Prevalence and molecular characteristics of mcr-1-positive Escherichia coli isolated from duck farms and the surrounding environments in coastal China.

The emergence of colistin-resistance is considered a threat to public health and colistin-resistant bacteria have recently been reported in animal, environmental and human sources. Whereas, the epidemic and dissemination of colistin-resistant bacteria in duck farms have not been surveyed, especially the surrounding environmental contamination from duck farms. We investigated the prevalence and molecular characteristics of mcr-1-positive E. coli from duck farms in coastal China. 360 mcr-1-positive E. coli isolates were collected from 1112 samples from duck farms and surrounding environments. The prevalence of mcr-1-positive E. coli in Guangdong province was higher than other two provinces we examined. PFGE analysis indicated clonal spread of mcr-1-positive E. coli between duck farms and surrounding environments, including water and soil. MLST analysis demonstrated that ST10 was more common than ST1011, ST117, and ST48. Phylogenomic analysis also suggested mcr-1-positive E. coli collected from distinct cities were assigned to the same lineage and mcr-1 was primarily located on IncI2 and IncHI2 plasmids. Genomic environment analysis showed mobile gene elements ISApl1 most likely plays a key role in the horizontal transmission of mcr-1. WGS further revealed that mcr-1 was found associated with 27 different ARGs. Our findings emphasize the urgent need for effective colistin resistance surveillance in humans, animals and the environment.

Phenotypic and Genomic Characterization of ST133 Siderophore-Encoding Extensively Drug-Resistant Enterobacter hormaechei.

We identified an ST133 extensively drug-resistant Enterobacter hormaechei, C210017, with increased virulence in the Galleria mellonella infection model. Genomic analysis suggested it carried antibiotic resistance genes blaKPC-2 and mcr-9.1, and genes iutAiucABCD and iroBCDEN encoding the virulence factor, siderophores. Comparative genomics of C210017 and the 178 ST133 E. hormaechei strains in the database suggested they all belonged to serotype O3 and most strains (77.5%) carried the IncHI2 superplasmids associated with the resistance, virulence, and adaptation of the host strain.

A self-attention-based neural network for three-dimensional multivariate modeling and its skillful ENSO predictions.

Large biases and uncertainties remain in real-time predictions of El Niño-Southern Oscillation (ENSO) using process-based dynamical models; recent advances in data-driven deep learning algorithms provide a promising mean to achieve superior skill in the tropical Pacific sea surface temperature (SST) modeling. Here, a specific self-attention-based neural network model is developed for ENSO predictions based on the much sought-after Transformer model, named 3D-Geoformer, which is used to predict three-dimensional (3D) upper-ocean temperature anomalies and wind stress anomalies. This purely data-driven and time-space attention-enhanced model achieves surprisingly high correlation skills for Niño 3.4 SST anomaly predictions made 18 months in advance and initiated beginning in boreal spring. Further, sensitivity experiments demonstrate that the 3D-Geoformer model can depict the evolution of upper-ocean temperature and the coupled ocean-atmosphere dynamics following the Bjerknes feedback mechanism during ENSO cycles. Such successful realizations of the self-attention-based model in ENSO predictions indicate its great potential for multidimensional spatiotemporal modeling in geoscience.

Enhanced Superconductivity and Upper Critical Field in Ta-Doped Weyl Semimetal Td -MoTe2.

Two-dimensional transition metal dichalcogenides are promising platforms for next-generation electronics and spintronics. The layered Weyl semimetal (W,Mo)Te2 series features structural phase transition, nonsaturated magnetoresistance, superconductivity, and exotic topological physics. However, the superconducting critical temperature of the bulk (W,Mo)Te2 remains ultralow without applying a high pressure. Here, we observe the significantly enhanced superconductivity with a transition temperature as large as about 7.5 K in bulk Mo1- x Tax Te2 single crystals upon Ta doping (0 ≤ x ≤ 0.22), which is attributed to an enrichment of density of states at the Fermi level. In addition, an enhanced perpendicular upper critical field of 14.5 T exceeding the Pauli limit is also observed in Td -phase Mo1- x Tax Te2 (x = 0.08), indicating the possible emergence of unconventional mixed singlet-triplet superconductivity owing to the inversion symmetry breaking. Our work provides a new pathway for exploring the exotic superconductivity and topological physics in transition metal dichalcogenides. This article is protected by copyright. All rights reserved.

