Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children's brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3-10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

ABSTRACT Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on children’s overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence children’s brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3–10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

Developmental coordination disorder (DCD) is a motor development disorder that affects an individual's growth and development, and may persist throughout life. It is not caused by intellectual or physical disability. Studies have suggested DCD often occurs in childhood, resulting in a series of abnormal manifestations that hinder children's normal development; cohort studies suggest a higher incidence in boys than in girls. Early diagnosis and appropriate interventions can help relieve symptoms. Unfortunately, the relevant research still needs to be further developed. In this paper, we first start from the definition of DCD, systematically investigate the relevant research papers in the past decades and summarize the current research hotspots and research trends in this field. After summarizing, it is found that this research field has attracted more researchers to join, the number of papers published has increased year by year and has become a hot spot in multidisciplinary research, such as education, psychology, sports rehabilitation, neurobiology, and neuroimaging. The continuous development of the correlation between perinatal factors and DCD, various omics studies, and neuroimaging methods also brings new perspectives and working targets to DCD research. DCD-related research will continue to deepen along the research direction of multivariate, multidimensional, and multimodal.

Neurodevelopmental disorders (NDDs) refer to a series of mental disorders that plague the motor and behavioral development of children in the K12 basic education stage. The etiology and pathogenesis of these disorders remain unclear. Multicenter Children's Brain Development Database under Perinatal Factors (PeriCBD) is established by the State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, relying on county/prefecture/district central hospitals to collect data on the brain development of children in high-incidence age groups of NDDs. The primary purpose is to construct a data information platform related to brain development patterns and individual differences in children aged 3-10 under perinatal factors. Meanwhile, the platform is expected to provide critical basic data for the national brain development research, predictive diagnosis, and treatment of NDDs in children. This paper takes the data collection work completed in Anyang Maternal and Child Health Hospital of Henan Province and the People's Hospital of Liangping District of Chongqing City as examples to introduce the organizational framework of PeriCBD, and clarify the unified collection, cleaning, and analysis process of subject behavior data and magnetic resonance imaging data. In addition, following the standardization in processes, such as data extraction, conversion, loading of database links, etc., the dataset aims to establish a paradigm for subsequent PeriCBD data collection and database were shown.

The T-2 toxin is a highly toxic trichothecene mycotoxin that would cause serious toxicity in humans and animals. Recent studies suggest that the central nervous system (CNS) is susceptible to T-2 toxin, which can easily cross the blood-brain barrier, accumulate in brain tissues, and cause neurotoxicity. The growing evidence indicates that oxidative damage and mitochondrial dysfunction play a critical role in T-2 toxin-induced neurotoxicity, but the mechanisms are still poorly understood. Our present study showed that T-2 toxin decreased cell viability and increased lactate dehydrogenase leakage in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner. T-2 toxin elicited prominent oxidative stress and mitochondrial dysfunction, as evidenced by the promotion of cellular reactive oxygen species generation, disruption of the mitochondrial membrane potential, depletion of glutathione and reduction of the cellular ATP content. T-2 toxin impaired mitochondrial biogenesis, including decreased mitochondrial DNA copy number and affected the nuclear factor erythroid 2 related factor 2 (NRF2) / peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) pathway by upregulating NRF2 mRNA and protein expression while inhibiting the expression of PGC-1α, nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). NRF2 knockdown was found to significantly exacerbate T-2 toxin-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravate mitochondrial biogenesis impairment. NRF2 knockdown compromised T-2 toxin-induced upregulation of NRF2, but augmented the inhibition of PGC-1α, NRF1, and TFAM by T-2 toxin. Taken together, these findings suggest that T-2 toxin-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells, at least in part by, NRF2/PGC-1α pathway-mediated mitochondrial biogenesis.

