Immune signature and phagocytosis of circulating DC subsets in healthy adults during aging.

Dendritic cells (DC) play a pivotal role in the onset and progression of immunosenescence-associated diseases, serving as a link between innate and adaptive immunity. Thus, there is a need to establish reference ranges for DC subset levels in healthy adults and investigate the potential impact of age on DC subset levels and phagocytic activity. Single-platform multi-color flow cytometry was performed to assess the proportions of circulating conventional type 1 DC (cDC1), conventional type 2 DC (cDC2), and plasmacytoid DC (pDC), as well as the percentages of CD80, CD86, CD83, PD-L1, and CD32 in cDC1, cDC2, and pDC. Reference ranges were established based on age and gender, and the percentage of circulating DC subsets in different age groups was compared. In addition, circulating DC were enriched using a magnetic bead sorting kit and co-cultured with polystyrene (PS) beads, categorized by age groups, followed by the evaluation of PS bead phagocytosis using light microscopy and flow cytometry. The results indicated that the percentages of circulating cDC1, cDC2, and CD32+cDC2 decreased with age (P < 0.05) and revealed age-related impairment in phagocytic percentage of cDC2 (P < 0.05). These findings provide a deeper understanding of the impact of age on the phenotype and phagocytic activity of DC subsets, shedding light on their role and function in immunosenescence.

Establishment of bone-targeted nano-platform and the study of its combination with 2-deoxy-d-glucose enhanced photodynamic therapy to inhibit bone metastasis.

At present, simple anti-tumor drugs are ineffective at targeting bone tissue and are not purposed to treat patients with bone metastasis. In this study, zoledronic acid (ZOL) demonstrated excellent bone-targeting properties as a bone-targeting ligand. The metal-organic framework (MOF) known as ZIF-90 was modified with ZOL to construct a bone-targeting-based drug delivery system. Chlorin e6 (Ce6) was loaded in the bone-targeted drug delivery system and combined with 2-deoxy-D-glucose (2-DG), which successfully treated bone tumors when enhanced photodynamic therapy was applied. The Ce6@ZIF-PEG-ZOL (Ce6@ZPZ) nanoparticles were observed to have uniform morphology, a particle size of approximately 210 nm, and a potential of approximately -30.4 mV. The results of the bone-targeting experiments showed that Ce6@ZPZ exhibited a superior bone-targeted effect when compared to Ce6@ZIF-90-PEG. The Ce6@ZPZ solution was subjected to 660 nm irradiation and the resulting production of reactive oxygen species increased over time, which could be further increased when Ce6@ZPZ was used in combination with 2-DG. Their combination had a stronger inhibitory capacity against tumor cells than either 2-DG or Ce6@ZPZ alone, increasing the rate of tumor cell apoptosis. The apoptosis rate caused by HGC-27 was 61.56% when 2-DG was combined with Ce6@ZPZ. In vivo results also showed that Ce6@ZPZ combined with 2-DG maximally inhibited tumor growth and prolonged mice survival compared to the other experimental groups. Therefore, the combination of PDT and glycolytic inhibitors serves as a potential option for the treatment of cancer.

A new strategy for the treatment of heavily pretreated metastatic breast cancer: A case report and review of the literature.

BACKGROUND: Breast cancer is one of the most common type of cancers worldwide and remains a critical health issue. Although there are numerous treatment options for advanced metastatic breast cancer, the results are not satisfactory, particularly for triple-negative breast cancer. New treatment modalities need to be explored. CASE PRESENTATION: We present the case of a breast cancer patient with multiple metastases who achieved a good response and tolerance to the combination treatment of utidelone plus capecitabine. After being treated with 10 cycles of combined treatment, the patient is now in a good general condition with a progression-free survival time of 10 months. CONCLUSION: To our knowledge, this is the first report of utidelone plus capecitabine successfully treating a patient with heavily pretreated metastatic breast cancer. This combined treatment offers a new option for patients with multi-drug resistant breast cancer.

Single-cell sequencing reveals the reproductive variations between primiparous and multiparous Hu ewes.

