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Background and Objectives: The high costs associated with biological agents often limit accessibility for many patients, whereas biosimilars allow the wider application of biological treatment. The objectives of this phase I clinical trial were to compare the pharmacokinetics, immunogenicity, and safety profiles of the biosimilar adalimumab-WIBP and the reference product Humira ® and to assess the precision of the bioequivalence evaluation., Methods: In this randomized, double-blind, parallel-group bioequivalence study, 164 healthy male Chinese participants were selected and randomly divided into two groups on a 1:1 ratio. The subjects were administered a single 40 mg subcutaneous dose of either adalimumab-WIBP or Humira ® . Blood samples extracted at multiple intervals after administration were analyzed to interpret pharmacokinetic parameters, and any adverse events were documented. Alongside ensuring safety measures, the subjects were monitored for immunogenicity., Results: The pharmacokinetic results demonstrated similar serum concentration-time curves in both groups. There were no significant differences in safety and no differences in immunogenicity profiles between the two groups. The bioequivalence was confirmed: the 90% confidence interval for the geometric mean ratio of the main pharmacokinetic parameters was within the range of 80-125%., Conclusion: The trial indicated the bioequivalence between adalimumab-WIBP and the reference product Humira ® based on pharmacokinetics, immunogenicity, and safety profile. These findings reinforce the use of the adalimumab-WIBP biosimilar as a possible therapeutic alternative to Humira ® ., Competing Interests: Declarations Conflict of interest Lu Yang, Xin Yue, Jiayou Zhang, Zejun Wang, and Yongbing Pan are employees of Wuhan Institute of Biological Products Co. Ltd., Wuhan, China. Funding This research was funded by the Wuhan Institute of Biological Products Co. Ltd., Wuhan, China. Human ethics approval declaration This study was conducted in line with the International Conference on Harmonization Standards for Good Clinical Practice, the Helsinki Declaration, and relevant national or international regulatory requirements. The study protocol was reviewed and approved by the hospital ethics committee (approval number: GCP-ICT-2019-28.01, approval date: May 13, 2019) and was registered at NMPA (CXSL1800014). Consent to participate Informed consent was obtained from all patients before undergoing any research procedures. Consent for publication Not applicable. Code availability Not applicable. Data availability Statement The datasets used in this study can be obtained from the corresponding author upon request. Author contributions All authors made a significant contribution to the work reported, whether that was in the conception, study design, execution, acquisition of data, analysis and interpretation or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Nasopharyngeal carcinoma (NPC) is a neoplasm related to inflammation; the expression of cytokines, such as CCL3, CCL4, CCL20, IL-1α, IL-1β, IL-6, IL-8, and IL-10, among others, is presumed to be associated with NPC occurrence and development. Therefore, the circulating levels of these cytokines may be potential biomarkers for assessing tumor aggressiveness, exploring cellular interactions, and monitoring tumor therapeutic responses. Numerous scholars have comprehensively explored the putative mechanisms through which these inflammatory factors affect NPC progression and therapeutic responses. Moreover, investigations have focused on elucidating the correlation between the systemic levels of these cytokines and the incidence and prognosis of NPC. This comprehensive review aims to delineate the advancements in research concerning the relationship between inflammatory factors and NPC while considering their prospective roles as novel prognostic and predictive biomarkers in the context of NPC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Liang, Kan, Wang, Lu, Mo and Zhang.)

Neuromorphic computing, a promising solution to the von Neumann bottleneck, is paving the way for the development of next-generation computing and sensing systems. Axon-multisynapse systems enable the execution of sophisticated tasks, making them not only desirable but essential for future applications in this field. Anisotropic materials, which have different properties in different directions, are being used to create artificial synapses that can mimic the functions of biological axon-multisynapse systems. However, the restricted variety and unadjustable conductive ratio limit their applications. Here, it is shown that anisotropic artificial synapses can be achieved on isotropic materials with externally localized doping via electron beam irradiation (EBI) and purposefully induced trap sites. By employing the synapses along different directions, artificial neural networks (ANNs) are constructed to accomplish variable neuromorphic tasks with optimized performance. The localized doping method expands the axon-multisynapse device family, illustrating that this approach has tremendous potentials in next-generation computing and sensing systems., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Arterioles are small blood vessels located just upstream of capillaries in nearly all tissues. The constriction and dilation of arterioles regulate tissue perfusion and are primary determinants of systemic blood pressure (BP). Abnormalities in arterioles are central to the development of major diseases such as hypertension, stroke, and microvascular complications of diabetes. Despite the broad and essential role of arterioles in physiology and disease, current knowledge of the functional genomics of arterioles is largely absent, partly because it is challenging to obtain and analyze human arteriole samples. Here, we report extensive maps of chromatin interactions, single-cell expression, and other molecular features in human arterioles and uncover new mechanisms linking human genetic variants to gene expression in vascular cells and the development of hypertension. Compared to large arteries, arterioles exhibited a higher proportion of pericytes which were strongly associated with BP traits. BP-associated single nucleotide polymorphisms (SNPs) were enriched in chromatin interaction regions in arterioles, particularly through enhancer SNP-promoter interactions, which were further linked to gene expression specificity across tissue components and cell types. Using genomic editing in animal models and human induced pluripotent stem cells, we discovered novel mechanisms linking BP-associated noncoding SNP rs1882961 to gene expression through long-range chromatin contacts and revealed remarkable effects of a 4-bp noncoding genomic segment on hypertension in vivo. We anticipate that our rich data and findings will advance the study of the numerous diseases involving arterioles. Moreover, our approach of integrating chromatin interaction mapping in trait-relevant tissues with SNP analysis and in vivo and in vitro genome editing can be applied broadly to bridge the critical gap between genetic discoveries and physiological understanding.

