Miracle-dz/UniFAR-FTUs huggingface dataset:
Deep Learning for Drug Design: an Artificial Intelligence Paradigm for Drug Discovery in the Big Data Era

Over the last decade, deep learning (DL) methods have been extremely successful and widely used to develop artificial intelligence (AI) in almost every domain, especially after it achieved its proud record on computational Go. Compared to traditional machine learning (ML) algorithms, DL methods still have a long way to go to achieve recognition in small molecular drug discovery and development. And there is still lots of work to do for the popularization and application of DL for research purpose, e.g., for small molecule drug research and development. In this review, we mainly discussed several most powerful and mainstream architectures, including the convolutional neural network (CNN), recurrent neural network (RNN), and deep auto-encoder networks (DAENs), for supervised learning and nonsupervised learning; summarized most of the representative applications in small molecule drug design; and briefly introduced how DL methods were used in those applications. The discussion for the pros and cons of DL methods as well as the main challenges we need to tackle were also emphasized.
Cytochrome c transcriptional activation and mRNA stability during contractile activity in skeletal muscle.

We evaluated contractile activity-induced alterations in cytochrome c transcriptional activation and mRNA stability with unilateral chronic stimulation (10 Hz, 3 h/day) of the rat tibialis anterior (TA) muscle for 1, 2, 3, 4, 5, and 7 days ( n = 3-11/group). Transcriptional activation was assessed by direct plasmid DNA injection into the TA with a chloramphenicol acetyltransferase (CAT) reporter gene linked to 326 bp of the cytochrome c promoter. Cytochrome c mRNA in stimulated muscles increased by 1.3- to 1.7-fold above control between 1 and 7 days. Cytochrome c protein was increased after 5 days of stimulation to reach levels that were 1.9-fold higher than control by 7 days. Cytochrome c mRNA stability, determined with an in vitro decay assay, was greater in stimulated TA than in control between 2 and 4 days, likely mediated by the induction of a cytosolic factor. In contrast, cytochrome c transcriptional activation was elevated only after 5 days of stimulation when mRNA stability had returned to control levels. Thus the contractile activity-induced increase in cytochrome c mRNA was due to an early increase in mRNA stability, followed by an elevation in transcriptional activation, leading to an eventual increase in cytochrome c protein levels.
Defective processing and expression of thiazide-sensitive Na-Cl cotransporter as a cause of Gitelman's syndrome.

Gitelman's syndrome is an autosomal recessive disorder of salt wasting and hypokalemia caused by mutations in the thiazide-sensitive Na-Cl cotransporter. To investigate the pathogenesis of Gitelman's syndrome, eight disease mutations were introduced into the mouse thiazide-sensitive Na-Cl cotransporter and studied by functional expression in Xenopus oocytes. Sodium uptake into oocytes that expressed the wild-type clone was more than sevenfold greater than uptake into control oocytes. Uptake into oocytes that expressed the mutated transporters was not different from control. Hydrochlorothiazide reduced Na uptake by oocytes expressing the wild-type gene to control values but had no effect on oocytes expressing the mutant clones. Western blots of oocytes injected with the wild-type clone showed bands representing glycosylated (125 kDa) and unglycosylated (110 kDa) forms of the transport protein. Immunoblot of oocytes expressing the mutated clones showed only the unglycosylated protein, indicating that protein processing was disrupted. Immunocytochemistry with an antibody against the transport protein showed intense membrane staining of oocytes expressing the wild-type protein. Membrane staining was completely absent from oocytes expressing mNCCR948X; instead, diffuse cytoplasmic staining was evident. In summary, the results show that several mutations that cause Gitelman's syndrome are nonfunctional because the mutant thiazide-sensitive Na-Cl cotransporter is not processed normally, probably activating the "quality control" mechanism of the endoplasmic reticulum.
Acupuncture for 'frequent attenders' with medically unexplained symptoms: a randomised controlled trial (CACTUS study).

