Miracle-dz/UniFAR-FTUs huggingface dataset:
Usefulness of Bnet, a Simple Linear Metric in Discerning Torsades De Pointes Risks in 28 CiPA Drugs

The Comprehensive in vitro Proarrhythmia Assay (CiPA) project suggested the torsade metric score (TMS) which requires substantial computing resources as a useful biomarker to predict proarrhythmic risk from human ether-à-go-go–related gene (hERG) and a few other ion channel block data. The TMS was useful to predict low TdP risks of drugs blocking Na+ (ranolazine) and Ca2+ (verapamil) channels as well as the hERG channel. However, Mistry asserted that the simple linear metric, Bnet reflecting net blockade of a few influential ion channels has similar predictive power. Here we compared the predictability of Bnet and TMS for the 12 training and 16 validation CiPA drugs which were pre-classified into three categories according to the known TdP risks (low, intermediate, and high risk) by CiPA. Bnet at 5×Cmax (Bnet5×Cmax) was calculated using the ion-channel IC50 and Hill coefficients of CiPA drugs collected from previous reports by the CiPA team and others. The receiver operating characteristic curve area under curve (ROC AUC) values for TMS and Bnet5×Cmax as performance metrics in discerning low versus intermediate/high risk categories for the 28 CiPA drugs were similar. However, Bnet5×Cmax was much inferior to TMS at discerning between intermediate- and high-risk drugs. Dynamic Bnet, which used in silico hERG dynamic parameters unlike conventional Bnet, improved the misspecification. Thus, we propose that Bnet5×Cmax is used for quick screening of TdP risks of drug candidates and if the “intermediate/high” risk is predicted by Bnet5×Cmax, in silico approaches, such as dynamic Bnet or TMS, may be further considered.
Structure and Function of Cochlear Gap Junctions and Implications for the Translation of Cochlear Gene Therapies

Connexins (Cxs) are ubiquitous membrane proteins that are found throughout vertebrate organs, acting as building blocks of the gap junctions (GJs) known to play vital roles in the normal function of many organs. Mutations in Cx genes (particularly GJB2, which encodes Cx26) cause approximately half of all cases of congenital hearing loss in newborns. Great progress has been made in understanding GJ function and the molecular mechanisms for the role of Cxs in the cochlea. Data reveal that multiple types of Cxs work together to ensure normal development and function of the cochlea. These findings include many aspects not proposed in the classic K+ recycling theory, such as the formation of normal cochlear morphology (e.g., the opening of the tunnel of Corti), the fine-tuning of the innervation of nerve fibers to the hair cells (HCs), the maturation of the ribbon synapses, and the initiation of the endocochlear potential (EP). New data, especially those collected from targeted modification of major Cx genes in the mouse cochlea, have demonstrated that Cx26 plays an essential role in the postnatal maturation of the cochlea. Studies also show that Cx26 and Cx30 assume very different roles in the EP generation, given that only Cx26 is required for normal hearing. This article will review our current understanding of the molecular structure, cellular distribution, and major functions of cochlear GJs. Potential implications of the knowledge of cochlear GJs on the design and implementation of translational studies of cochlear gene therapies for Cx mutations are also discussed.
Nano-casted N-Doped Carbon Created From a Task-Specific Protic Salt and Controlled Porous Glass

3-dimensionally interconnected macroporous carbons are versatile materials that can be used in catalysis, electrochemical devices, and separation technology. Herein, the synthesis of a nitrogen doped carbonaceous material with a well-defined nanoarchitecture via nano-casting is demonstrated. A novel carbon source, a task-specific protic salt, has been proposed to create nitrogen doped carbon by direct carbonization within the pores of controlled macroporous glass. After the removal of macroporous glass from the composite using an aqueous sodium hydroxide solution and upon further heat treatment, an oxidation resistant doped carbon with high nitrogen content (6 mass %) is obtained. The materials formed during the different stages of the nano-casting process exhibit interesting properties such as hierarchical porosity, very high nitrogen content (15 mass %), and increased oxidational stability. A combination of different properties to create tailor-made materials for different applications using this technique is possible.
Long-term local control and survival after preoperative radiochemotherapy in combination with deep regional hyperthermia in locally advanced rectal cancer.

