Miracle-dz/UniFAR-FTUs huggingface dataset:
Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking

Significance Voltage-gated ion channels, such as CaV2.2, consist of pore-forming and auxiliary subunits that interact through protein–protein interactions. We develop a small-molecule antagonist of the protein–protein interaction between the calcium channel alpha pore-forming domain (CaVα) and beta subunits (CaVβ). The compound suppresses trafficking of CaV2.2 channels to the cell membrane and inhibits CaV2.2 activity by acting intracellularly. This allows peripheral access and eliminates the need of intrathecal administration. Indeed, in vivo systemic administration of the small molecule reduces neuropathic pain behavior in animal models. Our compounds serve as chemical tools to explore the CaVα⋅CaVβ interaction in vivo and as a starting point for the development of therapeutics for the treatment of a range of disorders associated with calcium channels. Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1 subunit (CaVα1) that is engaged in protein–protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3 protein–protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3 protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1. Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3 Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.
Factors that determine the persistence and dropout of university students

Background: The increase of students in higher education means a more heterogeneous student body, complicating the identification of the variables that influence students' decisions to stay in or drop out of university. The objective of this study is to analyze the influence of these variables on students' decisions by establishing specific groups of students based on performance. Method: A study was carried out with 2,970 firstyear university students from Portugal, using the decision tree technique. Results: Academic performance is confirmed as a determining variable in the decision to remain or drop out, allowing us to establish three groups (high, medium and low achievement), in which different types of variables act as mediators: sex, type of course (licenciatura [BA] or mestrado integrado), the fact of studying at the students' first‐choice university or the mother's educational level. Conclusions: Without neglecting the weight of academic achievement as a priority variable, we must consider these secondary variables in the configuration of student groups in order to plan support policies to avoid higher‐risk students dropping out. &NA; Factores determinantes de la permanencia y abandono de los estudiantes universitarios. Antecedentes: el aumento de estudiantes en la educación superior supuso una mayor heterogeneidad del alumnado, complicando la identificación de las variables que influyen en la decisión de los estudiantes de permanecer o abandonar los estudios. El objetivo de este estudio es analizar la influencia de algunas variables en tal decisión estableciendo grupos específicos de estudiantes en función del rendimiento. Método: se ha realizado un estudio con 2.970 alumnos universitarios de primer año de Portugal recurriendo a la técnica de los árboles de decisión. Resultados: el rendimiento académico se corrobora como variable determinante en la decisión de permanencia o abandono, permitiendo establecer tres grupos (alto, medio y bajo rendimiento), en los cuales actúan como mediadoras de forma diferencial otro tipo de variables como: el sexo, el tipo de estudios realizados (licenciatura o mestrado integrado), el hecho de cursar estudios en la universidad elegida como primera opción o el nivel de estudios de la madre. Conclusiones: sin restar peso al rendimiento académico como variable prioritaria, debemos de considerar estas variables secundarias en la configuración de grupos de estudiantes de cara a planificar políticas de apoyo para evitar el abandono de los estudiantes en situación de mayor riesgo.
Human Urinary mRNA as a Biomarker of Cardiovascular Disease

Background mRNA in urine supernatant (US-mRNA) might encode information about renal and cardiorenal pathophysiology, including hypertension. H, whether the US-mRNA transcriptome reflects that of renal tissues and whether changes in renal physiology are detectable using US-mRNA is unknown. Methods We compared transcriptomes of human urinary extracellular vesicles and human renal cortex. To avoid similarities attributable to ubiquitously expressed genes, we separately analyzed ubiquitously expressed and highly kidney-enriched genes. To determine whether US-mRNA reflects changes in renal gene expression, we assayed cell-depleted urine for transcription factor activity of mineralocorticoid receptors (MR) using probe-based quantitative polymerase chain reaction. The urine was collected from prehypertensive individuals (n=18) after 4 days on low-sodium diet to stimulate MR activity and again after suppression of MR activity via sodium infusion. Results In comparing this US-mRNA and human kidney cortex, expression of 55 highly kidney-enriched genes correlated strongly (rs=0.82) while 8457 ubiquitously expressed genes correlated moderately (rs=0.63). Standard renin-angiotensin-aldosterone system phenotyping confirmed the expected response to sodium loading. Cycle threshold values for MR-regulated targets (SCNN1A, SCNN1G, TSC22D3) changed after sodium loading, and MR-regulated targets (SCNN1A, SCNN1G, SGK1, and TSC22D3) correlated significantly with serum aldosterone and inversely with urinary sodium excretion. Conclusions RNA-sequencing of urinary extracellular vesicles shows concordance with human kidney. Perturbation in human endocrine signaling (MR activation) was accompanied by changes in mRNA in urine supernatant. Our findings could be useful for individualizing pharmacological therapy in patients with disorders of mineralocorticoid signaling, such as resistant hypertension. More generally, these insights could be used to noninvasively identify putative biomarkers of disordered renal and cardiorenal physiology.
Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas

Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
QUANTITATIVE AND QUALITATIVE ANALYSIS OF THE THREE CAPILLARY PLEXUSES AND CHORIOCAPILLARIS IN PATIENTS WITH TYPE 1 AND TYPE 2 DIABETES MELLITUS WITHOUT CLINICAL SIGNS OF DIABETIC RETINOPATHY: A Prospective Pilot Study.

PURPOSE To separately evaluate the three retinal capillary plexuses and the choriocapillaris in patients with diabetes mellitus (DM) Type 1 and Type 2, without clinical signs of diabetic retinopathy. METHODS The study was prospective and cross-sectional. Only patients with age ≤55 years were included. We used a swept-source optical coherence tomography angiography device (Triton; Topcon, Tokyo, Japan) to obtain both quantitative and qualitative analysis of the retinal capillary plexuses (superficial capillary plexus; middle capillary plexus; and deep capillary plexus) and the choriocapillaris. RESULTS We included 17 patients with DM Type 1 (age 34.52 ± 11.05 years, 29 eyes), 17 patients with DM Type 2 (age 48.76 ± 3.26 years, 32 eyes), and 23 healthy control subjects (age 41.82 ± 8.97 years, 43 eyes). When compared with controls, vessel density in the central 1 mm was reduced in both DM Type 1 and DM Type 2 groups in the superficial capillary plexus (P = 0.05 and P = 0.02, respectively), and in DM Type 2 in the deep capillary plexus (P = 0.03). Foveal avascular zone was increased in the middle capillary plexus and deep capillary plexus of DM Type 2 group compared with controls (P = 0.03 and P = 0.02, respectively). Choriocapillary voids were more frequent in DM Type 1 and DM Type 2 compared with controls (P = 0.003 and P < 0.001, respectively). CONCLUSION Microvascular modifications are present in the three retinal capillary plexuses and the choriocapillaris in both DM Type 1 and DM Type 2 even in the absence of clinical signs of diabetic retinopathy.
Dyadic coping in specialized palliative care intervention for patients with advanced cancer and their caregivers: Effects and mediation in a randomized controlled trial

Specialized palliative care (SPC) interventions increasingly include patient‐caregiver dyads, but their effects on dyadic coping are unknown. We investigated whether an SPC and dyadic psychological intervention increased aspects of dyadic coping in patients with advanced cancer and their caregivers, whether dyad characteristics moderated effects and whether aspects of dyadic coping mediated significant intervention effects on caregivers' anxiety and depression.
Geometry and clustering with metrics derived from separable Bregman divergences

Separable Bregman divergences induce Riemannian metric spaces that are isometric to the Euclidean space after monotone embeddings. We investigate fixed rate quantization and its codebook Voronoi diagrams, and report on experimental performances of partition-based, hierarchical, and soft clustering algorithms with respect to these Riemann-Bregman distances.
Fractional Flow Reserve and Quality-of-Life Improvement After Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease

Background: Whether the benefit in quality of life (QOL) after percutaneous coronary intervention depends on the severity of the stenosis as determined by fractional flow reserve (FFR) remains unknown. This study sought to investigate the relationship between FFR values and improvement in QOL. Methods: From the FAME 1 and 2 trials (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), we identified 706 stable patients with coronary artery disease who had at least 1 lesion with an FFR⩽0.80 that was treated with percutaneous coronary intervention and 185 patients with coronary artery disease who had no lesion with an FFR⩽0.80 and were treated medically who served as a reference group. QOL was assessed by the European Quality of Life–5 Dimensions index at baseline, 1 month, and 1 year. We assessed the relationship between QOL improvement (defined as the change in European Quality of Life–5 Dimensions index from baseline) and FFR as a continuous value and according to abnormal FFR tertile. Results: QOL improved significantly after percutaneous coronary intervention in each abnormal FFR tertile, whereas it did not change in the reference group. The lowest abnormal FFR subgroup had the greatest improvement in QOL at 1 month (P<0.001). In mixed-effects models for repeated measures, lower FFR (P=0.002 for 1 month and 0.049 for 1 year), greater delta FFR (P=0.021 for 1 month and 0.025 for 1 year), and higher angina class (P=0.001 for 1 month and <0.001 for 1 year) were associated with the greatest magnitude of QOL improvement at both 1 month and 1 year. Conclusions: Among patients with stable coronary artery disease, FFR and angina severity predict QOL improvement after percutaneous coronary intervention. Clinical Trial Registration: URL: https://www.clinicaltrials. gov. Unique identifiers: NCT00267774 and NCT01132495.
Soft Tissue Sarcoma Cancer Stem Cells: An Overview

Soft tissue sarcomas (STSs) are an uncommon group of solid tumors that can arise throughout the human lifespan. Despite their commonality as non-bony cancers that develop from mesenchymal cell precursors, they are heterogeneous in their genetic profiles, histology, and clinical features. This has made it difficult to identify a single target or therapy specific to STSs. And while there is no one cell of origin ascribed to all STSs, the cancer stem cell (CSC) principle—that a subpopulation of tumor cells possesses stem cell-like properties underlying tumor initiation, therapeutic resistance, disease recurrence, and metastasis—predicts that ultimately it should be possible to identify a feature common to all STSs that could function as a therapeutic Achilles' heel. Here we review the published evidence for CSCs in each of the most common STSs, then focus on the methods used to study CSCs, the developmental signaling pathways usurped by CSCs, and the epigenetic alterations critical for CSC identity that may be useful for further study of STS biology. We conclude with discussion of some challenges to the field and future directions.
Selecting lipopeptide‐producing, Fusarium‐suppressing Bacillus spp.: Metabolomic and genomic probing of Bacillus velezensis NWUMFkBS10.5

The results of this study indicate that the maize rhizosphere remains a reservoir for microbial strains with unique beneficial properties. The study sought to provide an indigenous Bacillus strain with a bioprotective potential to alleviate maize fusariosis in South Africa. We selected seven Bacillus isolates (MORWBS1.1, MARBS2.7, VERBS5.5, MOREBS6.3, MOLBS8.5, MOLBS8.6, and NWUMFkBS10.5) with biosuppressive effects against two maize fungal pathogens (Fusarium graminearum and Fusarium culmorum) based on 16S rDNA gene characterization and lipopeptide gene analysis. The PCR analysis revealed that lipopeptide genes encoding the synthesis of iturin, surfactin, and fengycin might be responsible for their antifungal activities. Few of the isolates also showed possible biosurfactant capability, and their susceptibility to known antibiotics is indicative of their eco‐friendly attributes. In addition, in silico genomic analysis of our best isolate (Bacillus velezensis NWUMFkBS10.5) and characterization of its active metabolite with FTIR, NMR, and ESI‐Micro‐Tof MS confirmed the presence of valuable genes clusters and metabolic pathways. The versatile genomic potential of our Bacillus isolate emphasizes the continued relevance of Bacillus spp. in biological management of plant diseases.
Radar-based Feature Design and Multiclass Classification for Road User Recognition

The classification of individual traffic participants is a complex task, especially for challenging scenarios with multiple road users or under bad weather conditions. Radar sensors provide an – with respect to well established camera systems – orthogonal way of measuring such scenes. In order to gain accurate classification results, 50 different features are extracted from the measurement data and tested on their performance. From these features a suitable subset is chosen and passed to random forest and long short-term memory (LSTM) classifiers to obtain class predictions for the radar input. Moreover, it is shown why data imbalance is an inherent problem in automotive radar classification when the dataset is not sufficiently large. To overcome this issue, classifier binarization is used among other techniques in order to better account for underrepresented classes. A new method to couple the resulting probabilities is proposed and compared to others with great success. Final results show substantial improvements when compared to ordinary multiclass classification.
Toward Human-like Behavior Generation in Urban Environment Based on Markov Decision Process With Hybrid Potential Maps

