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Abstract Background Community-acquired pneumonia (CAP) is a common and serious condition that can be caused by a variety of pathogens. However, much remains unknown about how these pathogens interact with the lower respiratory commensals, and whether any correlation exists between the dysbiosis of the lower respiratory microbiota and disease severity and prognosis. Methods We conducted a retrospective cohort study to investigate the composition and dynamics of sputum microbiota in patients diagnosed with CAP. In total, 917 sputum specimens were collected consecutively from 350 CAP inpatients enrolled in six hospitals following admission. The V3-V4 region of the 16 S rRNA gene was then sequenced. Results The sputum microbiota in 71% of the samples were predominately composed of respiratory commensals. Conversely, 15% of the samples demonstrated dominance by five opportunistic pathogens. Additionally, 5% of the samples exhibited sterility, resembling the composition of negative controls. Compared to non-severe CAP patients, severe cases exhibited a more disrupted sputum microbiota, characterized by the highly dominant presence of potential pathogens, greater deviation from a healthy state, more significant alterations during hospitalization, and sparser bacterial interactions. The sputum microbiota on admission demonstrated a moderate prediction of disease severity (AUC = 0.74). Furthermore, different pathogenic infections were associated with specific microbiota alterations. Acinetobacter and Pseudomonas were more abundant in influenza A infections, with Acinetobacter was also enriched in Klebsiella pneumoniae infections. Conclusion Collectively, our study demonstrated that pneumonia may not consistently correlate with severe dysbiosis of the respiratory microbiota. Instead, the degree of microbiota dysbiosis was correlated with disease severity in CAP patients.

Abstract Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2’s repression of REST, which is enhanced by ADT-activated CREB1 signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology.

Abstract Low sperm motility is a significant contributor to male infertility. beta-defensins have been implicated in host defence and the acquisition of sperm motility; however, the regulatory mechanisms governing their gene expression patterns and functions remain poorly understood. In this study, we performed single-cell RNA and spatial transcriptome sequencing to investigate the cellular composition of testicular and epididymal tissues and examined their gene expression characteristics. In the epididymis, we found that epididymal epithelial cells display a region specificity of gene expression in different epididymal segments, including the beta-defensin family genes. In particular, Defb15, Defb18, Defb20, Defb25 and Defb48 are specific to the caput; Defb22, Defb23 and Defb26 to the corpus; Defb2 and Defb9 to the cauda of the epididymis. To confirm this, we performed mRNA fluorescence in situ hybridisation (FISH) targeting certain exon region of beta-defensin genes, and found some of their expression matched the sequencing results and displayed a close connection with epididimosome marker gene Cd63. In addition, we paid attention to the Sertoli cells and Leydig cells in the testis, along with fibroblasts and smooth muscle cells in the epididymis, by demonstrating their gene expression profile and spatial information. Our study provides a single-cell and spatial landscape for analysing the gene expression characteristics of testicular and epididymal environments and has important implications for the study of spermatogenesis and sperm maturation.

Abstract Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Abstract The time-varying temperature distributions on bridge structures may remarkably change structural performance, which may result in differential strain/stress responses on structural members compared with the design conditions. Therefore, it is crucial to have a comprehensive understanding of temperature distributions and its effects on bridges. In this study, taking advantage of structural health monitoring technology, 1-year field monitoring data collected from a long-span suspension bridge were used to investigate the temperature distributions and their effects on the steel box girder. Specifically, the distributions and probability statistics of temperatures on the top and bottom plates were firstly analyzed. Based on which, the transverse and vertical temperature differences on the box girder were further examined, moreover, the representative values of temperature differences for various return periods were calculated by exceedance probability method. At end, a temperature prediction method was proposed to simulated the temperature field distributions during bridge life cycle, to provide substantial temperature data for estimating future operation condition. The results of this study were beneficial to structural evaluation of in-service bridges to ensure their serviceability and integrity in the life cycle.

Abstract Background Idiopathic granulomatous mastitis (IGM) results in notable clinical symptoms and breast deformity. This study aimed to evaluate the clinical feasibility of microwave ablation (MWA) for the treatment of IGM through comparison with surgical excision. Methods From June 2016 to December 2020, a total of 234 consecutive patients admitted to the hospital were retrospectively included in this study. IGM was pathologically confirmed via breast biopsy in all included patients. These patients were divided into the MWA group (n = 91) and surgical group (n = 143) based on the type of treatment. Patients in both groups received oral prednisone prior to intervention. The clinical remission rate, recurrence rate, operative pain, complications, and BREAST Q score were compared between the two groups. Results There were 340 lesions in the MWA group, and 201 lesions in the surgical group were ultimately included. Significant differences in the complete remission rate (96.7% vs. 86.7%, p = 0.020), recurrence rate (3.3% vs. 13.3%, p = 0.020), operation time (48.7±14.6 min vs. 68.1±36.4 min, p

Backgroud: Thymic atrophy marks the onset of immune aging, precipitating developmental anomalies in T cells. Numerous clinical and preclinical investigations have underscored the regulatory role of Ganoderma lucidum spores (GLS) in T cell development. However, the precise mechanisms underlying this regulation remain elusive.Methods: In this study, a mice model of estradiol benzoate (EB)-induced thymic atrophy was constructed, and the improvement effect of GLS on thymic atrophy was evaluated. Then, we employs multi-omics techniques to elucidate how GLS modulates T cell development amidst EB-induced thymic atrophy in mice.Results: GLS effectively mitigates EB-induced thymic damage by attenuating apoptotic thymic epithelial cells (TECs) and enhancing the output of CD4+ T cells into peripheral blood. During thymic T cell development, sporoderm-removed GLS (RGLS) promotes T cell receptor (TCR) α rearrangement by augmenting V-J fragment rearrangement frequency and efficiency. Notably, biased Vα14-Jα18 rearrangement fosters double-positive (DP) to invariant natural killer T (iNKT) cell differentiation, partially contingent on RGLS-mediated restriction of peptide-major histocompatibility complex I (pMHCⅠ)-CD8 interaction and augmented CD1d expression in DP thymocytes, thereby promoting DP to CD4+ iNKT cell development. Furthermore, RGLS amplifies interaction between a DP subpopulation, termed DPsel-7, and plasmacytoid dendritic cells (pDCs), likely facilitating the subsequent development of double-negative iNKT1 cells. Lastly, RGLS suppresses EB-induced upregulation of Abpob and Apoa4, curbing the clearance of CD4+Abpob+ and CD4+Apoa4+ T cells by mTECs, resulting in enhanced CD4+ T cell output.Discussion: These findings indicate that the RGLS effectively mitigates EB-induced TEC apoptosis and compromised double-positive thymocyte development. These insights into RGLS’s immunoregulatory role pave the way for its potential as a T-cell regeneration inducer.

