Miracle-dz/UniFAR-FTUs huggingface dataset:
The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis

Abstract Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis. HES6 physically interacted with GATA1 and influenced the interaction of GATA1 with FOG1. Knockdown of HES6 impaired human erythropoiesis by decreasing GATA1 expression. Chromatin immunoprecipitation and RNA sequencing revealed a rich set of HES6- and GATA1-co-regulated genes involved in erythroid-related pathways. We also discovered a positive feedback loop composed of HES6, GATA1 and STAT1 in the regulation of erythropoiesis. Notably, erythropoietin (EPO) stimulation led to up-regulation of these loop components. Increased expression levels of loop components were observed in CD34+ cells of polycythemia vera patients. Interference by either HES6 knockdown or inhibition of STAT1 activity suppressed proliferation of erythroid cells with the JAK2V617F mutation. We further explored the impact of HES6 on polycythemia vera phenotypes in mice. The identification of the HES6–GATA1 regulatory loop and its regulation by EPO provides novel insights into human erythropoiesis regulated by EPO/EPOR and a potential therapeutic target for the management of polycythemia vera.
Evidence for biasing in the CfA survey

Intrinsically bright galaxies appear systematically more correlated than faint galaxies in the Center for Astrophysics redshift survey. The amplification of the two-point correlation function behaves exponentially with luminosity, being essentially flat up to the knee of the luminosity function, then increasing markedly. The amplification reaches a factor of 3.5e + or - 0.4 in the very brightest galaxies. The effect is dominated by spirals rather than ellipticals, so that the correlation function of bright spirals becomes comparable to that of normal ellipticals. Similar results are obtained whether the correlation function is measured in two or three dimensions. The effect persists to separations of a correlation length or more, and is not confined to the cores of the Virgo, Coma, and Abell 1367 clusters, suggesting that the effect is caused by biasing, that is, galaxies kindle preferentially in more clustered regions, rather than by gravitational relaxation.
What does ἐπί really mean? Contact and dimensionality of the landmark as basic semantic categories in the locative prepositional phrases with ἐπί

The spatial relations expressed by the preposition ἐπί can be clarified attending to the dimensionality of the landmark as a basic semantic category, along with the constant notion of contact, belonging to the prepo si tion. On the contrary, the orientation – from which the traditional explanations are derived – is important but clearly secondary. After explaining the coexistence and partial synonymy of ἐπί with dat. and gen. starting from the uses with three-dimensional landmarks, the study of the uses with twoand one-dimensional landmarks allows reformulation of the basic meaning of the preposition. In turn, this allows recognition of a system based on a very particular conceptual view about limits and ends in the different dimensions, a conceptual view in decline since Homer, although we can find other traces of it here and there, also in Latin.
External Validation and Comparison of a General Ward Deterioration Index Between Diversely Different Health Systems

OBJECTIVES: Implementing a predictive analytic model in a new clinical environment is fraught with challenges. Dataset shifts such as differences in clinical practice, new data acquisition devices, or changes in the electronic health record (EHR) implementation mean that the input data seen by a model can differ significantly from the data it was trained on. Validating models at multiple institutions is therefore critical. Here, using retrospective data, we demonstrate how Predicting Intensive Care Transfers and other UnfoReseen Events (PICTURE), a deterioration index developed at a single academic medical center, generalizes to a second institution with significantly different patient population. DESIGN: PICTURE is a deterioration index designed for the general ward, which uses structured EHR data such as laboratory values and vital signs. SETTING: The general wards of two large hospitals, one an academic medical center and the other a community hospital. SUBJECTS: The model has previously been trained and validated on a cohort of 165,018 general ward encounters from a large academic medical center. Here, we apply this model to 11,083 encounters from a separate community hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The hospitals were found to have significant differences in missingness rates (> 5% difference in 9/52 features), deterioration rate (4.5% vs 2.5%), and racial makeup (20% non-White vs 49% non-White). Despite these differences, PICTURE’s performance was consistent (area under the receiver operating characteristic curve [AUROC], 0.870; 95% CI, 0.861–0.878), area under the precision-recall curve (AUPRC, 0.298; 95% CI, 0.275–0.320) at the first hospital; AUROC 0.875 (0.851–0.902), AUPRC 0.339 (0.281–0.398) at the second. AUPRC was standardized to a 2.5% event rate. PICTURE also outperformed both the Epic Deterioration Index and the National Early Warning Score at both institutions. CONCLUSIONS: Important differences were observed between the two institutions, including data availability and demographic makeup. PICTURE was able to identify general ward patients at risk of deterioration at both hospitals with consistent performance (AUROC and AUPRC) and compared favorably to existing metrics.
DNA barcoding of Chinese snakes reveals hidden diversity and conservation needs