Association between dietary minerals and glioma: A case-control study based on Chinese population.

Background: As one of the essential nutrients for the human body, minerals participate in various physiological activities of the body and are closely related to many cancers. However, the population study on glioma is not sufficient. Objective: The purpose of this study was to evaluate the relationship between five dietary minerals and glioma. Methods: A total of 506 adult patients with glioma and 506 healthy controls were matched 1:1 according to age (±5 years) and sex. The food intake of the subjects in the past year was collected through the food frequency questionnaire, and the intakes of calcium, magnesium, iron, zinc, and copper in the diet were calculated. The logistic regression model was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for dietary minerals to gliomas. Results: After adjusting for confounders, higher intakes of calcium (OR = 0.65, 95% CI: 0.57-0.74), magnesium (OR = 0.18, 95% CI: 0.11-0.29), iron (OR = 0.04, 95% CI: 0.02-0.11), zinc (OR = 0.62, 95% CI: 0.54-0.73), and copper (OR = 0.22, 95% CI: 0.13-0.39) were associated with a significantly decreased risk of glioma. Similar results were observed in gliomas of different pathological types and pathological grades. The restriction cubic spline function suggested significant linear dose-response relationships between intakes of five minerals and the risk of glioma. When the dietary minerals exceeded a particular intake, the risk of glioma stabilized. Conclusion: Our study suggests that higher dietary intakes of calcium, magnesium, iron, zinc, and copper are associated with a decreased risk of glioma. However, the results of this study require further exploration of potential mechanisms in the future better to elucidate the effects of mineral intake on gliomas.

Sufficient coumarin accumulation improves apple resistance to Cytospora mali under high potassium status.

Cytospora canker, caused by Cytospora mali, is the most destructive disease in production of apples (Malus domestica). Adding potassium (K) to apple trees can effectively control this disease. However, the underlying mechanisms of apple resistance to C. mali under high-K status remain unknown. Here, we found that high K (HK, 9.30 g/kg) apple tissues exhibited high disease resistance. The resistance was impeded when blocking K channels, leading to susceptibility even under HK conditions. We detected a suite of resistance events in HK apple tissues, including upregulation of resistance genes, callose deposition, and formation of ligno-suberized tissues. Further multi-omics revealed that the phenylpropanoid pathway was reprogrammed by increasing K content from low K (LK, 4.30 g/kg) status, leading to increases of 18 antifungal chemicals. Among them, the physiological concentration of coumarin (1,2-benzopyrone) became sufficient to inhibit C. mali growth in HK tissues, and exogenous application could improve the C. mali resistance of LK apple branches. Transgenic apple calli overexpressing beta-glucosidase 40 (MdBGLU40), which encodes enzyme for coumarin synthesis, contained higher levels of coumarin and exhibited high resistance to C. mali even under LK conditions. Conversely, suppression of MdBGLU40 through RNAi reduced coumarin content and resistance in HK apple calli, supporting the importance of coumarin accumulation in vivo for apple resistance. Moreover, we found that the upregulation of transcription factor MdMYB1r1 directly activated MdBGLU40, and the binding affinity of MdMYB1r1 to the MdBGLU40 promoter increased in HK apple tissue, leading to high levels of coumarin and resistance in HK apple. Overall, we found that accumulation of defensive metabolites strengthened resistance in apple when raising K from insufficient to optimal status, and these results highlight the optimization of K content in fertilization practices as a disease management strategy.

Analysis of the effects of vertical joints on the stability of loess slope.