Persistent organic pollutants seriously affect the growth and development of crops. 1,2,4-Trichlorobenzene (TCB), as one of the most widely used chlorobenzenes, can affect the yield of japonica rice. However, existing research on the effect of TCB on japonica rice yield is not in-depth, and a basic understanding of commonality has not yet been formed. In this study, 28 conventional japonica rice varieties were selected to investigate the effects of TCB stress on their yield, yield composition, and TCB accumulation. This study also evaluated the efficiency of conventional tolerance indices in evaluating the TCB stress tolerance of japonica rice. The results showed that TCB caused sustained inhibition of the growth of japonica rice, which was considerably manifested in plant height, root length, soil plant analysis development (SPAD), and dry weight at different growth stages. Under TCB stress, TCB accumulation in various tissues of japonica rice increased sharply. TCB stress reduces the yield of japonica rice by reducing the number of panicles per hill, the number of spikelets per panicle, the grain filling percentage, and the grain weight. Overall, the results of this study indicate that TCB stress can cause a decrease in the yield of japonica rice, and the decrease in panicle number is the main reason. The conventional tolerance index can effectively evaluate the tolerance of japonica rice to TCB. The results of this study are substantial for the breeding and cultivation of japonica rice.

The dust pollution during the wet-mix shotcrete process in mines constitutes a crucial factor limiting the efficiency, cleanliness, and safety of wet-mix shotcrete support projects. To mitigate the potential harm to workers and enhance the dust control and occupational health capabilities of mines, a dynamic model for the dust generation during wet-mix shotcrete is constructed using the aerosol mechanics and the Hertz-Mindlin collision theory. In consideration of the characteristics of the wet-mix shotcrete process, a similar experimental apparatus for wet-mix shotcrete is established to analyze the dust generation characteristics under different process conditions. Additionally, focusing on the dust reduction mechanism of additives in the wet-mix shotcrete process, a study is conducted on the dust reduction performance of additives, leading to the formulation of a high-performance composite dust-reducing additive suitable for the wet-mix shotcrete process. The results show that the aerosol particles dispersed in the air during the wet-mix shotcrete process predominantly have diameters below 2 μm, with particles below 2 μm constituting over 90% of the particle count. Dust generation during wet-mix shotcrete is primarily influenced by factors such as spray distance, spray pressure, and water-cement ratio. The optimal spray distance should avoid extremes, and as the distance increases, the particle concentration shows a trend of initially decreasing and then increasing. Similarly, a spray pressure of 0.4 MPa is deemed suitable, and excessively high pressure leads to an increased rebound rate and dust concentration, while very low pressure results in insufficient kinetic energy for material adhesion to the sprayed surface. Simultaneously, maintaining material fluidity and reducing rebound rates and dust generation can be achieved by lowering the water-cement ratio. The composite dust-reducing additive, composed of setting accelerators, chelating agents, early strength agents, binders, and surfactants, is developed. Through orthogonal and optimization experiments, the final formula is determined as A-55%, B-3%, C-4.5%, D-0.5%, E-0.15%, and water-36.85%. Incorporating this composite dust-reducing additive reduces dust concentration during the wet-mix shotcrete process by approximately 57%, effectively lowering dust emissions and demonstrating a significant dust reduction effect.

Tuberculosis (TB) remains one of the deadliest chronic infectious diseases globally. Early diagnosis not only prevents the spread of TB but also ensures effective treatment. However, the absence of non-sputum-based diagnostic tests often leads to delayed TB diagnoses. Inflammation is a hallmark of TB, we aimed to identify biomarkers associated with TB based on immune profiling. We collected 222 plasma samples from healthy controls (HCs), disease controls (non-TB pneumonia; PN), patients with TB (TB), and cured TB cases (RxTB). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure the levels of 92 immune proteins. Based on differential analysis and the correlation with TB severity, we selected 9 biomarkers (CXCL9, PDL1, CDCP1, CCL28, CCL23, CCL19, MMP1, IFNγ and TRANCE) and explored their diagnostic capabilities through 7 machine learning methods. We identified combination of these 9 biomarkers that distinguish TB cases from controls with an area under the receiver operating characteristic curve (AUROC) of 0.89–0.99, with a sensitivity of 82–93% at a specificity of 88–92%. Moreover, the model excels in distinguishing severe TB cases, achieving AUROC exceeding 0.95, sensitivities and specificities exceeding 93.3%. In summary, utilizing targeted proteomics and machine learning, we identified a 9 plasma proteins signature that demonstrates significant potential for accurate TB diagnosis and clinical outcome prediction.

ABSTRACTChina, with the third largest share of global tuberculosis cases, faces a substantial challenge in its healthcare system as a result of the high burden of multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB). This study employs a genomic epidemiological approach to assess recent tuberculosis transmissions between individuals, identifying potential risk factors and discerning the role of transmitted resistant isolates in the emergence of drug-resistant tuberculosis in China. We conducted a population-based retrospective study on 5052 Mycobacterium tuberculosis (MTB) isolates from 70 surveillance sites using whole genome sequencing (WGS). Minimum spanning tree analysis identified resistance mutations, while epidemiological data analysis pinpointed transmission risk factors. Of the 5052 isolates, 23% (1160) formed 452 genomic clusters, with 85.6% (387) of the transmissions occurring within the same counties. Individuals with younger age, larger family size, new cases, smear positive, and MDR/RR were at higher odds for recent transmission, while higher education (university and above) and occupation as a non-physical workers emerged as protective factors. At least 61.4% (251/409) of MDR/RR-TB were likely a result of recent transmission of MDR/RR isolates, with previous treatment (crude OR = 2.77), smear-positive (cOR = 2.07) and larger family population (cOR = 1.13) established as risk factors. Our findings highlight that local transmission remains the predominant form of TB transmission in China. Correspondingly, drug-resistant tuberculosis is primarily driven by the transmission of resistant tuberculosis isolates. Targeted interventions for high-risk populations to interrupt transmission within the country will likely provide an opportunity to reduce the prevalence of both tuberculosis and drug-resistant tuberculosis.

AbstractA kind of highly dispersed ZrO2 modified Cs/SiO2-based catalyst was prepared via ligand–assisted impregnation strategy. The catalyst was then used to the aldol condensation reaction of methyl acetate (MAc) with formaldehyde (FA) to produce methyl acrylate (MA). The effect of highly dispersed ZrO2 promotion on Cs/SiO2 catalyst selectivity and activity was studied as well. Various techniques such as XRD, FT-IR, TEM, XPS, NH3-TPD, CO2-TPD, N2 physical adsorption, and solid-state MAS NMR were used to characterize the structural features, Cs species states, and acid–base properties of these catalysts. The use of Zr(acac)4 as a zirconium source for modifying Cs/SiO2 could be considered optimal for ligand-assisted impregnation. By modifying the highly dispersed ZrO2, more Cs–O–Si species and a suitable balance of acid–base sites were formed in the Zr–Cs/SiO2 catalyst. As a result, the catalyst showed significant improvements in selectivity and yield of MA under optimized reaction conditions. This study is beneficial for the development and optimization of catalysts for aldol condensation and provides a reference for future industrial applications.

