Miracle-dz/UniFAR-FTUs huggingface dataset:
In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism

Starting from 1972, colchicine is known as the most useful drug for prevention of familial Mediterranean fever attacks. However, some patients do not respond to colchicine treatment, even taken in high doses. Despite the fact, that different hypotheses have been proposed, the molecular mechanisms of colchicine resistance are not completely clear. It is generally known, that colchicine binds β-tubulin and inhibits microtubules polymerization. The β-tubulin gene has SNPs, which lead to amino acid substitutions, and some of them are located in colchicine binding site (CBS). We have assumed, that this SNPs can affect tubulin-colchicine interaction and might be the reason for colchicine resistance. With this in mind, we modeled 7 amino acid substitutions in CBS, performed molecular dynamics simulations of tubulin-colchicine complex and calculated binding energies for every amino acid substitution. Thus, our study shows, that two amino acid substitutions in the β-tubulin, namely A248T and M257V, reduce binding energy for approximately 2-fold. Based on this, we assume, that these amino acid substitutions could be the reason for colchicine resistance. Thus, our study gives a new insight into colchicine resistance mechanism and provides information for designing colchicine alternatives, that could be effective for colchicine resistant patients.
Causative and common PHOX2B variants define a broad phenotypic spectrum

Paired Like homeobox 2B (PHOX2B) is a gene crucial for the differentiation of the neural lineages of the autonomic nervous system (ANS), whose coding mutations cause congenital central hypoventilation syndrome (CCHS). The vast majority of PHOX2B mutations in CCHS is represented by expansions of a polyalanine region in exon 3, collectively defined PARMs (PolyAlanine Repeat Mutations), the minority being frameshift, missense and nonsense mutations, defined as NPARMs (Non‐PARMs). While PARMs are nearly exclusively associated with isolated CCHS, most of NPARMs is detected in syndromic CCHS, presenting with neuroblastoma and/or Hirschsprung disease. More recently, evidence of a complex role of PHOX2B in the pathogenesis of a wider spectrum of ANS disorders has emerged. Indeed, common and hypomorphic PHOX2B variants, including synonymous, polyalanine‐contractions, gene deletions may influence the occurrence of either apparent life‐threatening event (ALTE), Sudden Infant Death Syndrome (SIDS), neuroblastoma, or isolated HSCR, likely through small effects on PHOX2B expression levels. After an introduction to the role of PHOX2B in the ANS development, causative mutations, common variants, and gene expression deregulation of the PHOX2B gene are discussed, though the involvement of synonymous variants and contractions requires further confirmations with respect to ANS disorders and molecular mechanisms underlying the PHOX2B phenotypic heterogeneity.
First-Principle Calculation of High Absorption-TlGaTe2 for Photovoltaic Application

We use first-principle calculations based on hybrid functional and the Bethe-Salpeter equation method to investigate the electronic and optical properties of dichalcogenide TlGaTe2. Based on theoretical studies, TlGaTe2 has until recently been considered as an indirect band gap material, however; by employing more accurate hybrid functional model, we showed that although TlGaTe2 has an indirect band gap of 1.109 eV, it also exhibits a fundamental direct band gap of 1.129 eV. Our finding was further confirmed by the optical studies on TlGaTe2, which show that the absorption peak is registered at a photon energy of 1.129 eV. It was also shown that TlGaTe2 has high optical absorption peaks in the visible region. Based on phonon and elastic constant calculations, it was shown that TlGaTe2 is dynamically and mechanically stable. Our findings show that TlGaTe2 is a potential candidate for photovoltaic application.
Relationship between HDL Cholesterol Efflux Capacity, Calcium Coronary Artery Content, and Antibodies against ApolipoproteinA-1 in Obese and Healthy Subjects

Aims: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). Methods and Results: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = −0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = −0.46, p = 0.006; FRS: score r = −0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). Conclusions: We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk.
Work-Related Accumulated Fatigue among Doctors in Tertiary Hospitals: A Cross-Sectional Survey in Six Provinces of China

Objectives: “Karoshi” (death due to overwork) of doctors occurred frequently and attracted increasing attention in recent years in China. This study aimed to determine the prevalence of work-related accumulated fatigue of doctors and its associated factors in tertiary hospitals of China. Methods: A cross-sectional questionnaire survey was conducted on 1729 full-time doctors employed by 24 tertiary hospitals across eastern developed, central developing, and western underdeveloped regions of China. Accumulated fatigue was categorized into four levels using the “Self-diagnosis Checklist for Assessment of Workers’ Accumulated Fatigue” rated on a scale matrix considering both overwork and fatigue symptoms. Ordinal logistic regression analyses were performed to identify factors associated with work-related accumulated fatigue. Results: About 78.8% of respondents reported a “high level” of work-related accumulated fatigue, including 42.0% at a “very high” level. Male doctors and those aged between 30 and 45 years and who had a professional title were found to have higher levels of accumulative fatigue than others. Low salary and poor working conditions (in the western region) were also significantly associated with high levels of work-related accumulated fatigue (p < 0.05). Conclusion: High levels of work-related accumulated fatigue are prevalent in doctors working in tertiary hospitals in China. Male doctors establishing their early- and mid-careers are the high-risk group. Poor working conditions are associated with work-related accumulated fatigue.
Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning

Mitochondrial serine hydroxymethyl transferase isoform 2 (SHMT2) has attracted increasing attention as a pivotal catalyzing regulator of the serine/glycine pathway in the one-carbon metabolism of cancer cells. However, few inhibitors that target this potential anticancer target have been discovered. Quantitative characterization of the interactions between SHMT2 and its known inhibitors should benefit future discovery of novel inhibitors. In this study, we employed a recently developed alanine-scanning-interaction-entropy method to quantitatively calculate the residue-specific binding free energy of 28 different SHMT2 inhibitors that originate from a same skeleton. Major contributing residues from SHMT2 and chemical groups from the inhibitors were identified and the binding energy of each residue was quantitatively determined, revealing essential features of the protein-inhibitor interaction. The most important contributing residue is Y105 of the B chain followed by L166 of the A chain. The calculated protein-ligand binding free energies are in good agreement with the experimental results, and showed better correlation and smaller errors compared with those obtained using the conventional MM/GBSA with normal mode method. These results may aid the rational design of more effective SHMT2 inhibitors.
Sodium‐activated potassium channels moderate excitability in vascular smooth muscle

We report that a sodium‐activated potassium current, IKNa, has been inadvertently overlooked in both conduit and resistance arterial smooth muscle cells. IKNa is a major K+ resting conductance and is absent in cells of IKNa knockout (KO) mice. The phenotype of the IKNa KO is mild hypertension, although KO mice react more strongly than wild‐type with raised blood pressure when challenged with vasoconstrictive agents. IKNa is negatively regulated by angiotensin II acting through Gαq protein‐coupled receptors. In current clamp, KO arterial smooth muscle cells have easily evoked Ca2+‐dependent action potentials.
ILDMSF: Inferring Associations Between Long Non-Coding RNA and Disease Based on Multi-Similarity Fusion

The dysregulation and mutation of long non-coding RNAs (lncRNAs) have been proved to result in a variety of human diseases. Identifying potential disease-related lncRNAs may benefit disease diagnosis, treatment and prognosis. A number of methods have been proposed to predict the potential lncRNA-disease relationships. However, most of them may give rise to incorrect results due to relying on single similarity measure. This article proposes a novel framework (ILDMSF) by fusing the lncRNA similarities and disease similarities, which are measured by lncRNA-related gene and known lncRNA-disease interaction and disease semantic interaction, and known lncRNA-disease interaction, respectively. Further, the support vector machine is employed to identify the potential lncRNA-disease associations based on the integrated similarity. The leave-one-out cross validation is performed to compare ILDMSF with other state of the art methods. The experimental results demonstrate our method is prospective in exploring potential correlations between lncRNA and disease.
Metal and Polymeric Strain Gauges for Si-Based, Monolithically Fabricated Organs-on-Chips

Organ-on-chip (OOC) is becoming the alternative tool to conventional in vitro screening. Heart-on-chip devices including microstructures for mechanical and electrical stimulation have been demonstrated to be advantageous to study structural organization and maturation of heart cells. This paper presents the development of metal and polymeric strain gauges for in situ monitoring of mechanical strain in the Cytostretch platform for heart-on-chip application. Specifically, the optimization of the fabrication process of metal titanium (Ti) strain gauges and the investigation on an alternative material to improve the robustness and performance of the devices are presented. The transduction behavior and functionality of the devices are successfully proven using a custom-made set-up. The devices showed resistance changes for the pressure range (0–3 kPa) used to stretch the membranes on which heart cells can be cultured. Relative resistance changes of approximately 0.008% and 1.2% for titanium and polymeric strain gauges are respectively reported for membrane deformations up to 5%. The results demonstrate that both conventional IC metals and polymeric materials can be implemented for sensing mechanical strain using robust microfabricated organ-on-chip devices.
Effects of Temperature, Growth Media, and Photoperiod on Growth and Toxin Production of Azadinium spinosum

