Miracle-dz/UniFAR-FTUs huggingface dataset:
Calcium modulation of cardiac sodium channels

Modification of voltage‐gated Na+ channel (NaV) function by intracellular Ca2+ has been a topic of much controversy. Early studies relied on measuring NaV function in the absence or presence of intracellular Ca2+, and generated seemingly disparate results. Subsequent investigations revealed the mechanism(s) of Ca2+‐driven NaV modulation are complex and involve multiple accessory proteins. The Ca2+‐sensing protein calmodulin (CaM) has a central role in tuning NaV function to [Ca2+]i, but the mechanism has been obscured by other proteins (such as fibroblast growth factors (FGF) or CaM‐dependent kinase II (CaMKII)) that can also modify channel function or exert an influence in a Ca2+‐dependent manner. Significant progress has been made in understanding the architecture of full‐length ion channels and the structural and biophysical details of NaV–accessory protein interactions. Interdisciplinary structure–function studies are beginning to resolve the effect each interaction has on NaV gating. Carefully designed structure‐guided or strategically selected disease‐associated mutations are able to impair NaV–accessory protein interactions without altering other properties of channel function. Recently CaM was found to engage part of NaV1.5 that is required for channel inactivation with high affinity. Careful impairment of this interaction disrupted NaV1.5's ability to recover from inactivation. Such results support a paradigm of CaM‐facilitated recovery from inactivation (CFRI). How NaV–CaM, CaMKII and FGF/fibroblast growth factor homologous factor interactions affect the timing or function of CFRI in cardiomyocytes remain open questions that are discussed herein. Moreover whether CFRI dysfunction or premature activation underlie certain NaV channelopathies are important questions that will require further investigation.
Reconstructing the Geography of Speciation from Contemporary Biodiversity Data

Inferring the geographic mode of speciation could help reveal the evolutionary and ecological mechanisms that underlie the generation of biodiversity. Comparative methods have sought to reconstruct the geographic speciation history of clades, using data on phylogeny and species geographic ranges. However, inference from comparative methods has been limited by uncertainty over whether contemporary biodiversity data retain the historic signal of speciation. We constructed a process-based simulation model to determine the influence of speciation mode and postspeciation range evolution on current biodiversity patterns. The simulations suggest that the signal of speciation history remains detectable in species distributions and phylogeny, even when species ranges have evolved substantially through time. We extracted this signal by using a combination of summary statistics that had good power to distinguish speciation modes and then used these statistics to infer the speciation history of 30 plant and animal clades. The results point to broad taxonomic patterns in the modes of speciation, with strongest support for founder speciation in mammals and birds and strongest support for sympatric speciation in plants. Our model and analyses show that broad-scale comparative methods can be a powerful complementary approach to more focused genomic analyses in the study of the patterns and mechanisms of speciation.
Neutrophil-derived lactoferrin induces the inflammatory responses of rheumatoid arthritis synovial fibroblasts via Toll-like receptor 4.

OBJECTIVES Damage-associated molecular patterns (DAMPs) are proposed to drive aberrant stimulation of Toll-like receptors (TLRs) in rheumatoid arthritis (RA) inflamed joints. In the current study we investigated the role of the neutrophil-derived lactoferrin (LTF), as an endogenous ligand for TLR4 in the inflammatory response of RA synovial fibroblasts (RASFs). METHODS RASFs were stimulated with LTF, and the expressions of inflammatory cytokines in RASFs were measured. To clarify the TLR4 signalling pathway associated with LTF stimulation, a small molecular inhibitor of TLR4 (TAK242) and NF-κB inhibitor were used. The role of nuclear factor of activated T cells 5 (NFAT5) was identified using small interfering RNA. To reveal the interaction between NF-κB and NFAT5, cerulenin, which disrupts their interaction, was used. RESULTS Stimulation of RASFs with LTF significantly increased the expressions of inflammatory cytokines and chemokines, such as IL-6, CCL20 and IL-8, in RASFs. LTF enhanced the mRNA expressions of these cytokines in RASFs stimulated by TNF-α. TAK242 almost completely inhibited the expressions of inflammatory cytokines and chemokines in RASFs stimulated by LTF. The NF-κB inhibitor partially repressed the expressions of IL-6 and IL-8 mRNAs induced by LTF, but not CCL20 mRNA expression. On the other hand, NFAT5 silencing decreased the expressions of CCL20 and IL-8 mRNAs induced by LTF, but not IL-6 mRNA expression. Cerulenin repressed the expressions of IL-6, CCL20 and IL-8 in RASFs stimulated by LTF. CONCLUSIONS Neutrophil-derived LTF may play a role as an endogenous ligand for TLR4 expressed on RASFs. NFAT5-NF-κB enhanceosome might regulate the expressions of LTF-TLR4-responsive genes in RASFs.
Monocular 3D Tracking of Articulated Human Motion in Silhouette and Pose Manifolds

