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Abstract We investigated the clinical characteristics of primary aldosteronism (PA) screened from patients with hypertension in China. The participants were hypertensive patients who were suspected of PA and registered in the China Primary Aldosteronism Prospective Study. Plasma aldosterone‐to‐renin ratio (ARR) was used as the screening test. In patients screened positive for PA, that is, an ARR exceeding the thresholds and plasma aldosterone concentration (PAC) > 100 pg/mL, a confirmatory test was performed for diagnosis. Patients with PA underwent a CT scan and adrenal venous sampling for subtyping. Of the 1497 screened patients, 754 (50.4%) had an ARR exceeding the diagnostic threshold and 637 (84.5% of those eligible) were registered. These registered hypertensive patients with suspected PA had a mean (standard deviation) age of 52.6 ± 12.1 years, and included 442 (58.6%) women. In multiple stepwise logistic regression, the significant odds ratios for the presence of diagnosed (n = 490) versus suspected and non‐diagnosed PA (n = 147) were 4.54 (95% CI: 2.78‐7.39) for a history of hypokalemia, 0.79 (95% CI: 0.64‐0.98) for a 0.9 mmol/l higher serum total cholesterol, and 2.25 (95% CI: 1.63‐3.10) for a doubling of PAC in the supine or standing/sitting position. In multiple stepwise logistic regression, the significant odds ratios for the presence of unilateral (n = 135) versus bilateral PA (n = 53) were 3.04 (95% CI: 1.90‐4.87) for a 0.4 mmol/l lower minimum serum potassium concentration and 1.86 (95% CI: 1.20‐2.86) for a 0.3 mmol/l higher serum high‐density lipoprotein cholesterol. PA might be a biochemical continuum in the adrenal hypersecretion of aldosterone as well as hypokalemia.

Abstract Background Cryptococcosis is progressively acknowledged among people, irrespective of the human with or without immunodeficiency virus (HIV). This change in epidemiology has been recorded in recent years, prompting closer examination and a broader understanding of the disease manifestations and risk factors. Methods The data of cryptococcal infections in China during 11 years were retrospectively analyzed. According to the position of infection, the patients were categorized into the pulmonary infection group and extrapulmonary infection group. The composition of the two groups was compared, and the potential risk factors of disseminated infection were analyzed. Logistic regression was used to analyze the prognostic risk factors of the disease. Results A total of 165 patients were enrolled. 113 (68.5%) were male, and the age was 47.49 (18–82) years. 101 cases (61.2%) had a normal immune function and 64 cases (38.8%) had impaired immune function. 45 patients had extrapulmonary infection, involving the central nervous system, bone and joint, skin and bloodstream, and 120 patients had simple pulmonary infection. The mortality of the extrapulmonary infection group (48.9%) was significantly higher than that of the pulmonary infection group (0.8%). According to univariate logistic regression analysis, immune status (hazard ratio [HR], 4.476; 95% confidence interval [CI], 1.725–11.618; P = 0.002), infection position ([HR], 113.826; [CI], 14.607-886.967; P

Abstract Background Armadillo Repeat Containing X-Linked 1 (ARMCX1), a member of the ARM Repeat X-linked protein family, exerts inhibitory function in various tumors. However, its biological role in lung adenocarcinoma (LUAD) and the underlying molecular mechanisms require further exploration. Methods LUAD tissue microarrays and bioinformatic databases were used to evaluate the relationship between ARMCX1 and clinicopathological features. The influence of ARMCX1 on LUAD cell proliferation, migration, and invasion in vitro was determined by colony formation, CCK-8, EdU incorporation, cell cycle, wound healing, and Transwell assays. The impact of ARMCX1 on LUAD cell growth and metastasis in vivo was determined by subcutaneously transplanted tumor and pulmonary metastasis assays. Western blot, immunoprecipitation, immunofluorescence, cycloheximide, and proteasome inhibitor assays were finally conducted to explore the potential underlying molecular mechanisms. Results ARMCX1 expression was downregulated in clinical LUAD samples due to which patient prognoses were poor. Functional experiments indicated that ARMCX1 overexpression inhibited the growth and metastasis of LUAD cells in vitro and in vivo. The molecular mechanism suggested that ARMCX1 recruits the E3 ubiquitin ligase FBXW7 for mediating ubiquitinated degradation of c-Myc, suppressing its nuclear accumulation, and ultimately inactivating cell cycle and epithelial-mesenchymal transition (EMT) signals. Conclusion ARMCX1 inhibits LUAD cell proliferation and metastasis by interacting with c-Myc and enhancing its ubiquitination and degradation. Consequently, it can act as a tumor suppressor in this disease. These results suggest that ARMCX1 is a potential target in the treatment of LUAD.

Abstract Background A growing number of studies have demonstrated that the polar regions have the potential to be a significant repository of microbial resources and a potential source of active ingredients. Genome mining strategy plays a key role in the discovery of bioactive secondary metabolites (SMs) from microorganisms. This work highlighted deciphering the biosynthetic potential of an Arctic marine-derived strain Aspergillus sydowii MNP-2 by a combination of whole genome analysis and antiSMASH as well as feature-based molecular networking (MN) in the Global Natural Products Social Molecular Networking (GNPS). Results In this study, a high-quality whole genome sequence of an Arctic marine strain MNP-2, with a size of 34.9 Mb was successfully obtained. Its total number of genes predicted by BRAKER software was 13,218, and that of non-coding RNAs (rRNA, sRNA, snRNA, and tRNA) predicted by using INFERNAL software was 204. AntiSMASH results indicated that strain MNP-2 harbors 56 biosynthetic gene clusters (BGCs), including 18 NRPS/NRPS-like gene clusters, 10 PKS/PKS-like gene clusters, 8 terpene synthse gene clusters, 5 indole synthase gene clusters, 10 hybrid gene clusters, and 5 fungal-RiPP gene clusters. Metabolic analyses of strain MNP-2 grown on various media using GNPS networking revealed its great potential for the biosynthesis of bioactive SMs containing a variety of heterocyclic and bridge-ring structures. For example, compound G-8 exhibited a potent anti-HIV effect with an IC50 value of 7.2 nM and an EC50 value of 0.9 nM. Compound G-6 had excellent in vitro cytotoxicities against the K562, MCF-7, Hela, DU145, U1975, SGC-7901, A549, MOLT-4, and HL60 cell lines, with IC50 values ranging from 0.10 to 3.3 µM, and showed significant anti-viral (H1N1 and H3N2) activities with IC50 values of 15.9 and 30.0 µM, respectively. Conclusions These findings definitely improve our knowledge about the molecular biology of genus A. sydowii and would effectively unveil the biosynthetic potential of strain MNP-2 using genomics and metabolomics techniques.