AbstractPurpose: The aim of this study was to evaluate the impact of deep regional hyperthermia on long-term local control and survival in locally advanced non-metastatic rectal cancer. Methods: In total 103 patients with locally advanced non-metastatic rectal cancer were treated preoperatively with either neoadjuvant radiochemotherapy alone (n = 43) or the same treatment with additional deep regional hyperthermia (n = 60). The two groups were compared with respect to local control, overall survival (OS), disease-free survival (DFS), and distant metastases-free survival (DMFS). Results: Patients receiving additional hyperthermia had excellent long-term local control with a 5-year Kaplan-Meier estimate of 98% compared with 87% in the radiochemotherapy only group (p = 0.09). Five-year rates for OS (88% versus 76%, p = 0.08), DFS (77% versus 73%, p = n.s.) and DMFS (75% versus 77%, p = n.s.) were not statistically different between the two groups. Conclusion: Radiochemotherapy combined with hyperthermia resu.
Larger Resin Ducts Are Linked to the Survival of Lodgepole Pine Trees During Mountain Pine Beetle Outbreak

Periodic mountain pine beetle outbreaks have killed millions of hectares of lodgepole pine forests in western North America. Within these forests some pine trees often remain alive. It has been rarely documented whether anatomical defenses differ between beetle-killed and remaining live pine trees, especially at the northern latitudinal range of beetles in North America. In this study, we compared the resin duct-based anatomical defenses and radial growth between beetle-killed and live residual lodgepole pine trees, and we characterized the resin ducts and the growth of the residual trees before and after outbreak. We found that tree radial growth was not associated with tree survival. The best two predictors of tree survival were resin duct size and production (number per year). Trees having larger but fewer resin ducts showed higher survival probability compared to those with smaller but more abundant resin ducts annually. Residual trees had larger resin ducts prior to the outbreak and continued having so after the outbreak. We further categorized residual trees as healthy (having no signs or symptoms of insect or pathogen attacks), declining (with signs or symptoms of biotic attacks), and survived (from mountain pine beetle attacks during the outbreak) to investigate resin duct-based anatomical defenses among them. Healthy trees had consistently larger resin ducts than declining trees in the past 20 years in post-outbreak stands. Survival trees ranked between healthy and declining trees. Overall, these results demonstrate that resin duct size of lodgepole pine trees can be an important component of tree defenses against mountain pine beetle attacks and suggest that lodgepole pine trees with large resin ducts are likely to show resistance to future bark beetle attacks.
An Opportunity to Grow or a Label? Performance Appraisal Justice and Performance Appraisal Satisfaction to Increase Teachers’ Well-Being

Performance management is a key factor to enhance professional development and improve teaching quality. This process is successful only if teachers perceive it as fair, clear, and effective: namely, if it is satisfying. Carefully considering teachers’ attributions in the performance appraisal process is fundamental to better clarify the relations between performance management and positive individual outcomes. Therefore, this study aims to investigate the effects of perceived performance appraisal justice on teachers’ well-being, in terms of job performance, job satisfaction, and life satisfaction, hypothesizing the mediation role of performance appraisal satisfaction. Data from a sample of Italian teachers were analyzed through structural equation modeling. Results confirm the mediation role of performance appraisal satisfaction. In particular, perceived performance appraisal justice was positively associated to performance appraisal satisfaction, which, in turn, was positively associated with job performance, job satisfaction, life satisfaction. Consequently, performance appraisal satisfaction totally mediated the relations between performance appraisal justice and the outcomes considered. Findings are relevant for two reasons. First, they contribute to better understanding the performance management process in educational settings – an issue requiring further attention. Second, they contribute to highlighting the importance of performance management efficacy, which is essential not only to improve individual well-being but also to enhance teaching quality.
Theoretical Study of the Antioxidant Activity of Quercetin Oxidation Products