DNA barcoding has greatly facilitated studies of taxonomy, biodiversity, biological conservation, and ecology. Here, we establish a reliable DNA barcoding library for Chinese snakes, unveiling hidden diversity with implications for taxonomy, and provide a standardized tool for conservation management. Our comprehensive study includes 1638 cytochrome c oxidase subunit I (COI) sequences from Chinese snakes that correspond to 17 families, 65 genera, 228 named species (80.6% of named species) and 36 candidate species. A barcode gap analysis reveals gaps, where all nearest neighbour distances exceed maximum intraspecific distances, in 217 named species and all candidate species. Three species‐delimitation methods (ABGD, sGMYC, and sPTP) recover 320 operational taxonomic units (OTUs), of which 192 OTUs correspond to named and candidate species. Twenty‐eight other named species share OTUs, such as Azemiops feae and A. kharini, Gloydius halys, G. shedaoensis, and G. intermedius, and Bungarus multicinctus and B. candidus, representing inconsistencies most probably caused by imperfect taxonomy, recent and rapid speciation, weak taxonomic signal, introgressive hybridization, and/or inadequate phylogenetic signal. In contrast, 43 species and candidate species assign to two or more OTUs due to having large intraspecific distances. If most OTUs detected in this study reflect valid species, including the 36 candidate species, then 30% more species would exist than are currently recognized. Several OTU divergences associate with known biogeographic barriers, such as the Taiwan Strait. In addition to facilitating future studies, this reliable and relatively comprehensive reference database will play an important role in the future monitoring, conservation, and management of Chinese snakes.
Leveraging the ATP‐P2X7 receptor signalling axis to alleviate traumatic CNS damage and related complications

The P2X7 receptor is an exceptional member of the P2X purinergic receptor family, with its activation requiring high concentrations of extracellular adenosine 5ʹ‐triphosphate (ATP) that are often associated with tissue damage and inflammation. In the central nervous system (CNS), it is highly expressed in glial cells, particularly in microglia. In this review, we discuss the role and mechanisms of the P2X7 receptor in mediating neuroinflammation and other pathogenic events in a variety of traumatic CNS damage conditions, which lead to loss of neurological and cognitive functions. We raise the perspective on the steady progress in developing CNS‐penetrant P2X7 receptor‐specific antagonists that leverage the ATP‐P2X7 receptor signaling axis as a potential therapeutic strategy to alleviate traumatic CNS damage and related complications.
Sarsa(Λ)-Based Logistics Planning Approximated by Value Function with Policy Iteration

The logistics planning problem has been extensively investigated for a long time. However, with the increasing number of stochastic events occurred in road, increasing number of stochastic factors should be taken into consideration. A dynamic approach is used in this paper to solve the logistics planning problem in the common form of stochastic demand with the reinforcement learning framework which is able to optimize policy in unknown environments and uncertain cases. We take advantage of clustering method to extract states as main features for basis function so as to solve the dimensionality curse problems caused by stochastic settings. We also propose an approximation approach with the policy iteration restricted by the goal of minimal time differential error to approximate the stochastic cases of the real world, and then use the attained approximation parameters as input for the proposed Sarsa(Λ)-based logistics planning algorithm to determine the policy and action in accordance with the real world stochastic events. The benchmarking experimental results showed that the proposed algorithm has achieved improvements in almost all the test cases.
Problème général de la stabilité du mouvement