Vertical joints with different lengths and slope distances (the horizontal distance from joints to slope shoulder) are generated at the top of the loess slope because of the unloading and collapsibility of the loess. The existence of vertical joints is a significant risk factor for loess landslides. This paper applies three methods, including laboratory tests, numerical simulation and theoretical analysis, to analyze the influence of vertical joints on the stability of loess slope. Firstly, the typical failure mode and strength characteristics of the samples containing vertical joints are analyzed through the unconfined compressive strength test and triaxial compression test. Further, the effects of vertical joints with different lengths and the slope distance on the slope safety coefficient and sliding surface position are calculated by finite element numerical analysis. Finally, the formula for calculating the safety coefficient of loess slope with vertical joints is derived. The results show that: the joint bonding degree affects the sample's strength and failure rate. The strength of the sample with open vertical joints is less than that of closed ones, and the failure rate is greater than that of closed ones. When the length and the slope distances of the vertical joint are less than 5 m, the influence of vertical joints on the shape and position of the sliding surface will be small. When the length of the vertical joint is more than 5 m and less than 15 m, the safety factor of the slope decreases with the increase in the length of vertical joints. When the length of vertical joints reaches 15 m, and the slope distance is 10 m, the deterioration degree of vertical joints on the slope comes up to the peak. Statistical analysis shows that the dominant dip angle of shear fracture at the back edge of the landslide affected by the vertical joint surface is between 45° and 65°. The research results can be used for rapid calculation of the safety coefficient and rapid evaluation of slope stability of loess slope with vertical joints.

N6-methyladenosine mediates Nrf2 protein expression involved in PM2.5-induced pulmonary fibrosis.

It has been reported that particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) could induce epithelial-mesenchymal transition (EMT)- and extracellular matrix (ECM)-related pulmonary fibrosis (PF). The transcription factor Nrf2 alleviated PM2.5-induced PF by antagonizing oxidative stress. The N6-methyladenosine (m6A) modification plays a significant role in the stress response. However, the effect of m6A modification on the mechanisms of Nrf2-mediated defense against PM2.5-induced PF remained unknown. Here, we explored the role and the underlying molecular mechanisms of m6A methylation of Nrf2 mRNA in PM2.5-induced PF. We established filtered air (FA), unfiltered air (UA), and concentrated PM2.5 air (CA) group mice model and 0, 50, and 100 µg/mL PM2.5-treated 16HBE cell models. The extent of lung fibrosis in mice and fibrosis indicators were detected by histopathological analysis, immunohistochemical staining and western blotting. The molecular mechanism of m6A-modified Nrf2 was demonstrated by m6A-methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), qRT-PCR and T3 ligase-based PCR. Our data showed that PM2.5 exposure for 16 weeks could induce pulmonary fibrosis and activate Nrf2 signaling pathway. m6A methyltransferase METTL3 was upregulated after PM2.5 treatment in vivo and in vitro. Moreover, METTL3 mediated m6A modification of Nrf2 mRNA and promoted Nrf2 translation in mice and 16HBE cells after PM2.5 exposure. Mechanistically, three m6A-modified sites (1317, 1376 and 935; numbered relative to the first nucleotide of 3'UTR) of Nrf2 mRNA were identified in PM2.5-treatment 16HBE cells. Furthermore, the m6A binding proteins YTHDF1/IGF2BP1 promoted Nrf2 translation by binding to m6A residues of Nrf2 mRNA. Our results revealed the mechanism of m6A mediated Nrf2 signaling pathway against oxidative stress, which affected the development of PM2.5-induced PF.

Tumor Necrosis Factor α-Dependent Lung Inflammation Promotes the Progression of Lung Adenocarcinoma Originating From Alveolar Type II Cells by Upregulating MIF-CD74.

Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.

The emerging landscape of microfluidic applications in DNA data storage.