BACKGROUND Medically unexplained physical symptoms (MUPS) are common and difficult to treat. AIM To investigate the effectiveness of adding five-element acupuncture to usual care in 'frequent attenders' with MUPS. DESIGN AND SETTING Randomised controlled trial in four London general practices. METHOD Participants were 80 adults with MUPS, consulting GPs ≥8 times/year. The intervention was individualised five-element acupuncture, ≥12 sessions, immediately (acupuncture group) and after 26 weeks (control group). The primary outcome was 26-week Measure Yourself Medical Outcome Profile (MYMOP); secondary outcomes were wellbeing (W-BQ12), EQ-5D, and GP consultation rate. Intention-to-treat analysis was used, adjusting for baseline outcomes. RESULTS Participants (80% female, mean age 50 years, mixed ethnicity) had high health-resource use. Problems were 59% musculoskeletal; 65% >1 year duration. The 26-week questionnaire response rate was 89%. Compared to baseline, the mean 26-week MYMOP improved by 1.0 (95% confidence interval [CI] = 0.4 to 1.5) in the acupuncture group and 0.6 (95% CI = 0.3 to 0.9) in the control group (adjusted mean difference: acupuncture versus control -0.6 [95% CI = -1.1 to 0] P = 0.05). Other between-group adjusted mean differences were: W-BQ12 4.4 (95% CI = 1.6 to 7.2) P = 0.002; EQ-5D index 0.03 (95% CI = -0.11 to 0.16) P = 0.70; consultation rate ratio 0.90 (95% CI = 0.70 to 1.15) P = 0.4; and number of medications 0.56 (95% CI = 0.47 to 1.6) P = 0.28. All differences favoured the acupuncture group. Imputation for missing values reduced the MYMOP adjusted mean difference to -0.4 (95% CI = -0.9 to 0.1) P = 0.12. Improvements in MYMOP and W-BQ12 were maintained at 52 weeks. CONCLUSION The addition of 12 sessions of five-element acupuncture to usual care resulted in improved health status and wellbeing that was sustained for 12 months.
Enteric Virus Diversity Examined by Molecular Methods in Brazilian Poultry Flocks

Enteric viruses play an important role in the Brazilian poultry industry due to the economic impact of resulting low yields of broilers, layers, and breeders. The most common enteric viruses affecting commercial flocks in Brazil include Fowl Adenovirus of group I (FAdV-I), Chicken Parvovirus (ChPV), Chicken Astrovirus (CAstV), Avian Nephritis Virus (ANV), Infectious Bronchitis Virus (IBV), Avian Reovirus (AReo), and Avian Rotavirus (ARtV). The aim of this study was to identify single and multiple infections using data obtained from 270 samples from eleven Brazilian states, corresponding to the period between 2010 and 2017. This was accompanied by an analysis of the relationship between the age of birds, clinical signs, and geographical distribution, using Polymerase Chain Reaction (PCR) and Reverse Transcription-PCR (RT-PCR) techniques. Twenty-five profiles of virus combinations were detected. Single infections were encountered in 86.3% of samples, and multiple infections were present in the remaining 13.7%. Both single and multiple infections affected all kinds of commercial chickens with digestive problems, stunting syndrome, decreases in egg and meat production, increased mortality, and respiratory signs. FAdV-I, ChPV, CAstV, ANV, and ARtV were mostly detected in young broilers, in contrast with IBV, which was detected in hens from one to greater than 51 weeks of age. These results exhibit the complexity of enteric diseases and the still poorly understood role of each pathogen as a unique etiological agent.
FungiDB: An Integrated Bioinformatic Resource for Fungi and Oomycetes

FungiDB (fungidb.org) is a free online resource for data mining and functional genomics analysis for fungal and oomycete species. FungiDB is part of the Eukaryotic Pathogen Genomics Database Resource (EuPathDB, eupathdb.org) platform that integrates genomic, transcriptomic, proteomic, and phenotypic datasets, and other types of data for pathogenic and nonpathogenic, free-living and parasitic organisms. FungiDB is one of the largest EuPathDB databases containing nearly 100 genomes obtained from GenBank, Aspergillus Genome Database (AspGD), The Broad Institute, Joint Genome Institute (JGI), Ensembl, and other sources. FungiDB offers a user-friendly web interface with embedded bioinformatics tools that support custom in silico experiments that leverage FungiDB-integrated data. In addition, a Galaxy-based workspace enables users to generate custom pipelines for large-scale data analysis (e.g., RNA-Seq, variant calling, etc.). This review provides an introduction to the FungiDB resources and focuses on available features, tools, and queries and how they can be used to mine data across a diverse range of integrated FungiDB datasets and records.
Temporal-Specific Interaction of NF-YC and CURLY LEAF during the Floral Transition Regulates Flowering1[OPEN]

