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In recent years, with the continuous improvement of motor power density, oil cooling technology has been widely used in permanent magnet synchronous motors (PMSMs) for electric vehicles (EVs) as an efficient cooling method. A PMSM with a rated capacity of 53kW for hybrid electric vehicles (HEVs) is designed, and the motor is cooled by the oil injection pipe. In order to improve the heat dissipation efficiency of the end winding, the number of injection pipes and the structure of the nozzle are optimised, and a novel nozzle structure is proposed. By using the moving particle solution (MPS) method to simulate the fluid flow, the optimal cooling structure of the motor is determined. In addition, different from the equivalent winding model in the traditional temperature field simulation, a hairpin winding model that can more realistically reflect the geometry of the end winding is established. On this basis, the temperature field of the motor is simulated. It is verified that the cooling structure designed can effectively improve the thermal performance of the end winding. [ABSTRACT FROM AUTHOR]

Background: Rhino‐orbito‐cerebral mucormycosis (ROCM) is an opportunistic pathogenic fungal disease caused by the fungus mucor, and it is a life‐threatening fungal infection. The ulceration on the skin of the head and neck, accompanied by rhinitis, headache, orbital inflammation, and eyelid edema, should raise a high suspicion of Mucor infection in diabetic patients with inadequately controlled blood glucose. Case Description: The clinical data of a patient with ROCM were analyzed retrospectively, and the clinical features were analyzed. The patient was admitted to the hospital with "diabetic hyperosmotic coma" after presenting with fatigue, poor appetite, and disturbances in consciousness as initial symptoms. After improving relevant examinations, controlling underlying diseases, and administering antifungal treatment, the final clinical outcome was death. Conclusion: ROCM is more prevalent in patients with uncontrolled diabetes and varied clinical manifestations. The characteristic feature is an eschar‐like necrosis of the local skin or mucosa. The gold criteria for diagnosis are pathology and fungal culture; imaging examination does not reveal any specific manifestations. Early diagnosis and effective treatment are the keys. [ABSTRACT FROM AUTHOR]

This article presents a novel method for fastly obtaining orthotropic material parameters in permanent magnet synchronous motor. First, a theoretical model of the equivalent single cylindrical shell is introduced with three orthotropic material parameters by considering the orthotropic characteristics of the motor. Then, the relationship of three orthotropic material parameters and the axial mode order m, the radial mode order n and modal frequency f is established. On this basis, an analytical method with m = 0 is proposed to acquire three values, and its adaptability is pointed out. Meanwhile, based on the above obtained orthotropic material parameters, the calculation method of modal frequencies is presented. Finally, the modal test and finite‐element method are implemented to verify the rationality of the proposed method. [ABSTRACT FROM AUTHOR]

Background: Aging‐associated osteoporosis is frequently seen in the elderly in clinic, but efficient managements are limited because of unclear nosogenesis. The current study aims to investigate the role of melatonin on senescent bone marrow stromal cells (BMSCs) and the underlying regulating mechanism. Methods: Melatonin levels were tested by ELISA. Gene expression profiles were performed by RNA‐sequencing, enrichment of H3K36me2 on gene promoters was analyzed by Chromatin Immunoprecipitation Sequencing (ChIP‐seq), and chromatin accessibility was determined by Assay for Transposase‐Accessible Chromatin with high‐throughput sequencing (ATAC‐seq). Osteogenesis of BMSCs in vitro was measured by Alizarin Red and Alkaline Phosphatase staining, and in vivo effects of melatonin was assessed by histological staining and micro computed tomography (micro‐CT) scan. Correlation of NSD2 expression and severity of senile osteoporosis patients were analyzed by Pearson correlation. Results: Melatonin levels were decreased during aging in human bone marrow, accompanied by downregulation of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) expression in the senescent BMSCs. Melatonin stimulated the expression of NSD2 through MT1/2‐mediated signaling pathways, resulting in the rebalancing of H3K36me2 and H3K27me3 modifications to increase chromatin accessibility of the osteogenic genes, runt‐related transcription factor 2 (RUNX2) and bone gamma‐carboxyglutamate protein (BGLAP). Melatonin promoted osteogenesis of BMSCs in vitro, and alleviates osteoporosis progression in the aging mice. In clinic, severity of senile osteoporosis (SOP) was negatively correlated with melatonin level in bone marrow, as well as NSD2 expression in BMSCs. Similarly, melatonin remarkably enhanced osteogenic differentiation of BMSCs derived from SOP patients in vitro. Conclusions: Collectively, our study dissects previously unreported mechanistic insights into the epigenetic regulating machinery of melatonin in meliorating osteogenic differentiation of senescent BMSC, and provides evidence for application of melatonin in preventing aging‐associated bone loss. [ABSTRACT FROM AUTHOR]