Azaspiracids (AZAs) are microalgal toxins that can accumulate in shellfish and lead to human intoxications. To facilitate their study and subsequent biomonitoring, purification from microalgae rather than shellfish is preferable; however, challenges remain with respect to maximizing toxin yields. The impacts of temperature, growth media, and photoperiod on cell densities and toxin production in Azadinium spinosum were investigated. Final cell densities were similar at 10 and 18 °C, while toxin cell quotas were higher (~3.5-fold) at 10 °C. A comparison of culture media showed higher cell densities and AZA cell quotas (2.5–5-fold) in f10k compared to f/2 and L1 media. Photoperiod also showed differences, with lower cell densities in the 8:16 L:D treatment, while toxin cell quotas were similar for 12:12 and 8:16 L:D treatments but slightly lower for the 16:8 L:D treatment. AZA1, -2, and -33 were detected during the exponential phase, while some known and new AZAs were only detected once the stationary phase was reached. These compounds were additionally detected in field water samples during an AZA event.
Re-Potentiation of β-Lactam Antibiotic by Synergistic Combination with Biogenic Copper Oxide Nanocubes against Biofilm Forming Multidrug-Resistant Bacteria

Biofilm-associated tissue and device infection is a major threat to therapy. The present work aims to potentiate β-lactam antibiotics with biologically synthesized copper oxide nanoparticles. The synergistic combination of amoxyclav with copper oxide nanoparticles was investigated by checkerboard assay and time-kill assay against bacteria isolated from a burn wound and a urinary catheter. The control of biofilm formation and extracellular polymeric substance production by the synergistic combination was quantified in well plate assay. The effect of copper oxide nanoparticles on the viability of human dermal fibroblasts was evaluated. The minimum inhibitory concentration and minimum bactericidal concentration of amoxyclav were 70 μg/mL and 140 μg/mL, respectively, against Proteus mirabilis and 50 μg/mL and 100 μg/mL, respectively, against Staphylococcus aureus. The synergistic combination of amoxyclav with copper oxide nanoparticles reduced the minimum inhibitory concentration of amoxyclav by 16-fold against P. mirabilis and 32-fold against S. aureus. Above 17.5 μg/mL, amoxyclav exhibited additive activity with copper oxide nanoparticles against P. mirabilis. The time-kill assay showed the efficacy of the synergistic combination on the complete inhibition of P. mirabilis and S. aureus within 20 h and 24 h, respectively, whereas amoxyclav and copper oxide nanoparticles did not inhibit P. mirabilis and S. aureus until 48 h. The synergistic combination of amoxyclav with copper oxide nanoparticles significantly reduced the biofilm formed by P. mirabilis and S. aureus by 85% and 93%, respectively. The concentration of proteins, carbohydrates, and DNA in extracellular polymeric substances of the biofilm was significantly reduced by the synergistic combination of amoxyclav and copper oxide nanoparticles. The fibroblast cells cultured in the presence of copper oxide nanoparticles showed normal morphology with 99.47% viability. No cytopathic effect was observed. Thus, the study demonstrated the re-potentiation of amoxyclav by copper oxide nanoparticles.
Osthole: A Coumarin Derivative Assuage Thiram-Induced Tibial Dyschondroplasia by Regulating BMP-2 and RUNX-2 Expressions in Chickens

Avian tibial dyschondroplasia affects fast growing broiler chickens accounting for almost 30% of leg ailments in broilers. The present project was designed to assess the efficacy of osthole against avian tibial dyschondroplasia (TD). Two hundred and forty chickens were equally allocated into control, TD and osthole groups (n = 80). The TD and osthole group chickens were challenged with tetramethylthiuram disulfide (thiram) at 50 mg/kg of feed from 4–7 days, followed by osthole administration at 20 mg/kg orally to the osthole group only from 8–18 days. Thiram feeding resulted in lameness, increased mortality, and decreased production parameters, alkaline phosphatase (ALP), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-PX) levels, along with significantly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) levels, and growth plate size. Moreover, the genes and protein expressions of BMP-2 and RUNX-2 were significantly down-regulated in TD affected chickens (p < 0.05). Osthole administration showed promising results by alleviating lameness; increased ALP, SOD, T-AOC, and GSH-Px levels; and decreased the AST, ALT, and MDA levels significantly. It restored the size of the growth plate and significantly up-regulated the BMP-2 and RUNX-2 expressions (p < 0.05). In conclusion, the oxidative stress and growth plate anomalies could be assuaged using osthole.
Healthy for Life Pilot Study: A Multicomponent School and Home Based Physical Activity Intervention for Disadvantaged Children