The Huoshaoyun deposit in the Karakorum area of NW China is the world’s largest zinc-lead carbonate ore deposit. Here we investigate the genesis of the mineralization based on multiproxy investigations. The deposit contains zinc-lead carbonate and sulfide minerals, with smithsonite (Smt), cerussite (Cer), and sulfides accounting for 85%, 10%, and 5% of the total lead and zinc resources, respectively. Three ore-forming stages, involving Smt, Cer, and sulfides ores were summarized. The Smt mineralization is characterized by veined, massive, and stratified Smt forming horizontal sedimentary layered ore and vertical feeder veins similar to the SEDEX-type deposits. The sulfide and Cer veins display typical hydrothermal characteristics and are superimposed on the massive Smt ores. The Smt ores show high Li, Be, Cr, Y, Ba, Nd, Yb, and Zr contents, whereas the Cer veins have extremely high Sr contents (up to 3814–9174 ppm) and low Zr contents (less than 0.01 ppm). Galena and sphalerite show higher Cd concentrations compared to Smt and Cer ores.The Smt ores differ with different spatial locations, with Smt ores formed at the vent have δ66Zn values of +0.15‰ to +0.21‰, the massive Smt formed close to the vent show a value of +0.13‰, and those formed away from the vent show a value of 0.05‰, all values being close to 0. The sulfides have δ66Zn values of −0.09‰ to +0.04‰. The C-O isotopes of Smt ores are similar to both altered and unaltered host limestone, suggesting that the limestone was a potential source for carbon and oxygen. Quartz with veined Smt shows magmatic signatures with δ18OVSMOW of +1.14‰ to +2.23‰, high Pb (115–401 ppm) and Zn concentrations (390–997 ppm), whereas quartz associated with sulfide has meteoric fluid signature with the lowest δ18OVSMOW (−14‰ to −10.7‰), low Pb (11.6–49.0 ppm) and Zn (18.1–72.8 ppm) concentrations. The temperature of equilibration computed based on oxygen isotope fractionation between Smt and coeval quartz indicate a dual source with that of quartz derived from an aqueous fluid, whereas the source for Smt might involve CO2 or HCO3−.We trace multiple metallogenic stages for this deposit including exhalation, hydrothermal deposition, and fault-controlled sulfide vein formation. The largest orebody (III-1) preserves a 16 Mt reserve of Zn and was formed by crust-mantle interaction at ca. 195 Ma in the early development of the Linjitang post-arc rift system. Fluid convection, zinc enrichment driven by granitic magma, volcanic activity, and karst alteration induced by acid rain in a lagoonal environment promoted ore enrichment.

BackgroundRecent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer’s disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear.ObjectiveThe purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms.MethodsAlzheimer’s disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction.ResultsTestosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T’s protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function.ConclusionTestosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Abstract Lung cancer is one of the leading causes of cancer‐related deaths worldwide, with non‐small cell lung cancer (NSCLC) being the most prevalent type. This study investigates the role of TRIM11 gene in NSCLC and its underlying mechanism. NSCLC patients were recruited from our hospital and showed upregulated TRIM11 mRNA and protein expressions. Patients with high TRIM11 expression had lower survival rates. TRIM11 gene was found to promote cell proliferation and reduce ROS‐induced ferroptosis in NSCLC. Additionally, TRIM11 gene induced AMPK expression and its regulation affected TRIM11's effects on cell proliferation and ferroptosis in NSCLC. IP analysis revealed that TRIM11 protein interacted with AMPK protein in NSCLC. These data confirmed that TRIM11 promotes cell proliferation and reduces ROS‐induced ferroptosis in NSCLC through AMPK. Hence, TRIM11 is a potential target for the treatment of NSCLC and other cancers.

BackgroundIncreasing evidence indicating that coronavirus disease 2019 (COVID-19) increased the incidence and related risks of pericarditis and whether COVID-19 vaccine is related to pericarditis has triggered research and discussion. However, mechanisms behind the link between COVID-19 and pericarditis are still unknown. The objective of this study was to further elucidate the molecular mechanisms of COVID-19 with pericarditis at the gene level using bioinformatics analysis.MethodsGenes associated with COVID-19 and pericarditis were collected from databases using limited screening criteria and intersected to identify the common genes of COVID-19 and pericarditis. Subsequently, gene ontology, pathway enrichment, protein–protein interaction, and immune infiltration analyses were conducted. Finally, TF–gene, gene–miRNA, gene–disease, protein–chemical, and protein–drug interaction networks were constructed based on hub gene identification.ResultsA total of 313 common genes were selected, and enrichment analyses were performed to determine their biological functions and signaling pathways. Eight hub genes (IL-1β, CD8A, IL-10, CD4, IL-6, TLR4, CCL2, and PTPRC) were identified using the protein–protein interaction network, and immune infiltration analysis was then carried out to examine the functional relationship between the eight hub genes and immune cells as well as changes in immune cells in disease. Transcription factors, miRNAs, diseases, chemicals, and drugs with high correlation with hub genes were predicted using bioinformatics analysis.ConclusionsThis study revealed a common gene interaction network between COVID-19 and pericarditis. The screened functional pathways, hub genes, potential compounds, and drugs provided new insights for further research on COVID-19 associated with pericarditis.

Agrobacterium tumefaciens is a soil-borne pathogenic bacterium that causes crown gall disease in many plants. Chemotaxis offers A. tumefaciens the ability to find its host and establish infection. Being an aerobic bacterium, A. tumefaciens possesses one chemotaxis system with multiple potential chemoreceptors. Chemoreceptors play an important role in perceiving and responding to environmental signals. However, the studies of chemoreceptors in A. tumefaciens remain relatively restricted. Here, we characterized a cytoplasmic chemoreceptor of A. tumefaciens C58 that contains an N-terminal globin domain. The chemoreceptor was designated as Atu1027. The deletion of Atu1027 not only eliminated the aerotactic response of A. tumefaciens to atmospheric air but also resulted in a weakened chemotactic response to multiple carbon sources. Subsequent site-directed mutagenesis and phenotypic analysis showed that the conserved residue His100 in Atu1027 is essential for the globin domain’s function in both chemotaxis and aerotaxis. Furthermore, deleting Atu1027 impaired the biofilm formation and pathogenicity of A. tumefaciens. Collectively, our findings demonstrated that Atu1027 functions as an aerotaxis receptor that affects agrobacterial chemotaxis and the invasion of A. tumefaciens into its host.

