Association of peak expiratory flow with motoric cognitive risk syndrome among older adults.

Background: The association between lung function and motoric cognitive risk syndrome (MCR) is unclear. We aimed to explore the association of peak expiratory flow (PEF) with MCR using cross-sectional and longitudinal analyses. Methods: Within the CHARLS, 5095 participants were included in the cross-sectional analysis, and 4340 MCR-free participants were included in the longitudinal analysis. The PEF was assessed with a lung peak flow meter. MCR was characterized by cognitive complaints and a slow walking speed with normal mobility and without dementia. Logistic regression, Cox regression, and Laplace regression models were employed for data analysis. Results: In this cross-sectional study, logistic regression analyses revealed that continuous PEF was associated with MCR (odds ratio [OR], 0.998; 95% confidence interval [CI], 0.998, 0.999), and the ORs (95% CIs) of MCR prevalence were 0.857 (0.693, 1.061) for the middle tertile and 0.665 (0.524, 0.845) for the highest tertile compared to the lowest tertile. In a longitudinal cohort study, continuous PEF was dose-dependently associated with the risk of MCR. Compared with those in the lowest tertile of PEF, the hazard ratios (95% CIs) of incident MCR were 0.827 (0.661, 1,036) for the middle tertile and 0.576 (0.432, 0.767) for the highest tertile. Furthermore, compared with the lowest tertile, the highest tertile was associated with a delayed onset time of MCR of 0.484 (95% CI: 0.151, 0.817) years. Conclusion: A higher PEF was related to a lower prevalence of MCR and a lower risk for MCR, and a higher PEF also prolonged the onset time of MCR.

Relation of Cognitive Reserve Indicator to Heart Disease and Cardiac Structure and Function: A Large Community-Based Longitudinal Study.

BACKGROUND: High cognitive reserve (CR) has been related to lower dementia risk, but its association with heart disease (HD) is unknown. We aimed to explore the relation of CR to HD and cardiac structure and function. METHODS AND RESULTS: Within the UK Biobank, 349 907 HD-free participants were followed up. A composite CR indicator involving education/occupation attainment/television viewing time/confiding frequency/social connection frequency/variety of leisure activities was generated, and further categorized into low/moderate/high levels. Incident HD, including coronary HD, cardiac arrhythmia, and heart failure, was ascertained on the basis of medical records. During the follow-up, a subsample (n=31 182) underwent cardiac magnetic resonance imaging to assess ventricular structure and function. Data were analyzed using Cox regression, Laplace regression, and linear regression. Compared with low CR, the hazard ratio and 95% CI of any HD for high CR was 0.78 (0.75-0.80) (including 0.68 [0.66-0.71] for coronary HD, 0.91 [0.87-0.95] for cardiac arrhythmia, and 0.63 [0.58-0.68] for heart failure). Furthermore, high CR was associated with delayed HD onset by 1.59 (95% CI, 1.37-1.82) years compared with low CR. In cardiac magnetic resonance imaging data analysis, compared with low CR, high CR was associated with larger left ventricular end-diastolic volume (ß, 0.13 [95% CI, 0.09-0.17]), left ventricular end-systolic volume (ß, 0.05 [95% CI, 0.01-0.10]), left ventricular stroke volume (ß, 0.16 [95% CI, 0.12-0.21]), and left ventricular ejection fraction (ß, 0.08 [95% CI, 0.03-0.13]). CONCLUSIONS: High CR is associated with favorable HD health. Our findings suggest that the beneficial effect of CR is not limited to dementia but also HD.

CCL5/CCR5/CYP1A1 pathway prompts liver cancer cells to survive in the combination of targeted and immunological therapies.

Combination therapy of anti-programmed cell death protein-1 (PD-1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single-cell RNA sequencing (scRNA-seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA-seq) on CCL5-stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor-bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC.

The GE296_RS03820 and GE296_RS03830 genes are involved in capsular polysaccharide biosynthesis in Riemerella anatipestifer.