BACKGROUND: In the modern sheep production systems, the reproductive performance of ewes determines the economic profitability of farming. Revealing the genetic mechanisms underlying differences in the litter size is important for the selection and breeding of highly prolific ewes. Hu sheep, a high-quality Chinese sheep breed, is known for its high fecundity and is often used as a model to study prolificacy traits. In the current study, animals were divided into two groups according to their delivery rates in three consecutive lambing seasons (namely, the high and low reproductive groups with ≥ 3 lambs and one lamb per season, n = 3, respectively). The ewes were slaughtered within 12 h of estrus, and unilateral ovarian tissues were collected and analyzed by 10× Genomics single-cell RNA sequencing. RESULTS: A total of 5 types of somatic cells were identified and corresponding expression profiles were mapped in the ovaries of each group. Noticeably, the differences in the ovary somatic cell expression profiles between the high and low reproductive groups were mainly clustered in the granulosa cells. Furthermore, four granulosa cell subtypes were identified. GeneSwitches analysis revealed that the abundance of JPH1 expression and the reduction of LOC101112291 expression could lead to different evolutionary directions of the granulosa cells. Additionally, the expression levels of FTH1 and FTL in mural granulosa cells of the highly reproductive group were significantly higher. These genes inhibit necroptosis and ferroptosis of mural granulosa cells, which helps prevent follicular atresia. CONCLUSIONS: This study provides insights into the molecular mechanisms underlying the high fecundity of Hu sheep. The differences in gene expression profiles, particularly in the granulosa cells, suggest that these cells play a critical role in female prolificacy. The findings also highlight the importance of genes such as JPH1, LOC101112291, FTH1, and FTL in regulating granulosa cell function and follicular development.

Sericin suppresses high glucose-induced EMT in mouse podocytes via miR-30a-5p and its target Snai1.

The effect of sericin in high glucose (HG)-induced podocyte injury and the mechanisms involving Snai1 and miR-30a-5p were investigated. Bioinformatics and dual-luciferase reporter assay evaluated the relationship of Snai1 with miR-31a-5p. Podocyte injury mouse induced by HG were randomly divided into control (5.5mmol/L D-glucose), HG (30mmol/L D-glucose), HG + Sericin (30mmol/L D-glucose+600µg/ml sericin), miR-30a-5p inhibitor NC (sericin+30mmol/L D-glucose+miR-30a-5p inhibitor negative control) and miR-30a-5p inhibitor groups (sericin+30mmol/L D-glucose+miR-30a-5p inhibitor). The migration ability of podocytes was detected by Transwell assay. The expressions of Snai1, podocin, E-cadherin, FSP-1, ZO-1, α-SMA, Desmin, and miR-30a-5p were assessed with RT-qPCR and Western blot. Snai1 was one direct target of miR-30a-5p. HG group had significantly larger number of migrated podocytes and higher levels of Snai1, FSP-1, α-SMA and Desmin, but significantly lower levels of podocin, ZO-1 and E-cadherin than control and HG + Sericin group. These effects of sericin were reversed by miR-30a-5p inhibitor, as evidenced by increased podocyte migration and increased expressions of Snai1, α-SMA, FSP-1 and Desmin, whereas decreased expressions of podocin, ZO-1 and E-cadherin. Sericin may protect podocytes from damage caused by HG via up-regulating epithelial phenotype markers, down-regulating mesenchymal phenotype markers, and reducing migration of podocytes. The mechanism may be through targeting miR-30a-5p and its target Snai1.

Identification of MARK2, CCDC71, GATA2, and KLRC3 as candidate diagnostic genes and potential therapeutic targets for repeated implantation failure with antiphospholipid syndrome by integrated bioinformatics analysis and machine learning.

Background: Antiphospholipid syndrome (APS) is a group of clinical syndromes of thrombosis or adverse pregnancy outcomes caused by antiphospholipid antibodies, which increase the incidence of in vitro fertilization failure in patients with infertility. However, the common mechanism of repeated implantation failure (RIF) with APS is unclear. This study aimed to search for potential diagnostic genes and potential therapeutic targets for RIF with APS. Methods: To obtain differentially expressed genes (DEGs), we downloaded the APS and RIF datasets separately from the public Gene Expression Omnibus database and performed differential expression analysis. We then identified the common DEGs of APS and RIF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed, and we then generated protein-protein interaction. Furthermore, immune infiltration was investigated by using the CIBERSORT algorithm on the APS and RIF datasets. LASSO regression analysis was used to screen for candidate diagnostic genes. To evaluate the diagnostic value, we developed a nomogram and validated it with receiver operating characteristic curves, then analyzed these genes in the Comparative Toxicogenomics Database. Finally, the Drug Gene Interaction Database was searched for potential therapeutic drugs, and the interactions between drugs, genes, and immune cells were depicted with a Sankey diagram. Results: There were 11 common DEGs identified: four downregulated and seven upregulated. The common DEG analysis suggested that an imbalance of immune system-related cells and molecules may be a common feature in the pathophysiology of APS and RIF. Following validation, MARK2, CCDC71, GATA2, and KLRC3 were identified as candidate diagnostic genes. Finally, Acetaminophen and Fasudil were predicted as two candidate drugs. Conclusion: Four immune-associated candidate diagnostic genes (MARK2, CCDC71, GATA2, and KLRC3) were identified, and a nomogram for RIF with APS diagnosis was developed. Our findings may aid in the investigation of potential biological mechanisms linking APS and RIF, as well as potential targets for diagnosis and treatment.