It was recently shown that, when tested in cellular systems, quercetin oxidized products (Qox) have significantly better antioxidant activity than quercetin (Q) itself. The main Qox identified in the experiments are either 2,5,7,3′,4′-pentahydroxy-3,4-flavandione (Fl) or its tautomer, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (Bf). We have now performed a theoretical evaluation of different physicochemical properties using density functional theory (DFT) calculations on Q and its main Qox species. The most stable structures (for Q and Qox) were identified after a structural search on their potential energy surface. Since proton affinities (PAs) are much lower than the bond dissociation enthalpies (BDEs) of phenolic hydrogens, we consider that direct antioxidant activity in these species is mainly due to the sequential proton loss electron transfer (SPLET) mechanism. Moreover, our kinetic studies, according to transition state theory, show that Q is more favored by this mechanism. However, Qox have lower PAs than Q, suggesting that antioxidant activity by the SPLET mechanism should be a result of a balance between proclivity to transfer protons (which favors Qox) and the reaction kinetics of the conjugated base in the sequential electron transfer mechanism (which favors Q). Therefore, our results support the idea that Q is a better direct antioxidant than its oxidized derivatives due to its kinetically favored SPLET reactions. Moreover, our molecular docking calculations indicate a stabilizing interaction between either Q or Qox and the kelch-like ECH-associated protein-1 (Keap1), in the nuclear factor erythroid 2-related factor 2 (Nrf2)-binding site. This should favor the release of the Nrf2 factor, the master regulator of anti-oxidative responses, promoting the expression of the antioxidant responsive element (ARE)-dependent genes. Interestingly, the computed Keap1-metabolite interaction energy is most favored for the Bf compound, which in turn is the most stable oxidized tautomer, according to their computed energies. These results provide further support for the hypothesis that Qox species may be better indirect antioxidants than Q, reducing reactive oxygen species in animal cells by activating endogenous antioxidants.
Association Between Anti-bacterial Drug Use and Digestive System Neoplasms: A Systematic Review and Meta-analysis

Background: Anti-bacterial drugs are thought to be associated with several malignancies. Objective: We conducted a systematic review and meta-analysis to assess the association between antibacterial drug exposure and the risk of digestive system neoplasms. Methods: Relevant publications reporting a relationship between antibiotic use and the risk of cancer were identified in PubMed, EMBASE, and Cochrane Central Register through June 2018. The random-effects model was selected to pool the risk ratios (RRs) and determine 95% confidence intervals (95% CIs). We performed subgroup analyses by tumor organ site, individual antibacterial drug class, and drug dose accumulation. Results: A total of 17 eligible studies (four randomized trials and 13 observational studies) involving 77,284 cancer patients were included in our analyses. Anti-bacterial drug exposure slightly increased the risk of overall digestive system cancer (RR, 1.12; 95% CI, 1.10–1.14), stomach and small intestine (RR, 1.12; 95% CI, 1.07–1.17), anorectocolonic (RR, 1.08; 95% CI, 1.05–1.12), and hepatobiliary and pancreatic cancers (RR, 1.18; 95% CI, 1.14–1.22). For different anti-bacterial drugs classes, nitroimidazoles (RR, 1.17; 95% CI, 1.09–1.26) and quinolones (RR, 1.18; 95% CI, 1.11–1.26) showed a modest association with the risk of cancers incidence. The risks of digestive system cancers increased with the rise of drug dose accumulation: low (RR, 1.08; 95% CI, 1.05–1.11), intermediate (RR, 1.15; 95% CI, 1.12–1.18), and high (RR, 1.22; 95% CI, 1.18–1.26). Conclusions: Anti-bacterial drug exposure was associated with the risks of digestive system cancer occurrence in our analysis.
Differences in the Cortical Structure of the Whole Fibula and Tibia Between Long-Distance Runners and Untrained Controls. Toward a Wider Conception of the Biomechanical Regulation of Cortical Bone Structure

