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Dysregulation of the Hippo pathway occurs in a variety of cancers and often correlates with a poor prognosis. To further explore the potential role of Hippo pathway dysregulation in tumor development and progression, we investigated its downstream transcription factor TEAD4 in colorectal cancer (CRC). Increased expression and nuclear localization of TEAD4 were found in a significant portion of CRC tissues, in association with metastasis and a poor prognosis. In CRC cells, TEAD4 knockdown induced the mesenchymal–epithelial transition and decreased cell mobility in vitro and metastasis in vivo . Microarray analysis revealed that TEAD4 promoted cell adhesion and upregulated the epithelial–mesenchymal transition-related transcriptome in CRC cells. Vimentin was identified as a new direct target gene mediating TEAD4 function in CRC cells, whereby forced vimentin expression markedly reversed TEAD4-knockdown-induced cell morphological changes and decreased mobility. Interestingly, rescued expression of both WT TEAD4 and a Y429H mutant can reverse the mesenchymal–epithelial transition and increase vimentin expression, cell mobility and metastatic potential in TEAD4-knockdown CRC cells. The discrepant expression of YAP and TEAD4 in CRC tissues, the rescue ability of TEAD4 mutant defect in YAP binding and no effect on vimentin expression by YAP knockdown in CRC cells, all implicated a YAP-independent manner of TEAD4 function in CRC. Furthermore, vimentin positively correlated and CDH1 reversely correlated with the level of TEAD4 in CRC tissues and xenograft tumors. Our results suggest that TEAD4 nuclear expression can serve as a biomarker for CRC progression and poor prognosis. The transcription factor TEAD4 regulates a pro-metastasis transcription program in a YAP-independent manner in CRC, thus providing a novel mechanism of TEAD4 transcriptional regulation and its oncogenic role in CRC, independently of the Hippo pathway.

Background: The role of tumour-infiltrating inflammation in the prognosis of patients with colorectal cancer (CRC) has not been fully evaluated. The primary objective of our meta-analysis was to determine the impact of tumour-infiltrating inflammation on survival outcomes. Methods: Ovid MEDLINE and EMBASE were searched to identify studies reporting the prognostic significance of tumour-infiltrating inflammation for patients with CRC. The primary outcome measures were overall survival (OS), cancer-specific survival (CS) and disease-free survival (DFS). Results: A total of 30 studies involving 2988 patients were identified. Studies were subdivided into those considering the associations between CRC survival and generalised tumour inflammatory infiltrate ( n =12) and T lymphocyte subsets ( n =18). Pooled analyses revealed that high generalised tumour inflammatory infiltrate was associated with good OS (HR, 0.59; 95% CI, 0.48–0.72), CS (HR, 0.40; 95% CI, 0.27–0.61) and DFS (HR, 0.72; 95% CI, 0.57–0.91). Stratification by location and T lymphocyte subset indicated that in the tumour centre, CD3 + , CD8 + and FoxP3 + infiltrates were not statistically significant prognostic markers for OS or CS. In the tumour stroma, high CD8 + , but not CD3 + or FoxP3 + cell infiltrates indicated increased OS. Furthermore, high CD3 + cell infiltrate was detected at the invasive tumour margin in patients with good OS and DFS; and high CCR7 + infiltrate was also indicated increased OS. Conclusion: Overall, high generalised tumour inflammatory infiltrate could be a good prognostic marker for CRC. However, significant heterogeneity and an insufficient number of studies underscore the need for further prospective studies on subsets of T lymphocytes to increase the robustness of the analyses.

SummaryIn a random sample of postmenopausal Chinese women, the prevalence of radiographic vertebral fractures increased from 13% between ages 50 and 59 to over 50% after age 80 years. A model with seven clinical risk factors predicted the probability of vertebral fractures as well with as without BMD and better than a model with only three risk factors. More than half an hour of outdoor activity per day might correlate with lower risk of vertebral fracture in this population.IntroductionWe aimed to describe the prevalence and develop a model for prediction of radiographic vertebral fractures in a large random sample of postmenopausal Chinese women.MethodsWe enrolled 1760 women from an age-stratified random sample of postmenopausal women in Beijing, China. The presence of vertebral fracture was assessed by semi-quantitative grading of lateral thoracolumbar radiographs, risk factors by interview, bone mineral density (BMD) of the proximal femur and lumbar spine by dual x-ray absorptiometry (DXA), and markers of bone turnover from a fasting blood sample. Associations of these factors were analyzed in logistic models and discrimination by areas of receiver operating characteristics curves (AUC).ResultsThe prevalence of vertebral fracture, ranged from 13.4% ages 50 to 59 years old to 58.1% at age 80 years or older. Older age, a history of non-vertebral fracture, lower femoral neck BMD T-score, body mass index (BMI), height loss, housework, and less than half an hour of outdoor activity were significantly associated with increased probability of having a vertebral fracture. A model with those seven factors had a similar AUC with or without BMD and performed better than a simple model with three factors.ConclusionThis study is from a true random sample of postmenopausal women in urban China with high response rate. The prevalence of vertebral fractures in postmenopausal women in Beijing increases from 13% under age 60 to over 50% by age 80 years. A model with seven clinical risk factors with or without BMD is better than simple models and may guide the use of spine x-rays to identify women with vertebral fractures. More than half an hour of outdoor activity might correlate with lower risk of vertebral fracture in this population.