NF-YC proteins interact with the histone methyltransferase CLF and prevent the trimethylation of H3K27 on chromatin at the FT locus, thereby allowing FT expression and the initiation of flowering. The flowering time of higher plants is controlled by environmental cues and intrinsic signals. In Arabidopsis (Arabidopsis thaliana), flowering is accelerated by exposure to long-day conditions via the key photoperiod-induced factor FLOWERING LOCUS T (FT). Nuclear Factor-Y subunit C (NF-YC) proteins function as important mediators of epigenetic marks in different plant developmental stages and play an important role in the regulation of FT transcription, but the mechanistic details of this remain unknown. In this study, we show that Arabidopsis NF-YC homologs temporally interact with the histone methyltransferase CURLY LEAF (CLF) during the flowering transition. The binding of NF-YC antagonizes the association of CLF with chromatin and the CLF-dependent deposition of H3 lysine-27 trimethylation, thus relieving the repression of FT transcription and facilitating flowering under long-day conditions. Our findings reveal a novel mechanism of NF-YC/CLF-mediated epigenetic regulation of FT activation in photoperiod-induced flowering and, consequently, contribute to our understanding of how plants control developmental events in a temporal-specific regulatory manner.
Resveratrol Suppresses the Growth and Enhances Retinoic Acid Sensitivity of Anaplastic Thyroid Cancer Cells

Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I131 uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. Likewise, resveratrol induces cancer redifferentiation but, also in this case, its effects on ATCs remain unknown. These issues have been addresses in the current study using three human ATC cell lines (THJ-11T, THJ-16T, and THJ-21T) through multiple experimental approaches. The results reveal that RA exerts a small inhibitory effect on these cell lines. In comparison with normally cultured cells, the total cell number in resveratrol-treated THJ-16T and THJ-21T cultures significantly decreased (p < 0.05), and this effect was accompanied by reduced Cyclin D1 immuno-labeling, increased apoptotic fractions, and distinct caspase-3 activation. Resveratrol failed to inhibit growth but enhanced RA sensitivity of THJ-11T cells, suppressed peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ), and upregulated cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor beta (RAR-β) expression. Increased thyroglobulin (Tg) and E-cadherin levels and appearance of membranous E-cadherin were evidenced in resveratrol-treated THJ-11T cells. Our results demonstrate for the first time: (1) the therapeutic value of resveratrol by itself or in combination with RA in the management of ATCs, (2) the capacity of resveratrol to overcome RA resistance in ATC cells by reprogramming CRABP2/RAR- and fatty acid-binding protein 5 (FABP5)/PPAR-β/δ-mediated RA signaling, and (3) the redifferentiating potential of resveratrol in ATC cells.
Compressive and Thermal Properties of Recycled EPS Foams

Optimization of moulding process in order to maximize the recycled fraction in EPS products is a key industrial goal. To this end effects of quality and quantity of recycled EPS upon physical properties of products are studied. Results show, on the one hand, that the introduction of a recycled fraction brings to products with a reduced density. On the other hand, small modifications of the process parameters allow for a reduction in this density decrease. Furthermore, results show that mechanical and thermal behaviour of EPS depend only on the materials density apart from the possible presence of a recycled fraction.
miR-503 suppresses the proliferation and metastasis of esophageal squamous cell carcinoma by triggering autophagy via PKA/mTOR signaling

MicroRNA (miR)-503 is involved in the regulation of the malignant phenotype in multiple tumor types, and has been proven to be a novel diagnostic and therapeutic target; however, its function and mechanisms of action have not yet been fully elucidated in esophageal squamous cell carcinoma (ESCC). In the current study, we detected miR-503 expression by RT-qPCR and found that miR-503 expression was increased in ESCC, but negatively correlated with lymph node metastasis, TNM stage and tumor differentiation. Functionally, we confirmed that miR-503 inhibited the proliferation and metastasis of ESCC cells by triggering cellular autophagy. Mechanistically, we confirmed that miR-503 exerted its biological effects by targeting protein kinase CAMP-activated catalytic subunit alpha (PRKACA) in ESCC by dual luciferase reporter assay. Moreover, miR-503 was found to trigger autophagy in ESCC cells through the protein kinase A (PKA)/mammalian target of rapamycin (mTOR) pathway. Taken together, our results demonstrate that miR-503 suppresses the proliferation and metastasis of ESCC via the activation of autophagy, mediated by the PKA/mTOR signaling pathway.
Improving the Reliability of the Tube-Hydroforming Process by the Taguchi Method