The cortical structure of human fibula varies widely throughout the bone suggesting a more selective adaptation to different mechanical environments with respect to the adjacent tibia. To test this hypothesis, serial-pQCT scans of the dominant fibulae and tibiae of 15/15 men/women chronically trained in long-distance running were compared with those of 15/15 untrained controls. When compared to controls, the fibulae of trained individuals had similar (distally) or lower (proximally) cortical area, similar moments of inertia (MI) for anterior-posterior bending (xMI) and lower for lateral bending (yMI) with a lower “shape-index” (yMI/xMI ratio) throughout, and higher resistance to buckling distally. These group differences were more evident in men and independent of group differences in bone mass. These results contrast with those observed in the tibia, where, as expected, structural indicators of bone strength were greater in trained than untrained individuals. Proximally, the larger lateral flexibility of runners' fibulae could improve the ability to store energy, and thereby contribute to fast-running optimization. Distally, the greater lateral fibular flexibility could reduce bending strength. The latter appears to have been compensated by a higher buckling strength. Assuming that these differences could be ascribed to training effects, this suggests that usage-derived strains in some bones may modify their relative structural resistance to different kinds of deformation in different regions, not only regarding strength, but also concerning other physiological roles of the skeleton.
In vitro and in vivo Antidiabetic Properties of Phenolic Antioxidants From Sedum adenotrichum

Natural products serve as the mainstay of human life, and today, almost half of the drugs in clinical practice are the natural origin. Keeping in view the importance of medicinal plants and natural products, Sedum adenotrichum also known as Rosularia adenotrichum was selected for the present study. The crude extract of S. adenotrichum whole plant was obtained through a rotary evaporator. The extract was analyzed for a polyphenolic profile using high-performance liquid chromatography with a diode-array detector. The extract was subjected to detail in vivo antidiabetic study. In this study, body weight, blood glucose level, glycated hemoglobin, lipid profile, liver function tests, and renal function tests were performed in animal models. The extract was tested for in vitro α-glucosidase inhibition activity. Results of high-performance liquid chromatography with a diode-array detector chromatogram revealed a total of 22 polyphenolic compounds. No major change in body weight was noted in experimental animals. Alloxan induction led to a significant elevation in plasma glucose level. A significant decline was noted in blood glucose and glycated hemoglobin concentration in rats treated with the extract as well as with glibenclamide. Renal/liver function tests, lipid profile, alkaline phosphatase, and serum cholesterol were normalized by the extract-treated rats. The α-glucosidase inhibitory activity at 62.5 and 1,000 μg/ml was noted to be 63.97 and 80.80, respectively, both approaching to standard. The results reveal that the extract was rich in important phenolic compounds. In the antidiabetic potentials of the crude extract, there might be involved several pancreatic and extra-pancreatic mechanisms acting synergistically to induce the potent antidiabetic effect.
NCS-1 Deficiency Affects mRNA Levels of Genes Involved in Regulation of ATP Synthesis and Mitochondrial Stress in Highly Vulnerable Substantia nigra Dopaminergic Neurons

Neuronal Ca2+ sensor proteins (NCS) transduce changes in Ca2+ homeostasis into altered signaling and neuronal function. NCS-1 activity has emerged as important for neuronal viability and pathophysiology. The progressive degeneration of dopaminergic (DA) neurons, particularly within the Substantia nigra (SN), is the hallmark of Parkinson’s disease (PD), causing its motor symptoms. The activity-related Ca2+ homeostasis of SN DA neurons, mitochondrial dysfunction, and metabolic stress promote neurodegeneration and PD. In contrast, NCS-1 in general has neuroprotective effects. The underlying mechanisms are unclear. We analyzed transcriptional changes in SN DA neurons upon NCS-1 loss by combining UV-laser microdissection and RT-qPCR-approaches to compare expression levels of a panel of PD and/or Ca2+-stress related genes from wildtype and NCS-1 KO mice. In NCS-1 KO, we detected significantly lower mRNA levels of mitochondrially coded ND1, a subunit of the respiratory chain, and of the neuron-specific enolase ENO2, a glycolytic enzyme. We also detected lower levels of the mitochondrial uncoupling proteins UCP4 and UCP5, the PARK7 gene product DJ-1, and the voltage-gated Ca2+ channel Cav2.3 in SN DA neurons from NCS-1 KO. Transcripts of other analyzed uncoupling proteins (UCPs), mitochondrial Ca2+ transporters, PARK genes, and ion channels were not altered. As Cav channels are linked to regulation of gene expression, metabolic stress and degeneration of SN DA neurons in PD, we analyzed Cav2.3 KO mice, to address if the transcriptional changes in NCS-1 KO were also present in Cav.2. 3 KO, and thus probably correlated with lower Cav2.3 transcripts. However, in SN DA neurons from Cav2.3 KO mice, ND1 mRNA as well as genomic DNA levels were elevated, while ENO2, UCP4, UCP5, and DJ-1 transcript levels were not altered. In conclusion, our data indicate a possible novel function of NCS-1 in regulating gene transcription or stabilization of mRNAs in SN DA neurons. Although we do not provide functional data, our findings at the transcript level could point to impaired ATP production (lower ND1 and ENO2) and elevated metabolic stress (lower UCP4, UCP5, and DJ-1 levels) in SN DA neurons from NCS-1 KO mice. We speculate that NCS-1 is involved in stimulating ATP synthesis, while at the same time controlling mitochondrial metabolic stress, and in this way could protect SN DA neurons from degeneration.
Sulfate Mobility in Fen Peat and Its Impact on the Release of Solutes