Cellular senescence in liver diseases: From mechanisms to therapies.

Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.

Dynamics of Associative Polymers with High Density of Reversible Bonds.

An associative polymer carries many stickers that can form reversible associations. For more than 30 years, the understanding has been that reversible associations change the shape of linear viscoelastic spectra by adding a rubbery plateau in the intermediate frequency range, at which associations have not yet relaxed and thus effectively act as crosslinks. Here, we design and synthesize new classes of unentangled associative polymers carrying unprecedentedly high fractions of stickers, up to eight per Kuhn segment, that can form strong pairwise hydrogen bonding of ∼20k_{B}T without microphase separation. We experimentally show that reversible bonds significantly slow down the polymer dynamics but nearly do not change the shape of linear viscoelastic spectra. This behavior can be explained by a renormalized Rouse model that highlights an unexpected influence of reversible bonds on the structural relaxation of associative polymers.

A Single-Center Study Using IVUS to Guide Rotational Atherectomy for Chronic Renal Disease's Calcified Coronary Artery.

Objective: To assess the effectiveness and safety of an IVUS-guided rotational atherectomy (RA) percutaneous coronary intervention (PCI) in chronic renal patients with complex coronary calcification who are at risk for contrast-related acute kidney injury (AKI). Methods: From October 2018 to October 2021, 48 patients with chronic renal disease who were receiving PCI with RA at the General Hospital of NingXia Medical University were informed for data collection for this research. They were randomly assigned to the IVUS-guided RA group and the Standard RA group, which did not use IVUS. According to a clinical expert consensus document on rotational atherectomy in China, both PCI procedures were performed. The intravascular ultrasound (IVUS) results from the study group were used to describe the morphology of the lesion and to guide the selection of burrs, balloons, and stents. IVUS and angiography were used to evaluate the outcome in the end. IVUS-guided RA PCI and Standard RA PCI groups' effects and results were contrasted. Results: There were no appreciable differences in the clinical baseline characteristics between the IVUS-guided RA PCI group and the Standard RA PCI group. The average estimated glomerular filtration rate (eGFR) of two groups was (81.42 ± 20.22 vs 82.34 ± 22.19) mL/min/1.73 m2. Most of them (45.8% vs 54.2%) was in stage 60-90 mL/min/1.73m2. When compared to the standard RA PCI group, RA in IVUS-Guided group was more performed electively (87.5% vs 58.3%; p = 0.02). The IVUS-guided RA PCI group was associated with shorter fluoroscopy time (20.6 ± 8.4 vs 36 ± 22; p<0.01) and less contrast amount (32 ±16 vs 184 ±116mL; p<0.01) than Standard-RA group. Five patients in the Standard RA PCI group developed contrast-induced nephropathy, which was 5 times than the IVUS-guided RA PCI group (20.8% VS 4.1%; p=0.19). Conclusion: In chronic renal patients with complex coronary calcification, an IVUS-guided RA PCI technique is effective and safe. It can also lower the volume of contrast and perhaps the incidence of contrast-related AKI.

Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study.