It is crucial for automated vehicles to interact with the surrounding vehicles properly in urban environment that can make both passengers and surrounding drivers feel safe and at ease. In this paper, we propose a human-like behavior generation approach, which can make safe as well as efficient decisions and generate an appropriate path with the corresponding speed profile to interact with the surrounding vehicles. Firstly, a cumulative cost map is constructed by integrating the hybrid potential maps of the surrounding vehicles according to their categories. Subsequently, three candidate paths, i.e., a route-following path, an in-lane circumventing path and a collision-avoidance path, are extracted to form a Markov decision process (MDP) model. The optimal decision to cope with the current situation, e.g., when and how to perform a passing maneuver with parked vehicles in the host lane, are finally made in the MDP model such that the actual path and target speed profile will be generated. Particularly, three driving modes, i.e., Leisure Mode, Normat Mode and Efficiency Mode, are provided to the driver/passengers to adjust the decision making strategy such that the generated human-like automated driving commands will make them not only feel safe by the collision-free trajectories but also feel at ease by meeting their preferences and needs. Experimental results in various typical but challenging urban traffic scenes have substantiated the effectiveness of the proposed system.
Comparative Oxygen Consumption of Gastropod Holobionts from Deep-Sea Hydrothermal Vents in the Indian Ocean

Physiological traits are the foundation of an organism’s success in a dynamic environment, yet basic measurements are unavailable for many taxa and even ecosystems. We measured routine metabolism in two hydrothermal vent gastropods, Alviniconcha marisindica (n = 40) and the scaly-foot gastropod Chrysomallon squamiferum (n = 18), from Kairei and Edmond vent fields on the Central Indian Ridge (23–25°S, about 3000 meter depth). No previous studies have measured metabolism in any Indian Ocean vent animals. After recovering healthy animals to the surface, we performed shipboard closed-chamber respirometry experiments to compare oxygen uptake at different temperatures (10, 16, and 25 °C) at surface pressure (1 atm). The physiology of these species is driven by the demands of their chemoautotrophic symbionts. Chrysomallon has very enlarged respiratory and circulatory systems, and endosymbionts are housed in its trophosome-like internal esophageal gland. By contrast, Alviniconcha has chemoautotrophic bacteria within the gill and less extensive associated anatomical adaptations. Thus, we predicted that routine oxygen consumption of Chrysomallon might be higher than that of Alviniconcha. However, oxygen consumption of Chrysomallon was not higher than that of Alviniconcha, and, further, Chrysomallon maintained a steady metabolic demand in two widely separated experimental temperatures, while Alviniconcha did not. We interpret that these findings indicate that (1) the “trophosome” does not fundamentally increase oxygen requirement compared to other gastropod holobionts, and (2) cold temperatures (10 °C) induce a stress response in Alviniconcha, resulting in aberrantly high uptake. While these two large gastropod species co-occur, differences in oxygen consumption may reflect the separate niches they occupy in the vent ecosystem.
Sibling influence on children’s objectively measured physical activity: a meta-analysis and systematic review

Abstract Children without siblings (only children) have higher rates of obesity than children with siblings. Childhood obesity may be prevented by minimising sedentary behaviour and accumulating sufficient physical activity in young children. A growing number of articles have examined the influence of siblings on physical activity and sedentary behaviour, yet these articles have not been synthesised. Objective To synthesise literature and describe the influence of siblings on objectively measured physical activity and sedentary behaviour of children (ages 2–18 years). Design Outcomes were analysed in a systematic review and meta-analysis. Data sources PubMed, EMBASE, Web of Science and Medline OVID were searched for articles related to siblings, physical activity, sedentary behaviour and obesity outcomes from 1947 to March 2018. Eligibility criteria Articles that evaluated sibling status on physical activity objectively measured by accelerometer or pedometer were included. Results Nineteen articles, representing 17 independent datasets, were included in the review. Nine were included in the quantitative analysis. Pooled data from nine articles indicated children with siblings had higher moderate-to-vigorous physical activity (MVPA) relative to only children, with a potential dose response for higher number of children in household and higher MVPA (Mean Difference=3.13, 95% CI 1.90 to 4.35, p=0.001). Findings were mixed for the influence of siblings on sedentary behaviour and light physical activity. Summary/Conclusion Children with siblings had healthier physical activity patterns, as measured by accelerometer or pedometer, than did only children. Suggested mechanisms include peer modelling, encouraging active transport and sports participation, opportunity for playmate and serving as additional caregivers. Trial registration number CRD42017055463.