Riemerella anatipestifer is a pathogenic bacterium that causes duck serositis and meningitis, leading to significant harm to the duck industry. To escape from the host immune system, the meningitis-causing bacteria must survive and multiply in the bloodstream, relying on specific virulence factors such as capsules. Therefore, it is essential to study the genes involved in capsule biosynthesis in R. anatipestifer. In this study, we successfully constructed gene deletion mutants Δ3820 and Δ3830, targeting the GE296_RS03820 and GE296_RS03830 genes, respectively, using the RA-LZ01 strain as the parental strain. The growth kinetics analysis revealed that these two genes contribute to bacterial growth. Transmission and scanning electron microscopy (TEM and SEM) and silver staining showed that Δ3820 and Δ3830 produced the altered capsules and compounds of capsular polysaccharides (CPSs). Serum resistance test showed the mutants also exhibited reduced C3b deposition and decreased resistance serum killing. In vivo, Δ3820 and Δ3830 exhibited markedly declining capacity to cross the blood-brain barrier, compared to RA-LZ01. These findings indicate that the GE296_RS03820 and GE296_RS03830 genes are involved in CPSs biosynthesis and play a key role in the pathogenicity of R. anatipestifer. Furthermore, Δ3820 and Δ3830 mutants presented a tendency toward higher survival rates from RA-LZ01 challenge in vivo. Additionally, sera from ducklings immunized with the mutants showed cross-immunoreactivity with different serotypes of R. anatipestifer, including 1, 2, 7 and 10. Western blot and SDS-PAGE assays revealed that the altered CPSs of Δ3820 and Δ3830 resulted in the exposure of some conserved proteins playing the key role in the cross-immunoreactivity. Our study clearly demonstrated that the GE296_RS03820 and GE296_RS03830 genes are involved in CPS biosynthesis in R. anatipestifer and the capsule is a target for attenuation in vaccine development.

A novel and cost-effective real-time RT-PCR targeting 24 nucleotides deletion to differentiate PEDV wild-type and classical attenuated vaccine strains.

Porcine Epidemic Diarrhea Virus (PEDV) poses a significant threat to the swine industry, causing severe disease and resulting in substantial economic losses. Despite China's implementation of a large-scale vaccine immunization strategy in recent years, various strains of PEDV, including classical attenuated vaccine strains, continue to emerge in immunized pig herds. Here, we established a one-step real-time fluorescent reverse transcription PCR (one-step real-time RT-PCR) assay targeting a 24-nucleotide deletion in the ORF1 region of three PEDV classical attenuated vaccine strains, derived from classical strains. This assay effectively distinguishes between PEDV classical attenuated vaccine strains and wild-type strains, and we also explore the causes of this discriminatory target deficiency of this method through phylogenetic and recombination analysis. We found that these three classical attenuated vaccine strains exhibit closer phylogenetic relationships and higher sequence similarity with five cell-adapted strains. Recombination analysis revealed that although recombination is widespread in the PEDV genome, the 24-nucleotide deletion site remains stable without undergoing recombination and can be utilized as a target for identification. Further analysis revealed there are no enzyme cleavage sites near the 24-nucleotide site, suggesting that this deletion may have been lost during the process of culturing these viral strains in cells.The detection method we have established exhibits high specificity and sensitivity to PEDV, without cross-reactivity with other viruses causing diarrheal diseases. A total of 117 swine fecal samples were analyzed using this established one-step real-time reverse transcription PCR assay, indicating the presence of classical attenuated vaccine strains in pig herds in Gansu province, China. Additionally, the designed primer pairs and two probes can be placed in a single reaction tube to differentiate between these two types of strains, effectively reducing detection costs. These findings offer an efficient and cost-effective technological platform for clinical rapid identification testing of both wild-type and classical attenuated vaccine strains of PEDV, as well as for precise investigation of clinical data on natural infections and vaccine immunity in pig herds.

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank.