Abstract Background Chrysomycin A (CA) is a promising antibiotic for treatment of Gram-positive bacterial infections and cancers. In order to enhance CA yield, optimization of fermentation conditions and medium components was carried out on strain Streptomyces sp. 891-B6, an UV-induced mutant with improved CA titer compared with its wide-type marine strain 891. Results Using one-way experiment, the optimal fermentation conditions for CA production in 1-L shake flask were obtained as follows: 12 days of fermentation time, 5 days of seed age, 5% of inoculum volume ratio, 200 mL of loading volume and 6.5 of initial pH. By response surface methodology, the optimal medium components determined as glucose (39.283 g/L), corn starch (20.662 g/L), soybean meal (15.480 g/L) and CaCO3 (2.000 g/L). Conclusion Validation tests showed that the maximum yield of CA reached 1601.9 ± 56.7 mg/L, which was a 60% increase compared to the initial yield (952.3 ± 53.2 mg/L). These results provided an important basis for scale-up production of CA by strain 891-B6.

Abstract Lattice-based digital signature has become one of the widely recognized post-quantum algorithms because of its simple algebraic operation, rich mathematical foundation and worst-case security, and also an important tool for constructing cryptography. This survey explores lattice-based digital signatures, a promising post-quantum resistant alternative to traditional schemes relying on factoring or discrete logarithm problems, which face increasing risks from quantum computing. The study covers conventional paradigms like Hash-and-Sign and Fiat-Shamir, as well as specialized applications including group, ring, blind, and proxy signatures. It analyzes the versatility and security strengths of lattice-based schemes, providing practical insights. Each chapter summarizes advancements in schemes, identifying emerging trends. We also pinpoint future directions to deploy lattice-based digital signatures including quantum cryptography.

Summary: Background: Masked hypertension is associated with target organ damage (TOD) and adverse health outcomes, but whether antihypertensive treatment improves TOD in patients with masked hypertension is unproven. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial at 15 Chinese hospitals, untreated outpatients aged 30–70 years with an office blood pressure (BP) of

PURPOSETo characterize the pattern of post-treatment quality of life (QoL) for esophageal cancer (EC) survivors and construct models predicting their long-term QoL.METHODSOn the basis of a randomized trial in an EC high-risk region in China, we interviewed 363 EC survivors and 25,245 permanent residents matched with the survivors on age, sex, and township as the baseline. QoL was measured using three-level version of European Quality of Life 5-Dimensions instrument. We constructed piecewise mixed models estimating the QoL of EC survivors that varied by age, sex, patient type, hospital level, and therapy to ascertain QoL determinants.RESULTSThe post-treatment QoL of EC survivors dropped by 15.7% within the first year and recovered by 9.3% between 1 and 9 years compared with the baseline. Therapy was found to be a determinant of QoL, and a series of therapy-specific models were fitted accordingly, which all showed the pattern of decreasing rapidly and recovering gradually. Endoscopic treatment had the least impact on post-treatment QoL (7.5% drop within 5 years) compared with esophagectomy (12.2% drop within 1 year) and chemoradiotherapy (37.8% drop within 2 years). The usual activities dimension showed the greatest impairment among those patients (34.4% drop within 1 year).CONCLUSIONThis community-based study described the long-term QoL trajectory for EC survivors after different therapeutic modalities and constructed models to predict therapy-specific QoL at different time points after treatment. It provided new insights into decision making in treatment for EC from the perspective of QoL protection, offering a convenient tool for estimating quality-adjusted life-years.

Summary: Using noninvasive biomarkers to identify high-risk individuals prior to endoscopic examination is crucial for optimization of screening strategies for esophageal squamous cell carcinoma (ESCC). We conducted a nested case-control study based on two community-based screening cohorts to evaluate the warning value of serum metabolites for esophageal malignancy. The serum samples were collected at enrollment when the cases had not been diagnosed. We identified 74 differential metabolites and two prominent perturbed metabolic pathways, and constructed Metabolic Risk Score (MRS) based on 22 selected metabolic predictors. The MRS generated an area under the receiver operating characteristics curve (AUC) of 0.815. The model performed well for the within-1-year interval (AUC: 0.868) and 1-to-5-year interval (AUC: 0.845) from blood draw to diagnosis, but showed limited ability in predicting long-term cases (>5 years). In summary, the MRS could serve as a potential early warning and risk stratification tool for establishing a precision strategy of ESCC screening.

Abstract Background The transcription factors (TFs) in thermophilic cyanobacteria might represent a uniquely evolved gene repertoire in light of the strong selective pressure caused by hostile habitats. Understanding the molecular composition of the TF genes in thermophilic cyanobacteria will facilitate further studies regarding verifying their exact biochemical functions and genetic engineering. However, limited information is available on the TFs of thermophilic cyanobacteria. Herein, a thorough investigation and comparative analysis were performed to gain insights into the molecular composition of the TFs in 22 thermophilic cyanobacteria. Results The results suggested a fascinating diversity of the TFs among these thermophiles. The abundance and type of TF genes were diversified in these genomes. The identified TFs are speculated to play various roles in biological regulations. Further comparative and evolutionary genomic analyses revealed that HGT may be associated with the genomic plasticity of TF genes in Thermostichus and Thermosynechococcus strains. Comparative analyses also indicated different pattern of TF composition between thermophiles and corresponding mesophilic reference cyanobacteria. Moreover, the identified unique TFs of thermophiles are putatively involved in various biological regulations, mainly as responses to ambient changes, may facilitating the thermophiles to survive in hot springs. Conclusion The findings herein shed light on the TFs of thermophilic cyanobacteria and fundamental knowledge for further research regarding thermophilic cyanobacteria with a broad potential for transcription regulations in responses to environmental fluctuations.

Wind tunnel testing is a crucial method for studying aircraft flutter. Using heavy gas as the wind tunnel medium can mitigate the escalating issue of test models being overweight as advanced aircraft develop. This paper employs an analytical method for numerical calculations of three-dimensional (3D) wing flutter based on fluid–structure interaction (FSI). Flutter calculations for the Goland wing are conducted, and the results in the air medium are consistent with the literature. In contrast, significant differences in flutter behavior are observed in the heavy gas R134a medium. Compared to air, when the model reaches a critical state in R134a, the incoming flow velocity is lower, the incoming flow density is approximately 3 to 5 times air, and the incoming flow dynamic pressure is about 1.1 to 1.2 times that of air. The correction of heavy gas flutter data is crucial for wind tunnel testing. This paper proposes a correction method based on the unsteady transonic flow similarity law proposed by Bendiksen under quasi-steady conditions. Attempts are made to revise relevant published wind tunnel tests and heavy gas flutter calculation results. The transonic flutter similarity law effectively explains the flutter similarity of rigid models in both heavy gas and air media. Still, it fails in cases with highly reduced frequencies and low mass ratios, such as those encountered with flexible wings.

Flexible cages are widely used in marine aquaculture, yet their mechanical features in extreme seas are still unclear. This study proposes a numerical algorithm to solve the coupled response of the multiple cage systems. The net and mooring lines are modeled using the lumped-mass model, while the flexible floating collar system is assessed with the large-deformation FEM model, and the two models are coupled through an iterative scheme. Sea trials are conducted, and the motion of the cage is obtained using an image processing technique, which validates the numerical algorithm. Using the proposed numerical algorithm, a series of simulations are performed to investigate the response of flexible cages in extreme seas. Motions, line tensions, and structural sectional forces are studied, and the effects of factors such as the wavelength of incident waves and the diameter of collar pipes are investigated.