The modulation of inflammation is effective to treat many ocular surface diseases. Thus the low bioavailability of common anti-inflammatory eye-drops urges the development of ocular drug delivery systems to extend the ocular retention and enhance the cellular uptake for improving anti-inflammatory effect of eye-drops. Here we covalently conjugate two molecules of clinically anti-inflammatory drug (i.e., dexamethasone) with a small peptide (i.e., Tyr-Glu-Asn-Pro-Thr-Tyr) to generate an anti-inflammatory hydrogel eye-drop. With a self-assembled ability, the designed supramolecular hydrogel achieves gel-sol-gel transition by varying shearing forces which increases the pre-corneal retention of drug. The fluorescent imaging reveals the efficient cellular uptake of designed conjugate via clathrin-mediated endocytosis. A rodent model of endotoxin-induced uveitis verifies that the supramolecular hydrogel eye-drop suppresses inflammation responses without ocular irritation. As a rational approach to design anti-inflammatory drugs as eye-drops, this work overcomes the frequent instillation of clinical eye-drops and further improves the bioavailability of anti-inflammatory drugs, which may provide an effective and household way to fight ocular surface inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Arterioles are key determinants of the total peripheral vascular resistance, which, in turn, is a key determinant of arterial blood pressure. However, the amount of protein available from one isolated human arteriole may be less than 5 μg, making proteomic analysis challenging. In addition, obtaining human arterioles requires manual dissection of unfrozen clinical specimens. This limits its feasibility, especially for powerful multicenter clinical studies in which clinical specimens need to be shipped overnight to a research laboratory for arteriole isolation. We performed a study to address low-input, test overnight tissue storage and develop a reference human arteriolar proteomic profile. In tandem mass tag proteomics, use of a booster channel consisting of human induced pluripotent stem cell-derived endothelial and vascular smooth muscle cells (1:5 ratio) increased the number of proteins detected in a human arteriole segment with a false discovery rate of <0.01 from 1051 to more than 3000. The correlation coefficient of proteomic profile was similar between replicate arterioles isolated freshly, following cold storage, or before and after the cold storage (1-way analysis of variance; P = .60). We built a human arteriolar proteomic profile consisting of 3832 proteins based on the analysis of 12 arteriole samples from 3 subjects. Of 1945 blood pressure-relevant proteins that we curated, 476 (12.5%) were detected in the arteriolar proteome, which was a significant overrepresentation (χ 2 test; P < .05). These findings demonstrate that proteomic analysis is feasible with arterioles isolated from human adipose tissue following cold overnight storage and provide a reference human arteriolar proteome profile highly valuable for studies of arteriole-related traits., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shan, Hou, Wang, Chen and Liu.)

Polymer translocation is a fundamental topic in non-equilibrium physics and is crucially important to many biological processes in life. In the present work, we adopt two-dimensional Langevin dynamics simulations to study the forced and spontaneous translocation dynamics of an active filament. The influence of polymer stiffness on the underlying dynamics is explicitly analyzed. For the forced translocation, the results show a robust stiffness-induced inhibition, and the translocation time exhibits a dual-exponent scaling relationship with the bending modulus. Tension propagation (TP) is also examined, where we find prominent modifications in terms of both activity and stiffness. For spontaneous translocation into a pure solvent, the translocation time is almost independent of the polymer stiffness. However, when the polymer is translocated into a porous medium, an intriguing non-monotonic alteration of translocation time with increasing chain stiffness is demonstrated. The semiflexible chain is beneficial for translocation while the rigid chain is not conducive. Stiffness regulation on the diffusion dynamics of the polymer in porous media shows a consistent scenario. The interplay of activity, stiffness, and porous crowding provides a new mechanism for understanding the non-trivial translocation dynamics of an active filament in complex environments.

Recently, the increasing demand for data-centric applications is driving the elimination of image sensing, memory and computing unit interface, thus promising for latency- and energy-strict applications. Although dedicated electronic hardware has inspired the development of in-memory computing and in-sensor computing, folding the entire signal chain into one device remains challenging. Here an in-memory sensing and computing architecture is demonstrated using ferroelectric-defined reconfigurable two-dimensional photodiode arrays. High-level cognitive computing is realized based on the multiplications of light power and photoresponsivity through the photocurrent generation process and Kirchhoff's law. The weight is stored and programmed locally by the ferroelectric domains, enabling 51 (>5 bit) distinguishable weight states with linear, symmetric and reversible manipulation characteristics. Image recognition can be performed without any external memory and computing units. The three-in-one paradigm, integrating high-level computing, weight memorization and high-performance sensing, paves the way for a computing architecture with low energy consumption, low latency and reduced hardware overhead., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

This paper examined Chinese undergraduate students' perceptions of using videoconferencing in learning English as a foreign language (EFL) during the COVID-19 pandemic. The data were collected among 348 Chinese university students who attended sixteen-week learning of Integrated English Course through Tencent Meeting, the most widely used videoconferencing application in China. We adopted voluntary response sampling method in this cross-sectional study. Students completed an online survey on "Wenjuanxing", China's biggest online questionnaire distribution platform. A structural equation model (SEM) was constructed and analyses revealed that perceived ease of use and perceived usefulness were significant predictors of students' satisfaction and participation intention. Students' computer self-efficacy had a positive effect on their perceived ease of use, perceived usefulness, and participation intention while their frequency of using videoconferencing did not influence these variables. This study contributes to the existing literature on the acceptance of videoconferencing in the context of EFL learning and offers insights for developing up-to-date videoconferencing teaching strategies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Preeclampsia (PE) is usually associated with the accumulation of reactive oxygen species (ROS) resulting from heightened oxidative stress (OS). Ferroptosis is a unique type of lipid peroxidation-induced iron-dependent cell death distinct from traditional apoptosis, necroptosis, and pyroptosis and most likely contributes considerable to PE pathogenesis. At approximately 10-12 weeks of gestation, trophoblasts create an environment rich in oxygen and iron. In patients with PE, ferroptosis-related genes such as HIF1 and MAPK8 are downregulated, whereas PLIN2 is upregulated. Furthermore, miR-30b-5p overexpression inhibits solute carrier family 11 member 2, resulting in a decrease in glutathione levels and an increase in the labile iron pool. At the maternal-fetal interface, physiological hypoxia/reperfusion and excessive iron result in lipid peroxidation and ROS production. Owing to the high expression of Fpn and polyunsaturated fatty acid-containing phospholipid-related enzymes, including acyl-CoA synthetase long-chain family member 4, lysophosphatidylcholine acyl-transferase 3, and spermidine/spermine N1-acetyltransferase 1, trophoblasts become more susceptible to OS and ROS damage. In stage 1, the injured trophoblasts exhibit poor invasion and incomplete uterine spiral artery remodeling caused by ferroptosis, leading to placental ischemia and hypoxia. Subsequently, ferroptosis marked by OS occurs in stage 2, eventually causing PE. We aimed to explore the new therapeutic target of PE through OS in ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: Disclosures None.

