Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling

Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clinical benefits in nearly all types of solid tumours. Hence, the efficacy of HDACis in solid tumours remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumours to HDAC-targeted treatment. Methods: A hybrid molecule, Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analysed. The antitumour effects of Roxyl-zhc-84 on solid tumours were investigated by assessing cell growth, apoptosis and cell cycle in vitro and in three in vivo mouse models and compared to those of corresponding control inhibitors alone or in combination. Gene set enrichment analysis was performed, and relevant JAK1-STAT3-BCL2 signalling was identified in vitro and in vivo in mechanistic studies. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumour regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with additional JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumours to HDACi therapy.
Maternal vitamin D and E intakes in pregnancy and asthma to age 15 years: A cohort study

This study investigated whether the previously reported associations in this birth cohort between maternal vitamin D and E intakes during pregnancy and childhood wheeze/asthma outcomes at age 5 and 10 years are still evident at age 15 years. In a prospective study of 1924 children recruited in utero, maternal vitamin D and E intakes during pregnancy were assessed by food frequency questionnaire and the children completed raespiratory questionnaire at age 15 years. Treatment for asthma at age 15 was also ascertained using healthcare data. Maternal vitamin D and E intakes were also related to combined childhood asthma data collected at 1, 2, 5, 10, and 15 years of age. Symptom data were available for 747 (39%) 15‐year olds and healthcare data for 1689 (88%). There were no associations between maternal vitamin D and E intakes and childhood wheeze and asthma at age 15. Analysis of combined data collected between 1 and 15 years of age demonstrated that higher maternal vitamin D and E intakes during pregnancy were associated with a reduced likelihood of being diagnosed with asthma in the first 15 years: hazard ratio (95%CI) per quartile increase in vitamin intake of 0.87 (0.78,0.98) and 0.88 (0.78,0.98), respectively. Lower maternal vitamin D and E intakes during pregnancy are associated with increased risk of children wheezing and being diagnosed with asthma in the first 10 years but not after puberty, suggesting that post‐natal exposures predominate in the etiology of incident asthma as children transition through puberty into adulthood.
Functional classification of CATH superfamilies: a domain-based approach for protein function annotation

Motivation: Computational approaches that can predict protein functions are essential to bridge the widening function annotation gap especially since <1.0% of all proteins in UniProtKB have been experimentally characterized. We present a domain-based method for protein function classification and prediction of functional sites that exploits functional sub-classification of CATH superfamilies. The superfamilies are sub-classified into functional families (FunFams) using a hierarchical clustering algorithm supervised by a new classification method, FunFHMMer. Results: FunFHMMer generates more functionally coherent groupings of protein sequences than other domain-based protein classifications. This has been validated using known functional information. The conserved positions predicted by the FunFams are also found to be enriched in known functional residues. Moreover, the functional annotations provided by the FunFams are found to be more precise than other domain-based resources. FunFHMMer currently identifies 110 439 FunFams in 2735 superfamilies which can be used to functionally annotate > 16 million domain sequences. Availability and implementation: All FunFam annotation data are made available through the CATH webpages (http://www.cathdb.info). The FunFHMMer webserver (http://www.cathdb.info/search/by_funfhmmer) allows users to submit query sequences for assignment to a CATH FunFam. Contact: sayoni.das. 12@ucl.ac. uk Supplementary information: Supplementary data are available at Bioinformatics online.
Early neonatal vitamin A supplementation and infant mortality: an individual participant data meta-analysis of randomised controlled trials