The reliability and safety of fuel cell vehicle are crucial for the daily operation. Insulation resistance serves as a crucial index of vehicle reliability, especially when fuel cells operate at high voltages. Low insulation resistance can lead to vehicle malfunctions, exposing the operator to the risk of electric shock. In this study, long-term insulation resistance data from thirteen vehicles equipped with three different types of fuel cell systems are analyzed to diagnose possible low insulation resistance issues. For this purpose, a robust locally weighted scatterplot smoothing method is utilized to filter the original data. In this research, an insulation variation model is developed using a data-driven long short-term memory neural network to identify insulation resistance value anomalies caused by deionizer failure. The results indicate that the coefficient of determination of the failure model is 99.78 %. Moreover, current model efficiently identifies insulation faults resulting from reliability issues, such as conductivity issues of cooling pipes and erosion of vehicle wiring harnesses.

Abstract The lack of human‐derived in vitro models that recapitulate cervical pre‐cancerous lesions has been the bottleneck in researching human papillomavirus (HPV) infection‐associated pre‐cancerous lesions and cancers for a long time. Here, a long‐term 3D organoid culture protocol for high‐grade squamous intraepithelial lesions and cervical squamous cell carcinoma that stably recapitulates the two tissues of origin is described. Originating from human‐derived samples, a small biobank of cervical pre‐tumoroids and tumoroids that faithfully retains genomic and transcriptomic characteristics as well as the causative HPV genome is established. Cervical pre‐tumoroids and tumoroids show differential responses to common chemotherapeutic agents and grow differently as xenografts in mice. By coculture organoid models with peripheral blood immune cells (PBMCs) stimulated by HPV antigenic peptides, it is illustrated that both organoid models respond differently to immunized PBMCs, supporting organoids as reliable and powerful tools for studying virus‐specific T‐cell responses and screening therapeutic HPV vaccines. In this study, a model of cervical pre‐cancerous lesions containing HPV is established for the first time, overcoming the bottleneck of the current model of human cervical pre‐cancerous lesions. This study establishes an experimental platform and biobanks for in vitro mechanistic research, therapeutic vaccine screening, and personalized treatment for HPV‐related cervical diseases.

Abstract Caseinolytic protease proteolytic subunit (ClpP) and caseinolytic protease X (ClpX) are mitochondrial matrix peptidases that activate mitochondrial unfolded protein response to maintain protein homeostasis in the mitochondria. However, the role of ClpP and ClpX in spermatogenesis remains largely unknown. In this study, we demonstrated the importance of ClpP/ClpX for meiosis and spermatogenesis with two conditional knockout (cKO) mouse models. We found that ClpP/ClpX deficiency reduced mitochondrial functions and quantity in spermatocytes, affected energy supply during meiosis and attenuated zygotene-pachytene transformation of the male germ cells. The dysregulated spermatocytes finally underwent apoptosis resulting in decreased testicular size and vacuolar structures within the seminiferous tubules. We found mTORC1 pathway was over-activated after deletion of ClpP/ClpX in spermatocytes. Long-term inhibition of the mTORC1 signaling via rapamycin treatment in vivo partially rescue spermatogenesis. The data reveal the critical roles of ClpP and ClpX in regulating meiosis and spermatogenesis.

The innovative aquaculture equipment known as high-density polyethylene (HDPE) floating rafts has gained popularity among fishermen in the southeast coastal regions of China. Compared to deep-water anti-wave fish cages, the construction costs of HDPE floating rafts are 50% to 75% less. There is a dearth of comprehensive publicly available records of HDPE floating rafts sea trial data, despite substantial numerical studies on the motion response of aquaculture fish cages and scale model experiments under controlled-wave conditions. This study involves sea trial techniques under operational and extreme environmental conditions for motion responses of HDPE floating rafts, presents a comprehensive procedure for sea trials of HDPE floating rafts, summarizes the issues encountered during the trials, and suggests solutions. Using MATLAB for independent programming, motion videos and photos collected from the sea trials are processed for image capture, yielding the original time history curve of vertical displacement. Based on the sea trials’ data, including motion displacement, acceleration, mooring line force, overall deformation patterns, and current and wave data, recommendations are provided for the design and layout of HDPE floating rafts. Based on the Fast Fourier Transform (FFT) method for spectral analysis, the influence of interference items on the observational data is eliminated; the rationality of the observational data is verified in conjunction with the results of the Gabor Transform. This study offers a scientific analytical method for the structural design and safe operation of HDPE floating rafts and provides a reference for subsequent numerical simulations.

More and more offshore heavy oil resources are discovered and exploited as the focus of the oil and gas industry shifts from land to sea. However, unlike onshore heavy oil reservoirs, offshore heavy oil reservoirs not only have active edge and bottom water but also have different exploitation methods. In this paper, a typical special heavy oil reservoir in China was analyzed in detail, based on geology–reservoir–engineering integration technology. Firstly, it is identified as a self-sealing bottom water heavy oil reservoir by analyzing its geological characteristics and hydrocarbon accumulation mechanism. Secondly, the water cut is initially controlled by oil viscosity, but subsequently, by reservoir thickness through the analysis of oil and water production data. Thirdly, the bottom oil–water contact of the reservoir was re-corrected to build an accurate 3D geological model, based on the production history matching of a single well and the whole reservoir. Lastly, a scheme of thermal production coupled with cold production was proposed to exploit this special reservoir, and the parameters of steam, N2, and CO2 injection and production were optimized to predict oil production. This work can provide a valuable development model for the efficient exploitation of similar offshore special heavy oil reservoirs.

Abstract Background The effect of circular RNAs (circRNAs) is widely studied in various human cancers, including breast cancer (BC). Herein, circUSPL1 has been recognized as a new regulator for BC progression. However, the detailed biological function and molecular mechanism of circUSPL1 in BC remain vague. Methods The expression level of circUSPL1, miR‐1296‐5p and metastasis associated 1 (MTA1) was examined by quantitative reverse transcription PCR. BC cell proliferation, migration, invasion, apoptosis and aerobic glycolysis were analyzed by colony formation assay, 5‐ethynyl‐2′‐deoxyuridine assay, wound healing assay, transwell assay, flow cytometry and glycolysis corresponding kits, respectively. The protein level of Bcl‐2, Bax, HK2, GLUT1 and MTA1 was evaluated by western blot analysis. The relationship of miR‐1296‐5p and circUSPL1 or MTA1 was affirmed using dual‐luciferase reporter or RIP assays. A murine xenograft model was conducted to analyze the tumor growth in vivo. Results CircUSPL1 and MTA1 expression level was increased, but miR‐1296‐5p was particularly reduced in BC tissues and cells. CircUSPL1 deficiency significantly inhibited BC cell proliferation, migration, invasion, glycolysis, and promoted cell apoptosis. In addition, circUSPL1 directly targeted miR‐1296‐5p, and downregulation of miR‐1296‐5p eliminated the inhibitory action of circUSPL1 knockdown. Additionally, overexpression of miR‐1296‐5p repressed cell malignant properties, while the suppressive effects were overturned by MTA1 elevation. Lastly, silencing of circUSPL1 inhibited tumor growth by sponging miR‐1296‐5p and regulating MTA1. Conclusion CircUSPL1 deficiency repressed BC cell malignant phenotypes through reducing MTA1 via targeting miR‐1296‐5p, which might provide a theoretical basis for BC treatment.