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The Global Distribution and Epidemiology of Psychoactive Substance Use and Injection Drug Use Among Street-Involved Children and Youth: A Meta-Analysis

Abstract Background: Globally, street-involved children and youth (SICY) who work and live on/of the streets are at higher risk of increased psychoactive substances and injecting drug use. Objectives: The present study aimed to identify the prevalence, distribution, sociodemographic factors, and risk-taking behaviors associated with psychoactive substances and injecting drug use among SICY. Methods: Studies in English published from December 1 1985 to July 1 2022, were searched for on PubMed, Scopus, Cochrane, and Web of Science to identify primary studies on psychoactive substances and injecting drug use among SICY. The pooled-prevalence estimates were obtained using a robust fixed-effects model. Results: The most commonly reported life-time and current psychoactive substance was tobacco followed by cannabis, LSD/ecstasy, cocaine, methamphetamine, heroin and injection drug use. The results showed that life-time and current prevalence of methamphetamine and cannabis use, as well as life-time prevalence of cocaine, LSD/ecstasy, heroin, tobacco, and injecting drug use increased as age rose while current prevalence of cocaine and tobacco use decreased as age rose. SICY who were male, homeless, had parents who had died, had history of substance use among family members or best friends, had experienced violence, had casual sex partners, had a history of working in the sex trade, and had unprotected sex were all related to psychoactive substance use and injecting drug use. Conclusions: Research examining this population suffers from lack of studies, therefore, improving the knowledge for interventions aimed at reducing risk behaviors, particularly those related to the transmission of sexually transmitted infections such as HIV is of great importance.
An Updated Review of Epidemiologic Studies on the Relationship Between Exposure to Whole-Body Vibration and Low Back Pain

Abstract The aim of this paper is to update the information on the epidemiologic evidence of the adverse health effects of whole-body vibration (WBV) on the spinal system by means of a review of the epidemiologic studies published between 1986 and 1996. In a systematic search of epidemiologic studies of low back pain (LBP) disorders and occupations with exposure to WBV, 37 articles were retrieved. The quality of each study was evaluated according to criteria concerning the assessment of vibration exposure, assessment of health effects, and methodology. The epidemiologic studies reaching an adequate score on each of the above mentioned criteria, were included in the final review. A meta-analysis was also conducted in order to combine the results of independent epidemiologic studies. After applying the selection criteria, 16 articles reporting the occurrence of LBP disorders in 19 WBV-exposed occupational groups, reached a sufficient score. The study design was cross-sectional for 13 occupational groups, longitudinal for 5 groups and of case-control type for one group. The main reasons for the exclusion of studies were insufficient quantitative information on WBV exposure and the lack of control groups. The findings of the selected studies and the results of the meta-analysis of both cross-sectional and cohort studies showed that occupational exposure to WBV is associated with an increased risk of LBP, sciatic pain, and degenerative changes in the spinal system, including lumbar intervertebral disc disorders. Owing to the cross-sectional design of the majority of the reviewed studies, this epidemiologic evidence is not sufficient to outline a clear exposure–response relationship between WBV exposure and LBP disorders. Upon comparing the epidemiological studies included in this review with those conducted before 1986, it is concluded that research design and the quality of exposure and health effect data in the field of WBV have improved in the last decade.
BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders

ABSTRACT Introduction Anxiety disorders are common, disabling psychiatric conditions associated with excessive worry, irritability, and physiological symptoms of stress. Following insufficient response to psychological therapies, first-line pharmacological treatments for anxiety disorders suffer from inconsistent efficacy, addiction, and intolerable side-effect profiles (e.g. sedation), especially when used inappropriately or contrary to evidence-based guidelines. Developing anxiolytics acting via cholinergic modulation may provide novel options for the treatment of anxiety disorders, without the drawbacks of existing anxiolytics. Areas covered We review pharmacological treatment of anxiety disorders and proposed mechanisms of action in relation to the associated neural circuitry. We then consider the mechanism of action, pharmacodynamics, and pharmacokinetics of the negative-allosteric modulator of the alpha7 nicotinic receptor BNC210, an investigational anxiolytic so far employed in studies of those with social anxiety disorder, post-traumatic stress disorder, and agitation in hospitalized elderly. Lastly, we consider the environment of competitor compounds for this indication, and BNC210ʹs place within it, in both the present and near-future. Expert opinion : There is a relative paucity of data regarding BNC210, albeit the small amount of mostly non-peer reviewed data indicate it is a well-tolerated, effective anxiolytic. Phase III trials are required for proper appraisal of its utility.
Cancer Demographics and Time-to-Care in Belize

Abstract Background Belize is a middle-income Caribbean country with poorly described cancer epidemiology and no comprehensive cancer care capacity. In 2018, GO, Inc., a US-based NGO, partnered with the Ministry of Health and the national hospital in Belize City to create the first public oncology clinic in the country. Here, we report demographics from the clinic and describe time intervals to care milestones to allow for public health targeting of gaps. Patients and Methods Using paper charts and a mobile health platform, we performed a retrospective chart review at the Karl Heusner Memorial Hospital (KHMH) clinic from 2018 to 2022. Results During this time period, 465 patients with cancer presented to the clinic. Breast cancer (28%) and cervical cancer (12%) were most common. Most patients (68%) presented with stage 3 or 4 disease and were uninsured (78%) and unemployed (79%). Only 21% of patients ever started curative intent treatment. Median time from patient-reported symptoms to a biopsy or treatment was 130 and 189 days. For the most common cancer, breast, similar times were seen at 140 and 178 days. Time intervals at the clinic: <30 days from initial visit to biopsy (if not previously performed) and <30 days to starting chemotherapy. Conclusion This study reports the first clinic-based cancer statistics for Belize. Many patients have months between symptom onset and treatment. In this setting, the clinic has built infrastructure allowing for minimal delays in care despite an underserved population. This further affirms the need for infrastructure investment and early detection programs to improve outcomes in Belize.
Pharmacotherapeutic advances for splenomegaly in myelofibrosis

ABSTRACT Introduction Myelofibrosis is a hematologic malignancy with a variety of clinical manifestations including splenomegaly, which is present in approximately 80% of newly diagnosed patients. JAK inhibitors are the mainstay of pharmacologic treatment for splenomegaly in myelofibrosis, although spleen size reduction is not universal, and the duration of benefit is only moderately durable. Areas covered We first discuss the pathobiology of splenomegaly in myelofibrosis before detailing approved and novel pharmacotherapies that can reduce spleen size while also highlighting non-pharmacologic approaches. In this review, efficacy of these treatments is measured solely by spleen volume reduction, acknowledging that other outcome measures such as symptom improvement and survival are also critical. Expert opinion Currently, ruxolitinib can be administered to the majority of frontline patients although those with severe thrombocytopenia should receive pacritinib to address spleen burden. Momelotinib may be particularly well suited for patients with significant anemia and novel combination treatments in clinical development may improve the depth and duration of spleen responses. After frontline treatment failure, fedratinib, or pacritinib are commercial options for patients with persistent symptomatic splenomegaly. Novel agents given alone or in combination with a JAK inhibitor are being explored in trials, which may ameliorate splenomegaly and ultimately improve disease progression.
Expert Perspective: Management of the Psoriatic Arthritis Patient After Failure of One Tumor Necrosis Factor Inhibitor