This paper presents a robust computational framework for monocular 3D tracking of human movement. The main innovation of the proposed framework is to explore the underlying data structures of the body silhouette and pose spaces by constructing low-dimensional silhouettes and poses manifolds, establishing intermanifold mappings, and performing tracking in such manifolds using a particle filter. In addition, a novel vectorized silhouette descriptor is introduced to achieve low-dimensional, noise-resilient silhouette representation. The proposed articulated motion tracker is view-independent, self-initializing, and capable of maintaining multiple kinematic trajectories. By using the learned mapping from the silhouette manifold to the pose manifold, particle sampling is informed by the current image observation, resulting in improved sample efficiency. Decent tracking results have been obtained using synthetic and real videos.
Lizards at the Peak: Physiological Plasticity Does Not Maintain Performance in Lizards Transplanted to High Altitude

Warming climates are facilitating the range expansion of many taxa to habitats that were formerly thermally inhospitable, including to higher latitudes and elevations. The potential for such colonization, however, varies widely among taxa. Because environmental factors may interact to affect colonization potential, an understanding of underlying physiological and behavioral mechanisms is necessary to predict how species will respond to potentially suitable habitats. For example, temperature and oxygen availability will interact to shape physiological and performance traits. Our model species, the wall lizard, Podarcis muralis, is a widely distributed ectotherm that continues to expand its range in Europe despite being limited by cold temperatures at high elevations and latitudes. To test the potential for organisms to expand to warming high-altitude environments, we conducted a transplant experiment to quantify the within-individual effects of high-altitude hypoxia on physiological and performance traits. Transplanted lizards maintained individual differences in physiological traits related to oxygen capacity and metabolism (hemoglobin concentration, hematocrit, and peak postexhaustion metabolic rate), as well as performance traits tied to fitness (sprint speed and running endurance). Although lizards altered blood biochemistry to increase oxygen-carrying capacity, their performance was reduced at high altitude. Furthermore, lizards at high altitude suffered a rapid loss of body condition over the 6-wk experiment, suggesting an energetic cost to hypoxia. Taken together, this demonstrates a limited potential for within-individual plasticity to facilitate colonization of novel high-altitude environments.
Neural correlates of social well-being: gray matter density in the orbitofrontal cortex predicts social well-being in emerging adulthood

Abstract Social well‐being reflects the perception of one's social functioning, which plays an important role in physical and psychological health. However, the exact neuroanatomical substrate for social well‐being remains unclear. To address the issue, we employed the voxel‐based morphometry method to probe the neuroanatomical basis of individual variation in social well‐being in young healthy adults (n = 136). The results revealed a significant negative association between social well‐being and regional gray matter density (rGMD) in an anatomical cluster that mainly includes the left orbitofrontal cortex (OFC) that has been involved in emotion regulation and social cognition. Furthermore, a balanced 4‐fold cross‐validation using the machine learning approach revealed that rGMD in the left OFC could be reliably related to social well‐being. More importantly, the multiple mediation analysis revealed that neuroticism and dispositional forgiveness independently mediated the association between rGMD in the left OFC and social well‐being. In addition, all these results remained stable when subjective socioeconomic status was controlled. Together, our results provide the initial evidence that the OFC is a neuroanatomical substrate for social well‐being and demonstrate that the OFC is a crucial neural site linking neuroticism and dispositional forgiveness to social well‐being.
Chemopreventive efficacy zingerone (4‐[4‐hydroxy‐3‐methylphenyl] butan‐2‐one) in experimental colon carcinogenesis in Wistar rats