The actual saline aquifers is vertically distributed in multiple layers, with large differences in physical properties and serious heterogeneity of capillary pressure. During the sequestration of impure CO2, the capillary pressure will not only trap CO2 but also trap the accompanying impurity gas, affecting CO2 migration and sequestration. However, the entrapment of local capillary under the vertical multi-layer system is still unclear, and its impact on the sequestration efficiency of impure CO2 needs to be analyzed urgently. For this reason, stochastic statistical geological modeling and impure CO2-brine two-phase seepage model are combined to establish a vertical multi-layer impure CO2 sequestration and migration model in saline aquifers. Under the action of capillary pressure, the migration process and its plume development law are studied and the vertical migration rate of impure CO2 and the capillary pressure trapping ability are calculated quantitatively. Finally, through the sensitivity analysis, the capillary pressure, the influence of capillary pressure, heterogeneity, and impurity volume fraction on CO2 sequestration efficiency is clarified. The research results show that heterogeneous capillary pressure can effectively trap impure CO2 and increase the swept volume of impure CO2 in the lateral direction. With the increase of capillary pressure and its heterogeneity, local capillary trap volume and local capillary sequestration coefficient increase. However, the vertical migration rate of CO2 decreases significantly, and the difference between the vertical migration rate of impurity gas increases. When the capillary pressure decreases from top to bottom, the local capillary entrapment at the bottom decreases, and more impure CO2 will migrate to various areas in the upper part of the formation, which makes the local capillary sequestration coefficient of impure CO2 increase, and the residual sequestration coefficient of impure CO2 decrease. What’s more, it makes the vertical migration rate of CO2 increase and the difference between the vertical migration rate of impurity gas and impurity gas decrease. As the volume fraction of impurity gas increases, the buoyancy of impure CO2 and the vertical migration rate of impure CO2 increase. More impure CO2 migrates to the top of the formation, which makes the local capillary sequestration coefficient of impure CO2 decrease, while residual sequestration coefficient increases. Therefore, to ensure the safety of storage, impure CO2 containing few impurities should be selected as much as possible to inject into the saline aquifers with large capillary pressure, strong heterogeneity, and vertical capillary pressure increasing first and then decreasing from top to bottom.

Abstract The 3-ketoacyl-ACP synthase III (FabH), a key enzyme for bacteria growth, catalyses the last step of the initiation of bacterial fatty acid synthesis. Rice bacterial blight is caused by the pathogen Xanthomonas oryzae pv. oryzae (Xoo), which is widely studied as a model bacterium. Bioinformatics analysis showed that the X. oryzae pv. oryzae PXO99A genome encodes three FabH homologous proteins with unknown functions. In this study, we found that only PXO_02706 (fabH1) encodes a functional FabH, the key enzyme in the production of branched-chain fatty acid, which is essential for the branched-chain diffusible signal factor family signals in Xoo. Interestingly, we found that FabH1 is not essential for fatty acid biosynthesis in Xoo. Pathogenicity analysis showed that loss of fabH1 caused a significant decrease in virulence of Xoo. Genetic and phenotypic analyses revealed that fabH1 plays a key role in multiple Xoo virulence-related activities, including exopolysaccharide (EPS) production, biofilm formation, motility, and resistance to environmental stresses.

Summary: Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2−9 disrupt its secondary structure and charge properties, impeding phase separation. Maps−/− pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. MapsΔ2–9/Δ2–9 male mice expressing MAPS protein lacking aa 2–9 phenocopy Maps−/− mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.

ABSTRACT Equine infectious anemia (EIA) has a worldwide distribution and causes severe economic losses to the equine industry. The EIA virus (EIAV) genome sequences from different countries are highly diverse, which poses a great challenge for pathogen identification with PCR. Phylogenetic analysis showed that although gag is the most conserved structural gene, it still has great genome variability. Currently, most existing PCR methods are designed based on the gag gene sequence and therefore do not cover all the viral strains, especially Asian EIAV strains. In this study, we developed a tat-gag-based real-time quantitative PCR (TG-qPCR) for the detection of EIAV by targeting the fragment between the tat and gag genes, which was relatively conserved in all the known EIAV strains. The performance of the TG-qPCR was evaluated against that of the standard qPCR (recommended by WOAH) by testing viral RNA extracted from viral supernatants of EIAVDLV2-6 and EIAVUK3, proviral DNA from peripheral blood mononuclear cells of artificially immunized horses, and virus nucleic acid from EIAV positive serum samples. The TG-qPCR assay had high specificity, sensitivity, and reproducibility. The detection limit of the TG-qPCR assay was 1 copy/reaction for both viral RNA and proviral DNA based on the Poisson distribution. Compared to the qPCR, the TG-qPCR has better inclusivity and can detect not only Asian EIAV strains but also almost all the representative EIAV strains from other continents. The above results show that the TG-qPCR assay could serve as an effective tool for the early diagnosis of clinical EIA disease. IMPORTANCE Equine infectious anemia (EIA) has a worldwide distribution and causes significant losses to the equine industry worldwide. A reliable detection method is necessary to control the transmission of EIA virus (EIAV). Currently, most of the available real-time PCR assays, including the qPCR of recommended by WOAH, are developed according to the sequences of European or American EIAV strains; however, the primers and probe sequences have low homology with Asian EIAV strains. To the best of our knowledge, no qPCR method capable of the well detection of Asian EIAV strains, especially Chinese EIAV strains, has been published to date. The development of a sensitive, specific, and rapid qPCR assay for the detection of the EIAV strains is therefore of great importance.

