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Many systemic diseases, including Alzheimer disease (AD), diabetes mellitus (DM) and cardiovascular disease, are associated with microbiota dysbiosis. The oral and intestinal microbiota are directly connected anatomically, and communicate with each other through the oral-gut microbiome axis to establish and maintain host microbial homeostasis. In addition to directly, periodontal bacteria may also be indirectly involved in the regulation of systemic health and disease through the disturbed gut. This paper provides evidence for the role of periodontal bacteria in systemic diseases via the oral-gut axis and the far-reaching implications of maintaining periodontal health in reducing the risk of many intestinal and parenteral diseases. This may provide insight into the underlying pathogenesis of many systemic diseases and the search for new preventive and therapeutic strategies.

Atherosclerosis (AS) is a chronic inflammatory disease, involving a pathological process of endothelial dysfunction, lipid deposition, plaque rupture, and arterial occlusion, and is one of the leading causes of death in the world population. The progression of AS is closely associated with several inflammatory diseases, among which periodontitis has been shown to increase the risk of AS. Porphyromonas gingivalis (P. gingivalis), presenting in large numbers in subgingival plaque biofilms, is the “dominant flora” in periodontitis, and its multiple virulence factors are important in stimulating host immunity. Therefore, it is significant to elucidate the potential mechanism and association between P. gingivalis and AS to prevent and treat AS. By summarizing the existing studies, we found that P. gingivalis promotes the progression of AS through multiple immune pathways. P. gingivalis can escape host immune clearance and, in various forms, circulate with blood and lymph and colonize arterial vessel walls, directly inducing local inflammation in blood vessels. It also induces the production of systemic inflammatory mediators and autoimmune antibodies, disrupts the serum lipid profile, and thus promotes the progression of AS. In this paper, we summarize the recent evidence (including clinical studies and animal studies) on the correlation between P. gingivalis and AS, and describe the specific immune mechanisms by which P. gingivalis promotes AS progression from three aspects (immune escape, blood circulation, and lymphatic circulation), providing new insights into the prevention and treatment of AS by suppressing periodontal pathogenic bacteria.

Abstract Emerging evidence indicates that oral microbes are closely related to gastric microbes and gastric lesions, including gastric atrophy, intestinal metaplasia and gastric cancer (GC). Helicobacter pylori is a key pathogen involved in GC. However, the increasing prevalence of H. pylori-negative GC and gastric dysbiosis in GC patients emphasize the potential role of other microbial factors. In this review, we discussed the current evidence about the relationship between the oral–gastric microbial axis and oral and gastric health. Epidemiologic evidence indicates that poor oral hygiene is related to greater GC risk. Multiple oral-associated microbes are enriched in the stomach of GC patients. Once colonizing the stomach, oral-associated microbes Streptococcus anginosus and Prevotella melaninogenica, are involved in gastric inflammation or carcinogenesis. Microbial metabolites such as lactate, nitrite, and acetaldehyde promote malignant transformation. The stomach, as a checkpoint of microbial transmission in the digestive tract, is of great importance since the link between oral microbes and intestinal diseases has been emphasized. Still, new technologies and standardized metrics are necessary to identify potential pathogenetic microbes for GC and the core microbiota, interactions, richness, colonization, location and effect (CIRCLE). In the future, oral microbes could be candidates for noninvasive indicators to predict gastric diseases.

Abstract Objectives To examine the correlation between healthy lifestyle patterns, their change trajectories, and the risk of multimorbidity in adults. Methods Based on two representative national cohorts, the English Longitudinal Study of Aging (ELSA) and the Health and Retirement Study (HRS) including adults aged 50 years and over. We employed Cox regression, lifestyle change trajectories, and restricted mean survival times to explore the relationship between lifestyle (assessed by SCORE2, LE’8, and HLS scores) and multimorbidity. We also conducted mediation analysis to investigate the underlying mechanisms. Results A healthy lifestyle (higher LE’8, higher HLS, or lower SCORE2) can reduce the risk of multimorbidity. 2-10% lower multimorbidity risk per one-point increase in LE’8 and HLS. The hazard ratio of multimorbidity for improvements in unhealthy lifestyles or deterioration in healthy lifestyles compared to always healthy lifestyles ranged from 1.598 to 5.602. Besides, for LE’8 and HLS, participants with higher scores had a slower decrease in survival probability in ELSA. Triglyceride, C-reaction protein, fibrinogen, and cystatin C partly mediate the association between lifestyle and multimorbidity. Conclusions Keeping a healthy lifestyle over time can help reduce the risk of multimorbidity.

Abstract The aim of this study was to evaluate the prognostic value of peripheral blood inflammation indexes in patients with metastatic Colorectal Cancer (CRC) and to establish a predictive scoring system. A total of 324 CRC patients diagnosed through pathological examination from January 2017 to July 2022 at the Third Affiliated Hospital of Kunming Medical University were included. The prognosis of patients with metastatic CRC was examined, and the correlation between IL-10 expression in pathological tissues and IL-10 expression in serum was analyzed. The results showed that the prognosis of CRC was poorer when metastasis occurred (P

ABSTRACT Gastric precancerous lesions are thought to be precursors in the occurrence and development of gastric cancer through Correa's cascade. Recent studies have investigated the association between the oral microbiome and gastric precancerous lesions. However, there has yet to be a comprehensive synthesis review of the existing literature on the relationship between oral microbiome and gastric precancerous lesions. A systematic review was conducted to characterize the literature on the association between oral microbiome and gastric precancerous lesions. The studies show that oral microbiome is dynamic in individuals with gastric precancerous lesions. Oral-derived microorganisms were colonized in the gastric precancerous lesions. Interactions between oral and gastric microbiomes affect the response of the host immunity. The abnormal proliferation of oral-associated microorganisms may be linked to the reduction of gastric acid. The present review supports the potential association between oral microbiome and gastric precancerous lesions. However, the interactions are complex and multifaceted, which require further investigation.