Colorectal cancer is one of the most common cancers worldwide. Development of naturally occurring inexpensive and safe alternatives can be effective in suppressing colon related proliferations. Zingerone (4‐[4‐hydroxy‐3‐methylphenyl] butan‐2‐one), a polyphenolic alkanone of ginger, has massive pharmacological properties and thus can be used as promising candidate against various ailments. In the current study, we aimed at demonstrating the protective effect of zingerone against experimental colon carcinogenesis and elucidating its possible mechanism by studying inflammatory and Nrf‐2 signaling cascade. Four groups of animals (I‐IV) were made with six animals each. Group I (control) was given normal saline orally. Group II was given 1,2‐dimethylhydrazine (DMH) at the dose rate of 20 mg/kg body weight. Group III and IV were treated with DMH at the dose rate of 20 mg/kg body weight and also received oral treatment of zingerone at a dose rate of 50 and 100 mg/kg body weight, respectively, for first 5 weeks and animals were euthanized after 16 weeks. Our results reveal that DMH treated rats exhibited elevated ROS and MDA levels, increased activity of cytochrome P450 2E1 and serum marker enzyme carcinoembreyonic antigen (CEA), increased no of aberrant crypts of foci (ACF), and elevated expression of inflammatory and proliferative proteins. Nrf‐2 was downregulated by DMH treatment. Treatment with zingerone to DMH treated rats, resulted in alterations in the activity of the cytochrome P450 2E1 and CEA. In addition, immunostaining of NF‐kB‐p65, COX‐2, iNOS, and PCNA, Ki‐67 was suppressed by zingerone. Furthermore, zingerone administration also attenuated the level of IL‐6 and TNF‐α and it also helps in preserving mucous layer. Thus, zingerone could be considered as a good chemopreventive agent in experimental model of colon carcinogenesis. Further studies are required to study other pathways involved in colon carcinogenesis and their modulation buy zingerone.
Antithrombotic therapy during and after percutaneous coronary intervention in patients with atrial fibrillation.

A 64-year-old man has permanent atrial fibrillation and chronic hypertension. He has been treated with atenolol 50 mg daily, lisinopril 10 mg daily, and warfarin for the last 4 years. Otherwise, he is in good shape and employed full-time as a technical director of a large shipbuilding company. At a routine visit about 1 year ago, he complained of chest pain and dyspnea on exertion. An exercise myocardial scintigraphy showed a reversible defect in the anteroseptal region with a normal left ventricular ejection fraction. Simvastatin 40 mg daily was added to his medication, and the dose of atenolol was increased to 100 mg daily. His symptoms persisted and increased over the last several weeks. Coronary angiography showed single-vessel disease of the proximal left anterior descending coronary artery. The heart team decided that the best option would be percutaneous coronary intervention with a drug-eluting stent. During this procedure, the international normalized ratio was tapered to 2.0. The procedure was successful, and he was put on additional aspirin and clopidogrel. The patient had an uneventful recovery and was free of symptoms. He was seen 3 months after the procedure by his attending cardiologist, who stopped aspirin. One year after the procedure, the patient came for his follow-up visit, and his clopidogrel was discontinued. He remains on atenolol, lisinopril, simvastatin, and warfarin and is doing well. Dual antiplatelet therapy has become the cornerstone of the treatment of patients undergoing coronary stenting and of those with acute coronary syndromes with or without stent implantation. Although there is consensus about the indication for dual antiplatelet therapy, little evidence exists about the optimal duration of therapy. In patients surviving non–ST-segment–elevation acute coronary syndromes, 1 year of treatment is advised. …
Creation of a Curated Aquatic Toxicology Database: EnviroTox