Metal-organic framework (MOF)-based mixed matrix membranes (MMMs) have attracted significant attentions for their distinguished characteristics in pervaporation such as enhanced selectivity, increased permeability and improved mechanical strength through the synergistic integration of polymeric matrices and inorganic fillers. Although many publications have emerged in recent years focusing on MOF-based MMMs, this review specifically emphasizes the improvement of MOF-based pervaporation membranes through the design of dimension of fillers and microstructure. The challenges encountered in MOF-based MMMs for pervaporation and the essential requirements for practical separation applications are addressed. A brief summary of strategies is provided for designing MOF-based MMMs with desired microstructure, macrostructure and multicomponent characteristics by using MOFs as fillers. The latest progresses in novel MOF-based MMMs with specific compositions, controllable pore structure and improved compatibility for recovery of organics are also displayed. The broad application prospects of MOF-based MMMs in pervaporation are introduced, including recovery of ethyl alcohol, butanol and other organics. Moreover, the challenges faced in the practical application of MOF-based MMMs for recovery of organics are presented and the promising future directions are outlined.

Abstract Background Gut microbiota plays a significant role in host survival, health, and diseases; however, compared to other livestock, research on the gut microbiome of donkeys is limited. Results In this study, a total of 30 donkey samples of rectal contents from six regions, including Shigatse, Changdu, Yunnan, Xinjiang, Qinghai, and Dezhou, were collected for metagenomic sequencing. The results of the species annotation revealed that the dominant phyla were Firmicutes and Bacteroidetes, and the dominant genera were Bacteroides, unclassified_o_Clostridiales (short for Clostridiales) and unclassified_f_Lachnospiraceae (short for Lachnospiraceae). The dominant phyla, genera and key discriminators were Bacteroidetes, Clostridiales and Bacteroidetes in Tibet donkeys (Shigatse); Firmicutes, Clostridiales and Clostridiales in Tibet donkeys (Changdu); Firmicutes, Fibrobacter and Tenericutes in Qinghai donkeys; Firmicutes, Clostridiales and Negativicutes in Yunnan donkeys; Firmicutes, Fibrobacter and Fibrobacteres in Xinjiang donkeys; Firmicutes, Clostridiales and Firmicutes in Dezhou donkeys. In the functional annotation, it was mainly enriched in the glycolysis and gluconeogenesis of carbohydrate metabolism, and the abundance was the highest in Dezhou donkeys. These results combined with altitude correlation analysis demonstrated that donkeys in the Dezhou region exhibited strong glucose-conversion ability, those in the Shigatse region exhibited strong glucose metabolism and utilization ability, those in the Changdu region exhibited a strong microbial metabolic function, and those in the Xinjiang region exhibited the strongest ability to decompose cellulose and hemicellulose. Conclusion According to published literature, this is the first study to construct a dataset with multi-regional donkey breeds. Our study revealed the differences in the composition and function of gut microbes in donkeys from different geographic regions and environmental settings and is valuable for donkey gut microbiome research.

Abstract Background To explore the impact of preoperative 3D printing on the fixation of posterior rib fractures utilizing a memory alloy embracing device of rib under thoracoscopy. Methods The enrolled patients were divided into the 3D printing (11 patients) and the non-3D printing (18 patients) groups, based on whether a 3D model of ribs was prepared prior to surgery. Analysis was conducted comparing the average fixation time per fracture, postoperative fixation loss, and poor reduction of fractured end between the two groups. Results The average fixation time of each fracture was 27.2 ± 7.7 min in the 3D printing group and 29.3 ± 8.2 min in the non-3D printing group, with no statistically significant difference observed between the two groups (P > 0.05). The incidence of poor fracture fixation in the 3D printing group was statistically lower than that in the non-3D printing group (12.9% vs. 44.7%, P 0.05), and the dislocation rate of the fractured end was (9.7% vs. 31.9%, P

Pectin cellulose grafted with glycidyltrimethylammoniochloride (GTMAC) was successfully obtained following the processes of depectinfibrillation and cellulose cationization using ordinary Shatian pomelo peel produced in Yongzhou, Hunan, as the raw material. This is the first report on a new type of functionalized sodium alginate-immobilized material prepared from the fibers of pomelo peel. The material was prepared by combining modified pomelo peel cellulose and sodium alginate following the processes of physical and chemical double cross-linking. The prepared material was used to embed the target bacteria to achieve the biodegradation of p-aniline. The concentration of CaCl2 was adjusted when the alginate gelled, and the alginate to yuzu peel cellulose ratio was tuned. The immobilized material-embedded bacteria help achieve the best degradation effect. Bacteria are embedded during the process of the degradation of aniline wastewater, and the functionalization of the cellulose/sodium alginate-immobilized material results in unique surface structure performance. The performance of the prepared system is better than that of the single sodium alginate-based material characterized by a large surface area and good mechanical properties. The degradation efficiency of the system is improved significantly for the cellulose materials, and the prepared materials can potentially find applications in the field of bacteria-fixed technology. HIGHLIGHTS Pomelo peel fiber was extracted for the first time and used in the preparation of immobilized material.; By combining with sodium alginate, the specific surface area of the fixed material can be increased by the pomelo peel fiber with a spiral tube shape and rough surface.; The cationic-modified pomelo peel fiber can improve the mechanical properties and stability of the immobilized material by ionic bonding.;

Abstract The prickly nightshade Solanum rostratum, an annual malignant weed, is native to North America and has globally invaded 34 countries, causing serious threats to ecosystems, agriculture, animal husbandry, and human health. In this study, we constructed a chromosome-level genome assembly and annotation of S. rostratum. The contig-level genome was initially assembled in 898.42 Mb with a contig N50 of 62.00 Mb from PacBio high-fidelity reads. With Hi-C sequencing data scaffolding, 96.80% of the initially assembled sequences were anchored and orientated onto 12 pseudo-chromosomes, generating a genome of 869.69 Mb with a contig N50 of 72.15 Mb. We identified 649.92 Mb (72.26%) of repetitive sequences and 3,588 non-coding RNAs in the genome. A total of 29,694 protein-coding genes were predicted, with 28,154 (94.81%) functionally annotated genes. We found 99.5% and 91.3% complete embryophyta_odb10 genes in the pseudo-chromosomes genome and predicted gene datasets by BUSCO assessment. The present genomic resource provides essential information for subsequent research on the mechanisms of environmental adaptation of S. rostratum and host shift in Colorado potato beetles.