OBJECTIVE: This study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. METHODS: Within the UK Biobank, 40 436 dementia-free participants (age 40-70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6-8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. RESULTS: Compared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized ß [95 % CI]: -0.04 [-0.07, -0.02]) and lower regional fractional anisotropy (FA) (-0.08 [-0.13, -0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized ß: -0.04 to -0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (-0.03 [-0.05, -0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (-0.07 [-0.11, -0.02]). However, current long sleep was related to smaller total brain (-0.03 [-0.05, -0.02]), grey matter (-0.05 [-0.07, -0.03]), cortex (-0.05 [-0.07, -0.03]), regional subcortical volumes [standardized ß: -0.05 to -0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (-0.05 [-0.09, -0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). CONCLUSIONS: Both past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6-8 h' sleep duration for healthy brain aging.

ACBP4-WRKY70-RAP2.12 module positively regulates submergence-induced hypoxia response in Arabidopsis thaliana.

ACYL-CoA-BINDING PROTEINs (ACBPs) play crucial regulatory roles during plant response to hypoxia, but their molecular mechanisms remain poorly understood. Our study reveals that ACBP4 serves as a positive regulator of the plant hypoxia response by interacting with WRKY70, influencing its nucleocytoplasmic shuttling in Arabidopsis thaliana. Furthermore, we demonstrate the direct binding of WRKY70 to the ACBP4 promoter, resulting in its upregulation and suggesting a positive feedback loop. Additionally, we pinpointed a phosphorylation site at Ser638 of ACBP4, which enhances submergence tolerance, potentially by facilitating WRKY70's nuclear shuttling. Surprisingly, a natural variation in this phosphorylation site of ACBP4 allowed A. thaliana to adapt to humid conditions during its historical demographic expansion. We further observed that both phosphorylated ACBP4 and oleoyl-CoA can impede the interaction between ACBP4 and WRKY70, thus promoting WRKY70's nuclear translocation. Finally, we found that the overexpression of orthologous BnaC5.ACBP4 and BnaA7.WRKY70 in Brassica napus increases submergence tolerance, indicating their functional similarity across genera. In summary, our research not only sheds light on the functional significance of the ACBP4 gene in hypoxia response, but also underscores its potential utility in breeding flooding-tolerant oilseed rape varieties.

Association of daytime napping and nighttime sleep with all-cause mortality: A prospective cohort study of China Health and Retirement Longitudinal Study.

STUDY OBJECTIVES: The correlation of daytime napping and nighttime sleep duration on mortality was inconsistent. We aimed to explore their separate links to all-cause/premature mortality, and evaluate their combined impact on all-cause mortality risk. METHODS: All of 20617 (mean age: 56.90 ± 10.19, 52.18 % females) participants from China Health and Retirement Longitudinal Study were followed for a median of 7 years (interquartile range: 4-7) to detect death status. Baseline self-reported napping and sleep duration was categorized: napping as none, <60 min, 60-90 min, and ≥90 min, sleep as <6 h/night, 6-8 h/night, and ≥8 h/night. Death event was tracked, and premature death was defined using 2015 China's average life expectancy (73.64 years for men, and 79.43 years for women). Cox regression models analyzed the data. RESULTS: During follow-up, 1621 participants (7.86 %) died, including 985 (4.78 %) premature deaths. Compared to none nappers, napping ≥90 min associated with a higher risk of all-cause mortality (Hazard ratio, [HR] 1.23, 95 % confidence interval [CI] 1.06-1.42) and premature mortality (HR 1.23, 95 % CI 1.02-1.49), while napping <60 min correlated with a lower risk of premature mortality (HR 0.71, 95 % CI 0.54-0.95), after adjustment. Compared to sleep 6-8 h/night, nighttime sleep ≥8 h was associated with an increased risk of all-cause mortality (HR 1.20, 95 % CI 1.04-1.37) and premature mortality (HR 1.28, 95 % CI 1.08-1.52). Participants napping ≥90 min and sleeping ≥8 h had a multi-adjusted HR (95%CI) of 1.50 (95 % CI 1.17-1.92) for all-cause mortality, versus no napping and 6-8 h/night sleep. CONCLUSIONS: Prolonged napping and extended nighttime sleep linked to increased mortality risk, particularly in combination. Optimizing sleep patterns may have potential implication in mortality prevention.