Significance Results from this study represent a breakthrough in our understanding of posttranscriptional control of cholesterol metabolism and how microRNAs (miRNAs) are at the heart of cholesterol regulatory circuitry and homeostasis. Although cells are adept at maintaining proper cholesterol levels, it was unknown how cells posttranscriptionally coordinate cholesterol uptake, efflux, and synthesis. MicroRNA-223 (miR-223) transcription and expression are maintained by cholesterol, and, as a feedback network, miR-223 inhibits cholesterol biosynthesis and uptake and increases cholesterol efflux. This study clearly demonstrates the extensive role that miRNAs play in coordinating metabolic adaptation to disease and general homeostasis. This work highlights a unique regulatory control point for cholesterol homeostasis and illustrates how important the study of miRNAs is to the greater understanding of dyslipidemia and cardiovascular disease. MicroRNAs (miRNAs) regulate a wide variety of biological processes and contribute to metabolic homeostasis. Here, we demonstrate that microRNA-223 (miR-223), an miRNA previously associated with inflammation, also controls multiple mechanisms associated with cholesterol metabolism. miR-223 promoter activity and mature levels were found to be linked to cellular cholesterol states in hepatoma cells. Moreover, hypercholesterolemia was associated with increased hepatic miR-223 levels in athero-prone mice. miR-223 was found to regulate high-density lipoprotein-cholesterol (HDL-C) uptake, through direct targeting and repression of scavenger receptor BI, and to inhibit cholesterol biosynthesis through the direct repression of sterol enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 and methylsterol monooxygenase 1 in humans. Additionally, miR-223 was found to indirectly promote ATP-binding cassette transporter A1 expression (mRNA and protein) through Sp3, thereby enhancing cellular cholesterol efflux. Finally, genetic ablation of miR-223 in mice resulted in increased HDL-C levels and particle size, as well as increased hepatic and plasma total cholesterol levels. In summary, we identified a critical role for miR-223 in systemic cholesterol regulation by coordinated posttranscriptional control of multiple genes in lipoprotein and cholesterol metabolism.

Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response. VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared. The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation. The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.

This study aimed to determine the changing prevalence of five chronic non-communicable diseases (NCDs)- hypertension, coronary heart disease (CHD), stroke, chronic obstructive pulmonary disease (COPD), and asthma— and its multimorbidity (refers to the co-existence of two or more chronic diseases in an individual) across socioeconomic spectra in rural southwest China. Two cross-sectional health interviews and examination surveys were conducted among individuals aged ≥35 years in rural China. An individual socioeconomic position (SEP) index was constructed using principal component analysis. Anthropometric measurements, blood pressure, and post-bronchodilator spirometry tests were recorded for each participant. The mean age and proportion of men was 56.1 years and 48.4% in 2011, while was 56.6 years and 49.4% in 2021. From 2011 to 2021, the overall prevalence of hypertension, stroke and COPD increased from 26.1%, 1.1%, and 8.7% to 40.4%, 2.4%, and 12.8%, respectively (P < 0.01), while prevalence of CHD (2.1% vs. 2.2%) and asthma (1.4% vs. 1.5%) did not differ between the two study years (P > 0.05). The prevalence of NCDs multimorbidity increased from 2.3% to 9.7%, and was also observed among subgroups categorized by sex, age, ethnicity, level of education, income, and SEP (P < 0.01). In addition, the relative increases in the prevalence of multimorbidity were greater among men, old individuals, ethnic minorities, and those with low level of education and low SEP. Both in 2011 and 2021, ethnic minorities and individuals with lower level of education and low SEP had a higher prevalence of multimorbidity of the five studied chronic NCDs than their counterparts (P <0.01). The prevalence of NCDs multimorbidity increased substantially across all socioeconomic gradients in rural southwest China. Future interventions to further manage NCDs and their multimorbidity must be tailored to address socioeconomic factors.

