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PurposeTo explore the clinical characteristics of Micrococcus luteus bloodstream infection in an infant and characterize the phenotype and genotype of the isolated strains, as well as seek suitable infection models for assessing virulence.MethodsClinical data was collected from an infant patient diagnosed with M. luteus bloodstream infection. Metagenomic sequencing was performed on the isolated blood sample. The strain was isolated and underwent mass spectrometry, biochemical tests, antibiotic susceptibility assays, and whole-genome sequencing. The Galleria mellonella infection model was used to assess M. luteus virulence.ResultsPatient responded poorly to cephalosporins, but recovered after Linezolid treatment. Metagenomic sequencing identified M. luteus as the predominant species in the sample, confirming infection. They were identified as M. luteus with a high confidence level of 98.99% using mass spectrometry. The strain showed positive results for Catalase, Oxidase, and Urea tests, and negative results for Mannose, Xylose, Lactose, Mannitol, Arginine, and Galactose tests, consistent with the biochemical profile of M. luteus reference standards. M. luteus susceptibility to 15 antibiotics was demonstrated and no resistance genes were detected. Predicted virulence genes, including clpB, were associated with metabolic pathways and the type VI secretion system. The infection model demonstrated dose-dependent survival rates.ConclusionThe infant likely developed a bloodstream infection with M. luteus due to compromised immunity. Although the isolated strain is sensitive to cephalosporin antibiotics and has low pathogenicity in infection models, clinical treatment with cephalosporins was ineffective. Linezolid proved to be effective, providing valuable guidance for future clinical management of such rare infections.

Abstract Background Bread wheat (Triticum aestivum) is an allohexaploid that is generated by two subsequent allopolyploidization events. The large genome size (16 Gb) and polyploid complexity impede our understanding of how regulatory elements and their interactions shape chromatin structure and gene expression in wheat. The open chromatin enrichment and network Hi-C (OCEAN-C) is a powerful antibody-independent method to detect chromatin interactions between open chromatin regions throughout the genome. Results Here we generate open chromatin interaction maps for hexaploid wheat and its tetraploid and diploid relatives using OCEAN-C. The anchors of chromatin loops show high chromatin accessibility and are concomitant with several active histone modifications, with 67% of them interacting with multiple loci. Binding motifs of various transcription factors are significantly enriched in the hubs of open chromatin interactions (HOCIs). The genes linked by HOCIs represent higher expression level and lower coefficient expression variance than the genes linked by other loops, which suggests HOCIs may coordinate co-expression of linked genes. Thousands of interchromosomal loops are identified, while limited interchromosomal loops (0.4%) are identified between homoeologous genes in hexaploid wheat. Moreover, we find structure variations contribute to chromatin interaction divergence of homoeologs and chromatin topology changes between different wheat species. The genes with discrepant chromatin interactions show expression alteration in hexaploid wheat compared with its tetraploid and diploid relatives. Conclusions Our results reveal open chromatin interactions in different wheat species, which provide new insights into the role of open chromatin interactions in gene expression during the evolution of polyploid wheat.

Programmed cell death ligand 1 (PD-L1) is a critical biomarker for predicting the response to immunotherapy. However, traditional quantitative evaluation of PD-L1 expression using immunohistochemistry staining remains challenging for pathologists. Here we developed a deep learning (DL)-based artificial intelligence (AI) model to automatically analyze the immunohistochemical expression of PD-L1 in lung cancer patients. A total of 1,288 patients with lung cancer were included in the study. The diagnostic ability of three different AI models (M1, M2, and M3) was assessed in both PD-L1 (22C3) and PD-L1 (SP263) assays. M2 and M3 showed improved performance in the evaluation of PD-L1 expression in the PD-L1 (22C3) assay, especially at 1% cutoff. Highly accurate performance in the PD-L1 (SP263) was also achieved, with accuracy and specificity of 96.4 and 96.8% in both M2 and M3, respectively. Moreover, the diagnostic results of these three AI-assisted models were highly consistent with those from the pathologist. Similar performances of M1, M2, and M3 in the 22C3 dataset were also obtained in lung adenocarcinoma and lung squamous cell carcinoma in both sampling methods. In conclusion, these results suggest that AI-assisted diagnostic models in PD-L1 expression are a promising tool for improving the efficiency of clinical pathologists.