DNA has been considered a promising alternative to the current solid-state devices for digital information storage. The past decade has witnessed tremendous progress in the field of DNA data storage contributed by researchers from various disciplines. However, the current development status of DNA storage is still far from practical use, mainly due to its high material cost and time consumption for data reading/writing, as well as the lack of a comprehensive, automated, and integrated system. Microfluidics, being capable of handling and processing micro-scale fluid samples in a massively paralleled and highly integrated manner, has gradually been recognized as a promising candidate for addressing the aforementioned issues. In this review, we provide a discussion on recent efforts of applying microfluidics to advance the development of DNA data storage. Moreover, to showcase the tremendous potential that microfluidics can contribute to this field, we will further highlight the recent advancements of applying microfluidics to the key functional modules within the DNA data storage workflow. Finally, we share our perspectives on future directions for how to continue the infusion of microfluidics with DNA data storage and how to advance toward a truly integrated system and reach real-life applications.

Rational development of multicomponent mRNA vaccine candidates against mpox.

The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of Orthopoxvirus genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health emergency of international concern since July, 2022. Inspired by the unprecedent success of coronavirus disease 2019 (COVID-19) mRNA vaccines, the development of a safe and effective mRNA vaccine against MPXV is of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we rationally constructed and prepared a panel of multicomponent MPXV vaccine candidates encoding different combinations of viral antigens including M1R, E8L, A29L, A35R and B6R. In vitro and in vivo characterization demonstrated that two immunizations of all mRNA vaccine candidates elicit a robust antibody response as well as antigen specific Th1-biased cellular response in mice. Importantly, the penta- and tetra-component vaccine candidates AR-MPXV5 and AR-MPXV4a showed superior capability of inducing neutralizing antibodies as well as of protecting from VACV challenge in mice. Our study provides critical insights to understand the protection mechanism of MPXV infection and direct evidence supporting further clinical development of these multicomponent mRNA vaccine candidates.

Response evaluation of hepatocellular carcinoma treated with stereotactic body radiation therapy: magnetic resonance imaging findings.

PURPOSE: To summarize the magnetic resonance imaging manifestations of hepatocellular carcinoma (HCC) with and without progression after stereotactic body radiation therapy (SBRT) and evaluate the treatment effect using the modified Liver Reporting and Data System (LI-RADS). METHODS: Between January 2015 and December 2020, 102 patients with SBRT-treated HCC were included. Tumor size, signal intensity, and enhancement patterns at each follow-up period were analyzed. Three different patterns of enhancement: APHE and wash-out, non-enhancement, and delayed enhancement. For modified LI-RADS, delayed enhancement with no size increase were considered to be a "treatment-specific expected enhancement pattern" for LR-TR non-viable. RESULTS: Patients were divided into two groups: without (n = 96) and with local progression (n = 6). Among patients without local progression, APHE and wash-out pattern demonstrated conversion to the delayed enhancement (71.9%) and non-enhancement (20.8%) patterns, with decreased signal intensity on T1WI(92.9%) and DWI(99%), increased signal intensity on T1WI (99%), and decreased size. The signal intensity and enhancement patterns stabilized after 6-9 months. Six cases with progression exhibited tumor growth, APHE and wash-out, and increased signal intensity on T2WI/DWI. Based on the modified LI-RADS criteria, 74% and 95% showed LR-TR-nonviable in 3 and 12 months post-SBRT, respectively. CONCLUSIONS: After SBRT, the signal intensity and enhancement patterns of HCCs showed a temporal evolution. Tumor growth, APHE and wash-out, and increased signal intensity on T2WI/DWI indicates tumor progression. Modified LI-RADS criteria showed good performance in evaluating nonviable lesions after SBRT.

Pulsed Ultrasound-Mediated Enhancement on Transscleral and Transconjunctival Fluorescein Sodium Delivery to Rabbit Eye In Vivo.