Mendelian randomization is a technique used to examine the causal effect of a modifiable exposure on a trait using an observational study by utilizing genetic variants. The use of many instruments can help to improve the estimation precision but may suffer bias when the instruments are weakly associated with the exposure. To overcome the difficulty of high-dimensionality, we propose a model average estimator which involves using different subsets of instruments (single nucleotide polymorphisms, SNPs) to predict the exposure in the first stage, followed by weighting the submodels' predictions using penalization by common penalty functions such as least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP). The model averaged predictions are then used as a genetically predicted exposure to obtain the estimation of the causal effect on the response in the second stage. The novelty of our model average estimator also lies in that it allows the number of submodels and the submodels' sizes to grow with the sample size. The practical performance of the estimator is examined in a series of numerical studies. We apply the proposed method on a real genetic dataset investigating the relationship between stature and blood pressure., (© 2023 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

The structural and dynamical properties of active filamentous objects under macromolecular crowding have a great relevance in biology. By means of Brownian dynamics simulations, we perform a comparative study for the conformational change and diffusion dynamics of an active chain in pure solvents and in crowded media. Our result shows a robust compaction-to-swelling conformational change with the augment of the Péclet number. The presence of crowding facilitates self-trapping of monomers and, thus, reinforces the activity mediated compaction. In addition, the efficient collisions between the self-propelled monomers and crowders induce a coil-to-globulelike transition, indicated by a marked change of the Flory scaling exponent of the gyration radius. Moreover, the diffusion dynamics of the active chain in crowded solutions demonstrates activity-enhanced subdiffusion. The center of mass diffusion manifests rather new scaling relations with respect to both the chain length and Péclet number. The interplay of chain activity and medium crowding provides a new mechanism to understand the non-trivial properties of active filaments in complex environments.

Artificial intervention combined with stress acclimation was used to screen a heterotrophic nitrifying-aerobic denitrifying (HN-AD) bacterial, strain Rhodococcus SY24, resistant to linear alkylbenzenesulfonic acid (LAS) stress. When LAS was<15 mg/L, strain SY24 performed better cell growth and carbon source metabolism activity. The maximum nitrification and denitrification rates of SY24 under LAS stress could reach 1.18 mg/L/h and 1.05 mg/L/h, respectively, which were 13.80 % and 8.81 % higher than those of the original strain CPZ24. Higher LAS tolerance was seen in the functional genes (amoA, nxrA, napA, narG, nirK, nirS, norB, and nosZ). Response surface modeling revealed that 2 mg/L LAS, sodium succinate as a carbon source, 190 rams, and carbon/nitrogen 11 were the ideal culture conditions for SY24 to nitrogen removal under the LAS environment. This study offered a new screening strategy for the functional species, and strain SY24 showed significant LAS tolerance and HN-AD potential., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

Enormous production, use, and disposal of plastic goods present great challenges to environmental sustainability. Microplastics (MPs) are added into land which may serve as a larger MP repository than the ocean. Organic solid wastes and their biologically treated products can easily enter the soil and accumulate in soil systems. The current work deals with the extraction, identification, and distribution of MPs in typical organic solid wastes (food waste, livestock manure, and sludge) and their biologically treated products. The ecological risks of MPs were also preliminarily evaluated. The results showed that the abundance of MPs in organic solid wastes was in order of sludge > food waste > livestock manure. The main categories of MPs were fibers and films including PE, PP, and PET. The colors of MPs were mainly black, red, blue, and green. MPs generally exhibited bulges, depressions, cracks, or holes after biological treatment, and would be degraded into smaller fragments with potentially greater ecological risks. It was also found that the polymer risk index (H) of MPs in semi-dynamic composting products, compound fertilizer, and biogas residue of sedimentation tank sludge were higher than 10, reflecting their high ecological risk. Thus, it is recommended that the input of (micro)plastics to organic solid wastes streams should be minimized and related management should be established for the utilization of organic solid wastes and their biologically treated products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Valley pseudospin is an electronic degree of freedom that promises highly efficient information processing applications. However, valley-polarized excitons usually have short pico-second lifetimes, which limits the room-temperature applicability of valleytronic devices. Here, we demonstrate room-temperature valley transistors that operate by generating free carrier valley polarization with a long lifetime. This is achieved by electrostatic manipulation of the non-trivial band topology of the Weyl semiconductor tellurium (Te). We observe valley-polarized diffusion lengths of more than 7 μm and fabricate valley transistors with an ON/OFF ratio of 10 5 at room temperature. Moreover, we demonstrate an ion insertion/extraction device structure that enables 32 non-volatile memory states with high linearity and symmetry in the Te valley transistor. With ultralow power consumption (~fW valley contribution), we enable the inferring process of artificial neural networks, exhibiting potential for applications in low-power neuromorphic computing., (© 2022. The Author(s).)

Reward-modulated spike-timing-dependent plasticity (R-STDP) is a brain-inspired reinforcement learning (RL) rule, exhibiting potential for decision-making tasks and artificial general intelligence. However, the hardware implementation of the reward-modulation process in R-STDP usually requires complicated Si complementary metal-oxide-semiconductor (CMOS) circuit design that causes high power consumption and large footprint. Here, a design with two synaptic transistors (2T) connected in a parallel structure is experimentally demonstrated. The 2T unit based on WSe 2 ferroelectric transistors exhibits reconfigurable polarity behavior, where one channel can be tuned as n-type and the other as p-type due to nonvolatile ferroelectric polarization. In this way, opposite synaptic weight update behaviors with multilevel (>6 bit) conductance states, ultralow nonlinearity (0.56/-1.23), and large G max /G min ratio of 30 are realized. By applying positive/negative reward to (anti-)STDP component of 2T cell, R-STDP learning rules are realized for training the spiking neural network and demonstrated to solve the classical cart-pole problem, exhibiting a way for realizing low-power (32 pJ per forward process) and highly area-efficient (100 µm 2 ) hardware chip for reinforcement learning., (© 2022 Wiley-VCH GmbH.)

Objective: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD)., Methods: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product., Results: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein., Conclusion: The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.