Abstract Background Ischemia-reperfusion (IR) induces increased release of extracellular vesicles in the heart and exacerbates myocardial IR injury. We have previously shown that propofol attenuates hypoxia/reoxygenation (HR)-induced injury in human umbilical vein endothelial cells (HUVECs) and that microvesicles derived from propofol-treated HUVECs inhibit oxidative stress in endothelial cells. However, the role of microvesicles derived from propofol post-treated HUVECs ((HR + P)-EMVs) in IR-injured cardiomyocytes is unclear. In this study, we aimed to investigate the role of (HR + P)-EMVs in cardiac IR injury compared to microvesicles derived from hypoxic/reoxygenated HUVECs (HR-EMVs) and to elucidate the underlying mechanisms. Methods Hypoxia/reoxygenation (HR) models of HUVECs and AC16 cells and a mouse cardiac IR model were established. Microvesicles from HR-injured HUVECs, DMSO post-treated HUVECs and propofol post-treated HUVECs were extracted by ultra-high speed centrifugation, respectively. The above EMVs were co-cultured with HR-injured AC16 cells or injected intracardially into IR mice. Flow cytometry and immunofluorescence were used to determine the levels of oxidative stress and apoptosis in cardiomyocytes. Apoptosis related proteins were detected by Western blot. Echocardiography for cardiac function and Evans blue-TTC staining for myocardial infarct size. Expression of lncCCT4-2 in EMVs and AC16 cells was analysed by whole transcriptome sequencing of EMVs and RT-qPCR. The molecular mechanism of inhibition of myocardial injury by (HR + P)-EMVs was elucidated by lentiviral knockdown of lncCCT4-2, plasmid overexpression or knockdown of CCT4, and actinomycin D assay. Results In vitro and in vivo experiments confirmed that HR-EMVs exacerbated oxidative stress and apoptosis in IR-injured cardiomyocytes, leading to increased infarct size and worsened cardiac function. Notably, (HR + P)-EMVs induced significantly less oxidative stress and apoptosis in IR-injured cardiomyocytes compared to HR-EMVs. Mechanistically, RNA sequencing of EMVs and RT-qPCR showed that lncCCT4-2 was significantly upregulated in (HR + P)-EMVs and cardiomyocytes co-cultured with (HR + P)-EMVs. Reduction of lncCCT4-2 in (HR + P)-EMVs enhanced oxidative stress and apoptosis in IR-injured cardiomyocytes. Furthermore, the anti-apoptotic activity of lncCCT4-2 from (HR + P)-EMVs was achieved by increasing the stability of CCT4 mRNA and promoting the expression of CCT4 protein in cardiomyocytes. Conclusions Our study showed that (HR + P)-EMVs uptake by IR-injured cardiomyocytes upregulated lncCCT4-2 in cardiomyocytes and promoted CCT4 expression, thereby inhibiting HR-EMVs induced oxidative stress and apoptosis.

Abstract Background Trigger thumb is a pathologic condition of the digital pulleys and flexor tendons. To find a cutoff value of the cross-sectional area ratio of specific parts of the flexor pollicis longus tendon to diagnosis trigger thumb in the high-frequency ultrasound examination. Methods We evaluated 271 healthy volunteers and 57 patients with clinical diagnosis of trigger thumb. The cross-sectional area of the metacarpophalangeal joint of flexor pollicis longus tendon (C1) and the cross-sectional area of the midpoint of the first metacarpal of flexor pollicis longus tendon (C2) were analyzed. Results There is no difference between gender, age and left and right hands in the ratio of C1 to C2 (C1/ C2). The mean of C1/ C2 in the healthy thumb was 0.983 ± 0.103, which was significantly smaller in comparison to the diseased thumb (P

Injury rates in the construction industry have been high. Losses from a construction accident are not limited to the high expenses of the delay in construction and the compensations for the injured workers, sometimes even the worker's life. The worker's unsafe behaviors have been the direct cause of an accident, and it is urgent to reduce them effectively. This study examines the relationships between personality traits, psychological needs, and safety motivation. It attempts to provide evidence and support for using personality traits and psychological needs in improving practical construction safety interventions. First, the constructs for personality traits, psychological needs, and safety motivation have been contextualized for application in the construction industry. Second, hypotheses about the relationships among the three constructs were established based on the literature, and a social survey was conducted to collect data for testing the hypotheses. Third, structural equation modeling was used to investigate the association between the three key constructs. The study found that conscientiousness is associated with social identity and intrinsic safety motivation, and extraversion is related to the worker's self-efficacy and extrinsic motivation. Openness to experience is positively associated with work autonomy and self-efficacy; conscientiousness is positively related to social identity, as well as extraversion to self-efficacy, agreeableness to work autonomy, and neuroticism to self-efficacy. The findings of this study contribute toward a better understanding of how personality accounts for differences in psychological needs and safety motivation and how these differences can be used in customized safety interventions. This study guides using personality traits in promoting safety motivation and shows that assessing personality traits can be a helpful tool in designing customized safety interventions.

Epilepsy is one of the most common neurological disorders. Neuroinflammation involving the activation of microglia and astrocytes constitutes an important and common mechanism in epileptogenesis. Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that plays pathological roles in various inflammation-related diseases. Our previous study demonstrated that Trpm2 knockout exhibits therapeutic effects on pilocarpine-induced glial activation and neuroinflammation. However, whether TRPM2 in microglia and astrocytes plays a common pathogenic role in this process and the underlying molecular mechanisms remained undetermined. Here, we demonstrate a previously unknown role for microglial TRPM2 in epileptogenesis. Trpm2 knockout in microglia attenuated kainic acid (KA)-induced glial activation, inflammatory cytokines production and hippocampal paroxysmal discharges, whereas Trpm2 knockout in astrocytes exhibited no significant effects. Furthermore, we discovered that these therapeutic effects were mediated by upregulated autophagy via the adenosine monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in microglia. Thus, our findings highlight an important deleterious role of microglial TRPM2 in temporal lobe epilepsy.

Most bacteria use type II fatty acid synthesis (FAS) systems for synthesizing fatty acids, of which the conserved FabA-FabB pathway is considered to be crucial for unsaturated fatty acid (UFA) synthesis in gram-negative bacteria. Xanthomonas campestris pv. campestris, the phytopathogen of black rot disease in crucifers, produces higher quantities of UFAs under low-temperature conditions for increasing membrane fluidity. The fabA and fabB genes were identified in the X. campestris pv. campestris genome by BLAST analysis; however, the growth of the X. campestris pv. campestris fabA and fabB deletion mutants was comparable to that of the wild-type strain in nutrient and minimal media. The X. campestris pv. campestris ΔfabA and ΔfabB strains produced large quantities of UFAs and, altogether, these results indicated that the FabA-FabB pathway is not essential for growth or UFA synthesis in X. campestris pv. campestris. We also observed that the expression of X. campestris pv. campestris fabA and fabB restored the growth of the temperature-sensitive Escherichia coli fabA and fabB mutants CL104 and CY242, respectively, under non-permissive conditions. The in-vitro assays demonstrated that the FabA and FabB proteins of X. campestris pv. campestris catalyzed FAS. Our study also demonstrated that the production of diffusible signal factor family signals that mediate quorum sensing was higher in the X. campestris pv. campestris ΔfabA and ΔfabB strains and greatly reduced in the complementary strains, which exhibited reduced swimming motility and attenuated host-plant pathogenicity. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Fluorescence in situ hybridization (FISH) methods with high sensitivity are needed. Here the authors develop multiplex πFISH rainbow to detect a range of biomolecules; they also combine this with the hybridization chain reaction to develop πFISH+ technology for short nucleic acid fragment detection.

Fluorescent probe is an important tool for investigation of biological events in plant tissues. However, the research on small-molecule based fluorescent probe for plant imaging still stays at the initial stage. In order to noninvasively achieve the subcellular information of Arabidopsis thaliana, a two-photon and fluorene based fluorophore with a bi-oligo (ethylene glycol) functional group was synthesized. Under the laser's irradiation at 750 nm, the subcellular structures of Arabidopsis thaliana including stomata and root tips were clearly observed without slicing, which displayed significant superiorities over traditional single-photon excitation microscopy. Subsequently, the above functionalized fluorophore was further modified with a recognition group (dipicolylamine) to form a smart fluorescent probe (LJTP1). As results, LJTP1 not only can sensitively detect Cu2+/S2− with fluorescence “on-off-on” response in vitro and in vivo, but also can achieve noninvasive imaging in Arabidopsis thaliana tissues under two-photon microscopy. We believe this study will open up a new mind for noninvasive imaging in plant tissues.