Background: Accumulating evidence has demonstrated that gut microbiota dysbiosis correlated with altered metabolism are implicated in liver metabolic diseases. However, data on pediatric hepatic glycogen storage disease (GSD) are limited. Here, we aimed to investigate the features of the gut microbiota and metabolites in hepatic GSD children from China. Methods: Totals of 22 hepatic GSD patients and 16 age- and gender-matched healthy children were enrolled from the Shanghai Children's Hospital, China. Pediatric GSD patients were confirmed as having hepatic GSD via genetic diagnosis and/or liver biopsy pathology. The control group comprised children without any history of chronic diseases or clinically relevant GSD or symptoms of any other metabolic diseases. The baseline characteristics of the two groups were gender- and age-matched matched using chi-squared test and the Mann-Whitney U test, respectively. The gut microbiota, bile acids (BAs), and short chain fatty acids (SCFAs) were determined from the feces using 16S ribosomal RNA (rRNA) gene sequencing, ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and gas chromatography-mass spectrometry (GC-MS), respectively. Results: The alpha diversity of fecal microbiome was significantly lower in hepatic GSD patients [observed species richness (Sobs): P=0.011; abundance-based coverage estimator (ACE): P=0.011; Chao: P=0.011; Shannon: P<0.001], and their microbial community was more distanced from that of the control [principal coordinate analysis (PCoA) on genus level, unweighted UniFrac: P=0.011]. Relative abundances of phyla Firmicutes (P=0.030) and Bacteroidetes (P=0.029), families Lachnospiraceae (P=0.012), Ruminococcaceae (P=0.008), and Peptostreptococcaceare (P=0.031), genera Blautia (P=0.017), Eubacterium_hallii_group (P=0.032), and Faecalibacterium (P=0.017) were decreased, whereas phyla Actinobacteria (P=0.033), Proteobacteria (P=0.049), families Bifidobacteriaceae (P=0.030), Lactobacillaceae (P=0.034), and Veillonellaceae (P=0.033), genera Lactobacillus (P=0.011), Enterobater (P=0.034), and Veillonella (P=0.014) were increased in hepatic GSD. Altered microbial metabolisms were characterized by increased abundances of primary BAs (P=0.009) and decreased concentrations of SCFAs in hepatic GSD children. Furthermore, the altered bacterial genera were correlated with the changes of both fecal BAs and SCFAs. Conclusions: The hepatic GSD patients in this study presented with gut microbiota dysbiosis which correlated with altered BAs metabolism and fecal SCFAs changes. Further studies are needed to investigate the driver of these changes mediated by either the genetic defect, disease status, or diet therapy.

Entropic Mixing of Ring/Linear Polymer Blends.

The topological constraints of nonconcatenated ring polymers force them to form compact loopy globular conformations with much lower entropy than unconstrained ideal rings. The closed-loop structure of ring polymers also enables them to be threaded by linear polymers in ring/linear blends, resulting in less compact ring conformations with higher entropy. This conformational entropy increase promotes mixing rings with linear polymers. Here, using molecular dynamics simulations for bead-spring chains, ring/linear blends are shown to be significantly more miscible than linear/linear blends and that there is an entropic mixing, negative χ, for ring/linear blends compared to linear/linear and ring/ring blends. In analogy with small angle neutron scattering, the static structure function S(q) is measured, and the resulting data are fit to the random phase approximation model to determine χ. In the limit that the two components are the same, χ = 0 for the linear/linear and ring/ring blends as expected, while χ < 0 for the ring/linear blends. With increasing chain stiffness, χ for the ring/linear blends becomes more negative, varying reciprocally with the number of monomers between entanglements. Ring/linear blends are also shown to be more miscible than either ring/ring or linear/linear blends and stay in single phase for a wider range of increasing repulsion between the two components.

IKZF3 is a novel prognostic biomarker for head and neck squamous cell carcinoma: A study based on bioinformatics analysis.

In the past few years, immunotherapy of tumors has become an extensive research hotspot, and the value of IKZF family genes in the tumor microenvironment has also been increasingly recognized. However, the expression of the IKAROS family zinc finger 3 (IKZF3) gene in human head and neck squamous cell carcinoma (HNSCC) and its prognostic value were not reported for the main subset until now. In the present study, we analyzed the relationship between IKZF3 gene expression and the survival of HNSCC patients. To evaluate the potential of IKZF3 as a prognostic biomarker for HNSCC comprehensively, multiple online analysis tools, including UALCAN, cBioPortal, GEPIA, WebGestalt, String, Genomic Data Commons, and TIMER databases were utilized in our study. We observed that the HNSCC patients with higher IKZF3 expression tended to exhibit longer overall survival. Univariate and multivariate Cox regression analyses indicated that age and grade were independent prognostic indicators in HNSCC. Moreover, Gene Ontology and KEGG function enrichment analyses showed that several pathways in HNSCC might be pivotal pathways regulated by IKZF3, which revealed that IKZF3 was probably participating in the occurrence and development of HNSCC. Furthermore, the hypomethylation of the IKZF3 gene was closely associated with genes that observed mutation in HNSCC. IKZF3 was significantly correlated with several immune cells in HNSCC (e.g., CD8+ T cell, CD4+ cell, and dendritic cell). We explored the potential prognostic values and roles of the IKZF3 in HNSCC, revealing that IKZF3 was probably a novel and reliable prognostic biomarker for patients with HNSCC.