The tube-hydroforming process has undergone extremely rapid development. To ensure a reliable hydroforming process at the design stage, applying robust design methodologies becomes crucial to the success of the resulting process. The reliability of the tube-hydroforming process based on the tube wall thickness thinning ratio is studied in this paper. In order to improve the reliability of the process, the Taguchi method, which is capable of evaluating the effects of process variables on both the mean and variance of process output, is used to determine the optimal forming parameters for minimizing the variation and average value of the thinning ratio. Finite element simulation is used to analyze the virtual experiments according to the experimental arrays. A cross-extrusion hydroformed tube is employed as an example to illustrate the effectiveness of this approach.
Contribution of L-type Ca2+current to electrical activity in sinoatrial nodal myocytes of rabbits.

The role of L-type calcium current ( I Ca,L) in impulse generation was studied in single sinoatrial nodal myocytes of the rabbit, with the use of the amphotericin-perforated patch-clamp technique. Nifedipine, at a concentration of 5 μM, was used to block I Ca,L. At this concentration, nifedipine selectively blocked I Ca,L for 81% without affecting the T-type calcium current ( I Ca,T), the fast sodium current, the delayed rectifier current ( I K), and the hyperpolarization-activated inward current. Furthermore, we did not observe the sustained inward current. The selective action of nifedipine on I Ca,L enabled us to determine the activation threshold of I Ca,L, which was around -60 mV. As nifedipine (5 μM) abolished spontaneous activity, we used a combined voltage- and current-clamp protocol to study the effects of I Ca,L blockade on repolarization and diastolic depolarization. This protocol mimics the action potential such that the repolarization and subsequent diastolic depolarization are studied in current-clamp conditions. Nifedipine significantly decreased action potential duration at 50% repolarization and reduced diastolic depolarization rate over the entire diastole. Evidence was found that recovery from inactivation of I Ca,L occurs during repolarization, which makes I Ca,L available already early in diastole. We conclude that I Ca,L contributes significantly to the net inward current during diastole and can modulate the entire diastolic depolarization.
Bcl-2 inhibits ischemia-reperfusion-induced apoptosis in the intestinal epithelium of transgenic mice.

Little is known about the effects of ischemia-reperfusion on the inductive, commitment, or execution phases of apoptosis. We have created a genetically defined model to study the response of small intestinal epithelial cells to ischemia-reperfusion injury as a function of their proliferative status and differentiation. Occlusion of the superior mesenteric artery for 20 min in adult FVB/N or C57BL/6 mice results in the appearance of TUNEL-positive apoptotic cells in the jejunal epithelium within 4 h, with a maximum response occurring at 24 h. Stimulation of apoptosis is greater in postmitotic, differentiated epithelial cells located in the upper portions of villi compared with undifferentiated, proliferating cells in the crypts of Lieberkühn (7-fold vs. 2-fold relative to sham-operated controls). Comparisons of p53+/+ and p53-/- mice established that the apoptosis is p53 independent. To further characterize this response, we generated FVB/N transgenic mice that express human Bcl-2 in epithelial cells distributed from the base of crypts to the tips of their associated villi. The fivefold elevation in steady-state Bcl-2 concentration is not accompanied by detectable changes in the levels or cellular distributions of the related anti-apoptotic regulator Bcl-xL or of the proapoptotic regulators Bax and Bak and does not produce detectable effects on basal proliferation, differentiation, or death programs. The apoptotic response to ischemia-reperfusion is reduced twofold in the crypts and villi of transgenic mice compared with their normal littermates. These results suggest that both undifferentiated and differentiated cells undergo a commitment phase that is sensitive to Bcl-2. Forced expression of Bcl-2 also suppressed the p53-dependent death that occurs in proliferating crypt epithelial cells following γ-irradiation. Thus suppressibility by Bcl-2 operationally defines a common feature of the apoptosis induced in the crypt epithelium by these two stimuli.
The effect of certain disinfectant agents on alginate impression material