Abstract Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3–36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9–7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using “patient biomimetic twins” constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages.

Abstract Background Respiratory diseases are a major health burden, and educational inequalities may influence disease prevalence. We aim to evaluate the causal link between educational attainment and respiratory disease, and to determine the mediating influence of several known modifiable risk factors. Methods We conducted a two-step, two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS) and single nucleotide polymorphisms (SNPs) as instrumental variables for educational attainment and respiratory diseases. Additionally, we performed a multivariable MR analysis to estimate the direct causal effect of each exposure variable included in the analysis on the outcome, conditional on the other exposure variables included in the model. The mediating roles of body mass index (BMI), physical activity, and smoking were also assessed. Findings MR analyses provide evidence of genetically predicted educational attainment on the risk of FEV1 (β = 0.10, 95% CI 0.06, 0.14), FVC (β = 0.12, 95% CI 0.07, 0.16), FEV1/FVC (β = − 0.005, 95% CI − 0.05, 0.04), lung cancer (OR = 0.54, 95% CI 0.45, 0.65) and asthma (OR = 0.86, 95% CI 0.78, 0.94). Multivariable MR dicated the effect of educational attainment on FEV1 (β = 0.10, 95% CI 0.04, 0.16), FVC (β = 0.07, 95% CI 0.01, 0.12), FEV1/FVC (β = 0.07, 95% CI 0.01, 0.01), lung cancer (OR = 0.55, 95% CI 0.42, 0.71) and asthma (OR = 0.88, 95% CI 0.78, 0.99) persisted after adjusting BMI and cigarettes per day. Of the 23 potential risk factors, BMI, smoking may partially mediate the relationship between education and lung disease. Conclusion High levels of educational attainment have a potential causal protective effect on respiratory diseases. Reducing smoking and adiposity may be a target for the prevention of respiratory diseases attributable to low educational attainment.

ABSTRACT The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs.IMPORTANCEOur study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.

Abstract Background Lysine methyltransferase 2D (KMT2D) mediates mono‐methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D‐mediated H3K4me1 mark modulates gene expression in triple‐negative breast cancer (TNBC) progression is unresolved. Methods and Results We recognized Y‐box‐binding protein 1 (YBX1) as a “reader” of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP‐seq and RNA‐seq data indicated that YBX1 was co‐localized with KMT2D‐mediated H3K4me1 in the promoter regions of c‐Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c‐Myc and SENP1 in a KMT2D‐dependent manner. Conclusion Our results suggest that KMT2D‐mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c‐Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D‐H3K4me1‐YBX1 axis for TNBC treatment. Highlights YBX1 is a KMT2D‐mediated H3K4me1‐binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c‐Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c‐Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

Background and Aims: Chronic liver injury that results in cirrhosis and end-stage liver disease (ESLD) causes more than 1 million deaths annually worldwide. Although the impact of genetic factors on the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) has been previously studied, their contribution to the development of ESLD remains largely unexplored. Methods: We genotyped 6 MASLD-associated polymorphisms in healthy (n = 123), metabolic dysfunction-associated steatohepatitis (MASH) (n = 145), MASLD-associated ESLD (n = 72), and ALD-associated ESLD (n = 57) cohorts and performed multinomial logistic regression to determine the combined contribution of genetic, demographic, and clinical factors to the progression of ESLD. Results: Distinct sets of factors are associated with the progression to ESLD. The PNPLA3 rs738409:G and TM6SF2 rs58542926:T alleles, body mass index (BMI), age, and female sex were positively associated with progression from a healthy state to MASH. The PNPLA3 rs738409:G allele, age, male sex, and having type 2 diabetes mellitus were positively associated, while BMI was negatively associated with progression from MASH to MASLD-associated ESLD. The PNPLA3 rs738409:G and GCKR rs780094:T alleles, age, and male sex were positively associated, while BMI was negatively associated with progression from a healthy state to ALD-associated ESLD. The findings indicate that the PNPLA3 rs738409:G allele increases susceptibility to ESLD regardless of etiology, the TM6SF2 rs58542926:T allele increases susceptibility to MASH, and the GCKR rs780094:T allele increases susceptibility to ALD-associated ESLD. Conclusion: The PNPLA3, TM6SF2, and GCKR minor alleles influence the progression of MASLD-associated or ALD-associated ESLD. Genotyping for these variants in MASLD and ALD patients can enhance risk assessment, prompting early interventions to prevent ESLD.

Background Blood pressure (BP) trajectories from young adulthood through middle age are associated with cardiovascular risk. We examined the associations of hypertension risk factors with BP trajectories among a large diverse sample. Methods and Results We analyzed data from young adults, aged 18 to 39 years, with untreated BP

Summary: N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes. Furthermore, we show that FOXA2 promotes the migration and invasion of breast cancer cells by activating MMP14 expression. MMP14 is also upregulated in breast cancer tissues, where its expression level correlates with FOXA2 expression and poor clinical prognosis. Our study shows that the NatD-FOXA2-MMP14 axis functions as a key signaling pathway to promote the migratory and invasive capabilities of breast cancer cells, suggesting that NatD is a critical epigenetic modulator of cell invasion during breast cancer progression.