High-energy diet modify rumen microbial composition and microbial energy metabolism pattern in fattening sheep.

Higher dietary energy is often used to achieve better animal performance in mutton sheep production. Notably, changing the diet formula affects rumen fermentation and the microbiota of ruminants. In this study, we investigated the effect of dietary energy on rumen fermentation and ruminal microbiota in fattening sheep. Fifteen 2-month-old white-headed Suffolk sheep (♂) × Hu sheep (♀) crossbred lambs were randomly divided into three treatments based on the dietary energy of the feeds fed: 8.67 MJ/kg (Low energy (LE); n = 5), 10.38 MJ/kg (standard energy (CON); n = 5), and 12.31 MJ/kg (high energy (HE); n = 5) groups. After 70 days of feeding, sheep were slaughtered and the ruminal fluids were collected and analyzed to determine fermentation parameters. Microbiota was determined using metagenomics sequencing. Notably, the microbial cell protein (MCP) and butyric acid concentrations were significantly high in the HE group. Metagenomic sequencing revealed that ACE and Chao indexes of the HE group were significantly decreased. Four genera among the major classified taxa across all the kingdoms differed in relative abundance in the three dietary energy levels. The relative abundances of Prevotella_brevis, Succiniclasticum_ruminis, Prevotellace-ae_bacterium, and Lachnospiraceae_bacterium were significantly correlated with rumen fermentation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis further revealed that a high-energy diet increased lipid metabolism of microbiota. The Carbohydrate Active enzymes (CAZy) gene, which participates in energy metabolism, was upregulated, while genes regulating plant cell wall degradation were downregulated in the HE group. These results suggest that a high-energy diet had minimal influence on the rumen fermentation pattern but altered the composition of the rumen microbiota, enhancing microbial lipid metabolism and limiting crude fiber metabolism. The findings of this study provide scientific evidence of the effect of dietary energy on ruminant fermentation and fattening sheep production.

Biomechanical evaluation of two-level oblique lumbar interbody fusion combined with posterior four-screw fixation：A finite element analysis.

OBJECTIVE: By constructing the three-dimensional finite element model of two-level OLIF lumbar spine, the aim of this study was to demonstrate the feasibility and effectiveness of posterior four-screw fixation for treatment of two-level lumbar degenerative diseases from the perspective of biomechanics. METHODS: An intact L3-S1 segment nonlinear lumbar finite element model (M0) was constructed from the CT scanning data of a healthy adult. After verification, two-level OLIF procedure were simulated, and three patterns of finite element analysis models were constructed: two-level stand-alone OLIF group (M1), two-level OLIF + four-screw fixation group (M2) and two-level OLIF + six-screw fixation group (M3). Range of motion, stress of the cage, and stress of fixation were evaluated in the different models. RESULTS: Under various motion modes，the ROM of M2 and M3 were significantly lower than those of M1. The ROM reduction of M2 relative to M1 was much greater than that of M3 relative to M2. Moreover, the peak von Mises stresses of endplates in M2 were almost the same as those in M3. In terms of the maximum stresses of cages, M2 and M3 were essentially identical. Besides, the maximum stresses of posterior instrumentation in M2 and M3 were similar, which were mainly concentrated at the root of pedicle screws. CONCLUSION: There were no significant differences between M2 and M3 from the biomechanical analysis. In two-level OLIF, posterior four-screw fixation can replace six-screw fixation, which reduces surgical trauma and decreases economic burden of patients, and will be a cost-effective alternative.

Altered gut microbiota composition in children and their caregivers infected with the SARS-CoV-2 Omicron variant.