Sea-level rise coupled with land subsidence from wetland drainage exposes increasingly large areas of coastal peatlands to seawater intrusion. Seawater contains high concentrations of sulfate (SO42-), which can alter the decomposition of organic matter thereby releasing organic and inorganic solutes from peat. In this study, a flow-through reactor system was used in order to examine the transport of SO42- through peat as well as its effect on solute release. Moderately-decomposed fen peat samples received input solutions with SO42- concentrations of 0, 100, 700 and 2700 mg L-1; sample effluent was analyzed for a variety of geochemical parameters including dissolved organic carbon (DOC), dissolved inorganic carbon (DIC) and total dissolved nitrogen (TDN) as well as the concentrations of major cations and anions. The input solution remained anoxic throughout the experiment; however, no signs of a pronounced SO42- reduction were detected in the effluent. SO42- transport in the fen peat resembled non-reactive bromide (Br-) transport, indicating that in the absence of SO42- reduction the anion may be considered a conservative tracer. However, slightly elevated concentrations of DOC and TDN, associated with raised SO42- levels, suggest the minor desorption of organic acids through anion exchange. An increased solute release due to stimulated decomposition processes, including SO42- reduction, was observed for samples with acetate as an additional marine carbon source included in their input solution. The solute release of peats with different degrees of decomposition differed greatly under SO42--enriched conditions where strongly-decomposed fen peat samples released the highest concentrations of DOC, DIC and TDN. Overall, besides a cation-exchange related release of substances adsorbed in the peat, an input of increased SO42- concentrations in a peatland by itself might not lead to an increased solute release in the short-term. However, once SO42- reduction has commenced following long-term anoxic conditions or due to a biologically readily degradable carbon source, a SO42- input can stimulate the release of solutes, including DOC, DIC and TDN, from peat.
Diarrheagenic Escherichia coli Pathotypes From Children Younger Than 5 Years in Kano State, Nigeria

Diarrheagenic Escherichia coli (DEC) is one of the leading causes of gastrointestinal disorders worldwide and an important public health challenge. DEC infection is often underdiagnosed during routine microbiological analysis, especially in resource constrained settings; the use of molecular tests could however help to determine the distribution of DEC and its clinical significance. Here, a study to assess the prevalence of DEC in clinical samples from patients <5 years attending three hospitals in Kano state, Nigeria, was carried out. Samples from 400 patients and 50 controls were collected and screened for E. coli. Compatible colonies from 248 individuals (215 patients and 33 controls) were characterized using biochemical test, a set of real-time PCRs for detection of nine virulence factors (VF: eae, bfpA, elt, est, stx1, stx2, ehxA, aggR, and invA) associated with five DEC pathotypes (EPEC, ETEC, EHEC, EAEC, and EIEC) and antimicrobial susceptibility tests. One or more VFs typical of specific pathotypes were detected in 73.8% (183/248) of the isolates, with those associated with EAEC (36.3%), ETEC (17.3%), and EPEC (6.0%) being the most common, although proportion of specific pathotypes differed between hospitals. est was the only VF detected in a significantly higher proportion in cases compared to controls (P = 0.034). Up to 86.9% of DEC were resistant to at least one class of antibiotics, with trimethoprim-sulfamethoxazole being the least effective drug (77.6% resistance). Our results demonstrate the widespread circulation of different DEC pathotypes that were highly resistant to trimethoprim-sulfamethoxazole among children in Kano state, and highlight the need of characterizing the causative agents in cases of gastrointestinal disorders.