【Objective】This study is to explore the reduction effect of different growth patterns of submerged plants in controlling endogenous pollutants.【Method】A selection of typical meadow and canopy-type submerged plants, Sagittaria pygmaea Miq and Hydrilla verticillate, experimental simulation system using sediment from a heavily polluted water body and two types of submerged plants respectively. The study analysed the growth and expansion of S. pygmaea Miq and Hydrilla verticillate in the contaminated sediment, and investigated the changes in the concentrations of major pollutants in the sediment and overlying water of each system, as well as the characteristics of the microbial community structure in the surface sediment.【Result】Both submerged plants tolerated and expanded in the contaminated sediment in this study, with both the stem and root biomass of S. pygmaea Miq expanding 10-fold, but mainly within the upper and lower 10 cm of the sediment interface, The stem and leaf biomass of H. verticillate also expanded 10-fold throughout the overlying water space, but the root biomass remained unchanged. The removal of acid volatile sulphide (AVS), ferrous iron and ammonia nitrogen from the surface sediment (0-10 cm) of the S. pygmaea Miq system reached 80.57%, 67.43% and 72.48%, respectively, while the removal rates of ferrous iron and ammonia nitrogen in the H. verticillate system were only 24.75% and 61.41%, the removal rate of acid volatile sulphide (AVS) increased by 13.6%. The mean chlorophyll a concentrations in the overlying water were 9.61 μg/L and 9.39 μg/L for the H. pygmaea Miq and H. verticillate systems, respectively. The results of 16S rRNA high-throughput sequencing showed that there were significant differences in the composition of genera in the microbial communities of the surface sediments of the two systems, with the dominant genera in the S. pygmaea Miq system being Sulfurifustis and Nitrospira, while the dominant genera in the H. verticillate system being Cyanobium_PCC-6307, Spirochaeta_2, Sphingomonas and Geothermobacter with much higher relative abundance.【Conclusion】The S. pygmaea Miq were more effective in removing the reducing pollutants AVS, ferrous iron and ammonia nitrogen from the surface sediment, while. verticillate was more effective in controlling the growth of algae in the overlying water. The well-developed root system of S. pygmaea Miq promotes the development of microbial taxa for sulphur and ammonia nitrogen metabolism.

BackgroundThe Pooled Cohort Equations (PCEs) do not accurately estimate atherosclerotic cardiovascular disease (ASCVD) risk in certain populations. The 2018 AHA/ACC cholesterol guideline identified risk-enhancing factors as a supplement to PCEs-based risk assessment. However, the role of each risk-enhancing factor in ASCVD risk assessment has not been well quantified. Further, social determinants of health (SDOH) are not included in the PCEs nor considered as risk-enhancing factors in the US cholesterol guideline. We sought to evaluate ASCVD risk associated with each risk-enhancing factor and commonly collected SDOH including education, income, and employment status, and to assess if adding risk-enhancing factors and SDOH to the PCEs improve ASCVD risk prediction.MethodsWe included individuals aged 40 to 75 years, without ASCVD or diabetes at baseline, and with low-density lipoprotein cholesterol 70-189 mg/dL from two contemporary prospective cohort studies (MESA and REGARDS) and from Kaiser Permanente Southern California (KPSC). The primary endpoint was incident ASCVD defined as nonfatal myocardial infarction, fatal coronary heart disease, or fatal or nonfatal stroke over a 10-year period (median follow-up 10 years). We used Cox proportional hazards models to estimate associations between risk-enhancing factors and SDOH with ASCVD. We also assessed changes in model performance after adding risk-enhancing factors and SDOH to the PCEs.ResultsWe included 13,863 adults (mean age 60.7 years) from the prospective cohorts and 307,931 adults (mean age 54.8 years) from KPSC. Risk-enhancing factors including hypercholesterolemia, hypertriglyceridemia, metabolic syndrome, and chronic kidney disease were associated with a higher ASCVD risk, independent of 10-year risk estimated by the PCEs. Low education, low income, and unemployment were also associated with higher ASCVD risk. While adding individual risk-enhancing factors or SDOH to the PCEs had limited impact on model performance, adding multiple risk-enhancing factors and SDOH simultaneously led to modest improvements in discrimination (C-index increased by up to 0.07), calibration (integrated Brier score reduced by up to 2.3%), and net reclassification improvement up to 41.4%.ConclusionsThese findings suggest including SDOH and risk-enhancing factors may improve ASCVD risk assessment.

Abstract Mono‐methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone‐lysine N‐methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B‐cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA‐seq and ChIP‐seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D‐dependent H3K4me1 and EBF2 are predominantly over‐lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK‐LSD1, a selective inhibitor of lysine‐specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