The study aimed to develop and evaluate a multicomponent school and home based physical activity (PA) intervention in children in grades 3–7 (aged 8–13 years) and determine the psychological variables that influence PA; 10 × 1 h school-based training sessions, a home-based activity program and 4 × 1 h lifestyle workshops for parents. PA was assessed at an intervention and nearby control school using accelerometers and self-report at 3-time points: baseline, post intervention and 10-week follow-up. Self-efficacy, self-management strategies, enjoyment, perceived barriers to PA, outcome-expectancy and social support were evaluated. The study showed 73% of the children with complete data sets at the intervention school (n = 27) did not increase device measured moderate to vigorous PA (MVPA) in the after-school period (3 p.m. to 6 p.m.) or over the whole day or during school break time immediately following the intervention or at follow-up, as compared to 70% of children with complete data sets at the control school (n = 35; p > 0.05 for all). Overall, 59% of boys attained more than double the recommended 120 min of MVPA each day compared to 42% of girls (p = 0.013). At the baseline, children’s self-reported PA in the intervention school positively correlated with: outcome expectancy (R = 0.240, p = 0.015), enjoyment (R = 0.339, p < 0.001), self-efficacy (R = 0.399, p < 0.001), self-management (R = 0.617, p < 0.001), social support at home (R = 0.406, p < 0.001), and social support at school (R = 0.407, p < 0.001). Similar relationships were observed after the intervention and at follow-up. Focus groups with the children, parents and interviews with teachers identified areas for improvement of the intervention. In conclusion, while the multifaceted approach to improve PA was ineffective over the time span of the study, important predictors of PA in this sample of disadvantaged children were identified.
The Autophagy-Cilia Axis: An Intricate Relationship

Primary cilia are microtubule-based organelles protruding from the surface of almost all vertebrate cells. This organelle represents the cell’s antenna which acts as a communication hub to transfer extracellular signals into intracellular responses during development and in tissue homeostasis. Recently, it has been shown that loss of cilia negatively regulates autophagy, the main catabolic route of the cell, probably utilizing the autophagic machinery localized at the peri-ciliary compartment. On the other side, autophagy influences ciliogenesis in a context-dependent manner, possibly to ensure that the sensing organelle is properly formed in a feedback loop model. In this review we discuss the recent literature and propose that the autophagic machinery and the ciliary proteins are functionally strictly related to control both autophagy and ciliogenesis. Moreover, we report examples of diseases associated with autophagic defects which cause cilia abnormalities, and propose and discuss the hypothesis that, at least some of the clinical manifestations observed in human diseases associated to ciliary disfunction may be the result of a perturbed autophagy.
Traumatic brain injury in Portugal: progress in incidence and mortality

ABSTRACT Objectives: Traumatic brain injury continue to be a public health issue, mainly as a result of road accidents and falls. Current epidemiological studies appear to be necessary for a better understanding and monitoring of this problem. This paper analyzes the evolution of these cases in Portugal from the late 1990s to 2014. Methods: The number of hospital admissions and of total mortality in the country were analyzed regarding 2011 and 2014. The results were compared with values obtained previously, for 1997. Results: Incidence rate decreased, being 137/100 000 in 1997 and 65/100 000 in 2014. The mortality rate has also decreased from 17/100 000 to 10/100 000. However, between 2011 and 2014, there was a trend to increase the total number of cases. The incidence rate by age group also differs, with fewer cases in the young adult population in 2014 contrasting with a very high mortality among people aged 80 or older, of 57/100 000. Men continue to show a greater incidence, presenting more hospitalization cases (1.4:1), and higher mortality (2.3:1). Conclusions: The results are consistent with other studies, revealing a decrease in cases, but a high mortality in the elderly population, and the need of more preventive measures.
Live imaging the foreign body response in zebrafish reveals how dampening inflammation reduces fibrosis

ABSTRACT Implanting biomaterials in tissues leads to inflammation and a foreign body response (FBR), which can result in rejection. Here, we live image the FBR triggered by surgical suture implantation in a translucent zebrafish model and compare with an acute wound response. We observe inflammation extending from the suture margins, correlating with subsequent avascular and fibrotic encapsulation zones: sutures that induce more inflammation result in increased zones of avascularity and fibrosis. Moreover, we capture macrophages as they fuse to become multinucleate foreign body giant cells (FBGCs) adjacent to the most pro-inflammatory sutures. Genetic and pharmacological dampening of the inflammatory response minimises the FBR (including FBGC generation) and normalises the status of the tissue surrounding these sutures. This model of FBR in adult zebrafish allows us to live image the process and to modulate it in ways that may lead us towards new strategies to ameliorate and circumvent FBR in humans. This article has an associated First Person interview with the first author of the paper. Summary: A translucent zebrafish model allows a window on the pathological angiogenic and fibrotic response to suture implantation and how this can be modulated by genetically or pharmacologically dampening inflammation.