Abstract Morphological parameters of knee joint are related to race and nationality. At present, knee prosthesis come from white male population. Due to the mismatch between the prosthesis and other ethnic groups, the prosthesis life span is reduced, revision surgery and the patients’ economic burden are increased. There is no data of the Mongolian ethnic group. In order to treat patients more accurately, we measured the Mongolian data of the femoral condyle. A total of 122 knee joints were scanned in 61 volunteers (21 males and 40 females) with an average age of 23.259 ± 1.395 years. The Mimics software was used to reconstruct the 3D image and measure the data of each line. The data were analyzed by statistical methods such as t test, and P 0.05). (2) The different genders data of femoral condyle were statistically significant (P

Abstract Background Community-acquired pneumonia (CAP) is a major public health challenge worldwide. However, the aetiological and disease severity-related pathogens associated with CAP in adults in China are not well established based on the detection of both viral and bacterial agents. Methods A multicentre, prospective study was conducted involving 10 hospitals located in nine geographical regions in China from 2014 to 2019. Sputum or bronchoalveolar lavage fluid (BALF) samples were collected from each recruited CAP patient. Multiplex real-time PCR and bacteria culture methods were used to detect respiratory pathogens. The association between detected pathogens and CAP severity was evaluated. Results Among the 3,403 recruited eligible patients, 462 (13.58%) had severe CAP, and the in-hospital mortality rate was 1.94% (66/3,403). At least one pathogen was detected in 2,054 (60.36%) patients, with two or more pathogens were co-detected in 725 patients. The ten major pathogens detected were Mycoplasma pneumoniae (11.05%), Haemophilus influenzae (10.67%), Klebsiella pneumoniae (10.43%), influenza A virus (9.49%), human rhinovirus (9.02%), Streptococcus pneumoniae (7.43%), Staphylococcus aureus (4.50%), adenovirus (2.94%), respiratory syncytial viruses (2.35%), and Legionella pneumophila (1.03%), which accounted for 76.06–92.52% of all positive detection results across sampling sites. Klebsiella pneumoniae (p

Concrete structures usually have to experience some unfavorable environmental actions during their service life, leading to the mechanical properties degradation, moreover, cyclic loadings such as traffic loads, wind loads may further accelerate structural damage, therefore, improving durability of concrete is of vital for structures servicing in severe environment. Graphene oxide (GO), as a new nano-reinforced material, has ultra-high mechanical properties and large specific surface area as a concrete reinforcing material. This study entailed an examination of the properties of Graphene Oxide Concrete (GOC) with varying levels of GO incorporation (0, 0.02, 0.05, 0.08 wt%). It also encompassed an analysis of the fatigue properties of GOC under different stress levels and varying sulfate wetting and drying cycles. Additionally, the investigation delved into the degradation mechanisms affecting Graphene Oxide Concrete (GOC) when subjected to sulfate erosion conditions. Furthermore, the study assessed the mass loss of specimens and their fatigue life under diverse environmental conditions. The results showed that appropriate GO incorporations could enhance concrete’s mechanical and fatigue properties after sulfate attack. In addition, scanning electron microscope (SEM) analysis showed that GO could adjust the aggregation state of cement hydration products and its own reaction with some cement hydration crystals to form strong covalent bonds, to improve and enhance microstructural denseness.

ABSTRACT The polymorphism at amino acid 17 of quinolone resistance-determining region of GyrA has been stated with a potential role in fluoroquinolone susceptibility in different mycobacterial species. However, no study has provided dependable evidence so far. Here, we verified that gene-edited Mycobacterium abscessus mutants bearing Ser/Gly at this position were more susceptible to fluoroquinolones than their parent strain and the revertant that supports mycobacteria containing Ser/Gly at this position were more susceptible to fluoroquinolones than those containing Ala. IMPORTANCE Fluoroquinolones (FQs) play a key role in the treatment regimens against tuberculosis and non-tuberculous mycobacterial infections. However, there are significant differences in the sensitivities of different mycobacteria to FQs. In this study, we proved that this is associated with the polymorphism at amino acid 17 of quinolone resistance-determining region of Gyrase A by gene editing. This is the first study using CRISPR-associated recombination for gene editing in Mycobacterium abscessus to underscore the contribution of the amino acid substitutions in GyrA to FQ susceptibilities in mycobacteria.

Subduction zones play a critical role in the global carbon cycle by regulating carbon exchange between the Earth's surface and interior. Processes that are known to release carbon from the slab, including metamorphic decarbonation and carbonate dissolution, cannot explain the high CO2 flux in magmatic arcs. Slab melting is the least considered mechanism for carbon mobilization at subarc depths based on the high solidus temperatures of carbonated lithologies, which were experimentally determined under dry or H2O-absent conditions. Subducted sediments are major carbon carriers, however, their melting behaviour with excess H2O remains largely unexplored. Here, we perform fluid-present melting, high-pressure experiments at 750–1100 °C and 2.5–4 GPa using starting compositions similar to global average subducted sediments to determine the solidus, melting relations and carbonate stability fields. The onset of melting is between 750 and 800 °C at 2.5 GPa and between 850 and 900 °C at 4 GPa. Dolomite melts out on or close to the solidus, whereas crystalline aragonite persists >150 °C above the solidus. Flux melting of carbonated sediment at moderately hot subduction zones is examined to be feasible in the framework of the previously constructed dehydration history of the underlying serpentinites, providing a pathway to transfer carbon from the slab to the subarc mantle. However, complete breakdown of refractory aragonite requires at least 50 °C higher than that predicted for the hottest slab P‒T paths. Thus, even in the presence of H2O, partial subducted carbon may survive the melting event occurring at shallow regions and reach considerable mantle depths.

Abstract Objective APC (adenomatous polyposis coli) gene mutation is a central initialization in colon cancer tumorigenesis. However, the connection between APC gene mutation and immunotherapy efficacy for colon cancer remains unknown. This study aimed to explore the impact of APC mutation on immunotherapy efficacy for colon cancer. Methods Colon cancer data from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) were used for the combined analysis. Survival analysis was performed to evaluate the association between APC mutation and immunotherapy efficacy in colon cancer patients. The expressions of immune check point molecules, tumor mutation burden (TMB), CpG methylation level, tumor purity (TP), microsatellite instability (MSI) status and tumor-infiltrating lymphocyte (TIL) in the two APC status were compared to evaluate the associations between APC mutation and immunotherapy efficacy indicators. Gene set enrichment analysis (GSEA) was performed to identify signaling pathways related to APC mutation. Results APC was the most frequently mutated gene in colon cancer. The survival analysis demonstrated that APC mutation was correlated with a worse immunotherapy outcome. APC mutation was associated with lower TMB, lower expression of immune check point molecules (PD-1/PD-L1/PD-L2), higher TP, lower MSI-High proportion and less CD8 + T cells and follicular helper T cells infiltration. GSEA indicated that APC mutation up-regulated mismatch repair pathway, which may play a negative role in evoking an antitumor immune response. Conclusion APC mutation is associated with worse immunotherapy outcome and inhibition of antitumor immunity. It can be used as a negative biomarker to predict immunotherapy response.

Hydrous carbonatitic liquids can be generated from the subducting slab at temperatures as low as 850–900 °C which could confine the carbon cycle to depths of less than 200 km, according to high-pressure laboratory experiments on carbonated hydrous pelites.

Abstract Background Iris lactea var. chinensis, a perennial herbaceous species, is widely distributed and has good drought tolerance traits. However, there is little information in public databases concerning this herb, so it is difficult to understand the mechanism underlying its drought tolerance. Results In this study, we used Illumina sequencing technology to conduct an RNA sequencing (RNA-seq) analysis of I. lactea var. chinensis plants under water-stressed conditions and rehydration to explore the potential mechanisms involved in plant drought tolerance. The resulting de novo assembled transcriptome revealed 126,979 unigenes, of which 44,247 were successfully annotated. Among these, 1187 differentially expressed genes (DEGs) were identified from a comparison of the water-stressed treatment and the control (CK) treatment (T/CK); there were 481 upregulated genes and 706 downregulated genes. Additionally, 275 DEGs were identified in the comparison of the rehydration treatment and the water-stressed treatment (R/T). Based on Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) analysis, the expression levels of eight randomly selected unigenes were consistent with the transcriptomic data under water-stressed and rehydration treatment, as well as in the CK. According to Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, proline metabolism-related DEGs, including those involved in the ‘proline catabolic process’, the ‘proline metabolic process’, and ‘arginine and proline metabolism’, may play important roles in plant drought tolerance. Additionally, these DEGs encoded 43 transcription factors (TFs), 46 transporters, and 22 reactive oxygen species (ROS)-scavenging system-related proteins. Biochemical analysis and histochemical detection showed that proline and ROS were accumulated under water-stressed conditions, which is consistent with the result of the transcriptomic analysis. Conclusions In summary, our transcriptomic data revealed that the drought tolerance of I. lactea var. chinensis depends on proline metabolism, the action of TFs and transporters, and a strong ROS-scavenging system. The related genes found in this study could help us understand the mechanisms underlying the drought tolerance of I. lactea var. chinensis.

Soil heavy metal pollution poses a formidable challenge for environmental protection professionals. This study delves into the impact of zinc and lead pollution on the particle size distribution, liquid-plastic limit, permeability, shear strength, and other pertinent physical and engineering properties of clay. The alterations in the microstructure of soil contaminated by heavy metals were scrutinized using a scanning electron microscope. The findings reveal that as the concentration of heavy metals in contaminated soil rises, there is a concurrent decrease in the liquid limit, plasticity index, and silt content. This, in turn, leads to the deterioration of the original fluidity and plasticity of the soil, accompanied by a reduction in fine particles. Resistivity tests indicate that an escalation in water content results in a decrease in resistivity, an increase in porosity leads to an increase in resistivity, and an elevation in the concentration of heavy metals precipitates a sharp decline in resistivity due to the heightened conductivity of heavy metal ions. Heavy metal pollution induces structural changes in the soil, particularly in pore size, thereby influencing the permeability coefficient.

The purpose of this study is to explore the possibility of using graphene–zinc oxide–hydroxyapatite (GO/ZnO/nHAp) composite microspheres as bone regeneration materials by making use of the complementary advantages of nanocomposites, so as to provide reference for the clinical application of preventing and solving bacterial infection after implantation of synthetic materials. Firstly, GO/ZnO composites and hydroxyapatite nanoparticles were synthesized using the hydrothermal method, and then GO/ZnO/nHAp composite microspheres were prepared via high-temperature sintering. The graphene–zinc oxide–calcium phosphate composite microspheres were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS), energy dispersion spectroscopy (EDS), water contact angle measurement, degradation and pH determination, and differential thermal analysis (DiamondTG/DTA). The biocompatibility, osteogenic activity, and antibacterial activity of GO/ZnO/nHAp composite microspheres were further studied. The results of the cell experiment and antibacterial experiment showed that 0.5% and 1% GO-ZnO-nHAp composite microspheres not only had good biocompatibility and osteogenic ability but also inhibited Escherichia coli and Staphylococcus aureus by more than 45% and 70%. Therefore, GO/ZnO/nHAp composite microspheres have good physical and chemical properties and show good osteogenic induction and antibacterial activity, and this material has the possibility of being used as a bone regeneration material.

Some cancer cells migration and metastasis are characterized by the outgrowth of lamellipodia protrusions in which the underlying mechanism remains unclear. Evidence has confirmed that lamellipodia formation could be regulated by various adhesion molecules, such as CD44, and we previously reported that lamellipodia at the leading edge of luminal type breast cancer (BrCa) were enriched with high expression of CD44. In this study, we found that the overexpression of CD44s could promote lamellipodia formation in BrCa cells through inducing tissue type plasminogen activator (tPA) upregulation, which was achieved by PI3K/Akt signaling pathway activation. Moreover, we revealed that tPA could interact with LDL receptor related protein 1 (LRP1) to activate the downstream NFκB signaling pathway, which in turn facilitate lamellipodia formation. Notably, inhibition of the tPA/LRP1-NFkB signaling cascade could attenuate the CD44s-induced lamellipodia formation. Thus, our findings uncover a novel role of CD44s in driving lamellipodia outgrowth through tPA/LRP1-NFkB axis in luminal BrCa cells that may be helpful for seeking potential therapeutic targets.

IntroductionErigeron philadelphicus and Erigeron annuus are two ecologically destructive invasive plants from the Asteraceae family. Predicting the potential distribution pattern of two invasive alien Erigeron weeds can provide a scientific basis for prevent the further spread of these two weeds in China under climate change.MethodsBased on historical occurrence datasets and environmental variables, we optimized a MaxEnt model to predict the potential suitable habitats of E. philadelphicus and E. annuus. We also analyzed the shifts of distribution centroids and patterns under climate change scenarios.ResultsThe key variables that affect the potential geographical distribution of E. annuus and E. philadelphicus, respectively, are temperature seasonality and precipitation of the driest month. Moreover, topsoil sodicity and topsoil salinity also influence the distribution of E. philadelphicus. Under climate change, the overall suitable habitats for both invasive alien Erigeron weeds are expected to expand. The potential geographical distribution of E. annuus exhibited the highest expansion under the SSP245 climate scenario (medium forcing scenarios), whereas E. philadelphicus had the highest expansion under the SSP126 climate scenario (lower forcing scenarios) globally. The future centroid of E. annuus is projected to shift to higher latitudes specifically from Hubei to Hebei, whereas E. philadelphicus remains concentrated primarily in Hubei Province. The overlapping suitable areas of the two invasive alien Erigeron plants mainly occur in Jiangsu, Zhejiang, Fujian, Jiangxi, Hunan, Guizhou, and Chongqing, within China.DiscussionClimate change will enable E. annuus to expand into northeastern region and invade Yunnan Province whereas E. philadelphicus was historically the only suitable species. E. annuus demonstrates a greater potential for invasion and expansion under climate change, as it exhibits higher environmental tolerance. The predictive results obtained in this study can serve as a valuable reference for early warning systems and management strategies aimed at controlling the spread of these two invasive plants.