The GNAS locus is an imprinted site. The α‐subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation. [ABSTRACT FROM AUTHOR]

To improve the multiscale dynamic dispatching and distribution capacity of regional integrated energy, a multiscale dynamic time‐domain dispatching model of regional integrated energy with seasonal load difference is proposed. The master–slave game coordination planning model of regional comprehensive energy multiscale dispatching is constructed, and the difference fusion model of regional comprehensive energy multiscale dynamic dispatching is established by using the active and reactive power coordination control method according to the influence factors of voltage deviation and line overload absorption. Maximize the weight factors of the positive contribution of distributed photovoltaic (PV) power to the active distribution network. On the basis of the quantitative regulation analysis method of demand response power based on the equivalent slope of the load curve, establish an energy absorption capacity analysis model of seasonal load differentiation. On the basis of the dynamic interaction between different systems, a multiscale dynamic time‐domain analysis and dynamic simulation model of regional integrated energy is constructed by using the method of PV absorptive capacity assessment on both sides of demand uncertainty, to achieve multiscale dynamic time‐domain feature extraction of integrated energy and integrated scheduling of seasonal load differences. The simulation results show that the multiscale dynamic time‐domain allocation of regional comprehensive energy using this method improves the energy dispatching and balanced allocation capability, and the time‐domain dynamic allocation capability is good. Considering the terminal load demand and the electricity price demand formulated by the distribution network investment operators, the seasonal load response and comprehensive dispatching capability are improved. [ABSTRACT FROM AUTHOR]

Summary: Background: Inflammatory bowel diseases (IBD) have been related to high‐sugar dietary patterns, but the associations of different types of beverages with IBD risk are largely unknown. Aims: To examine any associations between intake of sugar‐sweetened beverages, artificially sweetened beverages and natural juices and IBD risk Methods: This cohort study included 121,490 participants in the UK Biobank who were free of IBD at recruitment. Intake of beverages was obtained from repeated 24‐h diet recalls in 2009–2012. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of beverage intake with IBD risk. Results: During a mean (standard deviation) follow‐up of 10.2 (1.5) years, we documented 510 incident IBD cases, (143 Crohn's disease (CD) and 367 ulcerative colitis (UC)). Compared to non‐consumers, participants consuming >1 unit per day of sugar‐sweetened beverages were at significantly higher risk of IBD (HR 1.51, 95% CI 1.11–2.05), but the trend was non‐significant (p‐trend = 0.170). This association was significant for CD (HR 2.05, 95% CI 1.22–3.46), but not for UC (HR 1.31, 95% CI 0.89–1.92). We did not observe significant associations for the consumption of artificially sweetened beverages or natural juices. Conclusions: Our findings suggest an association between consumption of sugar‐sweetened beverages, rather than artificially sweetened beverages or natural juices, and IBD risk. [ABSTRACT FROM AUTHOR]

Background: t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. Methods: An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA‐seq. NSG mouse‐based xenograft model and intra‐bone model were applied to qualify the synergistic effect in vivo. Results: We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain‐ and loss‐of‐functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ‐resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP‐1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. Conclusions: Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds. [ABSTRACT FROM AUTHOR]

In various reactive oxygen species (ROS)‐based antitumor approaches (e.g., photodynamic therapy), increasing attentions are made to improve ROS level, but the short lifetime that is another decisive hurdle of ROS‐based antitumor outcomes is not even explored yet. To address it, a photocleaved O2‐released nanoplatform is constructed to release and switch ROS into reactive nitrogen species (RNS) for repressing hypoxic breast tumor. Systematic explorations validate that the nanoplatforms can attain continuous photocontrolled O2 release, alleviate hypoxia, and elevate ROS level. More significantly, the entrapped PDE5 inhibitor (PDE5‐i) in this nanoplatform can be enzymatically decomposed into nitric oxide that further combines with ROS to generate RNS, enabling the persistent antitumor effect since RNS features longer lifetime than ROS. Intriguingly, ROS conversion into RNS can help ROS to evade the hypoxia‐induced resistance to ROS‐based antitumor. Eventually, RNS production unlocks robust antitumor performances along with ROS elevation and hypoxia mitigation. Moreover, this extraordinary conversion from ROS into RNS also can act as a general method to solve the short lifetime of ROS. [ABSTRACT FROM AUTHOR]

Summary: Objective: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel‐binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain‐of‐function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. Methods: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1R52H/F+ mice. Spontaneous epileptiform events in Fhf1R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure‐induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1BR52H protein was assayed by voltage‐clamp recordings of FHF‐deficient mouse cardiomyocytes infected with adenoviruses expressing wild‐type FHF1B or FHF1BR52H protein. Results: All Fhf1R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19–20‐day‐old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures immediately preceding loss of brain activity and death. Within 2–53 s after lethal seizure onset, heart rate abruptly declined from 572 ± 16 bpm to 108 ± 15 bpm, suggesting a parasympathetic surge accompanying seizures that may have contributed to SUDEP. Although ectopic overexpression of FHF1BR52H in cardiomyocytes induced a 15‐mV depolarizing shift in voltage of steady‐state sodium channel inactivation and slowed the rate of channel inactivation, heart rhythm was normal in Fhf1R52H/+ mice prior to seizure. Significance: The Fhf1 missense mutation p.Arg52His induces epileptic encephalopathy with full penetrance in mice. Both Fhf1 (p.Arg52His) and Scn8a (p.Asn1768Asp) missense mutations enhance sodium channel Nav1.6 currents and induce SUDEP with bradycardia in mice, suggesting an FHF1/Nav1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy. [ABSTRACT FROM AUTHOR]

SUMMARY: Starch synthesis is an essential feature of crop filling, but knowledge of the molecular mechanisms regulating the expression of starch synthesis genes (SSGs) is currently limited to transcription factors (TFs). Here, we obtained transcriptome, small RNAome, and DNA methylome data from maize (Zea mays) endosperms during multiple developmental stages and established a regulatory network atlas of starch synthesis. Transcriptome analysis showed a sharp transition at 9–10 days after pollination, when genes involved in starch and sucrose metabolism are upregulated and starch accumulates rapidly. Expression pattern analysis established a comprehensive network between SSGs and TFs. During maize endosperm development, the miRNAs with preferential repression of the expression of TFs, particularly the TFs regulating SSG expression, were extensively downregulated. Specifically, ZmMYB138 and ZmMYB115 affected the transcriptional activities of Du1/Wx and Ae1/Bt2 genes at their respective promoter regions. Remarkably, the two TFs were negatively regulated by the copious expression of Zma‐miR159k‐3p at the post‐transcriptional level. This suggests that miRNAs are important regulators of starch synthesis. Moreover, with the exclusion of the TFs, the expression of both SSGs and miRNAs was globally regulated by DNA methylation. Altogether, the present results (i) establish the regulatory functions of miRNAs and DNA methylation in starch synthesis and (ii) indicate that DNA methylation functions as a master switch. Significance Statement: Our knowledge of the molecular mechanisms regulating the expression of starch synthesis genes (SSGs) in crop cereals is currently limited to transcription factors (TFs). Here, we established a multi‐level transcriptional regulatory atlas of DNA methylation–miRNA–TF–SSGs in maize starch synthesis. In brief, the TFs regulate the expression of SSGs, while miRNAs modulate the expression of TFs, and the expression of SSGs and miRNAs, excluding TFs, is globally repressed by DNA methylation. [ABSTRACT FROM AUTHOR]

XLαs, the extra‐large isoform of alpha‐subunit of the stimulatory guanine nucleotide‐binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non‐sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth‐Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa‐B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass. [ABSTRACT FROM AUTHOR]

Accumulated evidence in the last decade implies that regulation of metabolism by p53 represents a reviving mechanism vital to prevent tumorigenesis. To gain a more in‐depth understanding of metabolic regulation by baseline levels of p53, we employed both metabolomics and transcriptomics analysis with human colon cancer cell‐line HCT116 depleted of p53. Metabolomics analyses with UPLC/quadrupole time‐of‐flight mass spectrometry identified 283 significantly changed metabolites including 138 important metabolites. Transcriptomics analysis with microarray revealed 1317 differentially expressed genes. By integrated analysis of both omics data, we found nucleotides metabolism and sulfur‐related metabolism are of great importance. Our study provided a pilot comprehensive view of the metabolism regulated by p53 and suggests several potential p53 targets in metabolism for further study. [ABSTRACT FROM AUTHOR]

The innate immune response provides the initial defence mechanism against infection by other organisms. However, an excessive immune response will cause damage to host tissues. In an attempt to identify microRNAs (miRNAs) that regulate the innate immune response in inflammation and homeostasis, we examined the differential expression of miRNAs using microarray analysis in the spleens of mice injected intraperitoneally with lipopolysaccharide (LPS) and saline, respectively. Following challenge, we observed 19 miRNAs up-regulated (1·5-fold) in response to LPS. Among these miRNAs, miR-1224, whose expression level increased 5·7-fold 6 hr after LPS injection and 2·3-fold after 24 hr, was selected for further study. Tissue expression patterns showed that mouse miR-1224 is highly expressed in mouse spleen, kidney and lung. Transfection of miR-1224 mimics resulted in a decrease in basal tumour necrosis factor-α (TNF-α) promoter reporter gene activity and a down-regulation of LPS-induced TNF-α mRNA in RAW264.7 cells. With public databases of miRNA target prediction, miR-1224 was shown to bind to the 3′ untranslated region (UTR) of Sp1 mRNA, whose coding product controls TNF-α expression at the transcriptional level. Furthermore, we found that in HEK-293 cells, the activity of the luciferase reporter bearing Sp1 mRNA 3′ UTR was down-regulated significantly when transfected with miR-1224 mimics. After transfection of miR-1224 in RAW264.7 cells, nucleus Sp1 protein level decreased, and when endogenous miR-1224 was blocked, the decrease was abolished. Therefore, we initially speculated that miR-1224 was a negative regulator of TNF-α in an Sp1-dependent manner, which was confirmed in vivo by chromatin immunoprecipitation assay, and might be involved in regulating the LPS-mediated inflammatory responses. [ABSTRACT FROM AUTHOR]

Background The aim of the present study was to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) injections in Chinese type 2 diabetic (T2D) patients. Methods The present multicenter randomized double-blind parallel placebo-controlled clinical trial enrolled patients who had been treated with a stable dose of metformin (≥1500 mg/day) for ≥12 weeks and had an HbA1c level between 7% and 11%. Subjects were randomly divided into three groups (1: 1: 1) and were treated with once weekly subcutaneous injections of either placebo or 100 or 200 μg PEX168 for 12 weeks. All subjects continued to receive metformin daily. Results After 12 weeks treatment, the adjusted least-squares mean of HbA1c reductions from baseline values in the 100 and 200 μg PEX168 groups were significantly higher than in the placebo group (−1.02% [95% confidence interval {CI} -1.33, −0.71), −1.36% [95% CI -1.68, −1.04], and 0.13% [95% CI -0.20, 0.45], respectively; P < 0.05). After treatment, 50% and 60.5% of subjects in the 100 and 200 μg PEX168 groups, respectively, achieved HbA1c levels <7% ( P < 0.01 for both vs placebo [HbA1c 11.1%]). The most frequent adverse reactions in the PEX168 groups were mild to moderate dose-dependent gastrointestinal reactions. There were no reports of hypoglycemia or pancreatitis in any of the groups. Conclusions Continuous 12 week treatment with PEX168 showed excellent safety and efficacy in T2D patients whose glucose was not well controlled with metformin alone. [ABSTRACT FROM AUTHOR]