Background Biannual vitamin A supplementation is a well-established survival tool for preschool children 6 months and older in vitamin A deficient populations but this schedule misses the opportunity to intervene on most young infant deaths. Randomised trials of neonatal vitamin A supplementation (NVAS) in the first few days of life to assess its impact on under 6-month mortality in low/middle-income countries have had varying results. Methods Investigators of 11 published randomised placebo-controlled NVAS trials (n=163 567 children) reanalysed their data according to an agreed plan and pooled the primary outcomes of mortality from supplementation through 6 and 12 months of age using random effects models and meta-regression. One investigator withdrew but allowed use of the data. Findings Overall there was no effect of NVAS on infant survival through 6 (risk ratio (RR) 0.97; 95% CI 0.89 to 1.06) or 12 months of age (RR 1.00; 95% CI 0.93 to 1.08) but results varied by study population characteristics. NVAS significantly reduced 6-month mortality among the trials conducted in Southern Asia (RR 0.87; 95% CI 0.77 to 0.98), in contexts with moderate or severe vitamin A deficiency (defined as 10% or higher proportion of women with serum retinol <0.7 µmol/L or 5% or more women with night blindness) (RR 0.87; 95% CI 0.80 to 0.94), early infant mortality was 30 or more per 1000 live births (RR 0.91; 95% CI 0.85 to 0.98), 75% or more of infant mortality occurred in the first 6 months of life (RR 0.92; 95% CI 0.84 to 1.01), or where >32% mothers had no schooling (RR 0.88; 95% CI 0.80 to 0.96). NVAS did not reduce mortality in the first 6 months of life in trials conducted in Africa, in contexts characterised by a low prevalence of vitamin A deficiency, lower rates of infant mortality and where maternal education was more prevalent. There was a suggestion of increased infant mortality in trials conducted in Africa (RR 1.07; 95% CI 1.00 to 1.15). Individual-level characteristics such as sex, birth weight, gestational age and size, age at dosing, parity, time of breast feeding initiation, maternal education and maternal vitamin A supplementation did not modify the impact of NVAS. Conclusion NVAS reduced infant mortality in South Asia, in contexts where the prevalence of maternal vitamin A deficiency is moderate to severe and early infant mortality is high; but it had no beneficial effect on infant survival in Africa, in contexts where the prevalence of maternal vitamin A deficiency is lower, early infant mortality is low.
Fast Distribution Grid Line Outage Identification with μPMU

The growing integration of distributed energy resources (DERs) in urban distribution grids raises various reliability issues due to DER's uncertain and complex behaviors. With a large-scale DER penetration, traditional outage detection methods, which rely on customers making phone calls and smart meters' "last gasp" signals, will have limited performance, because the renewable generators can supply powers after line outages and many urban grids are mesh so line outages do not affect power supply. To address these drawbacks, we propose a data-driven outage monitoring approach based on the stochastic time series analysis from micro phasor measurement unit ($\mu$PMU). Specifically, we prove via power flow analysis that the dependency of time-series voltage measurements exhibits significant statistical changes after line outages. This makes the theory on optimal change-point detection suitable to identify line outages via $\mu$PMUs with fast and accurate sampling. However, existing change point detection methods require post-outage voltage distribution unknown in distribution systems. Therefore, we design a maximum likelihood-based method to directly learn the distribution parameters from $\mu$PMU data. We prove that the estimated parameters-based detection still achieves the optimal performance, making it extremely useful for distribution grid outage identifications. Simulation results show highly accurate outage identification in eight distribution grids with 14 configurations with and without DERs using $\mu$PMU data.
Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: further evidence of association in Frontotemporal dementia

Ongoing research suggests that mitochondrial dysfunction is a common hallmark in neurodegenerative diseases, pointing to mitochondrial uncoupling process as a critical player. We recently reported that rs9472817-C/G, an intronic variant of neuronal mitochondrial uncoupling protein-4 (UCP4/SLC25A27) gene affects the risk of late onset Alzheimer's disease (LOAD), and that the variant's effect is strongly dependent on APOE-ε4 status. Here, we extended our analysis to a cohort of 751 subjects including late-onset familial and sporadic cases of frontotemporal dementia (FTD; 213), Parkinson disease (PD;96), and 442 healthy controls. In all subgroups, carriers of APOE-ε4 allele were at higher risk of disease. Regarding the rs9472817, no association was detected in familial FTD and both subgroups of PD patients. In sporadic FTD, as in LOAD, we found that the C allele increased the risk of disease of about 1.51-fold in a dose-dependent manner (p=0.013) independently from that conferred by APOE-ε4. Expression quantitative trait loci (eQTL) data of different brain regions suggest that rs9472817 likely exerts its effect by a cis-regulatory mechanism involving modulation of UCP4. If validated, the involvement of UCP4 in both FTD and LOAD might indicate interesting shared etiological factors which might give future therapeutic clues.
A Multisensor Fusion Method for Tool Condition Monitoring in Milling