ObjectiveTo explore the medical significance of methylated septin9 (mSEPT9) in monitoring recurrence and prognostic assessment in individuals with surgically treated colorectal cancer (CRC).MethodsTo investigate the role of Septin9 in colorectal cancer, we utilized the TIMER2.0 database to analyze its differential expression between tumor tissues and adjacent normal tissues. Colorectal cancer RNA-seq data from the TCGA database was downloaded and curated. The clinical relevance of mSEPT9 in colorectal cancer was explored by examining the correlation between Septin9 methylation levels and clinical characteristics using UALCAN and MethSurv software. Peripheral blood samples were obtained from 130 CRC subjects who underwent surgery for the detection of mSEPT9 and carcinoembryonic antigen (CEA) expression, along with collection of clinicopathological data such as age, gender, tumor site, TNM stage, and tumor differentiation. Patients were followed up for at least 3 years post-surgery until the death or final follow-up dates (31/12/2022). Additionally, peripheral blood samples were collected from 30 colorectal cancer surgery patients for mSEPT9 detection before and 7 days after surgery.ResultsThrough bioinformatic database analysis, we identified higher expression levels of SEPT9 mRNA in most tumor tissues compared to normal tissues. Similarly, both paired and unpaired CRC tissues exhibited elevated expression of Septin9 when compared to normal tissues. Following GO and KEGG analysis of Septin9 target genes, we discovered their significant associations with ncRNA metabolic processes, ribonucleoprotein complex biogenesis, spliceosomes, and viral carcinogenesis. Furthermore, the overexpression of mSeptin9 was observed in CRC tissues, and it demonstrated a correlation with colon cancer staging and histologic classification. In our clinical sample study, The positive rate of mSEPT9 in CRC patients 7 days after surgery was 43.44% lower than that of preoperative. The differences in TNM stage, tumor differentiation degree, and preoperative CEA expression level between the preoperative mSEPT9 positive and negative groups of CRC were statistically significant (P < 0.05). Recurrence free survival (RFS) and overall survival (OS) were shorter in the preoperative mSEPT9-positive group, meaning preoperative mSEPT9 status was a risk factor for CRC recurrence and prognosis (P < 0.05). The sensitivity, specificity, and AUC value of preoperative mSEPT9 and CEA levels for predicting postoperative recurrence in CRC patients were 88% vs. 72%, 56.19% vs. 55.24%, and 0.721 vs. 0.636 respectively, well the AUC value of the combined prediction of postoperative recurrence was 0.758.ConclusionThe detection of mSEPT9 combined with CEA in preoperative plasma helps predict recurrence in colorectal cancer patients.

Abstract Background Studies have indicated that long non-coding RNAs (lncRNAs) play important regulatory roles in many biological processes. However, the regulation of seed oil biosynthesis by lncRNAs remains largely unknown. Results We comprehensively identified and characterized the lncRNAs from seeds in three developing stages in two accessions of Brassica napus (B. napus), ZS11 (high oil content) and WH5557 (low oil content). Finally, 8094 expressed lncRNAs were identified. LncRNAs MSTRG.22563 and MSTRG.86004 were predicted to be related to seed oil accumulation. Experimental results show that the seed oil content is decreased by 3.1–3.9% in MSTRG.22563 overexpression plants, while increased about 2% in MSTRG.86004, compared to WT. Further study showed that most genes related to lipid metabolism had much lower expression, and the content of some metabolites in the processes of respiration and TCA (tricarboxylic acid) cycle was reduced in MSTRG.22563 transgenic seeds. The expression of genes involved in fatty acid synthesis and seed embryonic development (e.g., LEC1) was increased, but genes related to TAG assembly was decreased in MSTRG.86004 transgenic seeds. Conclusion Our results suggest that MSTRG.22563 might impact seed oil content by affecting the respiration and TCA cycle, while MSTRG.86004 plays a role in prolonging the seed developmental time to increase seed oil accumulation.

Colorectal cancer (CRC) represents 10% of all cancer types, making it the third leading cause of cancer-related deaths globally. Metastasis is the primary factor causing mortality in CRC patients. Approximately 22% of CRC-related deaths have metastasis present at diagnosis, with approximately 70% of these cases recurring. Recently, with the application of novel targeted drugs, targeted therapy has become the first-line option for individualized and comprehensive treatment of CRC. The management of these patients remains a significant medical challenge. The most prevalent targeted therapies for CRC in clinical practice focus on anti-vascular endothelial growth factor and its receptor, epidermal growth factor receptor (EGFR), and multi-target kinase inhibitors. In the wake of advancements in precision diagnosis and widespread adoption of second-generation sequencing (NGS) technology, rare targets such as BRAF V600E mutation, KRAS mutation, HER2 overexpression/amplification, and MSI-H/dMMR in metastatic colorectal cancer (mCRC) are increasingly being discovered. Simultaneously, new therapeutic drugs targeting these mutations are being actively investigated. This article reviews the progress in clinical research for developing targeted therapeutics for CRC, in light of advances in precision medicine and discovery of new molecular target drugs.

Summary: Highly pathogenic avian influenza A H5N1 viruses cause high mortality in humans and have pandemic potential. Effective vaccines and treatments against this threat are urgently needed. Here, we have refined our previously established model of lethal H5N1 infection in cynomolgus macaques. An inhaled aerosol virus dose of 5.1 log10 plaque-forming unit (pfu) induced a strong febrile response and acute respiratory disease, with four out of six macaques succumbing after challenge. Vaccination with three doses of adjuvanted seasonal quadrivalent influenza vaccine elicited low but detectable neutralizing antibody to H5N1. All six vaccinated macaques survived four times the 50% lethal dose of aerosolized H5N1, while four of six unvaccinated controls succumbed to disease. Although vaccination did not protect against severe influenza, vaccinees had reduced respiratory dysfunction and lower viral load in airways compared to controls. We anticipate that our macaque model will play a vital role in evaluating vaccines and antivirals against influenza pandemics.

Summary: HS3ST3B1-IT1 was identified as a downregulated long noncoding RNA in osteoarthritic cartilage. However, its roles and mechanisms in the pathogenesis of osteoarthritis (OA) are unclear. In this study, we demonstrated that the expressions of HS3ST3B1-IT1 and its maternal gene HS3ST3B1 were downregulated and positively correlated in osteoarthritic cartilage. Overexpression of HS3ST3B1-IT1 significantly increased chondrocyte viability, inhibited chondrocyte apoptosis, and upregulated extracellular matrix (ECM) proteins, whereas HS3ST3B1-IT1 knockdown had the opposite effects. In addition, HS3ST3B1-IT1 significantly ameliorated monosodium-iodoacetate-induced OA in vivo. Mechanistically, HS3ST3B1-IT1 upregulated HS3ST3B1 expression by blocking its ubiquitination-mediated degradation. Knockdown of HS3ST3B1 reversed the effects of HS3ST3B1-IT1 on chondrocyte viability, apoptosis, and ECM metabolism. AlkB homolog 5 (ALKBH5)-mediated N6-methyladenosine (m6A) demethylation stabilized HS3ST3B1-IT1 RNA. Together, our data revealed that ALKBH5-mediated upregulation of HS3ST3B1-IT1 suppressed OA progression by elevating HS3ST3B1 expression, suggesting that HS3ST3B1-IT1/HS3ST3B1 may serve as potential therapeutic targets for OA treatment.