The index case, a 36-year-old woman, had psoriasis (PsO) on her scalp, arms, legs, and trunk since age 25 years that was inadequately controlled with topical agents. She has a past medical history of treated hypertension and depression. She is an active smoker. Three years prior to our case evaluation, she developed polyarthritis, inflammatory back pain, and plantar fasciitis. Methotrexate (MTX) was added to her treatment regimen, first administered orally then subcutaneously, but the patient stated she could only tolerate 12.5 mg/week due to gastrointestinal and systemic adverse events. The dose of 12.5 mg/week resulted in minimal benefit. In addition, the patient was recently married and reported that pregnancy was being considered, and therefore treatment with MTX was stopped. She then experienced a flare of PsO and arthritis. Physical examination was notable for the presence of moderate-to-severe PsO (12% affected body surface area [BSA]), 6–7 swollen and tender joints, and evidence of mild erosive changes on hand radiographs. Monotherapy with adalimumab 40 mg every other week was initiated. The patient improved during treatment with adalimumab over 10 weeks, with 60–70% improvement in her clinical symptoms overall, but continued to experience mild residual joint pain and signs of PsO (2–4% BSA). Approximately 3 months ago, she noted profound fatigue, 90 minutes of morning stiffness, and diffuse joint pain. She found it difficult to continue her work in retail and reported feeling frustrated, anxious, and depressed. Her skin PsO also worsened and became more bothersome to her. On physical examination, her blood pressure was 140/90 mm Hg, pulse rate was 72 beats per minute, and body mass index was 35 kg/m. She had psoriasiform plaques on her trunk and extremities (8% BSA). Musculoskeletal examination revealed 6 tender and 4 swollen joints, and she had a Disease Activity Index for PsA (DAPSA) score of 29 (a DAPSA score of >28 represents high disease activity). There were multiple tender entheses, most notably in the plantar fasciae, left Achilles tendon, and the left elbow lateral condyle. Pain was elicited in the right sacroiliac (SI) joint on provocative testing, and also at several locations unassociated with entheses.
Some Remarks on the Morphosemantics of Multiple Causative Sequences

0. Introduction There is a diverse array of languages which employ more than one morpheme dedicated to causation. This is not surprising considering the numerous complexities involved in encoding a causative event and all of the linguistic domains it implicates, such as animacy, transitivity, lexical semantics, eventivity, and pragmatics (Shibatani 1976b, 2001; Shibatani and Pardeshi 2002; Dixon 2000). There is a subset of those multiple morphological causative languages in which the causatives can occur simultaneously in a fixed sequence on a verb stem. An example of this is found in the Tsimshian language, Gitksan (Rigsby 1986; Tarpent 1987), and Tarascan, a Mesoamerican isolate (Maldonado & Nava 2002). Whereas English (1) expresses indirect causation analytically, both Gitksan (2) and Tarascan (3) can achieve indirect causation synthetically through the morphology of ‘stacking’ causatives on the verb:
The role of skeletal muscle mass on cardiovascular disease risk: an emerging role on modulating lipid profile

Purpose of review The purpose of this review was to present updated evidence on the role of skeletal muscle mass on cardiometabolic health. Recent findings Increased lean, and especially skeletal, muscle mass has been associated with better cardiometabolic health in various epidemiological studies, even in younger age groups. In addition, the link between skeletal muscle mass and adult lipid profile is of interest. A preliminary analysis using the data from the ATTICA prospective cohort study (2002–2022) supports this association. Summary Skeletal muscle mass has many metabolic functions (i.e., glucose, insulin and protein metabolism, mitochondrial function, arterial stiffness, inflammation, oxidative stress, brain function, hormone status). Given its associations with the lipid profile and overall cardiometabolic risk, skeletal muscle mass stands among the emerging risk factors for cardiovascular diseases. In addition to only using body mass index or fat distribution, more studies should evaluate lean mass and its prognostic and predictive ability regarding chronic diseases.