Breeding high-efficiency heterotrophic nitrifying-aerobic denitrifying (SND) bacteria is important for the removal of biological nitrogen in wastewater treatment. In this study, a high-efficiency SND mutant strain, ΔRhodococcus sp. CPZ 24, was obtained by ultraviolet-diethyl sulfate compound mutagenesis. The maximum nitrification and denitrification rates were 3.77 and 1.37 mg·L -1 ·h -1 , respectively 30.30 % and 17.10 % higher than those of wild bacteria. Biolog technology and network model analysis revealed that ΔCPZ 24 significantly improved the utilisation ability and metabolic activity of organic carbon sources. Furthermore, the expression levels of the nitrogen removal function genes nxrA, nosZ, amoA, and norB in strain ΔCPZ 24 increased significantly. In actual sewage, mutant bacteria ΔCPZ 24 have a 95.05 % ammonia-nitrogen degradation rate and a 96.67 % nitrate-nitrogen degradation rate. These results suggested that UV-DES compound mutation was a successful strategy to improve the nitrogen removal performance of SND bacteria in wastewater treatment., (Copyright © 2022. Published by Elsevier Ltd.)

Background: As a rare mitochondrial disease, combined oxidative phosphorylation deficiency 14 (COXPD14) is caused by biallelic variants in the phenylalanyl-tRNA synthetase 2, mitochondrial gene (FARS2) with clinical features of developmental delay, an elevated lactate level, early-onset encephalopathy, liver failure, and hypotonia. The objectives of this study were to analyze the clinical and molecular features of two Chinese siblings affected with COXPD14, and to review relevant literature., Methods: Mutation screening was performed by whole exome sequencing (WES) in combination with Sanger sequencing validation to identify the disease-causing variants of the two patients., Results: The two siblings presented with severe clinical features and both progressed aggressively and failed to survive after treatment abandonment. We identified two compound heterozygous FARS2 variants c.925G>A p.Gly309Ser and c.943G>C p.Gly315Arg in this proband, which were inherited from the unaffected father and mother, respectively. In addition, Sanger sequencing confirmed that the elder affected sister carried the same compound heterozygous variants. The c.925G>A p.Gly309Ser variant is known and commonly reported in COXPD14 patients, while c.943G>C p.Gly315Arg is a novel one. Neither of the variants was found in 100 Chinese healthy controls. Both variants were classified as "deleterious" and were located in the highly conserved regions of the protein. The above results suggested that the two variants were likely causative in this COXPD14-affected pedigree., Conclusions: Our study expands the mutation spectrum of FARS2 and highlights the importance of genetic testing in the diagnosis of diseases with a wide variety of phenotypes, especially in the differential diagnosis of diseases., (© 2022. The Author(s).)

Objectives: This study aimed to explore the effect of subjective age on loneliness in old adults, and the mediating role of resilience and self-esteem in subjective age and loneliness., Methods: Approximately 450 old adults from Jiangxi, Hunan, Henan provinces completed the third edition of the Loneliness Scale (UCLA-LS III), Age Decade Scale (ADS), Connor-Davidson Resilience Scale (CD-RISC), and Self-Esteem Scale (SES)., Results: (1) Subjective age was significantly positively correlated with loneliness. (2) Resilience, self-esteem, and loneliness were significantly negatively correlated. (3) Subjective age affected loneliness through the mediating effects of resilience and self-esteem, respectively. (4) Resilience and self-esteem played a chain mediating role between subjective age and loneliness., Conclusion: Resilience and self-esteem can directly affect the loneliness of the old adults alone and can also affect the loneliness of the old adults through the chain mediating effect of resilience and self-esteem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Zhang, Yao, Zhang, Wang, Zhao and Huang.)

Modern electronics demand transistors with extremely high performance and energy efficiency. Charge-based transistors with conventional semiconductors experience substantial heat dissipation because of carrier scattering. Here, we demonstrate low-loss topological phase change transistors (TPCTs) based on tellurium, a Weyl semiconductor. By modulating the energy separation between the Fermi level and the Weyl point of tellurium through electrostatic gate modulation, the device exhibits topological phase change between Weyl (Chern number ≠ 0) and conventional (Chern number = 0) semiconductors. In the Weyl ON state, the device has low-loss transport characteristics due to the global topology of gauge fields against external perturbations; the OFF state exhibits trivial charge transport in the conventional phase by moving the Fermi level into the bandgap. The TPCTs show a high ON/OFF ratio (10 8 ) at low operation voltage (≤2 volts) and high ON-state conductance (39 mS/μm). Our studies provide alternative strategies for realizing ultralow power electronics.

Although a number of theories have been suggested, including roles for oxidative stress, an abnormal maternal-fetal interface, and genetic and environmental factors, the etiopathology of pre-eclampsia (PE) remains unclear. Maternal immune tolerance is important for maintaining pregnancy, and researchers have increasingly focused on the critical roles of cytokines in the pathogenesis of PE in recent years. The assessment of candidate genetic polymorphisms in PE could partially elucidate the mechanisms of susceptibility to disease, and contribute to seeking for new diagnosis and treatment methods of PE. PE can lead to severe complications, and even the death of both mother and fetus. Although the complex pathology is not yet clear, some evidence suggested that the occurrence of PE is related to inflammatory factors. We reviewed the current understandings of roles of cytokines in PE, and provided an extensive overview of the role of single nucleotide chain polymorphisms (SNPs) in the genes potentially underlying the pathophysiology of PE., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein that plays an important role in nucleotide excision repair and can reduce oxidative stress, which may be involved in the development of preeclampsia (PE). Therefore, the aim of this study was to explore whether XPC polymorphisms were relevant to the genetic susceptibility to PE in Chinese Han women., Method: A total of 1276 healthy pregnant women were included as the control group and 958 pregnant women with PE as the case group. DNA was extracted from peripheral blood samples to perform genotyping of loci rs2228001 and rs2228000 in XPC through real-time quantitative polymerase chain reaction (PCR). The relationship between XPC and susceptibility to PE was evaluated by comparing the genotypic and allelic frequencies between the two groups of pregnant women., Results: Polymorphism of rs2228000 may be associated with PE risk and allele T may play a protective role (genotype, χ2 = 38.961, P < 0.001 and allele χ2 = 21.746 P < 0.001, odds ratio (OR) = 0.885, 95% confidence interval (CI) = 0.840-0.932). No significant difference was found between the two groups in rs2228001,(genotype χ2 = 3.148, P = 0.207 and allele χ2 = 0.59, P = 0.442, OR = 1.017, 95% CI = 0.974-1.062). When the frequencies of genotypes and alleles for early- and late-onset PE, mild PE and severe PE were compared with those of controls, the results were consistent with the large clinical sample., Conclusion: Our data suggest that the genetic variant rs2228000 in XPC may be associated with PE risk in Chinese Han women, and that pregnant women with the TT genotype have a reduced risk of PE. Further investigations are needed to confirm these findings in other regions or larger prospective populations., (© 2021. The Author(s).)