Background: Long-term ambient particulate matter (PM) exposure exerts detrimental effects on cardiovascular health. Evidence on the relation of chronically exposed ambient PM10 and PM2.5 with coronary stenosis remains lacking. Our aim was to investigate the association of PM10 and PM2.5 with coronary stenosis in patients undergoing coronary angiography. Methods: We performed a retrospective cohort study consisting of 7513 individuals who underwent coronary angiography in Fujian Province, China, from January 2019 to December 2021. We calculated a modified Gensini score (GS) to represent the degree of stenosis in coronary arteries by selective coronary angiography. We fitted linear regressions and logistic models to assess the association of PM10 and PM2.5 with coronary stenosis. We employed restricted cubic splines to describe the exposure-response curves. We performed mediation analyses to assess the potential mediators. Results: Long-term ambient PM10 and PM2.5 (prior three years average) exposure was significantly associated with the GS, with a breakpoint concentration of 47.5 μg/m3 and 25.8 μg/m3 for PM10 and PM2.5, respectively, above which we found a linear positive exposure-response relationship of ambient PM with GS. Each 10 µg /m3 increase in PM10 exposure (β: 4.81, 95 % CI: 0.44–9.19) and PM2.5 exposure [β: 10.50, 95 % CI: 3.14–17.86] were positively related to the GS. The adjusted odds ratio (OR) for each 10 µg/m3 increment in PM10 exposure on severe coronary stenosis was 1.33 (95 % CI: 1.04–1.76). Correspondingly, the adjusted OR for PM2.5 was 1.87 (95 % CI: 1.24–2.99). The mediation analysis indicated that the effect of PM10 on coronary stenosis may be partially mediated through total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, serum creatinine and blood urea nitrogen, and the effect of PM2.5 may be mediated in part by hemoglobin A1c. Conclusion: Our study provides the first evidence that chronic ambient PM10 and PM2.5 exposure was associated with coronary stenosis assessed by GS in patients with suspected coronary artery disease and reveals its potential mediators.

Abstract Background Enterococcus faecalis (E. faecalis) plays an important role in the failure of root canal treatment and refractory periapical periodontitis. As an important virulence factor of E. faecalis, extracellular polysaccharide (EPS) serves as a matrix to wrap bacteria and form biofilms. The homologous rnc gene, encoding Ribonuclease III, has been reported as a regulator of EPS synthesis. In order to develop novel anti-biofilm targets, we investigated the effects of the rnc gene on the biological characteristics of E. faecalis, and compared the biofilm tolerance towards the typical root canal irrigation agents and traditional Chinese medicine fluid Pudilan. Methods E. faecalis rnc gene overexpression (rnc+) and low-expression (rnc−) strains were constructed. The growth curves of E. faecalis ATCC29212, rnc+, and rnc− strains were obtained to study the regulatory effect of the rnc gene on E. faecalis. Scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and crystal violet staining assays were performed to evaluate the morphology and composition of E. faecalis biofilms. Furthermore, the wild-type and mutant biofilms were treated with 5% sodium hypochlorite (NaOCl), 2% chlorhexidine (CHX), and Pudilan. The residual viabilities of E. faecalis biofilms were evaluated using crystal violet staining and colony counting assays. Results The results demonstrated that the rnc gene could promote bacterial growth and EPS synthesis, causing the EPS-barren biofilm morphology and low EPS/bacteria ratio. Both the rnc+ and rnc− biofilms showed increased susceptibility to the root canal irrigation agents. The 5% NaOCl group showed the highest biofilm removing effect followed by Pudilan and 2% CHX. The colony counting results showed almost complete removal of bacteria in the 5% NaOCl, 2% CHX, and Chinese medicine agents’ groups. Conclusions This study concluded that the rnc gene could positively regulate bacterial proliferation, EPS synthesis, and biofilm formation in E. faecalis. The rnc mutation caused an increase in the disinfectant sensitivity of biofilm, indicating a potential anti-biofilm target. In addition, Pudilan exhibited an excellent ability to remove E. faecalis biofilm.

Abstract Ultrasensitive flexible pressure sensors with excellent linearity are essential for achieving tactile perception. Although microstructured dielectrics have endowed capacitive sensors with ultrahigh sensitivity, the compromise of sensitivity with increasing pressure is an issue yet to be resolved. Herein, a spontaneously wrinkled MWCNT/PDMS dielectric layer is proposed to realize the excellent sensitivity and linearity of capacitive sensors for tactile perception. The synergistic effect of a high dielectric constant and wrinkled microstructures enables the sensor to exhibit linearity up to 21 kPa with a sensitivity of 1.448 kPa−1 and a detection limit of 0.2 Pa. Owing to these merits, the sensor monitors subtle physiological signals such as various arterial pulses and respiration. This sensor is further integrated into a fully multimaterial 3D‐printed soft pneumatic finger to realize material hardness perception. Eight materials with different hardness values are successfully discriminated, and the capacitance of the sensor varies linearly (R2 > 0.975) with increasing hardness. Moreover, the sensitivity to the material hardness can be tuned by controlling the inflation pressure of the soft finger. As a proof of concept, the finger is used to discriminate pork fats with different hardness, paving the way for hardness discrimination in clinical palpation.