In order to ensure the safe and stable operation of high voltage direct current (HVDC) systems, this paper studies the lightning overvoltage at the neutral point of the HVDC converter transformer. The work first introduces the basic types of lightning overvoltage based on the CIGRE Benchmark 500 kV HVDC transmission system which is modeled in the electromagnetic transient program (EMTP) software. The high-frequency model of the HVDC transmission system is considered where lightning overvoltage at the converter transformer neutral point is studied at different values of the small reactance connected at neutral point grounding and different lightning strike locations. Although increasing the small reactance value can effectively suppress the lightning current, the lightning overvoltage will gradually increase. When the neutral point is grounded by 11 Ω small reactance, the lightning overvoltage is most serious, where the peak value can reach 415 kV. Also, the farther the lightning strike position from the converter transformer, the smaller the lightning overvoltage.

Here the authors delineate the dynamic changes in 3D genome and epigenome of differentiating macrophages and during infection with Mycobacterium tuberculosis. They reveal a role for NF-κB upon infection and identify SNPs in disease-susceptible loci, including rs1873613 that is located in the anchor of a dynamic chromatin loop.

Abstract Chinese fir (Cunninghamia lanceolata) is one of southern China's most important native tree species, which has experienced noticeable climate-induced changes. Published papers (1978–2020) on tree growth of Chinese fir forests in China were collected and critically reviewed. After that, a comprehensive growth data set was developed from 482 sites, which are distributed between 102.19° and 130.07°E in longitude, between 21.87° and 37.24°N in latitude and between 5 and 2260 m in altitude. The dataset consists of 2265 entries, including mean DBH (cm), mean H (m), volume (m3), biomass (dry weight) (kg) (stem (over bark) biomass, branches biomass, leaves biomass, bark biomass, aboveground biomass, roots biomass, total trees biomass) and related information, i.e. geographical location (Country, province, study site, longitude, latitude, altitude, slope, and aspect), climate (mean annual precipitation-MAP and mean annual temperature-MAT), stand description (origin, age, canopy density and stand density), and sample regime (plot size, number and investigation year). Our results showed that (1) the best prediction of height was obtained using nonlinear composite model Height = $$1.3 + 34.23*(1 - {\text{e}}^{{\left( { - 0.01025*{\text{DBH}}^{1.347} } \right)}} )$$ 1.3 + 34.23 ∗ ( 1 - e - 0.01025 ∗ DBH 1.347 ) , (R2 = 0.8715, p aboveground (96.55%) > stems (with bark) (96.17%) > barks (88.95%) > roots (86.71%), and explained greater than 64% variability in branch biomass. The foliage biomass equation was the poorest among biomass components (R2 = 0.6122). The estimation equations derived in this study are particularly suitable for the Chinese fir forests in China. This dataset can provide a theoretical basis for predicting and assessing the potential of carbon sequestration and afforestation activities of Chinese fir forests on a national scale.

Due to the exquisite ability of cancer stemness to facilitate tumor initiation, metastasis, and cancer therapy resistance, targeting cancer stemness is expected to have clinical implications for cancer treatment. Genes are fundamental for forming and maintaining stemness. Considering shared genetic programs and pathways between embryonic stem cells and cancer stem cells, we conducted a study analyzing transcriptomic data of embryonic stem cells for mining potential cancer stemness genes. Firstly, we integrated co-expression and regression models and predicted 820 stemness genes. Results of gene enrichment analysis confirmed the good prediction performance for enriched signatures in cancer stem cells. Secondly, we provided an application case using the predicted stemness genes to construct a breast cancer stemness network. Mining on the network identified CD44, SOX2, TWIST1, and DLG4 as potential regulators of breast cancer stemness. Thirdly, using the signature of 31,028 chemical perturbations and their correlation with stemness marker genes, we predicted 67 stemness inhibitors with reasonable accuracy of 78%. Two drugs, namely Rigosertib and Proscillaridin A, were first identified as potential stemness inhibitors for melanoma and colon cancer, respectively. Overall, mining embryonic stem cell data provides a valuable way to identify cancer stemness regulators.

Abstract Sulfide minerals hold significant importance in both fundamental science and industrial advancement. However, certain natural sulfide minerals, such as NaFe3S5·2H2O (NFS), pose great challenges for exploitation and synthesis due to their high susceptibility to oxidation. To date, no successful precedent exists for synthesizing NFS. Here, a novel approach to synthesizing low‐cost and pollution‐free NFS with high stability using the high‐pressure hydrothermal method based solely on knowledge of its chemical formula is presented. Moreover, an innovative strategy inspired by the cicada's molting process to develop unstable natural materials is proposed. The mechanical, thermal, optical, electrochemical, and magnetic properties of the NFS are thoroughly investigated. The storage of lithium, sodium, and potassium ions is primarily concentrated in the gap between (0 0 1) crystal planes. Additionally, as a catalyst for hydrogen evolution reaction (HER) at 10 mA cm−2, micron‐sized NFS exhibits an excellent overpotential of 6.5 mV at 90 °C, surpassing those of reported HER catalysts of similar size. This research bridges the gap in the sulfide mineral family, overcomes limitations of the high‐pressure hydrothermal method, and paves the way for future synthesis of natural minerals, lunar minerals, and Martian minerals.

ABSTRACT Bacterial morphology is largely determined by the spatial and temporal regulation of peptidoglycan (PG) biosynthesis. Ovococci possess a unique pattern of PG synthesis different from the well studied Bacillus, and the mechanism of the coordination of PG synthesis remains poorly understood. Several regulatory proteins have been identified to be involved in the regulation of ovococcal morphogenesis, among which DivIVA is an important one to regulate PG synthesis in streptococci, while its mechanism is largely unknown. Here, the zoonotic pathogen Streptococcus suis was used to investigate the regulation of DivIVA on PG synthesis. Fluorescent d-amino acid probing and 3D-structured illumination microscopy found that DivIVA deletion caused abortive peripheral PG synthesis, resulting in a decreased aspect ratio. The phosphorylation-depleted mutant (DivIVA3A) cells displayed a longer nascent PG and became longer, whereas the phosphorylation-mimicking mutant (DivIVA3E) cells showed a shorter nascent PG and became shorter, suggesting that DivIVA phosphorylation is involved in regulating peripheral PG synthesis. Several DivIVA-interacting proteins were identified, and the interaction was confirmed between DivIVA and MltG, a cell wall hydrolase essential for cell elongation. DivIVA did not affect the PG hydrolysis activity of MltG, while the phosphorylation state of DivIVA affected its interaction with MltG. MltG was mislocalized in the ΔdivIVA and DivIVA3E cells, and both ΔmltG and DivIVA3E cells formed significantly rounder cells, indicating an important role of DivIVA phosphorylation in regulating PG synthesis through MltG. These findings highlight the regulatory mechanism of PG synthesis and morphogenesis of ovococci. IMPORTANCE The peptidoglycan (PG) biosynthesis pathway provides a rich source of novel antimicrobial drug targets. However, bacterial PG synthesis and its regulation is a very complex process involving dozens of proteins. Moreover, unlike the well studied Bacillus, ovococci undergo unusual PG synthesis with unique mechanisms of coordination. DivIVA is an important regulator of PG synthesis in ovococci, while its exact role in regulating PG synthesis remains poorly understood. In this study, we determined the role of DivIVA in regulating lateral PG synthesis of Streptococcus suis and identified a critical interacting partner, MltG, in which DivIVA influenced the subcellular localizations of MltG through its phosphorylation. Our study characterizes the detailed role of DivIVA in regulating bacterial PG synthesis, which is very helpful for understanding the process of PG synthesis in streptococci.