Purpose: To investigate the efficacy and safety of pulsed ultrasound (PUS) in enhancing fluorescein sodium (NaF) transport to the rabbit eye through the transscleral and transconjunctival routes in vivo. Methods: PUS and NaF were applied onto the supratemporal sclera/conjunctiva of healthy rabbit eyes. PUS (1 MHz, 2.37 W/cm2, 30% duty cycle, 5-min application time) was performed 3 times with a 5-min interval. In the same process, NaF was administered to the eye without PUS in the control. NaF concentrations in the vitreous and retina-choroid were determined by fluorescence measurement. The safety of PUS application was assessed based on temperature and intraocular pressure measurements, clinical observations, electroretinography, histology, and Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling assay. Results: In comparison to the control, higher NaF concentrations were found in the retina-choroid following transscleral (2.45-fold) and transconjunctival (2.97-fold) PUS applications (P < 0.05). NaF concentrations in the vitreous were 3.15 and 5.86 times greater in transscleral and transconjunctival PUS applications, respectively, compared with those obtained without PUS application (P < 0.05), and NaF level in the vitreous after transconjunctival PUS application was 2.61 times that of transscleral PUS application (P < 0.05). Ocular findings were transient and mild conjunctival injection, with no other structural and functional changes in PUS-treated eyes. Conclusions: PUS treatment can improve transscleral and transconjunctival delivery of NaF efficiently and safely. Transscleral and transconjunctival PUS applications offer potential clinical benefit in increasing drug penetration to the posterior segments of the eye for the noninvasive treatment of ocular diseases.

[Effect of sulfur fumigation on quality and safety of Lilii Bulbus].

Lilii Bulbus is a commonly used Chinese herbal medicine with both medicinal and edible values, while the market products usually has the problem of sulfur fumigation. Therefore, the quality and safety of Lilii Bulbus products deserve attention. In this study, ultra-high performance liquid chromatography-time of flight-tandem mass spectrometry(UPLC-Q-TOF-MS/MS) was combined with principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) to analyze the differential components of Lilii Bulbus before and after sulfur fumigation. We identified ten markers generated after sulfur fumigation, summarized their mass fragmentation and transformation patterns, and verified the structures of phenylacrylic acid markers of sulfur fumigation. At the same time, the cytotoxicity of the aqueous extracts of Lilii Bulbus before and after sulfur fumigation was evaluated. The results showed that in the concentration range of 0-800 mg·L~(-1), the aqueous extract of Lilii Bulbus after sulfur fumigation had no significant effect on the viability of human liver LO2 cells, human renal proximal tubular HK-2 cells, and rat adrenal pheochromocytoma PC-12 cells. Moreover, the viability of the cells exposed to the aqueous extract of Lilii Bulbus before and after sulfur fumigation showed no significant difference. This study identified phenylacrylic acid and furostanol saponins as markers of sulfur-fumigated Lilii Bulbus for the first time, and made clear that proper sulfur fumigation of Lilii Bulbus would not produce cytotoxicity, providing a theoretical basis for the rapid identification and quality and safety control of sulfur-fumigated Lilii Bulbus.

MXene-Based Aptameric Fluorosensor for Sensitive and Rapid Detection of COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-caused COVID-19 pandemic has rapidly escalated into the largest global health emergency, which pushes to develop detection kits for the detection of COVID-19 with high sensitivity, specificity, and fast analysis. Here, aptamer-functionalized MXene nanosheet is demonstrated as a novel bionanosensor that detects COVID-19. Upon binding to the spike receptor binding domain of SARS-CoV-2, the aptamer probe is released from MXene surface restoring the quenched fluorescence. The performances of the fluorosensor are evaluated using antigen protein, cultured virus, and swab specimens from COVID-19 patients. It is evidenced that this sensor can detect SARS-CoV-2 spike protein at final concentration of 38.9 fg mL-1 and SARS-CoV-2 pseudovirus (limit of detection: 7.2 copies) within 30 min. Its application for clinical samples analysis is also demonstrated successfully. This work offers an effective sensing platform for sensitive and rapid detection of COVID-19 with high specificity.

Direct and indirect costs for families of children with autism spectrum disorder in China.