Abstract Stretchable electronic skin (e‐skin) paves the way for applications that exceed the scope of intrinsic rigid devices and hard‐to‐stretch sensors. The broad application range of flexible e‐skins benefits from device architectures that can simultaneously provide mechanical flexibility and superior sensitivity. Classic fractal design provides a simple architecture to achieve the desired flexibility through structural design for improved wear comfort, but at the expense of sensor sensitivity. In this study, the proposed method addresses the trade‐off between stretchability and sensitivity in fractal design. A high‐sensitivity e‐skin is obtained by eliminating the effect of negative charge on the output by applying the concept of electromechanical coupling. This concept for designing e‐skins with high sensitivity is validated through the delicate patterning of hard‐to‐stretch functional materials. Further, human speech signals are acquired through the integration of e‐skin with signal processing circuits, and speech pattern recognition is realized using machine learning. The stretchable e‐skin with an enhanced gauge factor illustrates the wider application of this concept for improving the sensitivity of stretchable electronic functional materials.

Soil displacement caused by frost heave and thawing settlement will pose a great threat to the structural safety of buried pipelines. Herein, a numerical solution model for parameterization of pipeline stress-strain response under the action of displacement caused by thawing settlement was established with the nonlinear finite element program ABAQUS and the INP programming language. The accuracy of model was verified with the test results. Meanwhile, the distribution characteristics of pipeline strain were studied through the analysis of influencing factors. The results show that: for X65 pipeline passing through the ice-rich permafrost area where the thawing settlement area is in small width, the maximum axial strain is located in the center of the thawing settlement area, and the tensile strain of the pipeline is greater than the compressive strain, so that the entire pipeline is in the state of tension. However, when the thawing settlement area is wider than 60 m, the pipeline is subjected to thawing settlement together with the ground, with bending strain as the maximum strain, which is located at the edge of the thawing settlement area. Besides, the widening of thawing settlement area will not affect the pipeline strain significantly. Therefore, attention should be paid to the identification of the range of thawing settlement areas in the geohazard monitoring. Generally, for the thawing settlement areas with small width, pipeline strain in the center and edge of thawing settlement areas should be monitored, while for those thawing settlement areas with width larger than 60 m, the pipeline strain at the edge of thawing settlement areas should be monitored.

Owing to messenger RNA's unique biological advantages, it has received increasing attention to be used as a therapeutic, known as mRNA-based gene therapy. It is critical to have an ideal strategy of mRNA gene therapy for glioma, which grows in a special environment. In the present study, we screened out a safe and efficient transfection reagent for intracranial delivery of synthetic mRNA in mouse brain. First, in order to analyze the effect of different transfection reagents on the intracranial delivery of mRNA, the synthetic luciferase mRNA was wrapped with two different transfection reagents and microinjected into the brain at the fixed point. The expression status of delivered mRNA was monitored by a small animal imaging system. The possible reagent-induced biological toxicity was evaluated by behavioral and blood biochemical measurements. Then, to test the therapeutic effect of our intracranial delivery mRNA model on glioma, synthetic modified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA was used as an example of therapeutic application. This model demonstrated that synthetic mRNA could be successfully delivered into the brain using commercially available transfection reagents, and TransIT-mRNA showed better results than in vivo-jetPEI kit. This model can be applied in precise targeting and personalized gene therapy of glioma.

Background: Household solid-fuel burning contributes to indoor air pollution and is linked to poor cognitive function, but how solid cooking fuel use leads to cognitive decline over time is not well elaborated. Objective: We examine the associations of solid cooking fuel with cognitive function among three nationally representative cohorts. Methods: This study uses data from the 2010–2018 China Family Panel Studies (CFPS), the 2011–2018 China Health and Retirement Longitudinal Study (CHARLS) and the 2003–2015 Mexican Health and Aging Study (MHAS) in adults over the age of 50. Time varying Cox model was conducted to measure the association between cooking fuel types and cognitive decline. Mediation analysis was used to estimate the potential mediation effects on the associations of cooking fuel types with cognitive decline risk. Results: Respondents in CFPS, CHARLS, and MHAS relied on solid cooking fuel at baseline approximately 56 %, 51 %, and 12 %, respectively. Using solid fuel was consistently associated with higher risk of cognitive decline in three cohorts (CFPS: HR = 1.300 [95 % CI: 1.201, 1.407], CHARLS: HR = 1.179 [95 % CI: 1.059, 1.312], MHAS: HR = 1.237 [95 % CI: 1.123, 1.362]). Compared to those with persistent solid fuel, persistent clean fuel and change from solid fuel to clean fuel were associated with a lower risk of cognitive decline. Hypertension, diabetes, physical activity, dyslipidemia and high-density lipoprotein cholesterol (HDL-C) may partially mediate the cognitive decline caused by solid fuel use. Of the cognitive decline burden, 18.23 % (95 % CI: 12.21 %, 24.73 %) in CFPS, 8.90 % (95 % CI: 2.93 %, 15.52 %) in CHARLS and 2.92 % (95 % CI: 1.52 %, 4.46 %) in MHAS of cognitive decline cases attributable to solid cooking fuel use. Conclusion: The use of solid cooking fuel is associated with a higher risk of cognitive decline. It is essential to promote the expanded use of clean fuel to protect cognitive health.