The fifth-generation atmospheric reanalysis of the European Center for Medium-Range Weather Forecasts (ERA5) is the latest reanalysis product. However, the reliability of ERA5 to capture extreme temperatures is still unclear over China. Hence, based on conventional meteorological station data, a new criterion (DISO) was used to validate the ERA5 capturing extreme temperature indices derived from the Expert Team on Climate Change Detection and Indices (ETCCDI) across the six subregions of China on different timescales. The conclusions are as follows: the original daily temperatures (mean temperature, maximum temperature, and minimum temperature) can be well reproduced by ERA5 reanalysis over China. ERA5 tends to exhibit more misdetection for the duration of extreme temperature events than extreme temperature intensity and frequency. In addition, ERA5 performed best in the summer and worst in the winter, respectively. The trend of absolute indices (e.g., TXx and TNx), percentile-based indices (e.g., TX90p, TX10p, TN90p, and TN10p), and duration indices (e.g., WSDI, CSDI, and GSL) can be captured by ERA5, but ERA5 failed to capture the tendency of the diurnal temperature range (DTR) over China. Spatially, ERA5 performs well in southeastern China. However, it remains challenging to accurately recreate the extreme temperature events in the Tibetan Plateau. The elevation difference between the station and ERA5 grid point contributes to the main bias of reanalysis temperatures. The accuracy of ERA5 decreases with the increase in elevation discrepancy.

ERA5 is the fifth-generation atmospheric reanalysis of the European Center for Medium-Range Weather Forecasts, with high spatiotemporal resolution and global coverage. However, the reliability of ERA5 for simulating extreme precipitation events is still unclear over China. In this study, 12 extreme precipitation indices and a comprehensive quantitative distance between indices of simulation and observation were used to evaluate ERA5 precipitation from three fundamental aspects: intensity, frequency, and duration. The geomorphological regionalization method was used to divide the subregions of China. The results showed that the ability of ERA5 to simulate annual total precipitation was better than that of daily precipitation. For the intensity indices, ERA5 performs well for simulating the PRCPTOT (annual total wet days precipitation) over China. ERA5 performs better on RX5day (max 5-days precipitation amount) and R95p (very wet days), especially in eastern China, than on RX1day (max 1-day precipitation amount) and R99p (extremely wet days). For the frequency indices, the ability of the ERA5 simulation increased as the amount of precipitation increased, except for northwestern China. However, the ability of ERA5 to simulate R50 mm (number of extreme heavy precipitation days) decreased. For the duration indices, ERA5 was better at simulating drought events than wet events in eastern China. Our results highlight the need for ERA5 to enhance the simulation of trend changes in extreme precipitation events.

HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR–double KO (ALKO), and ALDH2 rs671–knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency–induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.

The environmental bacterium Pseudomonas mosselii produces antagonistic secondary metabolites with inhibitory effects on multiple plant pathogens, including Ralstonia solanacearum, the causal agent of bacterial wilt. In this study, an engineered P. mosselii strain was generated to express R. solanacearum ripAA, which determines the incompatible interactions with tobacco plants. The ripAA gene, together with its native promoter, was integrated into the P. mosselii chromosome. The resulting strain showed no difference in antimicrobial activity against R. solanacearum. Promoter-LacZ fusion and RT-PCR experiments demonstrated that the ripAA gene was transcribed in culture media. Compared with that of the wild type, the engineered strain reduced the disease index by 9.1% for bacterial wilt on tobacco plants. A transcriptome analysis was performed to identify differentially expressed genes in tobacco plants, and the results revealed that ethylene- and jasmonate-dependent defense signaling pathways were induced. These data demonstrates that the engineered P. mosselii expressing ripAA can improve biological control against tobacco bacterial wilt by the activation of host defense responses.

HMG-CoA reductase (HMGCR) is the rate-limiting enzyme in cholesterol biosynthesis and the target for cholesterol-lowering therapy. Acetaldehyde dehydrogenase 2 (ALDH2) is primarily responsible for detoxifying ethanol-derived acetaldehyde and endogenous lipid aldehydes derived from lipid peroxidation. Epidemiological and Genome Wide Association Studies (GWAS) have linked an inactive ALDH2 rs671 variant, responsible for alcohol flush in nearly 8% world population and 40% of Asians, with cholesterol levels and higher risk of cardiovascular disease (CVD) but the underlying mechanism remains elusive. Here we find that the cholesterol levels in the serum and liver of ALDH2 knockout (AKO) and ALDH2 rs671 knock-in (AKI) mice are significantly increased, consistent with the increase of intermediates in the cholesterol biosynthetic pathways. Mechanistically, mitochondrial ALDH2 translocates to the endoplasmic reticulum to promote the formation of GP78/Insig1/HMGCR complex to increase HMGCR degradation through ubiquitination. Conversely, ALDH2 mutant or ALDH2 deficiency in AKI or AKO mice stabilizes HMGCR, resulting in enhanced cholesterol synthesis, which can be reversed by Lovastatin. Moreover, ALDH2-regulated cholesterol synthesis is linked to the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs). Together, our study has identified that ALDH2 is a novel regulator of cholesterol synthesis, which may play an important role in CVD.