Tool fault diagnosis in numerical control (NC) machines plays a significant role in ensuring manufacturing quality. Tool condition monitoring (TCM) based on multisensors can provide more information related to tool condition, but it can also increase the risk that effective information is overwhelmed by redundant information. Thus, the method of obtaining the most effective feature information from multisensor signals is currently a hot topic. However, most of the current feature selection methods take into account the correlation between the feature parameters and the tool state and do not analyze the influence of feature parameters on prediction accuracy. In this paper, a multisensor global feature extraction method for TCM in the milling process is researched. Several statistical parameters in the time, frequency, and time–frequency (Wavelet packet transform) domains of multiple sensors are selected as an alternative parameter set. The monitoring model is executed by a Kernel-based extreme learning Machine (KELM), and a modified genetic algorithm (GA) is applied in order to search the optimal parameter combinations in a two-objective optimization model to achieve the highest prediction precision. The experimental results show that the proposed method outperforms the Pearson’s correlation coefficient (PCC) based, minimal redundancy and maximal relevance (mRMR) based, and Principal component analysis (PCA)-based feature selection methods.
Ontological Analysis for Description Logics Knowledge Base Debugging

Formal ontology provides axiomatizations of domain independent principles which, among other applications,can be used to identify modeling errors within a knowledge base. The Ontoclean methodology is probably the best-known illustration of this strategy, but its cost in terms of manual work is often considered dissuasive. This article investigates the applicability of such debugging strategies to Description Logics knowledge bases, showing that even a partial and shallow analysis rapidly performed with a top-level ontology can reveal the presence of violations of common sense, and that the bottleneck, if there is one, may instead reside in the resolution of the resulting inconsistency or incoherence.
Training Load and Baseline Characteristics Associated With New Injury/Pain Within an Endurance Sporting Population: A Prospective Study.

Purpose: To determine the association between training-load (TL) factors, baseline characteristics, and new injury and/or pain (IP) risk in an endurance sporting population (ESP). Methods: Ninety-five ESP participants from running, triathlon, swimming, cycling, and rowing disciplines initially completed a questionnaire capturing baseline characteristics. TL and IP data were submitted weekly over a 52-wk study period. Cumulative TL factors, acute:chronic workload ratios, and exponentially weighted moving averages were calculated. A shared frailty model was used to explore time to new IP and association to TL factors and baseline characteristics. Results: 92.6% of the ESP completed all 52 wk of TL and IP data. The following factors were associated with the lowest risk of a new IP episode: (a) a low to moderate 7-d lag exponentially weighted moving averages (0.8-1.3: hazard ratio [HR] = 1.21; 95% confidence interval [CI], 1.01-1.44; P = .04); (b) a low to moderate 7-d lag weekly TL (1200-1700 AU: HR = 1.38; 95% CI, 1.15-1.65; P < .001); (c) a moderate to high 14-d lag 4-weekly cumulative TL (5200-8000 AU: HR = 0.33; 95% CI, 0.21-0.50; P < .001); and (d) a low number of previous IP episodes in the preceding 12 mo (1 previous IP episode: HR = 1.11; 95% CI, 1.04-1.17; P = .04). Conclusions: To minimize new IP risk, an ESP should avoid high spikes in acute TL while maintaining moderate to high chronic TLs. A history of previous IP should be considered when prescribing TLs. The demonstration of a lag between a TL factor and its impact on new IP risk may have important implications for future ESP TL analysis.
Interferons and Dry Eye in Sjögren’s Syndrome