ABSTRACT Drug-resistant tuberculosis (TB) poses a major threat to global TB control; consequently, there is an urgent need to develop novel anti-TB drugs or strategies. Host-directed therapy (HDT) is emerging as an effective treatment strategy, especially for drug-resistant TB. This study evaluated the effects of berbamine (BBM), a bisbenzylisoquinoline alkaloid, on mycobacterial growth in macrophages. BBM inhibited intracellular Mycobacterium tuberculosis (Mtb) growth by promoting autophagy and silencing ATG5, partially abolishing the inhibitory effect. In addition, BBM increased intracellular reactive oxygen species (ROS), while the antioxidant N-acetyl-L-cysteine (NAC) abolished BBM-induced autophagy and the ability to inhibit Mtb survival. Furthermore, the increased intracellular Ca2+ concentration induced by BBM was regulated by ROS, and BAPTA-AM, an intracellular Ca2+-chelating agent, could block ROS-mediated autophagy and Mtb clearance. Finally, BBM could inhibit the survival of drug-resistant Mtb. Collectively, these findings provide evidence that BBM, a Food and Drug Administration (FDA)–approved drug, could effectively clear drug-sensitive and -resistant Mtb through regulating ROS/Ca2+ axis-mediated autophagy and has potential as an HDT candidate for TB therapy. IMPORTANCE It is urgent to develop novel treatment strategies against drug-resistant TB, and HDT provides a promising approach to fight drug-resistant TB by repurposing old drugs. Our studies demonstrate, for the first time, that BBM, an FDA-approved drug, not only potently inhibits intracellular drug-sensitive Mtb growth but also restricts drug-resistant Mtb by promoting macrophage autophagy. Mechanistically, BBM activates macrophage autophagy by regulating the ROS/Ca2+ axis. In conclusion, BBM could be considered as an HDT candidate and may contribute to improving the outcomes or shortening the treatment course of drug-resistant TB.

The teaching of the optimization algorithm is a new kind of swarm intelligence optimization technique, which is superior in optimizing many simple functions. Still, it is not evident in processing some complex problems (group and teaching classification). Achieving automatic matching and knowledge transfer in online courses is imperative in mathematics education. This study proposes a design scheme MTCBO-LR (multiobjective capability optimizer-logistic regression), based on multitask optimization, which enables precise knowledge transfer and data interaction among many educators. It incorporates the standard TLBO algorithm to optimize, provides a variety of learning tactics for students at different stages of mathematics instruction, and is capable of adaptively adjusting these strategies in response to actual teaching needs. Experimental results on various datasets reveal that the proposed method enhances searchability and group diversity in various optimization extremes and outperforms similar methods in resolving to multitask teaching problems.

Tuberculosis (TB) remains a major underdiagnosed public health threat worldwide, being responsible for more than 10 million cases and one million deaths annually. TB diagnosis has become more rapid with the development and adoption of molecular tests, but remains challenging with traditional TB diagnosis, but there has not been a critical review of this area. Here, we systematically review these approaches to assess their diagnostic potential and issues with the development and clinical evaluation of proposed CRISPR-based TB assays. Based on these observations, we propose constructive suggestions to improve sample pretreatment, method development, clinical validation, and accessibility of these assays to streamline future assay development and validation studies.

Abstract Background Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) remains a global health issue. The characterized virulent M. tb H37Rv, avirulent M. tb H37Ra and BCG strains are widely used as reference strains to investigate the mechanism of TB pathogenicity. Here, we attempted to determine metabolomic signatures associated with the Mycobacterial virulence in human macrophages through comparison of metabolite profile in THP-1-derived macrophages following exposure to the M. tb H37Rv, M. tb H37Ra and BCG strains. Results Our findings revealed remarkably changed metabolites in infected macrophages compared to uninfected macrophages. H37Rv infection specifically induced 247 differentially changed metabolites compared to H37Ra or BCG infection. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed H37Rv specifically induces tryptophan metabolism. Moreover, quantitative PCR (qPCR) results showed that indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) which converts the tryptophan to a series of biologically second metabolites were up-regulated in H37Rv-infected macrophages compared to H37Ra- or BCG-infected macrophages, confirming the result of enhanced tryptophan metabolism induced by H37Rv infection. These findings indicated that targeting tryptophan (Trp) metabolism may be a potential therapeutic strategy for pulmonary TB. Conclusions We identified a number of differentially changed metabolites that specifically induced in H37Rv infected macrophages. These signatures may be associated with the Mycobacterial virulence in human macrophages. The present findings provide a better understanding of the host response associated with the virulence of the Mtb strain.

Abstract Background G protein-coupled receptor (GPCR) is the most targeted protein family by the FDA-approved drugs. GPCR-kinase 3 (GRK3) is critical for GPCR signaling. Our genomic analysis showed that GRK3 expression correlated with poor prognosis of gastric adenocarcinoma (GAC) patients. However, GRK3’s functions and clinical utility in GAC progression and metastases are unknown. Methods We studied GRK3 expression in normal, primary, and metastatic GAC tissues. We identified a novel GRK3 inhibitor, LD2, through a chemical-library screen. Through genetic and pharmacologic modulations of GRK3, a series of functional and molecular studies were performed in vitro and in vivo. Impact of GRK3 on YAP1 and its targets was determined. Results GRK3 was overexpressed in GAC tissues compared to normal and was even higher in peritoneal metastases. Overexpression (OE) of GRK3 was significantly associated with shorter survival. Upregulation of GRK3 in GAC cells increased cell invasion, colony formation, and proportion of ALDH1 + cells, while its downregulation reduced these attributes. Further, LD2 potently and specifically inhibited GRK3, but not GRK2, a very similar kinase to GRK3. LD2 highly suppressed GAC cells’ malignant phenotypes in vitro. Mechanistically, GRK3 upregulated YAP1 in GAC tissues and its transcriptional downstream targets: SOX9, Birc5, Cyr61 and CTGF. Knockdown (KD) YAP1 rescued the phenotypes of GRK3 OE in GAC cells. GRK3 OE significantly increased tumor growth but LD2 inhibited tumor growth in the PDX model and dramatically suppressed peritoneal metastases induced by GRK3 OE. Conclusions GRK3, a poor prognosticator for survival, conferred aggressive phenotype. Genetic silencing of GRK3 or its inhibitor LD2 blunted GRK3-conferred malignant attributes, suggesting GRK3 as a novel therapeutic target in advanced GAC.