Natural alkaloids originating from actinomycetes and synthetic derivatives have always been among the important suppliers of small-molecule drugs. Among their biological sources, Streptomyces is the highest and most extensively researched genus. Marine-derived Streptomyces strains harbor unconventional metabolic pathways and have been demonstrated to be efficient producers of biologically active alkaloids; more than 60% of these compounds exhibit valuable activity such as antibacterial, antitumor, anti-inflammatory activities. This review comprehensively summarizes novel alkaloids produced by marine Streptomyces discovered in the past decade, focusing on their structural features, biological activity, and pharmacological mechanisms. Future perspectives on the discovery and development of novel alkaloids from marine Streptomyces are also provided.

Abstract Developing low‐cost and high‐voltage manganese (Mn)‐based Na superionic conductor (NASICON) cathode materials have attracted extensive interest. The low capacity and cycling instability of Na4MnAl(PO4)3 (NMAP), however, limits its performance in sodium‐ion batteries (SIBs). Herein, a binary Na4Mn0.5Fe0.5Al(PO4)3 (MNFAP) is fabricated to ease the structural instability and, in turn, deliver an improved reversible capacity of 102 mAh g−1 at 0.1 C and a high energy density of 287.7 Wh kg−1. The synergistic interaction of Fe and Mn in Na4Mn0.5Fe0.5Al(PO4)3/C composite leads to a one‐phase solid‐solution reaction mechanism with high structural reversibility. Theoretical calculations have also been performed to explain the upshifted voltage platform of both Fe2+/Fe3+ and Mn3+/Mn4+ redox potentials. The rational design of NASICON‐type cathodes by regulating their composition with dual metal ions provides new perspectives for developing high‐performance SIBs.

ObjectiveIn this paper, the hydrostatic resistance of a planing craft is studied using the high-precision numerical simulation method to improve the numerical prediction accuracy. MethodsThe three-dimensional viscous flow field of a planing craft in calm water is numerically simulated using the computational fluid dynamics (CFD) method combined with the Savitsky method and overset grid technique, and the flow field characteristics of the craft under different load coefficients and speeds are analyzed. ResultsThe calculated results of the resistance, sinkage and trim angle of the planing craft are in good agreement with the experimental results, and the spray phenomenon and distribution of water and air on the bottom of the craft are simulated normally, which shows that this method can accurately and effectively predict the resistance performance of planing craft. With the increase in the load coefficient, the peak value of the pressure coefficient on the keel increases, and the position of the pressure center moves forward. With the increase in speed, the peak value of the pressure coefficient on the keel decreases, the position of the pressure center gradually moves towards the stern, the angle between the stagnation line and the longitudinal section in the center plane decreases, the depth of the cavity behind the transom decreases, and the length of the cavity increases. ConclusionsThis study provides an accurate and effective numerical calculation method for the resistance prediction of planing craft, and can provide technical support for the numerical study of the hydrodynamic performance of such craft.

Abstract The natural design and coupling of biological structures are the root of realizing the high strength, toughness, and unique functional properties of biomaterials. Advanced architecture design is applied to many materials, including metal materials, inorganic nonmetallic materials, polymer materials, and so on. To improve the performance of advanced materials, the designed architecture can be enhanced by bionics of biological structure, optimization of structural parameters, and coupling of multiple types of structures. Herein, the progress of structural materials is reviewed, the strengthening mechanisms of different types of structures are highlighted, and the impact of architecture design on the performance of advanced materials is discussed. Architecture design can improve the properties of materials at the micro level, such as mechanical, electrical, and thermal conductivity. The synergistic effect of structure makes traditional materials move toward advanced functional materials, thus enriching the macroproperties of materials. Finally, the challenges and opportunities of structural innovation of advanced materials in improving material properties are discussed.

Exploring new antibacterial materials is of great significance for limiting the transmission of germs and protecting human health. Although Ag and oxide nanoparticles have both been extensively used in the field of antibacterial, it is still urgently need to figure out how to combine their characteristics for sterilization. Herein, ZnO/In2O3‐Ag nanofibers are prepared with uniformly dispersed Ag through a facile method of electrospinning and subsequent sintering. The obtained nanofibers are of high purity and have diameters from 90 to 110 nm. The silver is in a zero‐valent state, which is beneficial for sterilization. The quantitative test of bacterial activity shows that the nanofibers are bactericidal for both Staphylococcus aureus and Escherichia coli, with an especially strong inhibitory effect on E. coli. At relatively low concentrations, 98% of E. coli can be killed. Herein, light is shed on exploring more complexes of oxide nanomaterials and Ag for sterilization.

Background Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.Methods We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.Results We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.Conclusions We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.

In Xanthomonas spp., the biosynthesis of the yellow pigment xanthomonadin and fatty acids originates in the type II polyketide synthase (PKS II) and fatty acid synthase (FAS) pathways, respectively. The acyl carrier protein (ACP) is the central component of PKS II and FAS and requires posttranslational phosphopantetheinylation to initiate these pathways. In this study, for the first time, we demonstrate that the posttranslational modification of ACPs in X. campestris pv. campestris is performed by an essential 4′-phosphopantetheinyl transferase (PPTase), XcHetI (encoded by Xc_4132). X. campestris pv. campestris strain XchetI could not be deleted from the X. campestris pv. campestris genome unless another PPTase-encoding gene such as Escherichia coli acpS or Pseudomonas aeruginosa pcpS was present. Compared with wild-type strain X. campestris pv. campestris 8004 and mutant XchetI::PapcpS, strain XchetI::EcacpS failed to generate xanthomonadin pigments and displayed reduced pathogenicity for the host plant, Brassica oleracea. Further experiments showed that the expression of XchetI restored the growth of E. coli acpS mutant HT253 and, when a plasmid bearing XchetI was introduced into P. aeruginosa, pcpS, which encodes the sole PPTase in P. aeruginosa, could be deleted. In in vitro enzymatic assays, XcHetI catalyzed the transformation of 4′-phosphopantetheine from coenzyme A to two X. campestris pv. campestris apo-acyl carrier proteins, XcAcpP and XcAcpC. All of these findings indicate that XcHetI is a surfactin PPTase-like PPTase with a broad substrate preference. Moreover, the HetI-like PPTase is ubiquitously conserved in Xanthomonas spp., making it a potential new drug target for the prevention of plant diseases caused by Xanthomonas.[Graphic: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Equine piroplasmosis (EP) is a parasitic disease caused by Theileria equi (T. equi), Babesia caballi (B. caballi) and Theileria haneyi (T. haneyi). This disease is considered to be reportable by the World Organization for Animal Health (WOAH). Real-time quantitative PCR (qPCR) is regarded as a straightforward, rapid and sensitive diagnostic method to detect pathogens. However, qPCR has not been employed in the various epidemiological investigations of T. haneyi. In this study, we developed a new qPCR method to detect T. haneyi based on the chr1sco (chromosome 1 single-copy open reading frame (ORF)) gene, which has no detectable orthologs in T. equi or B. caballi. A TaqMan MGB probe was used in the development of the qPCR assay. A plasmid containing the chr1sco gene was constructed and used to establish the standard curves. The novel qPCR technique demonstrated great specificity for detecting additional frequent equine infectious pathogens and sensitivity for detecting diluted standard plasmids. This qPCR was further validated by comparison with an optimized nested PCR (nPCR) assay in the analysis of 96 clinical samples. The agreement between the nPCR assay and the established qPCR assay was 85.42%. The newly established method could contribute to the accurate diagnosis of T. haneyi infections in horses.