Ultrathin two-dimensional (2D) semiconductors are regarded as a potential channel material for low-power transistors with small subthreshold swing and low leakage current. However, their dangling bond–free surface makes it extremely difficult to deposit gate dielectrics with high-quality interface in metal-oxide-semiconductor (MOS) field-effect transistors (FETs). Here, we demonstrate a low-temperature process to transfer metal gate to 2D MoS 2 for high-quality interface. By excluding extrinsic doping to MoS 2 and increasing contact distance, the high–barrier height Pt-MoS 2 Schottky junction replaces the commonly used MOS capacitor and eliminates the use of gate dielectrics. The MoS 2 transferred metal gate (TMG) FETs exhibit sub-1 V operation voltage and a subthreshold slope close to thermal limit (60 mV/dec), owing to intrinsically high junction capacitance and the high-quality interface. The TMG and back gate enable logic functions in a single transistor with small footprint.

Background: AcMNPV is a model organism of baculovirus, and Spodoptera frugiperda is one of its hosts. Disclosing the role of ac106/107 in AcMNPV infecting Spodoptera frugiperda 9 (Sf9) cells is of great significance for modifying AcMNPV as a microbial insecticide. This work constructed recombinant baculovirus that knocking out, repairment and overexpression of ac106/107 and explored the effects of Ac106/107 on the proliferation of progeny viruses. Moreover, the potential mechanism and targets of ac106/107 were further revealed., Results: First, compared with the Bacmid-EGFP transfection group, the progeny virus does not proliferate after knocking out of ac106/107, and the proliferation ability increases by 14.5% at 72 h post transfection (h p.t.) when overexpression of ac106/107. However, knockout, repairment and overexpression of ac106/107 have no effect on viral DNA replication. Secondly, Ac106/107-EGFP was located in the cytoplasm and nucleus. Transcription level of late viral genes and viral RNA polymerase subunit genes in the Bacmid ac106/107KO -EGFP transfection group and Bacmid-Ac106/107-EGFP transfection group was reduced and increased, respectively. Thirdly, AcMNPV would increase the glucose utilization and lactate consumption of the host Sf9 cells, and Bacmid ac106/107KO -EGFP transfection group had lower glucose consumption and lactic acid accumulation than Bacmid-EGFP, Bacmid ac106/107KO -Ac106/107(rep)-EGFP and Bacmid-Ac106/107-EGFP transfection groups., Conclusion: Ac106/107 can enter the nucleus and affect transcription of viral RNA polymerase subunit genes, which in turn affects the transcription of late genes, and ultimately affects virus proliferation and energy metabolism in host cells. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

With the further development of the construction of "smart mine," the establishment of three-dimensional (3D) point cloud models of mines has become very common. However, the truck operation caused the 3D point cloud model of the mining area to contain dust points, and the 3D point cloud model established by the Context Capture modeling software is a hollow structure. The previous point cloud denoising algorithms caused holes in the model. In view of the above problems, this paper proposes the point cloud denoising method based on orthogonal total least squares fitting and two-layer extreme learning machine improved by genetic algorithm (GA-TELM). The steps are to separate dust points and ground points by orthogonal total least squares fitting and use GA-TELM to repair holes. The advantages of the proposed method are listed as follows. First, this method could denoise without generating holes, which solves engineering problems. Second, GA-TELM has a better effect in repairing holes compared with the other methods considered in this paper. Finally, this method starts from actual problems and could be used in mining areas with the same problems. Experimental results demonstrate that it can remove dust spots in the flat area of the mine effectively and ensure the integrity of the model., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Jingli Wang et al.)

Highly active Ti/Sb-SnO 2 electrodes were fabricated using sol-gel spin coating procedure, which exhibited a rough, uniform and multilayer coating structure. The effects of different Sb-SnO 2 film layers on the physiochemical, electrochemical properties and pollutant degradability of electrodes and the mechanism were evaluated on a systematic basis. The electrodes with more active layers exhibited higher electro-catalytic performance. Upon exceeding 8 layers, the promotion effect of the coating was reduced. Considering various factors, this paper recommends preparing Ti/Sb-SnO 2 electrodes coated with 8 layers to obtain higher electro-catalytic ability in landfill leachate treatment. The specific number of coating layers should be determined according to the electrode requirements. This work provided a theoretical basis and technical support for the preparation of Ti-SnO 2 electrodes with high electro-catalytic activity and stability, while it still remains a great challenge to achieve an excellent balance between performance and stability before Ti/Sb-SnO 2 electrodes can be implemented on a large scale in wastewater treatment.