Background: Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown. Methods: MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis. Results: KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression. Conclusion: Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.

Forward photoproduction of \\[J/\\psi \\] can be used to extract generalized parton distributions (GPDs) of gluons. We analyze the process at twist-3 level and study relevant classifications of twist-3 gluon GPDs. At leading power or twist-2 level the produced \\[J/\\psi \\] is transversely polarized. We find that at twist-3 the produced \\[J/\\psi \\] is longitudinally polarized. Our study shows that in the high-energy limit the twist-3 amplitude is only suppressed by the inverse power of the heavy quark mass relatively to the twist-2 amplitude. This indicates that the power correction to the cross-section of unpolarized \\[J/\\psi \\] can have a sizable effect.The poles in the hard factor convoluted with twist-3 gluon GPDs may concern the GPDs discontinuities, which will be briefly discussed in this work. We have also derived the amplitude of the production of \\[h_c\\] at twist-3, but the result contains end-point singularities. The production of other quarkonia has been briefly discussed.

Exploring the composition and structure of the faecal microbial community improves the understanding of the role of the gut microbiota in the gastrointestinal function and the egg-laying performance of hens. Therefore, detection of hen-microbial interactions can explore a new breeding marker for the selection of egg production due to the important role of the gut microbiome in the host's metabolism and health. Recently, the gut microbiota has been recognised as a regulator of host performance, which has led to investigations of the productive effects of changes in the faecal microbiome in various animals. In the present study, a metagenomics analysis was applied to characterise the composition and structural diversity of faecal microbial communities under two selections of egg-laying performance, high (H, n = 30) and low (L, n = 30), using 16S rRNA-based metagenomic association analysis. The most abundant bacterial compositions were estimated based on the operational classification units among samples and between the groups from metagenomic data sets. The results indicated that Firmicutes phylum has higher significant (P < 0.01) in the H group than in the L group. In addition, higher relative abundance phyla of Bacteroides and Fusobacteria were estimated in the H group than the L group, contrasting the phyla of Actinobacteria, Cyanobacteria and Proteobacteria were more relative abundance in the L group. The families (Lactobacillus, Bifidobacterium, Acinetobacter, Flavobacteriaceae, Lachnoclostridum and Rhodococcus) were more abundant in the H group based on the comparison between the H and L groups. Meanwhile, three types of phyla (Proteobacteria, Actinobacteria and Cyanobacteria) and six families (Acinetobacter, Avibacterium, Clostridium, Corynebacterium, Helicobacter and Peptoclostridium) were more abundant in the L group (P < 0.01). Overall, the selection of genotypes has enriched a relationship between the gut microbiota and the egg-laying performance. These findings suggest that the faecal microbiomes of chickens with high egg-laying performance have more diverse activities than those of chickens with low egg-laying performance, which may be related to the metabolism and health of the host and egg production variation.

SummaryThis study built a micro-simulation Markov model to determine the treatment threshold of osteoporosis in postmenopausal women in Mainland China. Treatment with zoledronate is cost-effective when FRAX-based (Fracture risk assessment tool) fracture probability is over 7%.IntroductionThe purpose of this study is to estimate FRAX-based fracture probabilities in Mainland China using real-world data, at which intervention could be cost-effective.MethodsWe developed a micro-simulation Markov model to capture osteoporosis states and relevant morbidities including hip fracture, vertebral fracture, and wrist fracture. Baseline characteristics including incidences of osteoporosis and distribution of risk factors were derived from the Peking Vertebral Fracture study, the largest prospective cohort study of postmenopausal women in Mainland China. We projected incidences of fractures and deaths by age groups under two treatment scenarios: 1) no treatment, and 2) zoledronate. We also projected total quality-adjusted life-years (QALY) and total costs including fracture management and osteoporosis drugs for cost-effectiveness analysis. Cost-effective intervention thresholds were calculated based on the Chinese FRAX model.ResultsTreatment with zoledronate was cost-effective when the 10-year probability of major osteoporotic fracture based on FRAX was above 7%. The FRAX threshold increased by age from 51 to 65 years old, and decreased in elder age groups, ranging from 4% to 9%.ConclusionsUsing real-world data, our model indicated that widespread use of zoledronate was of both clinical and economic benefit among Chinese postmenopausal women. Using a FRAX-based intervention threshold of 7% with zoledronate should permit cost-effective access to therapy to patients and contribute to reducing the disease burden of osteoporosis in Mainland China.