Abstract This meta-analysis aimed to analyze retinal microvasculature features in eyes with Behçet’s disease (BD) using optical coherence tomography angiography (OCTA). Electronic databases, including PubMed, Web of Science, Embase, and Cochrane Library, were comprehensively searched for published studies comparing retinal microvasculature characteristics between eyes with BD and controls. Continuous variables were calculated using the mean difference (MD) with 95% confidence interval (CI). Review Manager software (version 5.30) was used to conduct statistical analysis. A total of 13 eligible studies involving 599 eyes with BD and 622 control eyes were included in the meta-analysis. The pooled results showed that the macular whole enface superficial and deep vessel density (VD) values measured by OCTA were significantly lower in eyes with BD than in control eyes (superficial VD: MD = − 3.05, P

In this paper, a novel guidance law based on a reinforcement learning (RL) algorithm is presented to deal with the maneuvering target interception problem using a deep deterministic policy gradient descent neural network. We take the missile’s line-of-sight (LOS) rate as the observation of the RL algorithm and propose a novel reward function, which is constructed with the miss distance and LOS rate to train the neural network off-line. In the guidance process, the trained neural network has the capacity of mapping the missile’s LOS rate to the normal acceleration of the missile directly, so as to generate guidance commands in real time. Under the actor-critic (AC) framework, we adopt the twin-delayed deep deterministic policy gradient (TD3) algorithm by taking the minimum value between a pair of critics to reduce overestimation. Simulation results show that the proposed TD3-based RL guidance law outperforms the current state of the RL guidance law, has better performance to cope with continuous action and state space, and also has a faster convergence speed and higher reward. Furthermore, the proposed RL guidance law has better accuracy and robustness when intercepting a maneuvering target, and the LOS rate is converged.

Freak wave occurs unexpectedly in the ocean with an extreme wave crest and focused wave energy, resulting in many marine accidents. The interaction between a container ship and freak waves in beam sea is studied in this paper to better understand the influence of freak waves on ships. A three-dimensional in-house solver is developed and validated for the freak wave generation and the wave-ship interaction. Characteristics of the interaction process, motion responses of the ship and the green water loadings induced by the freak waves are obtained and analyzed. Comparisons are carried out to reveal the influences of the freak wave crest and sequence on the roll, heave and impact pressures. Relations between motion responses of the ship and the green water event are discussed. Influences of ship speeds on the wave-ship interaction are addressed.

Pyroptosis, a gasdermin-mediated inflammatory cell death, could be harnessed therapeutically to improve response to cancer immunotherapy. Here the authors report the development of recombinant adeno-associated viruses to deliver the pore-forming N-terminal domain of gasdermin into cancer cells, promoting pyroptosis and anti-tumor immune responses in preclinical cancer models.

Abstract Here, we report a case of unilateral adrenal aldosterone and cortisol co‐secreting adenoma. A 34‐year‐old man with a history of severe hypertension for one year was detected hypokalemia (2.42 mmol/L lowest) and unilateral adrenal mass in a size of 71 mm*63 mm. Measurements of plasma aldosterone concentration and plasma renin activity showed marked increases. Primary aldosteronism was diagnosed. To exclude adrenal malignancy, the function of zona fasciculate was evaluated, and 24‐h urine free cortisol was found abnormal in a testing. Further examinations revealed that circadian rhythm of serum cortisol disappeared and 2 mg‐dexamethasone suppression test was positive. The final diagnosis was secondary hypertension, primary aldosteronism and subclinical Cushing's syndrome. After unilateral adrenalectomy, his blood pressure was normalized and biochemical parameters in the normal range. In conclusion, in patients with a large aldosterone‐producing adenoma, the function of zona fasciculate might have to be evaluated for the identification of aldosterone and cortisol co‐secreting neoplasms.

Abstract Background The association of early-life undernutrition and dyslipidemia found in previous studies may be confounded by the uncontrolled age difference between exposed and unexposed participants. The study aimed to investigate the association of early-life undernutrition and the risk of dyslipidemia in adulthood with good control of the age variable. Methods We took the Great Chinese Famine (1959–1961) as a natural experiment of severe undernutrition. This study was based on the baseline investigation of a population-based cohort in rural China. Undernutrition in early life was defined as being exposed to famine at younger than 3 years of age. Three approaches including Adjustment, Restriction, and Matching were applied to control the confounding effect of age. Logistic regression models were applied to evaluate the association between early-life famine and the presence of dyslipidemia. Stratified analysis by gender was also performed, and potential effect modification was tested by adding the interaction term of the famine exposure variable and gender into the model. Results Undernutrition in early life was associated with increased risk of borderline high and above (BHA) levels of total cholesterol (TC, ORAdjustment = 1.61; ORRestriction = 1.56; ORMatching = 1.87), triglycerides (TG, ORAdjustment = 1.33; ORRestriction = 1.30; ORMatching = 1.34), low-density lipoprotein cholesterol (LDL-C, ORAdjustment = 1.75; ORRestriction = 1.53; ORMatching = 1.77) and dyslipidemia (ORAdjustment = 1.52; ORRestriction = 1.45; ORMatching = 1.60), as well as high levels of TC, TG, LDL-C and dyslipidemia. An inverse association of undernutrition and risk of low high-density lipoprotein cholesterol (HDL-C) was found. Female participants with undernutrition experience had an increased risk of BHA TG and LDL-C (TG: ORAdjustment, female = 1.45; ORRestriction, female = 1.39; ORMatching, female = 1.51; LDL-C: ORAdjustment, female = 2.11; ORRestriction, female = 1.80; ORMatching, female = 2.15), but this association was not found in males. Conclusion Early-life undernutrition increased the risk of TC, TG, LDL-C, and dyslipidemia. Gender would significantly modify this effect for TG and LDL-C. These results emphasize the importance of nutritional conditions in the early stages of life to long-term health consequences.