Dental impressions must be considered the potential to transmit the serious diseases to all dental personal who routinely handle them; it is therefore recommended to disinfect dental impressions for all patients. Materials and methods: Five alginate impressions were made of bronze model with a complex surface of small pyramids and flat surface in the middle part using perforated acrylic resin trays. These impressions were treated separately with selected disinfecting agent (Hexyl tiethyl ammonium chloride salt, Tetra butyl ammonium iodide salt, Iodophor, Ethanol and 2-propanol). Dimensional accuracy, surface detail reproduction, setting time was investigated after disinfection of alginate. The data was analyzed by a computerized statistical program. Results: The results showed that the dimensional change was statistically in significant for most of the dimensions at 5 percent level except some measurement show slight significant difference related to dimensional accuracy. Regarding reproduction of surface details, the results showed insignificant difference of the mean scores of experimental groups among the three evaluators. It was found that treating the alginate with the selected disinfecting agents will accelerate the setting time of the material. Conclusion: The testing disinfecting agents can be used safely regarding dimensional accuracy and surface detail reproduction, although setting time will be influenced compared to control alginate.
Relevance search and anomaly detection in bipartite graphs

Many real applications can be modeled using bipartite graphs, such as users vs. files in a P2P system, traders vs. stocks in a financial trading system, conferences vs. authors in a scientific publication network, and so on. We introduce two operations on bipartite graphs: 1) identifying similar nodes (relevance search), and 2) finding nodes connecting irrelevant nodes (anomaly detection). And we propose algorithms to compute the relevance score for each node using random walk with restarts and graph partitioning; we also propose algorithms to identify anomalies, using relevance scores. We evaluate the quality of relevance search based on semantics of the datasets, and we also measure the performance of the anomaly detection algorithm with manually injected anomalies. Both effectiveness and efficiency of the methods are confirmed by experiments on several real datasets.
Using cAMP Sensors to Study Cardiac Nanodomains

3′,5′-cyclic adenosine monophosphate (cAMP) signalling plays a major role in the cardiac myocyte response to extracellular stimulation by hormones and neurotransmitters. In recent years, evidence has accumulated demonstrating that the cAMP response to different extracellular agonists is not uniform: depending on the stimulus, cAMP signals of different amplitudes and kinetics are generated in different subcellular compartments, eliciting defined physiological effects. In this review, we focus on how real-time imaging using fluorescence resonance energy transfer (FRET)-based reporters has provided mechanistic insight into the compartmentalisation of the cAMP signalling pathway and allowed for the precise definition of the regulation and function of subcellular cAMP nanodomains.
Tooth loss and risk of colorectal cancer: a dose–response meta-analysis of prospective cohort studies

Background Previous studies have indicated that tooth loss is associated with colorectal cancer risk but have presented controversial results. Methods We conducted a dose–response meta-analysis in order to investigate the correlation between tooth loss and colorectal cancer risk. Up to August 2017, six eligible studies were included in this meta-analysis. Results Our results showed statistically significant association between tooth loss and colorectal cancer (OR =1.08, 95% CI: 1.03–1.15, P<0.001). In addition, we obtained the best fit at an inflection point of every two tooth loss in piecewise regression analysis, and the summary relative risk (RR) of colorectal cancer for an increase of every two tooth loss was 1.06 (95% CI: 1.02–1.11, P<0.001). Furthermore, tooth loss was significantly associated with colorectal cancer risk in Caucasia (RR: 1.18; 95% CI: 1.09–1.28; P<0.001) and Asia (RR: 1.06; 95% CI: 1.02–1.10; P<0.001). Moreover, tooth loss was significantly associated with a higher risk of colon cancer (RR: 1.09; 95% CI: 1.02–1.17; P<0.001) and rectal cancer (RR: 1.08; 95% CI: 1.01–1.17; P<0.001). Conclusion Subgroup meta-analyses showed consistency with the primary findings. Considering these promising results, increasing tooth loss may be harmful to our health, and maintenance of our oral health is essential.
Detection of protein adsorption on hydroxyapatite using electromagnetic sensors

Hydroxyapatite (HA) is the main inorganic component of bone and possesses electrical properties. Thick films of HA have shown pressure induced capacitance changes, the dielectric behavior of HA thick films over the GHz range has been investigated. This chapter discusses microwave properties describing different type of microwave resonators. The interaction of proteins and HA over the GHz range will be discussed.