LAY ABSTRACT: This is the first comprehensive national study to explore the direct and indirect costs for families of children with autism spectrum disorder in China. The increasing prevalence of autism spectrum disorder highlights a growing need for resources to provide care for families of children with autism spectrum disorder. The medical and nonmedical costs and parents' productivity loss have caused a serious burden on their families. Our objective is to estimate the direct and indirect costs for the families of children with autism spectrum disorder in China. The target population was parents of children with autism spectrum disorder. We analyzed the costs using cross-sectional data from a Chinese national family survey with children aged 2-6 years (N = 3236) who were clinically diagnosed with autism spectrum disorder. Family data from 30 provinces in China were obtained. Cost items included direct medical costs, direct nonmedical costs, and indirect costs. In this study, we found that the largest part of family costs for autism spectrum disorder are nonmedical costs and productivity loss. Autism spectrum disorder has imposed a huge economic burden on parents having children with autism spectrum disorder in China, who need more support than the current health care system provides.

Increased clonal dissemination of OXA-232-producing ST15 Klebsiella pneumoniae in Zhejiang, China from 2018 to 2021.

BACKGROUND: OXA-232-producing Klebsiella pneumoniae was first identified in China in 2016, and its clonal transmission was reported in 2019. However, there are no prevalence and genotypic surveillance data available for OXA-232 in China. Therefore, we investigated the trends and characteristics of OXA-232 type carbapenemase in Zhejiang Province, China from 2018 to 2021. METHODS: A total of 3278 samples from 1666 patients in the intensive care units were collected from hospitals in Zhejiang Province from 2018 to 2021. Carbapenem-resistant isolates were initially selected by China Blue agar plates supplemented with 0.3 µg/ml meropenem, and further analyzed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry identification, immune colloidal gold technique, conjugation experiment, antimicrobial susceptibility testing and whole genome sequencing. RESULTS: A total of 79 OXA-producing strains were recovered, with the prevalence increased from 1.8% [95% confidence interval (CI): 0.7-3.7%] in 2018 to 6.0% (95% CI: 4.4-7.9%) in 2021. Seventy-eight strains produced OXA-232 and one produced OXA-181. The blaOXA-232 gene in all strains was located in a 6141-bp ColKP3-type non-conjugative plasmid and the blaOXA-181 gene was located in a 51,391-bp ColKP3/IncX3-type non-conjugative plasmid. The blaOXA-232-producing K. pneumoniae was dominated (75/76) by isolates of sequence type 15 (ST15) that differed by less than 80 SNPs. All OXA-producing strains (100%, 95% CI: 95.4-100.0%) were multidrug-resistant. CONCLUSIONS: From 2018 to 2021, OXA-232 is the most prevalent OXA-48-like derivative in Zhejiang Province, and ST15 K. pneumoniae isolates belonging to the same clone are the major carriers. The transmission of ColKP3-type plasmid to E. coli highlighted that understanding the transmission mechanism is of great importance to delay or arrest the propagation of OXA-232 to other species.

The effect of real-ambient PM2.5 exposure on the lung and gut microbiomes and the regulation of Nrf2.

The influence of air pollution on human health has sparked widespread concerns across the world. Previously, we found that exposure to ambient fine particulate matter (PM2.5) in our "real-ambient exposure" system can result in reduced lung function. However, the mechanism of organ-specific toxicity is still not fully elucidated. The balance of the microbiome contributes to maintaining lung and gut health, but the changes in the microbiome under PM2.5 exposure are not fully understood. Recently, crosstalk between nuclear factor E2-related factor 2 (Nrf2) and the microbiome was reported. However, it is unclear whether Nrf2 affects the lung and gut microbiomes under PM2.5 exposure. In this study, wild-type (WT) and Nrf2-/- (KO) mice were exposed to filtered air (FA) and real ambient PM2.5 (PM) in the " real-ambient exposure" system to examine changes in the lung and gut microbiomes. Here, our data suggested microbiome dysbiosis in lung and gut of KO mice under PM2.5 exposure, and Nrf2 ameliorated the microbiome disorder. Our study demonstrated the detrimental impacts of PM2.5 on the lung and gut microbiome by inhaled exposure to air pollution and supported the protective role of Nrf2 in maintaining microbiome homeostasis under PM2.5 exposure.