Flexible, rapid, and predictive approaches that do not require the use of large numbers of vertebrate test animals are needed because the chemical universe remains largely untested for potential hazards. Development of robust new approach methodologies and nontesting approaches requires the use of existing information via curated, integrated data sets. The ecological threshold of toxicological concern (ecoTTC) represents one such new approach methodology that can predict a conservative de minimis toxicity value for chemicals with little or no information available. For the creation of an ecoTTC tool, a large, diverse environmental data set was developed from multiple sources, with harmonization, characterization, and information quality assessment steps to ensure that the information could be effectively organized and mined. The resulting EnviroTox database contains 91 217 aquatic toxicity records representing 1563 species and 4016 unique Chemical Abstracts Service numbers and is a robust, curated database containing high‐quality aquatic toxicity studies that are traceable to the original information source. Chemical‐specific information is also linked to each record and includes physico‐chemical information, chemical descriptors, and mode of action classifications. Toxicity data are associated with the physico‐chemical data, mode of action classifications, and curated taxonomic information for the organisms tested. The EnviroTox platform also includes 3 analysis tools: a predicted‐no‐effect concentration calculator, an ecoTTC distribution tool, and a chemical toxicity distribution tool. Although the EnviroTox database and tools were originally developed to support ecoTTC analysis and development, they have broader applicability to the field of ecological risk assessment. Environ Toxicol Chem 2019;9999:1–12. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
A simplified definition of histologic improvement in ulcerative colitis and its association with disease outcomes up to 30 weeks from initiation of therapy: Post-hoc analysis of three clinical trials.

Background & Aims Histologic evaluation is a meaningful complement to endoscopic and clinical measures in ulcerative colitis (UC). There is a need for a definition of histologic improvement that can be used in clinical trials, and any such definition must be predictive of disease outcomes. Methods Biopsies were collected from clinical trials (PURSUIT-SC [n=98], JAK-UC [n=219], and PROgECT [n=103]) in patients with moderate-to-severe UC. A pathologist assessed biopsies in a blinded fashion using the Geboes score. A dichotomous histologic improvement endpoint was defined by selecting Geboes score elements according to their association strength with endoscopic healing. Fisher's exact test and Cramer's V assessed the association of histology with other measures. Results Using PURSUIT-SC biopsies, histologic improvement was defined as absence of erosion or ulceration, absence of crypt destruction, and <5% of crypts with epithelial neutrophil infiltration. Histologic improvement was associated with endoscopic healing, as >90% of those with endoscopic healing in JAK-UC (week 8) and PROgECT (week 30) achieved histologic improvement. In JAK-UC, patients with histologic improvement had lower disease activity than non-healers (Mayo score=3.8 versus 7.5) at week 8. Week 4 histologic improvement was a strong indicator of histologic improvement, endoscopic healing, and clinical response or remission at week 8 (all P<0.005). In PROgECT, 73% of patients with histologic improvement at week 6 achieved histologic improvement at week 30 (P=0.0013). Conclusions Histologic improvement based on a simplified, dichotomous Geboes score is associated with favorable endoscopic and clinical outcomes across multiple clinical studies and two therapeutic mechanisms of action. ClinicalTrials.gov number NCT00487539, (PURSUIT-SC); NCT01959282, (JAK-UC); NCT01988961, (PROgECT).
Population pharmacokinetics of intravenous colistin in pediatric patients: Implications for selection of dosage regimens.

Background Intravenous colistin is widely used to treat infections in pediatric patients. Unfortunately, there is a paucity of pharmacological information to guide selection of dosage regimens. The daily dose recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) is the same body weight-based dose traditionally used in adults. The aim was to increase understanding of the patient factors that influence the plasma concentration of colistin, and assess the likely appropriateness of the FDA and EMA dosage recommendations. Methods Five patients with median age 1.75 (range 0.1-6.25) years, weight 10.7 (2.9-21.5) kg and creatinine clearance 179 (44-384) mL/min/1.73m 2 received 8-hourly intravenous infusions of colistimethate. Median daily dose was 0.21 (0.20-0.21) million IU/kg, equivalent to 6.8 (6.5-6.9) mg colistin base activity per kg/day. Plasma concentrations of colistimethate and formed colistin were subjected to population pharmacokinetic modeling to explore patient factors influencing the concentration of colistin. Results Median average steady-state plasma concentration of colistin (Css,avg) was 0.88 mg/L; individual values ranged widely (0.41-3.50 mg/L), even though all patients received the same body weight-based daily dose. Despite that the daily dose was ~33% above the upper limit of the FDA and EMA recommended dose range, only 2 patients achieved Css,avg ≥2mg/L; the remaining 3 patients had Css,avg <1mg/L. The pharmacokinetic covariate analysis revealed that clearances of colistimethate and colistin were related with creatinine clearance. Conclusions The FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal function is an important determinant of dosing in these patients.
Phenotypic variability in two siblings with monogenic diabetes due to the same ABCC8 gene mutation