BACKGROUND: Gut microbiota alterations have been implicated in the pathogenesis of coronavirus disease 2019 (COVID-19). This study aimed to explore gut microbiota changes in a prospective cohort of COVID-19 children and their asymptomatic caregivers infected with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) Omicron variant. METHODS: A total of 186 participants, including 59 COVID-19 children, 50 asymptomatic adult caregivers, 52 healthy children (HC), and 25 healthy adults (HA), were recruited between 15 April and 31 May 2022. The gut microbiota composition was determined by 16S rRNA gene sequencing in fecal samples collected from the participants. Gut microbiota functional profiling was performed by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) software. RESULTS: The gut microbiota analysis of beta diversity revealed that the fecal microbial community of COVID-19 children remained far distantly related to HC. The relative abundances of the phyla Actinobacteria and Firmicutes were decreased, whereas Bacteroidetes, Proteobacteria, and Verrucomicrobiota were increased in COVID-19 children. Feces from COVID-19 children exhibited notably lower abundances of the genera Blautia, Bifidobacterium, Fusicatenibacter, Streptococcus, and Romboutsia and higher abundances of the genera Prevotella, Lachnoclostridium, Escherichia-Shigella, and Bacteroides than those from HC. The enterotype distributions of COVID-19 children were characterized by a high prevalence of enterotype Bacteroides. Similar changes in gut microbiota compositions were observed in asymptomatic caregivers. Furthermore, the microbial metabolic activities of KEGG (Kyoto Encyclopedia of Genes and Genomes) and COG (cluster of orthologous groups of proteins) pathways were perturbed in feces from subjects infected with the SARS-CoV-2 Omicron variant. CONCLUSION: Our data reveal altered gut microbiota compositions in both COVID-19 children and their asymptomatic caregivers infected with the SARS-CoV-2 Omicron variant, which further implicates the critical role of gut microbiota in COVID-19 pathogenesis.

A study of the efficacy of sacubitril/valsartan plus dapagliflozin combination treatment in pulmonary arterial hypertension due to left heart disease.

OBJECTIVE: To determine the efficacy of sacubitril/valsartan plus dapagliflozin in the treatment of patients with pulmonary arterial hypertension (PAH) due to left heart disease and to explore new treatment regimen for PAH due to left heart disease. METHODS: This study is a randomized controlled trial (RCT) study of 120 patients with PAH due to left heart disease admitted to the cardiovascular department of our hospital from Dec. 2019 to Dec. 2021. The patients were randomized 1:1 to the study group and control group. All patients were given baseline treatments targeting left heart disease and symptoms of PAH. In addition to the baseline treatments, patients in the control group were given sacubitril/valsartan tablets, while patients in the study group were given sacubitril/valsartan tablets plus dapagliflozin tablets. After 6 months of treatment, parameters including left heart function and exercise tolerance, Hemodynamics (left ventricular end systolic diameter [LVSED], left ventricular end diastolic diameter [LVEDD], left ventricular ejection fraction [LVEF], 6 min walk distance (6MWD), mean pulmonary artery pressure (mPAP) and pulmonary artery systolic pressure (PASP)), vascular endothelial function (plasma endothelin (ET) -1 and nitric oxide [NO]), heart failure markers (plasma N-terminal pro-brain natriuretic peptide (NT-proBNP)], inflammatory factors (serum C reactive protein [CRP], interleukin (IL)-6, and tumor necrosis factor (TNF)-α], and adverse drug reactions (ADRs) were assessed in both groups. RESULTS: Both groups had reduced LVESD and LVEDD, increased LVEF, and extended 6MWD after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P < 0.05). In addition, both the mPAP and PASP showed a decrease, and the mPAP and PASP in the study group were lower than those in the control group (p<0.05). Furthermore, both groups had decreased plasma ET-1 and NT-proBNP but increased plasma NO after 6 months of treatment. The improvements in these parameters were significantly greater in the study group than in the control group (all P < 0.05). Serum CRP, IL-6 and TNF-α levels were decreased in both groups after 6 months of treatment, and were significantly lower in the study group than in the control group (all P < 0.05). There was no significant difference in the overall incidence of ADRs between the two groups (P > 0.05). CONCLUSION: Sacubitril/valsartan plus dapagliflozin in the treatment with PAH due to left heart disease can improve left heart function of patients by improving vascular endothelial functions and alleviating inflammation, which helps to reduce the PAH process. Therefore, this combination treatment is safe and effective in PAH due to left heart disease.

ZNF281 drives hepatocyte senescence in alcoholic liver disease by reducing HK2-stabilized PINK1/Parkin-mediated mitophagy.

We investigated the role of zinc-finger protein 281 (ZNF281), a novel molecule, in ethanol-induced hepatocyte senescence and uncovered the potential mechanism. Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol-fed mice livers and ethanol-treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol-caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence-associated ß-galactosidase-positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence-associated secretory phenotype and proinflammatory cytokines (IL-1ß and IL-6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence-associated proteins including p53, p21, p16, high mobility group AT-hook 1, and phospho-histone H2A.X and telomerase-associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol-induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2-PINK1/Parkin signalling-mediated mitophagy. Mechanistically, ZNF281 directly bound to 5'-GGCGGCGGGCGG-3' motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno-associated virus encoding ZNF281 shRNA protected mice from alcohol feeding-caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.

Discovering childhood in contemporary China: Toward a multisystems perspective.

Despite the remarkable improvements that have been achieved in the field of child development in contemporary China, there remain daunting challenges. To explore and address these issues, we organize this special issue "Child development in contemporary China: Toward a multisystems perspective." In this collection, we introduce theoretically-informed empirical research conducted by scholars worldwide and organize these research articles into four general themes: policy/program intervention regarding child development, migration status and child development, parenting/grandparenting and child development, and school/after-school engagement and child development. These articles keep abreast of theoretical, methodological, and practical innovations in the field, aiming to provide new evidence to enrich the understanding of the patterns and potential mechanisms that would lead to a (dis)advantaged childhood in China.

Study on the correlation between ceramic and chronic obstructive pulmonary disease in Foshan City / 中华劳动卫生职业病杂志

Objective: To study the correlation between ceramic and chronic obstructive pulmonary disease (COPD), and explore its related risk factors. Methods: In January 2021, five representative ceramic enterprises were selected from Chancheng District, Nanhai District, Gaoming District and Sanshui District of Foshan City. The ceramic workers who came to Chancheng Hospital of Foshan First People's Hospital for physical examination from January to October 2021 were selected as the research objects, and 525 people were included. Conduct questionnaire survey and pulmonary function test. Logistic regresion was performed to analyze the influencing facters of COPD among ceramic workers. Results: The subjects were (38.51±1.25) years old, 328 males and 197 females, and the detection rate of COPD was 9.52% (50/525). The incidence of respiratory symptoms such as dyspnea, chronic cough, wheezing and chest tightness, the detection rates of abnormal lung age, abnormal lung function and COPD in males were higher than those in females (P<0.05). The logistic regression analysis showed that male, age, working years, smoking status and family history of COPD were the risk factors for COPD among ceramic workers (P<0.05) . Conclusion: The ceramic workers are the high risk population of COPD. We should do a good job in health education, and do a regular physical examination to find the changes of lung function in time, and prevent the occurrence of COPD as soon as possible.

Force-driven active dynamics of thin nanorods in unentangled polymer melts.

Recent advances in the functional material and biomedical applications of nanorods call for a fundamental understanding of the active motion of nanorods in a viscoelastic medium. Molecular dynamics simulations are performed to investigate a model system consisting of force-driven active thin nanorods in a melt of unentangled polymers. The activeness of a thin nanorod arises from a constant external force applied uniformly along the rod. The simulations demonstrate that the active force overcomes the randomness of the diffusive motion and results in a ballistic motion along the direction of the applied force at long timescales. The constant speed of the force-driven ballistic motion is determined by the balance of the active force and the friction from the coupling of the nanorod with the polymer viscosity. The friction coefficient, which is computed as the ratio of the active force and the speed, decreases as the active force increases. The origin of the reduction in the friction coefficient is the high speed that allows the nanorod to renew its local environment faster than the relaxation time of melt chains. A scaling theory is developed to quantify the dependence of the friction coefficient on the strength of the active force. The simulations also demonstrate that the force-driven ballistic motion suppresses the rotational diffusion of the rod and cuts off the de-correlation of the rod axis with time. On the scaling level, the long-time trajectory of a force-driven active nanorod piercing through unentangled polymers may be described as a stretched array of "active blobs", where the short-time random-walk trajectory within an active blob is unperturbed by the active force.