Argonaute proteins, which consist of AGO1, AGO2, AGO3 and AGO4, are key players in microRNA-mediated gene silencing. So far, few non-microRNA related biological roles of AGO4 have been reported. Here, we first found that AGO4 had low expression in non-small cell lung cancer (NSCLC) patient tumor tissues and could suppress NSCLC cell proliferation and metastasis. Subsequent studies on the mechanism showed that AGO4 could interact with the tripartite motif-containing protein 21 (TRIM21) and the glucose-regulated protein 78 (GRP78). AGO4 promoted ubiquitination of GRP78 by stabilizing TRIM21, a new specific ubiquitin E3 ligase for promoting K48-linked polyubiquitination of GRP78 confirmed in this paper, which resulted in induced cell apoptosis and inhibited autophagy by activating mTOR signal pathway. Further studies showed that p53 had dominant effects on TRIM21-GRP78 axis by directly increasing the expression of TRIM21 in p53 wild-type cells and AGO4 may alternatively regulate TRIM21-GRP78 axis in p53-deficient cells. We also found that overexpression of AGO4 results in suppression of multiple p53-deficient cell growth both in vivo and vitro. Together, we showed for the first time that the AGO4-TRIM21-GRP78 axis, as a new regulatory pathway, may be a novel potential therapeutic target for p53-deficient tumor treatment.

Complement receptor 3 (CD11b/CD18) is an important receptor that mediates adhesion, phagocytosis and chemotaxis in various immunocytes. The conidia of the medically-important pathogenic fungus, Aspergillus fumigatus can be internalized into alveolar epithelial cells to disseminate its infection in immunocompromised host; however, the role of CR3 in this process is poorly understood. In the present study, we investigated the potential role of CR3 on A. fumigatus internalization into type II alveolar epithelial cells and its effect on host intracellular PA content induced by A. fumigatus. We found that CR3 is expressed in alveolar epithelial cells and that human serum and bronchoalveolar lavage fluid (BALF) could improve A. fumigatus conidial internalization into A549 type II alveolar epithelial cell line and mouse primary alveolar epithelial cells, which were significantly inhibited by the complement C3 quencher and CD11b-blocking antibody. Serum-opsonization of swollen conidia, but not resting conidia led to the increase of cellular phosphatidic acid (PA) in A549 cells during infection. Moreover, both conidial internalization and induced PA production were interfered by CD11b-blocking antibody and dependent on FAK activity, but not Syk in alveolar epithelial cells. Overall, our results revealed that CR3 is a critical modulator of Aspergillus fumigatus internalization into alveolar epithelial cells.

新型冠状病毒肺炎(简称“新冠肺炎”)疫情是一场严重危害人类健康以及经济和社会发展的重大疫情.化学消毒剂是有效阻击新冠肺炎疫情蔓延、实现疫情精准防控的重要手段.然而,过量使用化学消毒剂以及防护意识薄弱已成为当前疫情防控中较为关注的问题.这些化学消毒剂本身均具有一定的毒性,特别是过量使用时有可能导致明显的健康危害甚至危及生命安全,其毒性风险值得高度重视和警惕.

目的 了解新型冠状病毒肺炎期间武汉地区医院消毒剂的使用情况.方法 采用自行设计问卷和现场调研等方法调查了疫情较为严重的武汉地区医院的消毒剂使用情况,调查内容包括消毒剂的种类、使用频次、使用量及使用范围等.结果 新冠肺炎期间最常用的消毒剂是含氯类和醇类消毒剂;每天工作场所中消毒频率以3次(52.85％)及3次以上(22.36％)居多,个人每天手部使用消毒剂在10次以上的达到182人(73.98％).大部分人(210人,85.37％)按照说明书的浓度配制使用消毒剂,超过一半的人(137人,55.69％)所在工作场所中单次消毒剂使用量>500 mL.截止至3月,工作场所累计消毒时间几乎全部超过10 d以上.216人(87.80％)所处的工作环境为全方位消毒(空气、物体表面和地面消毒).结论 建议在消毒过程中按照合理使用和按需配制的原则,最大限度保障医护人员和就医人群的身体健康.

目的 调查分析新冠肺炎疫情期间部队营区消毒剂的使用及防护情况,发现问题并提出建议对策.方法 主要采用问卷调查方式,基于互联网平台对北京、武汉、西安等地的部队营区进行消毒剂使用和防护调查,并进行统计分析.结果 通过问卷了解到新冠疫情期间营区进行消杀作业最常用的消毒剂是含氯类(84等)消毒剂和75％乙醇,大多数工作场所消毒每天集中消毒2次(48.39％)或3次(36.69％);单次消毒剂使用量主要集中在10-100 ml(41.13％),能够按照说明书浓度配制消毒剂的占比90.32％;消毒范围以全方位消毒为主(46.37％),包括空气消毒、物体表面消毒和地面消毒;截止到4月中旬,大部分营区累计消毒时间已超过60天(70.97％);营区内专业消杀作业人员培训率为57.72％,经过培训的人员防护率明显高于未培训人员(P<0.05).结论 部队营区消毒剂使用存在过度消毒及培训不足、防护不规范等现象,部分单位有待加强消毒作业规范和防护指导.

目的 建立住院患者医院下呼吸道感染预测模型,构建新的、简单的风险评分方法.方法 以2014年多家医院感染调查数据为训练集,建立住院患者医院下呼吸道感染的Lasso-logistic回归预测模型,选择贝叶斯信息准则(BIC)最小模型为最终模型,将回归系数放大相同倍数建立评分方法,以2015、2016年调查数据为验证集,并与文献建立的风险评分方法进行比较.结果 Lasso过程共进行360步,第24步时BIC最小(6 690.4),正则化参数λ=130.8.风险评分方法包含1 7个条目,数量是文献风险评分方法的1/4,DeLong's检验显示,两评分方法验证集受试者工作特征曲线下面积(AUC)差异无统计学意义(Z-0.371,P-0.710),决策曲线几乎重合,净重新分类指数为-0.0149,差异无统计学意义(Z--1.301,P-0.193),整体鉴别指数为0.006,改善差异有统计学意义(P=0.014).结论 利用Lassologistic回归模型建立了住院患者医院下呼吸道感染风险简单评分方法,该方法的条目相对简洁,预测效果准确.

Aspergillus fumigatus is able to internalize into lung epithelial cells to escape from immune attack for further dissemination. We previously reported that gliotoxin, a major mycotoxin of A. fumigatus, promotes this internalization; however, the mechanism remained unclear. Here, we report that gliotoxin is able to induce cofilin phosphorylation in A549 type II human pneumocytes. Either too high or too low a level of cofilin phosphorylation blocked the gliotoxin-induced actin cytoskeleton rearrangement and A. fumigatus internalization. LIM domain kinase 1 (LIMK1) and its upstream small GTPases (Cdc42 and RhoA, but not Rac1) predominantly mediated the gliotoxin-induced cofilin phosphorylation and A. fumigatus internalization. Simultaneously, gliotoxin significantly stimulated an increase in cAMP; however, adding an antagonist of PKA did not block gliotoxin-induced A. fumigatus internalization. In vivo, exogenous gliotoxin helped gliotoxin synthesis deficient strain gliPΔ invade into the lung tissue and the lung fungal burden increased markedly in immunosuppressed mice. In conclusion, these data revealed a novel role of gliotoxin in inducing cofilin phosphorylation mostly through the Cdc42/RhoA-LIMK1 signaling pathway to promote actin cytoskeleton rearrangement and internalization of A. fumigatus into type II human pneumocytes.

ABSTRACT The use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus. Though widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus. This study showed that elevated MIC values of imidazole drugs were observed against A. fumigatus isolates with TR34/L98H/S297T/F495I mutation, but not among isolates with TR34/L98H mutation. Short-tandem-repeat (STR) typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR34/L98H/S297T/F495I strains from China were genetically different from the predominant major clade comprising most of the azole-resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences suggested that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. In vitro antifungal susceptibility testing of different recombinants with cyp51A mutations further confirmed the association of the F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus.

Through some specific amino acid residues, cofilin, a ubiquitous actin depolymerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae; however, this modulation in a major fungal pathogen, Aspergillus fumigatus, was still unclear. Hereby, it was found, first, that mutations on several charged residues in cofilin to alanine, D19A-R21A, E48A, and K36A, increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks, including mitochondrial membrane potential depolarization, cytochrome c release, upregulation of metacaspases, and DNA cleavage, in A. fumigatus Two of these mutations (D19A-R21A and K36A) increased acetyl coenzyme A and ATP concentrations by triggering fatty acid β-oxidation. The upregulated acetyl coenzyme A affected the ergosterol biosynthetic pathway, leading to overexpression of cyp51A and -B, while excess ATP fueled ATP-binding cassette transporters. Besides, both of these mutations reduced the susceptibility of A. fumigatus to azole drugs and enhanced the virulence of A. fumigatus in a Galleria mellonella infection model. Taken together, novel and key charged residues in cofilin were identified to be essential modules regulating the mitochondrial function involved in azole susceptibility, apoptosis, and virulence of A. fumigatus.

Aspergillus fumigatus is a major pathogen of invasive pulmonary aspergillosis. The small GTPase, Rho1, of A. fumigatus is reported to comprise a potential regulatory subunit of β-1,3-glucan synthase and is indispensable for fungal viability; however, the role of AfRho1 on the growth, cell wall integrity, and pathogenesis of A. fumigatus is still poorly understood. We constructed A. fumigatus mutants with conditional- and overexpression of Rho1 and found that defects of AfRho1 expression led to the reduction of β-1,3-glucan and glucosamine moieties on the cell wall, with down-regulated transcription of genes in the cell wall integrity signaling pathway and a decrease of calcofluor white (CFW)-stimulated mitogen-activated protein kinase (MpkA) phosphorylation and cytoplasmic leakage compared to those of the wild-type strain (WT). In addition, down-regulation of AfRho1 expression caused much higher sensitivity of A. fumigatus to H2O2 and alkaline pH compared to that of WT. Decrease of AfRho1 expression also attenuated the A. fumigatus pathogenicity in Galleria mellonella and inhibited conidial internalization into lung epithelial cells and inflammatory factor release. In contrast, overexpression of Rho1 did not alter A. fumigatus morphology, susceptibility to cell wall stresses, or pathogenicity relative to its parental strain. Taken together, our findings support AfRho1 as an essential regulator of the cell wall integrity, stress response, and pathogenesis of A. fumigatus.

Aspergillus fumigatus (A. fumigatus) is an opportunistic pathogenic fungus. Its conidia are very easy to be inhaled. Thereby, it is generally assumed that A. fumigatus might cause allergic bronchopulmonary aspergillosis (ABPA) in immunocompetent hosts and might induce invasive pulmonary aspergillosis (IPA) in immunocompromised individuals. The pulmonary epithelial cell layer is not only the first physical barrier but also it can play an important role in host innate immune response by internalizing pathogenic microbes and releasing inflammatory cytokines. Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that plays an important role in asthma and many other pulmonary inflammatory diseases. But the role of cAMP and its signaling pathways in pulmonary epithelial cell during lung diseases induced by A. fumigatus are unclear. Our data indicate that A. fumigatus resting conidia significantly inhibited the production of cAMP in the pulmonary epithelial cell line A549, a response being absent using the pigment-deletion strain ΔpksP. Purified DHN-melanin ghost (MG) from A. fumigatus resting conidia also significantly decreased host cell cAMP level. Intriguingly, MG restored the ability of ΔpksP to inhibit cAMP production in A549 cells. Other melanins, such as synthetic DOPA-melanin and DOPA-melanin from Sepia officinalis also inhibited the cAMP production. Similarly, resting conidia and MG inhibited cAMP production both in bronchial epithelial cell BEAS2B and macrophage RAW264.7. Intriguingly, both resting conidia and melanin increased the expression of Epac1 and Epac2 in A549 cells, leaving the expression and activity of PKA unchanged. Collectively, our data suggest that MG of A. fumigatus, host cell cAMP and its effector Epac may play important roles during A. fumigatus interaction with pulmonary epithelial cells.

Although belonging to one of the most common type of nosocomial infection, there was currently no simple prediction model for lower respiratory tract infections (LRTIs). This study aims to develop a risk index based system for predicting nosocomial LRTIs based on data from a large point-prevalence survey. Among the 49328 patients included, the prevalence of nosocomial LRTIs was 1.70% (95% confidence interval [CI], 1.64% to 1.76%). The areas under the receiver operating characteristic (ROC) curve for logistic regression and fisher discriminant analysis were 0.907 (95% CI, 0.897 to 0.917) and 0.902 (95% CI, 0.892 to 0.912), respectively. The constructed risk index based system also displayed excellent discrimination (area under the ROC curve: 0.905 [95% CI, 0.895 to 0.915]) to identify LRTI in internal validation. Six risk levels were generated according to the risk score distribution of study population, ranging from 0 to 5, the corresponding prevalence of nosocomial LRTIs were 0.00%, 0.39%, 3.86%, 12.38%, 28.79% and 44.83%, respectively. The sensitivity and specificity of prediction were 0.87 and 0.79, respectively, when the best cut-off point of risk score was set to 14. Our study suggested that this newly constructed risk index based system might be applied to boost more rational infection control programs in clinical settings.

GADD45A (growth arrest and DNA damage inducible alpha), a stress response gene induced by genotoxic and nongenotoxic stresses, is implicated in various key processes, including the control of cell cycle checkpoints and DNA repair. The expression of GADD45A is directly regulated by numerous transcription factors, with p53 being the most representative. Moreover, post-transcriptional regulation also plays a role in GADD45A expression. However, little is known about the regulatory effects of microRNAs (miRNAs) on GADD45A expression. As a potential tumour suppressor, miR-138 has pleiotropic biological functions in various cancers. We have previously reported p53-mediated activation of miR-138 in human non-small-cell lung cancer (NSCLC) cells. In this study, we found that miR-138 specifically targeted AGO2, which affects the stability and maturation of miR-130b. Decreased expression of miR-130b promoted the expression of GADD45A and resulted in the G2/M phase arrest and proliferation inhibition in human NSCLC cells. Our results suggested that p53 could alternatively upregulate GADD45A in human NSCLC cells through a post-transcriptional pathway in which miR-138 is involved.

Aim: To assess the effectiveness of antibiotic therapy against five indicator bacteria in a Chinese hospital using an index-based approach. Methods: The study population comprises 1031 patients who had one clinically significant bacterial isolate in 2008, 2010 and 2013. Drug resistance index (DRI) based on pathogens was calculated. Results: The adaptive DRIs for Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus decreased, while both adaptive and fixed DRIs for Acinetobacter spp. increased from 2008 to 2013. The adaptive DRIs for Escherichia coli increased from 2008 to 2013, while the fixed DRIs exhibited a decreasing trend. Conclusion: DRI could be used to demonstrate the changes of antimicrobial resistance and prescribing over time as a result of evolutionary processes and governmental regulatory interference.

In recent years, p53 was identified to regulate the expression of many miRNAs and was also regulated by miRNAs. In this paper, we found that miR-138 showed a pronounced increase after p53 activation in human non-small cell lung cancer (NSCLC) cells, which is mediated by p53 binding sites in the promoter region of its host gene, but this did not happen with rat and mouse cells. More interestingly, we found that p53 could be also regulated by miR-138 in mouse and rat cells, but not in the human NSCLC cells. Our results suggest the existence of species-specific differences of the regulations of miRNA against its targets and the regulations of miRNA itself by other proteins.