The impact of COVID-19 pandemic on emotional and behavioral problems of children with autism spectrum disorder and developmental delay aged 1-6 years in China.

Introduction: The COVID-19 pandemic outbreak have caused increased levels of emotional and behavioral problems, particularly among people with pre-existing mental health conditions. Young individuals with autism spectrum disorders (ASD) and developmental delay (DD) are particularly at risk due to their vulnerability. The purpose of this study was to look into the different effects of the COVID-19 pandemic on 1-6-year-old children with ASD and DD. Methods: Parents and guardians of children with ASD completed an online survey that included questions about their children's socio-demographics characteristics, the effects of the COVID-19 outbreak on their health, and what they needed in order to deal with the conditions of the pandemic. Results: This study compared 4,138 children with ASD to 711 children with DD. Children with ASD had a higher risk of having more emotional and behavioral problems than children with DD (OR 1.38, 95% CI 1.12-1.70). Compared to parent-oriented rehabilitation at home, discontinuing rehabilitation had a higher likelihood of negative emotional and behavioral change (OR 1.67, 95% CI 1.41-1.98). Having teachers' online support had a higher likelihood of negative emotional and behavioral change for ASD children (OR 1.26, 95% CI 1.03-1.54). Conclusions: This article provided evidence that children with developmental disabilities, particularly ASD, were at risk for a variety of challenges to their emotional functioning during the COVID-19 period, and that online support was not an ideal way for children with ASD to receive effective educational intervention in China.

Upregulated TGF-ß1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling.

AIMS/HYPOTHESIS: Glucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-ß is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-ß levels to human glucose metabolism and the mechanism by which TGF-ß enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-ß-promoted hepatic gluconeogenesis would allow us to better understand the process of normal glucose production and the pathophysiology of this process in type 2 diabetes. This study aimed to investigate the contribution of upregulated TGF-ß1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-ß1 in glucose metabolism. METHODS: Serum levels of TGF-ß1 were measured by ELISA in 74 control participants with normal glucose tolerance and 75 participants with type 2 diabetes. Human liver tissue was collected from participants without obesity and with or without type 2 diabetes for the measurement of TGF-ß1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-ß1 receptor, in mediating the effect of TGF-ß1 on glucagon signalling, we generated Smad3 knockout mice. Glucose levels in Smad3 knockout mice were measured during prolonged fasting and a glucagon tolerance test. Mouse primary hepatocytes were isolated from Smad3 knockout and wild-type (WT) mice to investigate the underlying molecular mechanisms. Smad3 phosphorylation was detected by western blotting, levels of cAMP were detected by ELISA and levels of protein kinase A (PKA)/cAMP response element-binding protein (CREB) phosphorylation were detected by western blotting. The dissociation of PKA subunits was measured by immunoprecipitation. RESULTS: We observed higher levels of serum TGF-ß1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA1c and fasting blood glucose levels. In addition, hyperactivation of the CREB and Smad3 signalling pathways was observed in the liver of participants with type 2 diabetes. Treating WT mouse primary hepatocytes with TGF-ß1 greatly potentiated glucagon-stimulated PKA/CREB phosphorylation and hepatic gluconeogenesis. Mechanistically, TGF-ß1 treatment induced the binding of Smad3 to the regulatory subunit of PKA (PKA-R), which prevented the association of PKA-R with the catalytic subunit of PKA (PKA-C) and led to the potentiation of glucagon-stimulated PKA signalling and gluconeogenesis. CONCLUSIONS/INTERPRETATION: The hepatic TGF-ß1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-ß1 and/or preventing hyperactivation of TGF-ß1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes.