors are closely associated with the follicular growth and development in ovarian.