Objective Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

Bistable morphing structures are widely used as actuation mechanisms in soft actuators, soft robotics, energy absorbers, mechanical computers, optical lenses, meta materials, and flexible electronics. However, untethered actuators, repetitive actuators, and hybrid-assembly (containing in-plane-assembly and out-of-plane-assembly) actuators remain challenging to realize using existing bistable structures, which hinders the novel application of such actuators in research, engineering, and daily life. This problem is solved by fabricating a magnet-driven soft bistable actuator (MSBA) unit. The self-buckling of the circular polydimethylsiloxane (PDMS) sheet ensures the bistability of the actuator and allows it to operate as an independent unit, free of external constraints. The reorientation of neodymium-iron-boron (NdFeB) microparticles embedded in the PDMS sheet enables the dome-shaped actuators to exhibit repetitive snapping under the stimulus of a direction-switching magnetic field. The potential of this MSBA unit in bionics, electronics, and biomechanics applications is demonstrated in systematic studies involving modification of the buckling deflection and magnetic moment density. The MSBA unit exhibits excellent performance in hybrid designs and intelligent systems. [ABSTRACT FROM AUTHOR]

The task of smog control in China is still arduous compared with developed economies. To address the problems associated with the uncertain of smog pollution, this paper establishes a new EGM (even grey model) (1, 1) prediction model based on the kernel and degree of greyness under the condition that the possibility.function is known. The original EGM(1,1) prediction model based on the interval grey number sequence is constructed under circumstances where the possibility function is unknown. For testing the proposed model, the daily AQI data of Nanjing, Jiangsu Province, China, was selected. Also, this paper uses another fiveforecasting models and compares the results with the new model. The results show that the daily AQI index of Nanjing presents a significant downward trend excluding seasonal factors, and the prediction accuracy of the new EGM (1,1) model is also higher than that of other forecasting models. [ABSTRACT FROM AUTHOR]

Obesity and related inflammation are critical for the pathogenesis of insulin resistance, but the underlying mechanisms are not fully understood. Formyl peptide receptor 2 (FPR2) plays important roles in host immune responses and inflammation-related diseases. We found that Fpr2 expression was elevated in the white adipose tissue of high-fat diet (HFD)-induced obese mice and db/db mice. The systemic deletion of Fpr2 alleviated HFD-induced obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hepatic steatosis. Furthermore, Fpr2 deletion in HFD-fed mice elevated body temperature, reduced fat mass, and inhibited inflammation by reducing macrophage infiltration and M1 polarization in metabolic tissues. Bone marrow transplantations between wild-type and Fpr2-/- mice and myeloid-specific Fpr2 deletion demonstrated that Fpr2-expressing myeloid cells exacerbated HFD-induced obesity, insulin resistance, glucose/lipid metabolic disturbances, and inflammation. Mechanistic studies revealed that Fpr2 deletion in HFD-fed mice enhanced energy expenditure probably through increasing thermogenesis in skeletal muscle; serum amyloid A3 and other factors secreted by adipocytes induced macrophage chemotaxis via Fpr2; and Fpr2 deletion suppressed macrophage chemotaxis and lipopolysaccharide-, palmitate-, and interferon-γ-induced macrophage M1 polarization through blocking their signals. Altogether, our studies demonstrate that myeloid Fpr2 plays critical roles in obesity and related metabolic disorders via regulating muscle energy expenditure, macrophage chemotaxis, and M1 polarization. [ABSTRACT FROM AUTHOR]

Impairment of the immune system is a developing concern in evaluating the toxicity of cadmium(Cd). In the present study, we investigated if Cd could impair cutaneous wound healing through interfering with inflammation after injury.We found that exposure ofmice to CdCl2 through drinking water at doses of 10, 30, and 50mg/l for 8weeks significantly impaired cutaneous wound healing. Chronic 30mg/l CdCl2 treatment elevatedmurine blood Cd level comparable to that of low dose Cd-exposed humans, had no effect on blood total and differential leukocyte counts, but reduced neutrophil infiltration, chemokines (CXCL1 and CXCl2), and proinflammatory cytokines (TNFa, IL-1b, and IL-6) expression in wounded tissue at early stage after injury.Wounded tissue homogenates from CdCl2-treatedmice had lower chemotactic activity for neutrophils than those fromuntreatedmice.Mechanistic studies showed that chronic Cd treatment suppressed ERK1/2 and NF-jB p65 phosphorylation in wounded tissue at early stage after injury. Compared with neutrophils isolated fromuntreatedmice, neutrophils from CdCl2 treatedmice and normal neutrophils treated with CdCl2 in vitro both had lower chemotactic response, calciummobilization and ERK1/2 phosphorylation upon chemoattractant stimulation. Collectively, our study indicate that chronic low-dose Cd exposure impaired cutaneous wound healing by reducing neutrophil infiltration through inhibiting chemokine expression and neutrophil chemotactic response, and suppressing proinflammatory cytokine expression. Cdmay suppress chemokine and proinflammatory expression through inactivating ERK1/2 and NF-jB, and inhibit neutrophil chemotaxis by attenuating calciummobilization and ERK1/2 phosphorylation in response to chemoattractants. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes. [ABSTRACT FROM AUTHOR]