The rural domestic waste (RDW) compost has been widely used in agriculture and horticulture, but little is known about microplastics (MPs) in RDW composting. The current work deals with the abundance and characteristics of MPs in RDW composting, and the effects of composting processes on the composition of MPs. Compost samples from two RDW treatment stations were investigated, and a lab-scale experiment was carried out to verify the possible release of MPs from macroplastics (>25 mm) contained in the RDW during composting. MPs were identified using stereo-microscope and μ-FTIR. The average abundance of MPs (0.05-5 mm) in the RDW compost products was 2400 ± 358 items/kg (dry weight), and the main MPs shapes were fibers and films. Polyester, polypropylene (PP) and polyethylene (PE) were the most common polymer types. MPs having a size <1 mm accounted for more than 50% of the total quantity. With the progress of composting, the proportion of MPs having size <1 mm increased, and more foam MPs were observed in the late stage of composting. Under the influence of mechanical force, oxidation and biodegradation, a piece of expanded polystyrene (EPS), PP and PE macroplastic could release 4-63 MPs particles during the composting. Thus, the RDW compost was a significant source of MPs in soils, and the MPs in compost products were closely related to the quantity and type of plastic waste present in RDW, which helped to suggest better MPs control strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Industrial-scale composting of food waste (FW) was performed at different aeration frequencies (C&#95;5&#95;25: 5 min aeration + 25 min interval, C&#95;10&#95;20: 10 min aeration + 20 min interval, C&#95;15&#95;15: 15 min aeration + 15 min interval and CK: stuffiness) to ascertain the optimal aeration frequency to accomplish polymerization and humification of compost. The tested aeration frequencies affected the oxygen uptake rate, oxygen spatial distribution, and ultimately influenced the humification of compost. Extensive aeration was not beneficial to accumulate nitrogen and phosphorus during composting. Aeration frequency influenced the succession of bacterial community primarily through affecting O 2 concentration and the release of various enzymes by these bacteria. Regulating O 2 concentration by adjusting aeration strategies may provide guidance for accelerating maturity of composting. Considering various factors, this paper recommends the scheme of heating period (C&#95;5&#95;25), thermophilic period (C&#95;15&#95;15) and psychrophilic period (no aeration)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Gestational diabetes mellitus (GDM) is a pregnancy-specific carbohydrate intolerance Which can cause a large number of perinatal and postpartum complications. The members of Transforming growth factor-β (TGF-β) superfamily play key roles in the homeostasis of pancreatic β-cell and may involve in the development of GDM. This study aimed to explore the association between the polymorphisms of TGF-β1, TGF-β3 and the risk to GDM in Chinese women., Methods: This study included 919 GDM patients (464 with preeclampsia and 455 without preeclampsia) and 1177 healthy pregnant women. TaqMan allelic discrimination real-Time PCR was used to genotype the TGF-β1 (rs4803455) and TGF-β3 (rs2284792 and rs3917201), The Hardy-Weinberg equilibrium (HWE) was evaluated by chi-square test., Results: An increased frequency of TGF-β3 rs2284792 AA and AG genotype carriers was founded in GDM patients (AA vs. AG + GG: χ 2  = 6.314, P = 0.012, OR = 1.270, 95%CI 1.054-1.530; AG vs. GG + AA: χ 2  = 8.545, P = 0.003, OR = 0.773, 95%CI 0.650-0.919). But there were no significant differences in the distribution of TGF-β1 rs4803455 and TGF-β3 rs3917201 between GDM and healthy women. In addition, no significant differences were found in allele and genotype frequencies among GDM patients with preeclampsia (PE)., Conclusions: The AA and AG genotype of TGF-β3 rs2284792 polymorphism may be significantly associated with increased risk of GDM in Chinese population.

We propose and demonstrate a broadband tunable single-longitudinal-mode (SLM) erbium-doped fiber laser based on a microfiber knot resonator (MKR). The MKR is made from a double-ended fiber taper and employed for SLM filtering based on the Vernier effect. An unpumped erbium-doped fiber is used in the fiber laser cavity to suppress mode-hopping for a stabilized SLM laser operation. When combined with an optical fiber filter, widely tunable SLM laser generation is achieved. The proposed SLM laser can be tuned from 1545 to 1565 nm with a high side-mode suppression ratio of about 55 dB and a high stability.

In this study, we aimed to evaluate the suppressive abilities of berberine (BBR) on MCF-7 and MDA-MB-231 cells and confirm its underlying mechanisms on miR-214-3p. We first built a panel of 18 miRNAs and 9 lncRNAs that were reported to participate in the mechanism of breast cancer. The RT-qPCR results suggested that BBR illustrated a dosage-dependent pattern in the stimulation to miR-214-3p in both MCF-7 and MDA-MB-231 cells. Then, we performed gain-and-lose function tests to validate the role of miR-214-3p contributing to the anticancer effects of BBR. Both BBR and miR-214-3p mimic reduced the cell viability, repressed migration and invasion capacities, increased rates of total apoptotic cells and ratio of Bax/Bcl-2, and increased the percentage of G2/M cells of MCF-7 and MDA-MB-231 cells by colony formation and CKK8 assay, scratch wound healing and gelatin-based 3D conformation assay, transwell invasion assay, and cell cycle analysis, respectively. However, miR-214-3p inhibitor counteracted all these effects of BBR. Based on the bioinformatics analysis and dual-luciferase reporter test, we identified binding sites between SCT and miR-214-3p. We further confirmed that BBR massively and dose-dependently reduced the mRNA expression and protein levels of SCT in both MCF-7 and MDA-231 cells. We testified that both miR-214-3p mimic and BBR could decrease the mRNA expression and protein levels of SCT, while miR-214-3p inhibitor weakened these reductions. In conclusion, BBR suppressed MCF-7 and MDA-MB-231 breast cancer cells by upregulating miR-214-3p and increasing its inhibition to SCT., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Congyuan Zhu et al.)

Properly stratifying high-risk individuals with early stage hepatocellular carcinoma (HCC) is essential to identify patients in which the potentially therapies can be offered. To this context, we systematically investigated the prognostic value of epigenetic clock with early stage HCC as well as the association with other molecular characteristics., We computed DNA methylation (DNAm) age of 256 early stage HCC patients and 50 normal samples from TCGA by Horvath clock model. The characteristics of two DNAm age subgroups were differentiated regarding HBV expression, pathway activity, epigenomic, and genomic alteration. Cox regression and restricted cubic spline (RCS) analysis were utilized to evaluate the prognostic value of epigenetic acceleration., DNAm age was significantly associated with chronological age in normal tissue but largely disrupted in tumors ( P < .001), and showed significant negative correlation with HBV expression ( P < .05). We identified two DNAm age groups (DNAmAge-ACC and DNAmAge-DEC), and the former presented with an immunoactive phenotype (all FDRs<0.05 in enrichment analysis), CpG island hypermethylation ( P < .001), and lower mutation burden ( P = .018). Every 10-year increase in DNAm age was associated with a 18% decrease in fatality after adjustment for major clinical variables; DNAmAge-ACC had 50% lower mortality risk than DNAmAge-DEC (HR: 0.50, 95% CI: 0.27-0.94, P = .03). RCS revealed the fatality risk significantly decreased as epigenetic age accelerated ( P = .04). Conclusions., In summary, we highlighted the prognostic value of epigenetic age acceleration for early stage HCC; better prognosis, relatively lower HBV load, and higher enrichment of immune signatures were tightly associated with epigenetic age accelerated tumors.

The atomic structure of quasi one-dimensional (1D) van der Waals materials can be regarded as the stacking of atomic chains to form thin flakes or nanoribbons, which substantially differentiates them from typical two-dimensional (2D) layered materials and 1D nanotube/nanowire array. Here we present our studies on quasi 1D gold selenide (AuSe) that possesses highly anisotropic crystal structure, excellent electrical conductivity, giant magnetoresistance, and unusual reentrant metallic behavior. The low in-plane symmetry of AuSe gives rise to its high anisotropy of vibrational behavior. In contrast, quasi 1D AuSe exhibits high in-plane electrical conductivity along the directions of both atomic chains and perpendicular one, which can be understood as a result of strong interchain interaction. We found that AuSe exhibits a near quadratic nonsaturating giant magnetoresistance of 1841% with the magnetic field perpendicular to its in-plane. We also observe unusual reentrant metallic behavior, which is caused by the carrier mismatch in the multiband transport. Our works help to establish fundamental understandings on quasi 1D van der Waals semimetallic AuSe and identify it as a new candidate for exploring giant magnetoresistance and compensated semimetals., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2020 Science China Press. Published by Elsevier B.V. All rights reserved.)

Although non-invasive prenatal testing has been widely used, it has certain limitations. As the gold standard of prenatal diagnosis, G-banding karyotype analysis is time-consuming and laborious. Fluorescence in situ hybridization (FISH), as a method for detecting samples with non-radioactive signals, does not require cell culture and has a short turnover time, and can diagnose aneuploidies of chromosomes 13, 18, 21, X, Y with efficiency, which can solve the problems such as insufficient testing ability and long diagnosis period for karyotype analysis. To standardize the procedures of prenatal FISH assay and enhance laboratory quality management, the Expert Committee of the Prenatal Screening and Diagnosis Laboratory of the Clinical Test Center of the National Health Commission and the Inter-laboratory Quality Assessment Committee of the Neonatal Genetic and Metabolic Disease Screening Laboratory have formulated this consensus.

Hardware implementation of an artificial neural network requires neuromorphic devices to process information with low energy consumption and high heterogeneity. Here we demonstrate an electrolyte-gated synaptic transistor (EGT) based on a trigonal selenium ( t -Se) nanosheet. Due to the intrinsic low conductivity of the Se channel, the t -Se synaptic transistor exhibits ultralow energy consumption, less than 0.1 pJ per spike. More importantly, the intrinsic low symmetry of t -Se offers a strong anisotropy along its c - and a -axis in electrical conductance with a ratio of up to 8.6. The multiterminal EGT device exhibits an anisotropic response of filtering behavior to the same external stimulus, which enables it to mimic the heterogeneous signal transmission process of the axon-multisynapse biostructure in the human brain. The proof-of-concept device in this work represents an important step to develop neuromorphic electronics for processing complex signals.

The use of reporter genes to non-invasively image molecular processes inside cells has significant translational potential, particularly in the context of systemically administered gene therapy vectors and adoptively administered cells such as immune or stem cell based therapies. Bacterial nitroreductase enzymes possess ideal properties for reporter gene imaging applications, being of non-human origin and possessing the ability to metabolize a range of clinically relevant nitro(hetero)cyclic substrates. Methods: A library of eleven Escherichia coli nitroreductase candidates were screened for the ability to efficiently metabolize 2-nitroimidazole based positron emission tomography (PET) probes originally developed as radiotracers for hypoxic cell imaging. Several complementary methods were utilized to detect formation of cell-entrapped metabolites, including various in vitro and in vivo models to establish the capacity of the 2-nitroimidazole PET agent EF5 to quantify expression of a nitroreductase candidate. Proof-of-principle PET imaging studies were successfully conducted using 18 F-HX4. Results: Recombinant enzyme kinetics, bacterial SOS reporter assays, anti-proliferative assays and flow cytometry approaches collectively identified the major oxygen-insensitive nitroreductase NfsA from E. coli (NfsA&#95;Ec) as the most promising nitroreductase reporter gene. Cells expressing NfsA&#95;Ec were demonstrably labelled with the imaging agent EF5 in a manner that was quantitatively superior to hypoxia, in monolayers (2D), multicellular layers (3D), and in human tumor xenograft models. EF5 retention correlated with NfsA&#95;Ec positive cell density over a range of EF5 concentrations in 3D in vitro models and in xenografts in vivo and was predictive of in vivo anti-tumor activity of the cytotoxic prodrug PR-104. Following PET imaging with 18 F-HX4, a significantly higher tumor-to-blood ratio was observed in two xenograft models for NfsA&#95;Ec expressing tumors compared to the parental tumors thereof, providing verification of this reporter gene imaging approach. Conclusion: This study establishes that the bacterial nitroreductase NfsA&#95;Ec can be utilized as an imaging capable reporter gene, with the ability to metabolize and trap 2-nitroimidazole PET imaging agents for non-invasive imaging of gene expression., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2., Methods: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao 2 ) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao 2 ) to the fraction of inspired oxygen (Fio 2 ) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first., Results: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events., Conclusions: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: The aim of this study was to identify the key differentially expressed genes (DEGs) and high-risk gene mutations in breast ductal carcinoma in situ (DCIS)., Methods: Raw data (GSE36863) were downloaded from the database of Gene Expression Omnibus (GEO), including three DCIS samples (DCIS cell lines MCF10.DCIS, Sum102, and Sum225) and one normal control sample (normal mammary epithelial cell line MCF10A). The DEGs were analyzed using NOIseq and annotated via DAVID. Motif scanning in the promoter region of DEGs was performed via SeqPos. Additionally, single nucleotide variations (SNVs) were identified via GenomeAnalysisTK and SNV risk was assessed via VarioWatch. Mutant genes with a high frequency and risk were validated by RT-PCR analyses., Results: Finally, 5391, 7073, and 7944 DEGs were identified in DCIS, Sum102, and Sum22 cell lines, respectively, when compared with MCF10A. VENN analysis of the three cell lines revealed 603 upregulated and 1043 downregulated DEGs, including 16 upregulated and 36 downregulated transcription factor (TF) genes. In addition, six TFs each (e.g., E2F1 and CREB1) were found to regulate the core up- and downregulated DEGs, respectively. Furthermore, SNV detection results revealed 1104 (MCF10.DCIS), 2833 (Sum102), and 1132 (Sum22) mutation sites. Four mutant genes (RWDD4, SDHC, SEPT7, and SFN) with high frequency and risk were identified. The results of RT-PCR analysis as well as bioinformatics analysis consistently demonstrated that the expression of RWDD4, SDHC, SEPT7, and SFN was downregulated in the tumor tissues as compared with that in adjacent non-tumor tissues., Conclusions: The differentially expressed TFs, TFs regulating DEGs (e.g., E2F1 and CREB1), and high-frequency mutant genes (RWDD4, SDHC, SEPT7, and SFN) might play key roles in the pathogenesis of DCIS.