Various cytokines, including interferon (IFN)-γ and IL-17, are augmented, and autoreactive T cells and B cells are activated in the immune pathogenesis of Sjögren’s syndrome (SS). In particular, IFNs are involved in both the early stages of innate immunity by high level of type I IFN in glandular tissue and sera and the later stages of disease progression by type I and type II IFN producing T cells and B cells through B cell activating factor in SS. Genetically modified mouse models for some of these molecules have been reported and will be discussed in this review. New findings from human SS and animal models of SS have elucidated some of the mechanisms underlying SS-related dry eye. We will discuss IFN-γ and several other molecules that represent candidate targets for treating inflammation in SS-related dry eye.
Assembly of a Complete Mitogenome of Chrysanthemum nankingense Using Oxford Nanopore Long Reads and the Diversity and Evolution of Asteraceae Mitogenomes

Diversity in structure and organization is one of the main features of angiosperm mitochondrial genomes (mitogenomes). The ultra-long reads of Oxford Nanopore Technology (ONT) provide an opportunity to obtain a complete mitogenome and investigate the structural variation in unprecedented detail. In this study, we compared mitogenome assembly methods using Illumina and/or ONT sequencing data and obtained the complete mitogenome (208 kb) of Chrysanthemum nankingense based on the hybrid assembly method. The mitogenome encoded 19 transfer RNA genes, three ribosomal RNA genes, and 34 protein-coding genes with 21 group II introns disrupting eight intron-contained genes. A total of seven medium repeats were related to homologous recombination at different frequencies as supported by the long ONT reads. Subsequently, we investigated the variations in gene content and constitution of 28 near-complete mitogenomes from Asteraceae. A total of six protein-coding genes were missing in all Asteraceae mitogenomes, while four other genes were not detected in some lineages. The core fragments (~88 kb) of the Asteraceae mitogenomes had a higher GC content (~46.7%) than the variable and specific fragments. The phylogenetic topology based on the core fragments of the Asteraceae mitogenomes was highly consistent with the topologies obtained from the corresponding plastid datasets. Our results highlighted the advantages of the complete assembly of the C. nankingense mitogenome and the investigation of its structural variation based on ONT sequencing data. Moreover, the method based on local collinear blocks of the mitogenomes could achieve the alignment of highly rearrangeable and variable plant mitogenomes as well as construct a robust phylogenetic topology.
Evolution of the Social Survey in England Since Booth

As conceived and executed by Booth, the social survey was a procedure for transposing impressions regarding squalid living conditions into objective evidence and had three fundamental characteristics: (1) definition and measurement; (2) penetrating description; and (3) analysis of interrelations of conditions and causes. During the last fifty years there has been evident in the many subsequent surveys undertaken in England an improvement under the first and third of these headings, largely owing to a development in statistical technique and a wider grasp of its value for such a purpose. Illustrative of this development are the works of Rowntree and Bowley, and more recently those of Mess, Owen, Jennings, and others. Some recent surveys have been so delimited in scope as scarcely to satisfy the definition of that them. The unsolved problem in the social survey is that of developing reliable methods for measuring intelligence and temperament.
Spices and Atherosclerosis

Cardiovascular disease is one of the leading causes of death and disability in the world. Atherosclerosis, characterized by lipid accumulation and chronic inflammation in the vessel wall, is the main feature of cardiovascular disease. Although the amounts of fruits and vegetables present in the diets vary by country, diets, worldwide, contain large amounts of spices; this may have positive or negative effects on the initiation and development of atherosclerosis. In this review, we focused on the potential protective effects of specific nutrients from spices, such as pepper, ginger, garlic, onion, cinnamon and chili, in atherosclerosis and atherosclerotic cardiovascular disease. The mechanisms, epidemiological analysis, and clinical studies focusing on a variety of spices are covered in this review. Based on the integrated information, we aimed to raise specific recommendations for people with different dietary styles for the prevention of atherosclerotic cardiovascular disease through dietary habit adjustments.
Gluten-Free Diet and Its ‘Cousins’ in Irritable Bowel Syndrome

Functional disorders are common, with irritable bowel syndrome (IBS) being the commonest and most extensively evaluated functional bowel disorder. It is therefore paramount that effective therapies are available to treat this common condition. Diet appears to play a pivotal role in symptom generation in IBS, with a recent interest in the role of dietary therapies in IBS. Over the last decade, there has been a substantial increase in awareness of the gluten-free diet (GFD), with a recent focus of the role of a GFD in IBS. There appears to be emerging evidence for the use of a GFD in IBS, with studies demonstrating the induction of symptoms following gluten in patients with IBS. However, there are questions with regards to which components of wheat lead to symptom generation, as well as the effect of a GFD on nutritional status, gut microbiota and long-term outcomes. Further studies are required, although the design of dietary studies remain challenging. The implementation of a GFD should be performed by a dietitian with a specialist interest in IBS, which could be achieved via the delivery of group sessions.
Chitosan-Stabilized Ag Nanoparticles with Superior Biocompatibility and Their Synergistic Antibacterial Effect in Mixtures with Essential Oils

Silver nanoparticles (AgNPs) are considered a promising alternative to the use of antibiotics in fighting multidrug-resistant pathogens. However, their use in medical application is hindered by the public concern regarding the toxicity of metallic nanoparticles. In this study, rationally designed AgNP were produced, in order to balance the antibacterial activity and toxicity. A facile, environmentally friendly synthesis was used for the electrochemical fabrication of AgNPs. Chitosan was employed as the capping agent, both for the stabilization and to improve the biocompatibility. Size, morphology, composition, capping layer, and stability of the synthesized nanoparticles were characterized. The in vitro biocompatibility and antimicrobial activities of AgNPs against common Gram-negative and Gram-positive bacteria were evaluated. The results revealed that chitosan-stabilized AgNPs were nontoxic to normal fibroblasts, even at high concentrations, compared to bare nanoparticles, while significant antibacterial activity was recorded. The silver colloidal dispersion was further mixed with essential oils (EO) to increase the biological activity. Synergistic effects at some AgNP–EO ratios were observed, as demonstrated by the fractionary inhibitory concentration values. Our results reveal that the synergistic action of both polymer-stabilized AgNPs and essential oils could provide a significant efficiency against a large variety of microorganisms, with minimal side effects.
Toward an Intelligent Agent for Fraud Detection - The CFE Agent

One of the primary realms into which artiﬁcial intelligence research has ventured is that of psychometric tests. It has been debated since Alan Turing proposed the Turing Test whether performance on tests should serve as the metric by which we should determine whether a machine is intelligent. This is an idea that may either solidify or challenge, depending on the reader’s predisposition, one’s sense of what artiﬁcial intelligence really is. As will be discussed in this paper, there is a history of efforts to create agents that perform well on tests in the spirit of an interpretation of artiﬁcial intelligence called “Psychometric AI”. However, the focus of this paper is to describe a machine agent, hereafter called the CFE Agent, developed in this tradition. The CFE Exam is a gateway to certiﬁcation in the Association of Certiﬁed Fraud Examiners (ACFE), a widely recognized professional credential within the fraud examiner profession. The CFE Agent attempts to emulate the successful performance of a human test taker, us-ing what would appear to be simplistic natural language processing approaches to answer test questions. But it is also hoped that the the reader will be convinced that the same core technologies can be successfully applied within the larger domain of fraud detection. Further work will also be brieﬂy discussed, in which we attempt to take these techniques to the next level, a deeper level, by which we can get a better sense of the knowledge the agent is using, and how that knowledge is being applied to formulate answers.