IntroductionChilling injury is a major hindrance to cucumber fruit quality during cold storage.Methods and ResultsIn this study, we evaluated the effects of fucoidan on fruit quality, reactive oxygen species homeostasis, and energy metabolism in cucumbers during cold storage. The results showed that, compared with the control cucumber fruit, fucoidan-treated cucumber fruit exhibited a lower chilling injury index and less weight loss, as well as reduced electrolyte leakage and malondialdehyde content. The most pronounced effects were observed following treatment with fucoidan at 15 g/L, which resulted in increased 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radical scavenging rates and reduced superoxide anion production rate and hydrogen peroxide content. The expression and activity levels of peroxidase, catalase, and superoxide dismutase were enhanced by fucoidan treatment. Further, fucoidan treatment maintained high levels of ascorbic acid and glutathione, and high ratios of ascorbic acid/dehydroascorbate and glutathione/oxidized glutathione. Moreover, fucoidan treatment increased the activities of ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase and their gene expression. Fucoidan treatment significantly delayed the decrease in ATP and ADP, while preventing an increase in AMP content. Finally, fucoidan treatment delayed the decrease of energy charge and the activities and gene expression of H+-ATPase, Ca2+-ATPase, cytochrome c oxidase, and succinate dehydrogenase in cucumber fruits.ConclusionAltogether, our findings indicate that fucoidan can effectively enhance antioxidant capacity and maintain energy metabolism, thereby improving cucumber cold resistance during cold storage.

Compared to magnetic resonance imaging (MRI) and X-ray computed tomography (CT), ultrasound imaging is safer, faster, and more widely applicable. However, the use of conventional ultrasound in transcranial brain imaging for adults is predominantly hindered by the high acoustic impedance contrast between the skull and soft tissue. This study introduces a 3D AI algorithm, Brain Imaging Full Convolution Network (BIFCN), combining waveform modeling and deep learning for precise brain ultrasound reconstruction. We constructed a network comprising one input layer, four convolution layers, and one pooling layer to train our algorithm. In the simulation experiment, the Pearson correlation coefficient between the reconstructed and true images was exceptionally high. In the laboratory, the results showed a slightly lower but still impressive coincidence degree for 3D reconstruction, with pure water serving as the initial model and no prior information required. The 3D network can be trained in 8 h, and 10 samples can be reconstructed in just 12.67 s. The proposed 3D BIFCN algorithm provides a highly accurate and efficient solution for mapping wavefield frequency domain data to 3D brain models, enabling fast and precise brain tissue imaging. Moreover, the frequency shift phenomenon of blood may become a hallmark of BIFCN learning, offering valuable quantitative information for whole-brain blood imaging.

Streptococcus mutans constantly coexists with Candida albicans in plaque biofilms of early childhood caries (ECC). The progression of ECC can be influenced by the interactions between S. mutans and C. albicans through exopolysaccharides (EPS). Our previous studies have shown that rnc, the gene encoding ribonuclease III (RNase III), is implicated in the cariogenicity of S. mutans by regulating EPS metabolism. The DCR1 gene in C. albicans encodes the sole functional RNase III and is capable of producing non-coding RNAs. However, whether rnc or DCR1 can regulate the structure or cariogenic virulence of the cross-kingdom biofilm of S. mutans and C. albicans is not yet well understood. By using gene disruption or overexpression assays, this study aims to investigate the roles of rnc and DCR1 in modulating the biological characteristics of dual-species biofilms of S. mutans and C. albicans and to reveal the molecular mechanism of regulation. The morphology, biomass, EPS content, and lactic acid production of the dual-species biofilm were assessed. Quantitative real-time polymerase chain reaction (qRT-PCR) and transcriptomic profiling were performed to unravel the alteration of C. albicans virulence. We found that both rnc and DCR1 could regulate the biological traits of cross-kingdom biofilms. The rnc gene prominently contributed to the formation of dual-species biofilms by positively modulating the extracellular polysaccharide synthesis, leading to increased biomass, biofilm roughness, and acid production. Changes in the microecological system probably impacted the virulence as well as polysaccharide or pyruvate metabolism pathways of C. albicans, which facilitated the assembly of a cariogenic cross-kingdom biofilm and the generation of an augmented acidic milieu. These results may provide an avenue for exploring new targets for the effective prevention and treatment of ECC.

Abstract Range ambiguity suppression is a significant problem in traditional pulse‐Doppler radar systems, especially when the pulse repetition frequency is set high to avoid Doppler ambiguity. One possible way to deal with such problem is to apply the noise radar system, by transmitting pulse‐agile waveforms and using a group of matched filters as the receiver to accumulate the power of unambiguous echoes while dispersing the range‐ambiguous ones. However, when strong targets or heavy clutters exist, the dispersed ambiguous power is still high, which leads to high range‐Doppler sidelobes and overwhelms the weak targets. This paper explores a new way to deal with the range‐ambiguity suppression problem in noise radar. The range‐ambiguity suppression as a sparse recovery problem is formulated, and then both the unambiguous and ambiguous targets (and/or clutters) can be simultaneously reconstructed. The proposed method can enhance the range‐ambiguity suppression performance and synthetic an ambiguity‐free range‐Doppler map with a low sidelobe level, which ensures the weak target recovery performance even in a cluttered environment.