Unbalanced inflammatory reactions and oxidative stress are inseparably interconnected, and both may play crucial roles in the pathophysiological mechanisms of preeclampsia (PE). In the published previous studies, we have genotyped for SNPs that related to inflammation (rs2227485, rs153109, rs17855750, rs2027432, rs2275913, rs763780, rs4819554, and rs13015714) and oxidative stress (rs1695, rs4680, rs1800566, rs4807542, rs713041, rs7579, rs230813, rs1004467, rs3824755, and rs9932581) to investigate whether these polymorphisms were associated with susceptibility to PE in a Chinese Han population. In this present study, we collected these data of experimental and clinical from above studies for haplotype analysis of inflammation-related SNPs in 631 PE patients and 720 normal pregnancy and oxidative stress-related SNPs in 342 PE patients and 457 normal pregnancies for susceptibility to PE. The data of genotype distribution and allele frequency comparisons after correction for multiple comparisons (P/8 or P/10) showed 2 among the 8 candidate inflammation-related SNPs have significant differences (rs2027432 genotype χ 2 = 407.377, p < 0.001, p < 0.00625). Moreover, the minor alleles of rs2027432 T (minor allele  χ 2 = 450.923, p < 0.001, p < 0.00625; OR = 21.439, 95%CI = 15.181-30.278) and rs4819554 G (minor allele  χ 2 = 163.465, p < 0.001, p < 0.00625; OR = 5.814, 95%CI = 4.380-7.719) were confirmed as risk allele of PE, respectively. Our analysis revealed rs2027432 (TT) of NLRP3 and rs4819554 (GG) of IL-17RA are risk factors for PE. However, no significant difference was found at the oxidative stress-related SNPs. In the candidate loci for oxidative stress, we also identified 3 SNP matches (rs4807542 and rs713041, rs230813 and rs75799, rs1004467 and rs3824755) that had high linkage disequilibrium (LD) with each other and were selected as a block ( r 2 = 0.98, r 2 = 0.97, r 2 = 0.97, r 2 > 0.9), and the GT and GC haplotypes of rs4807542 and rs713041 in GPX4 showed significant differences between the PE and control groups ( χ 2 = 5.143, p = 0.0233, p < 0.05; χ 2 = 6.373, p = 0.0116, p < 0.05). So, we inferred that polymorphisms of NLRP3 rs2027432 and IL-17RA rs4819554, which are related to inflammation, and the rs713041 variant of GPX4 , which is related to oxidative stress, were associated with susceptibility to PE. The GT and GC haplotypes of rs4807542 and rs713041 in GPX4 may increase the risk of PE in the Chinese Han population., Competing Interests: All authors claim no conflict of interest., (Copyright © 2020 Aiping Chen et al.)

Background: In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia., Methods: In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020., Findings: Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure., Interpretation: The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection., Funding: National Key R&D Program of China., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l +/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

Objectives : The involvement of oxidative stress in the pathophysiology of preeclampsia (PE) has been already suggested. In this present study, we aimed to investigate the association of the genetic frequency of heme oxygense-1 ( HMOX1 ) polymorphism with PE in Chinese Han women. Methods : We researched the genetic distribution of rs2071746 polymorphism in HMOX1 by the TaqMan allelic discrimination real-time PCR between 1235 PE patients and 1720 healthy women. Results : We found there were't significant differences in the distribution of HMOX1 rs2071746 polymorphism in PE compared to the control group (rs2071746, genotype χ 2 = 0.282, P = 0.869 and allele χ 2 = 0.027, P = 0.869, OR = 1.009, 95% = 0.909-1.120). Conclusion : The rs2071746 polymorphism in HMOX1 might not be related to PE in Chinese women, although further investigations should be conducted to confirm our findings.

Background: Excessive reactive oxygen species from endothelial mitochondria in type 2 diabetes individuals (T2DM) may occur through multiple related mechanisms, including production of mitochondrial reactive oxygen species (mtROS), inner mitochondrial membrane (Δψ m ) hyperpolarization, changes in mitochondrial mass and membrane composition, and fission of the mitochondrial networks. Inner mitochondrial membrane proteins uncoupling protein-2 (UCP2) and prohibitin (PHB) can favorably impact mtROS and mitochondrial membrane potential (Δψ m ). Circulating levels of UCP2 and PHB could potentially serve as biomarker surrogates for vascular health in patients with and without T2DM., Methods: Plasma samples and data from a total of 107 individuals with (N = 52) and without T2DM (N = 55) were included in this study. Brachial artery flow mediated dilation (FMD) was measured by ultrasound. ELISA was performed to measure serum concentrations of PHB1 and UCP2. Mitochondrial membrane potential was measured from isolated leukocytes using JC-1 dye., Results: Serum UCP2 levels were significantly lower in T2DM subjects compared to control subjects (3.01 ± 0.34 vs. 4.11 ± 0.41 ng/mL, P = 0.04). There were no significant differences in levels of serum PHB. UCP2 levels significantly and positively correlated with FMDmm (r = 0.30, P = 0.03) in T2DM subjects only and remained significant after multivariable adjustment. Within T2DM subjects, serum PHB levels were significantly and negatively correlated with UCP2 levels (ρ = - 0.35, P = 0.03)., Conclusion: Circulating UCP2 levels are lower in T2DM patients and correlate with endothelium-dependent vasodilation in conduit vessels. UCP2 could be biomarker surrogate for overall vascular health in patients with T2DM and merits additional investigation.