ABCC8 gene mutations with different inheritance patterns have been well described to cause transient and permanent forms of neonatal diabetes with onset of hyperglycemia commonly before the age of 6 months, and rare cases between 6 and 12 months. However, recent analyses have also demonstrated ABCC8 gene mutations in patients with monogenic diabetes (maturity onset diabetes of the young, MODY), with milder clinical phenotypes and later onset of hyperglycemia. We report two siblings with diabetes mellitus due to a novel homozygous p.(Phe1068Ile) (c.3202T>A) missense mutation of the ABCC8 gene, but significantly different phenotypes. The index case was diagnosed with diabetes due to an incidental finding of hyperglycemia at the age of 3 years, while her younger sibling presented with severe hyperglycemia and hyperosmolar dehydration at the age of 10 weeks. The possibility of a significant discordance in the correlation between genotype and phenotype needs to be taken into account when ABCC8 mutation dependent diabetes occurs within the same family. Genetic screening in children with diabetes from consanguineous family needs consideration, especially in case of negative autoantibodies and early onset of hyperglycemia.
Structure and function of the bird fovea

The cellular structure and functional relevance of the bird fovea are still incompletely understood. This review gives an overview of the cellular composition of the bird fovea, with special regard to Müller glial cells that provide the mechanical stability of the foveal tissue. A survey of previous data shows that the visual acuity of different bird groups (with the exception of owls) depends on the eye size, while the shape of the foveal pit does not correlate with the visual acuity. Among various bird groups, the foveal pit may have two depths, shallow (80‒120 µm) or deep (190‒240 µm). There is a long‐lasting debate whether the bird fovea acts as a local image enlarger or as a focus indicator and movement detector. These functions are supported by the refraction of the incoming light at the tissue surface. However, it was shown that Müller cells form highly refractive layers in the centre and walls of the deep avian fovea (Nature, 1978, 275, 127). Analysis of the light path through the tissue may suggest that Müller cell layers serve at least two optical functions: magnification of the image in the foveal centre and light focusing into a point within and/or a ring around the foveal centre. It is suggested that Müller glial cells contribute to various optical functions of the bird fovea.
Prognostic significance of inflammation-based indexes in patients with stage III/IV colorectal cancer after adjuvant chemoradiotherapy

Abstract Inflammation-based indexes such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation indexes (SII) have been reported to be associated with prognosis in cancer patients. The aim of this study was to estimate the prognostic significance of inflammation-based indexes such as NLR, PLR, LMR, and SII in stage III/IV colorectal cancer (CRC) patients undertaking adjuvant chemoradiotherapy (CRT). Two hundred twenty stage III/IV CRC patients were enrolled in this study. Inflammatory indexes were defined as follows: NLR = absolute neutrophil counts/absolute lymphocyte counts; PLR = absolute platelet counts/absolute lymphocyte counts; LMR = absolute lymphocyte counts/absolute monocyte counts; SII = absolute neutrophil counts × absolute platelet counts/absolute lymphocyte counts. The correlations between indexes and prognosis were evaluated using the Cox proportional hazard model. The results of univariate analysis demonstrated that NLR, PLR, and SII were significantly associated with progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed that SII (P = .030) was an independent predictor of PFS, and NLR (P = .047) was an independent prognostic factor of OS. Those inflammation-based indexes could provide a convenient and secure method to predict the outcomes of stage III/IV CRC patients receiving adjuvant CRT.