Abstract Background Advances in regenerative medicine technologies have been strongly proposed in the management of thyroid diseases. Mechanistically, the adoption of thyroid bioengineering requires a scaffold that shares a similar three-dimensional (3D) space structure, biomechanical properties, protein component, and cytokines to the native extracellular matrix (ECM). Methods 24 male New Zealand white rabbits were used in this experimental study. The rabbit thyroid glands were decellularized by immersion/agitation decellularization protocol. The 3D thyroid decellularization scaffolds were tested with histological and immunostaining analyses, scanning electron microscopy, DNA quantification, mechanical properties test, cytokine assay and cytotoxicity assays. Meanwhile, the decellularization scaffold were seeded with human thyroid follicular cells, cell proliferation and thyroid peroxidase were determined to explore the biocompatibility in vitro. Results Notably, through the imaging studies, it was distinctly evident that our protocol intervention minimized cellular materials and maintained the 3D spatial structure, biomechanical properties, ECM composition, and biologic cytokine. Consequently, the decellularization scaffold was seeded with human thyroid follicular cells, thus strongly revealing its potential in reinforcing cell adhesion, proliferation, and preserve important protein expression. Conclusions The adoption of our protocol to generate a decellularized thyroid scaffold can potentially be utilized in transplantation to manage thyroid diseases through thyroid bioengineering.

Innate lymphoid cells (ILCs) develop from ILC progenitors in the bone marrow. Various ILC precursors (ILCPs) with different ILC subset lineage potentials have been identified based on the expression of cell surface markers and ILC-associated key transcription factor reporter genes. This study characterized an interleukin (IL)-7Rα+IL-18Rα+ ILC progenitor population in the mouse bone marrow with multi-ILC lineage potential on the clonal level. Single-cell gene expression analysis revealed the heterogeneity of this population and identified several subpopulations with specific ILC subset-biased gene expression profiles. The role of IL-18 signaling in the regulation of IL-18Rα+ ILC progenitors and ILC development was further investigated using Il18- and Il18r1-deficient mice, in vitro differentiation assay, and adoptive transfer model. IL-18/IL-18R-mediated signal was found to not be required for early stages of ILC development. While Il18r1-/- lymphoid progenitors were able to generate all ILC subsets in vitro and in vivo like the wild-type counterpart, increased IL-18 level, as often occurred during infection or under stress, suppressed the growth of ILCP/ILC in an IL-18Ra-dependent manner via inhibiting proliferation and inducing apoptosis.

Background: Vincristine (VCR) is used in the clinic as an anti-tumor drug. VCR can cause pulmonary fibrosis (PF), leading to respiratory failure. The transformation of fibroblasts into myofibroblasts may play a key role in PF. The present study attempted to reveal the molecular mechanism of VCR-induced PF and the possible involvement of the mitogen-activated protein kinase (MAPK) signaling pathway.Methods: Human embryonic lung fibroblasts (HELFs) were treated with different concentrations of VCR. Inhibitors of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 MAPK were added to HELFs. Cell proliferation state was assessed using cell counting kit-8 and by directly counting the number of cells. The expressions of vimentin and α-smooth muscle actin (α-SMA) were investigated using western blot and immunofluorescence analyses. Activation of ERK and P38 was estimated by the expression of phosphorylated p38 MAPK (p-p38), p38 MAPK, phosphorylated ERK1/2 (p-ERK1/2) and ERK1/2 using western blot analysis. Enzyme-linked immunosorbent assay was used to estimate the level of collagen I in cell culture supernatants.Results: Results showed that VCR promoted cellular proliferation, secretion of collagen I and the expression of vimentin and α-SMA. High expression of p-p38 and p-ERK1/2 was associated with the activation of the MAPK signaling pathway. MAPK inhibitors SB203580 and PD98059 suppressed the expression of the above proteins.Conclusion: Our study revealed that VCR could promote the differentiation of fibroblasts into myofibroblasts by regulating the MAPK signal pathway, which may be a promising way to treat VCR-induced PF.

A tunable pulsed dual-wavelength laser is presented based on an Nd:YVO4/Nd:GdVO4 combined crystals pair as amplifying medium. By employing pulse width adjustment of an 808 nm laser diode pumping, and a Cr4+:YAG crystal for Q-switching, synchronized dual-wavelength laser pulses were obtained at 1063 nm and 1064 nm. Time jitter between the two wavelength pulses is reduced to about 10% of the laser pulse duration. Adjusting the pump beam operation parameters and tuning the crystals pair steady-state temperature between 10 °C and 50 °C, the frequency separation between the dual-wavelength laser pulses gradually decreases from 344.11 GHz to 305.99 GHz. The relative peak powers and the pulses time synchronization remain stable during their frequency separation tuning.

Active fault is a major geological hazard threat to submarine pipelines, which may subject to excessive axial deformation and fail from the faulting. Thus an improved analytical method for strain of submarine pipeline under strike-slip faulting was proposed in this paper. The nonlinear constitutive relation of pipeline materials was considered based on the linear strengthening model, and the influence of soil nonlinear constraint on the response of the pipe structure was accurately calculated through the nonlinear soil spring model with ideal elastic-plastic constitutive relation. From the differential control equation of the pipeline stress, analytical results of the axial strain in the pipeline were derived and the expression of the pipe elongation was obtained. Based on the equilibrium equation and iterative calculation, the stress and strain of the pipeline can finally be accurately calculated. Compared with the finite element calculation results, the improved analytical method for pipe strain has higher calculation accuracy than the existing recommended method (i.e. Newmark method).

PEDOT:PSS conductive polymers have received tremendous attention over the last two decades owing to their high conductivity, ease of processing, and biocompatibility. As a flexible versatile material, PEDOT:PSS can be developed into various forms and has had a significant impact on emerging sensing applications. This review covers the development of PEDOT:PSS from material to physical sensors. We focus on the morphology of PEDOT:PSS in the forms of aqueous dispersions, solid films, and hydrogels. Manufacturing processes are summarized, including coating, printing, and lithography, and there is particular emphasis on nanoimprinting lithography that enables the production of PEDOT:PSS nanowires with superior sensing performance. Applications to various physical sensors, for humidity, temperature, pressure, and strain, are demonstrated. Finally, we discuss the challenges and propose new directions for the development of PEDOT:PSS.