Abstract Background The global incidence of dry eye disease (DED) is very high. DED seriously affects the quality of life of patients; however, the current curative effect of medicine for moderate to severe DED is poor. This randomized clinical trial was planned to investigate the effect of acupuncture compared with artificial tears (AT) on moderate to severe DED. Methods A randomized clinical trial was performed at 2 hospitals in China. 120 DED patients were randomly equally divided into an acupuncture and an artificial tear group. Either acupuncture or artificial tears was performed for an 8-week period, and a 24-week follow-up was performed. The primary outcome measure was the Schirmer-I test (SIT) change from baseline. The secondary outcome measures included the numerical rating scale (NRS) change from baseline for improvement in ocular symptoms, the ocular surface disease index (OSDI), the tear-film break-up time (TBUT), corneal fluorescein staining (CFS), and acupuncture acceptability. Adverse events also were monitored and documented. Results For the primary outcome, the mean changes from baseline in the SIT values were significantly different between the acupuncture (5.75 [2.53–9.75]) and AT (0.52 [− 1.18–2.46]) groups at week 8 with a between difference of 5.23 (P < 0.05). Between-group differences of 8.49 in OSDI score change from baseline differed significantly at week 8 (P < 0.05). However, between-group differences of the changes in the average symptom NRS score, TBUT, and CFS did not differ significantly at week 8. Five cases experienced acupuncture-related adverse events. Conclusions This randomized clinical trial found that acupuncture at BL1 significantly promoted tear secretion. Acupuncture showed greater benefits than AT for moderate to severe DED. However, the study findings warrant verification. Trial registration Registration number: ChiCTR1800015831. Name of trial registry: Efficacy and safety of acupuncture in the treatment of moderate to severe dry eye disease: a randomized controlled trial. Registered on 23 April 2018 ( https://clinicaltrials.gov/ ).

Patients with hepatitis B virus (HBV)-related liver cirrhosis (LC) are at high risk for hepatocellular carcinoma (HCC). Limitations in the early detection of HCC give rise to poor survival in this high-risk population. Here, we performed comprehensive metabolomics on health individuals and HBV-related LC patients with and without early HCC. Compared to non-HCC patients (N = 108) and health controls (N = 80), we found that patients with early HCC (N = 224) exhibited a specific plasma metabolome map dominated by lipid alterations, including lysophosphatidylcholines, lysophosphatidic acids and bile acids. Pathway and function network analyses indicated that these metabolite alterations were closely associated with inflammation responses. Using multivariate regression and machine learning approaches, we identified a five-metabolite combination that showed significant performances in differentiating early-HCC from non-HCC than α-fetoprotein (area under the curve values, 0.981 versus 0.613). At metabolomic levels, this work provides additional insights of metabolic dysfunction related to HCC progressions and demonstrates the plasma metabolites might be measured to identify early HCC in patients with HBV-related LC.

The utilization of ventilation and spray cooling technology is becoming increasingly popular in high-temperature workplaces due to its convenience and environmental friendliness. To investigate the coupled cooling effect of ventilation and spray in a construction tunnel, we established a droplet evaporation model under convective heat transfer conditions by combining the convective heat transfer theory and the droplet heat and mass transfer model. Based on this model, the study focused on the energy change of droplet evaporation in a moving medium by using numerical simulation in the context of a railroad construction tunnel. The material of the droplets used in the study was water. According to the simulation and field measurement results, it was obtained that, firstly, increased air volume of the tunnel and reduced airflow temperature could make the convective heat exchange stronger between the airflow and the wall. Secondly, the particle size of droplets formed by spraying was mainly 30–40 μm in the tunnel. A part of the droplets was evaporated in the high-temperature environment, and another part was trapped by the rock wall and ground. Third, adopting the coupled cooling method of ventilation and spray, the temperature and humidity fields in the tunnel changed significantly, and a low-temperature and high-humidity zone appeared near the nozzle. At the same time, the evaporation rate of droplets increased, the heat index of the workplace decreased, and the cooling effect was effective. Therefore, the coupled cooling method of ventilation and spray can effectively improve the thermal environment in high-temperature construction tunnels and enhance the thermal comfort of personnel. This study serves as a reference for the parameters and cooling effect of ventilation and spray cooling systems in construction sites.

Workers in deep coal mines are often exposed to hyperthermal conditions, which is a health and safety hazard. Although many novel approaches have been proposed in recent years, air distribution optimization combined with thermal analysis based on existing cooling systems has rarely been conducted. Here, heat dissipation in the deep mine environment was estimated based on field measurements and numerical simulations. A pilot study was conducted to validate the performance of the multistage cooling system and optimize the distribution ventilation. The results show that the “2 + 3” layout (Two air cooler outlets are in the machine lane, and three air cooler outlets are in the open-off cut) was superior to other schemes in terms of the temperature field and energy consumption. In addition, the outlet air temperature should be set to ≤20 °C, and the air volumetric flowrate of the longest outlet should be > 400 m3/min to improve the thermal environment of the wind lane. This effectively reduces the average temperature of the entire working face by 4.6–5.1 °C compared to the situation without cooling measures, thereby increasing the comfortable zone of the working face (

Abstract Lithium–air batteries (LABs), owing to their ultrahigh theoretical energy density, are recognized as one of the next‐generation energy storage techniques. However, it remains a tricky problem to find highly active cathode catalyst operating within ambient air. In this contribution, a highly active Fe2Mo3O12 (FeMoO) garnet cathode catalyst for LABs is reported. The experimental and theoretical analysis demonstrate that the highly stable polyhedral framework, composed of FeO octahedrons and MO tetrahedrons, provides a highly effective air catalytic activity and long‐term stability, and meanwhile keeps good structural stability. The FeMoO electrode delivers a cycle life of over 1800 h by applying a simple half‐sealed condition in ambient air. It is found that surface‐rich Fe vacancy can act as an O2 pump to accelerate the catalytic reaction. Furthermore, the FeMoO catalyst exhibits a superior catalytic capability for the decomposition of Li2CO3. H2O in the air can be regarded as the main contribution to the anode corrosion and the deterioration of LAB cells could be attributed to the formation of LiOH·H2O at the end of cycling. The present work provides in‐depth insights to understand the catalytic mechanism in air and constitutes a conceptual breakthrough in catalyst design for efficient cell structure in practical LABs.

Abstract Collective detachment of cancer cells at the invading front could generate efficient metastatic spread. However, how cancer cell clusters shed from the leading front remains unknown. We previously reported that the dynamic expression of CD44 in breast cancers (BrCas) at collectively invading edges was associated with tumor-associated macrophages (TAMs). In this study, we first observed that the highly expressed CD44 (CD44high) cancer cell clusters were located in the BrCa circulating vessels, accompanied by CD206+ TAMs. Next, we identified that the cancer cell clusters can be converted to an invasive CD44high state which was induced by TAMs, thus giving rise to CD44-associated signaling mediated cohesive detachment. Then, we showed that disrupting CD44-signaling inhibited the TAMs triggered cohesive detaching using 3D organotypic culture and mouse models. Furthermore, our mechanistic study showed that the acquisition of CD44high state was mediated by the MDM2/p53 pathway activation which was induced by CCL8 released from TAMs. Blocking of CCL8 could inhibit the signaling cascade which decreased the CD44-mediated cohesive detachment and spread. Our findings uncover a novel mechanism underlying collective metastasis in BrCas that may be helpful to seek for potential targets.