Lenvatinib plus anti-PD-1 antibodies as conversion therapy for patients with unresectable intermediate-advanced hepatocellular carcinoma: a single-arm, phase II trial.

BACKGROUND: Over 70% of the patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage and lose the opportunity for radical surgery. Combination therapy of tyrosine kinase inhibitors (TKIs) and anti-programmed cell death protein-1 (PD-1) antibodies has achieved a high tumor response rate in both the first-line and second-line treatment of advanced HCC. However, few studies have prospectively evaluated whether TKIs plus anti-PD-1 antibodies could convert unresectable intermediate-advanced HCC into resectable disease. METHODS: This single-arm, phase II study enrolled systemic therapy-naïve adult patients with unresectable Barcelona Clinic Liver Cancer stage B or C HCC. Patients received oral lenvatinib one time per day plus intravenous anti-PD-1 agents every 3 weeks (one cycle). Tumor response and resectability were evaluated before the fourth cycle, then every two cycles. The primary endpoint was conversion success rate by investigator assessment. Secondary endpoints included objective response rate (ORR) by independent imaging review (IIR) assessment per modified RECIST (mRECIST) and Response Evaluation Criteria in Solid Tumors, V.1.1 (RECIST 1.1), progression-free survival (PFS) and 12-month recurrence-free survival (RFS) rate by IIR per mRECIST, R0 resection rate, overall survival (OS), and safety. Biomarkers were assessed as exploratory objectives. RESULTS: Of the 56 eligible patients enrolled, 53 (94.6%) had macrovascular invasion, and 16 (28.6%) had extrahepatic metastasis. The median follow-up was 23.5 months. The primary endpoint showed a conversion success rate of 55.4% (31/56). ORR was 53.6% per mRECIST and 44.6% per RECIST 1.1. Median PFS was 8.9 months, and median OS was 23.9 months. Among the 31 successful conversion patients, 21 underwent surgery with an R0 resection rate of 85.7%, a pathological complete response rate of 38.1%, and a 12-month RFS rate of 47.6%. Grade ≥3 treatment-related adverse events were observed in 42.9% of patients. Tumor immune microenvironment analysis of pretreatment samples displayed significant enrichment of CD8+ T cells (p=0.03) in responders versus non-responders. CONCLUSION: Lenvatinib plus anti-PD-1 antibodies demonstrate promising efficacy and tolerable safety as conversion therapy in unresectable HCC. Pre-existing CD8+ cells are identified as a promising biomarker for response to this regimen. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry, ChiCTR1900023914.

A high-concentrate diet induces mitochondrial dysfunction by activating the MAPK signaling pathway in the mammary gland of dairy cows.

Subacute rumen acidosis can lead to mastitis in dairy cows. Mitochondrial dysfunction is closely related to the inflammatory response. This experiment was conducted to investigate the effects of a high-concentrate diet on mammary gland inflammation and mitochondrial damage in dairy cows. Twelve Holstein dairy cows in mid-lactation were randomly divided into 2 groups and fed a 40% concentrate (low concentrate, LC) diet or a 60% concentrate (high concentrate, HC) diet. Cows were fed individually, and the experiment lasted for 3 wk. After the experiment, mammary gland tissue, blood, and rumen fluid were collected. Compared with the LC diet, the HC diet significantly decreased rumen pH; the pH was <5.6 for more than 3 h. The HC diet also increased the concentration of LPS in the blood (7.17 ± 1.25 µg/mL vs. 12.12 ± 1.26 µg/mL), which indicated that feeding the HC diet successfully induced subacute rumen acidosis. The HC diet also increased the concentration of Ca2+ (34.80 ± 4.23 µg/g vs. 46.87 ± 7.24 µg/g) in the mammary gland and upregulated the expression of inflammatory factors IL-6 (1,128.31 ± 147.53 pg/g vs. 1,538.42 ± 241.38 pg/g), IL-1ß (69.67 ± 5.86 pg/g vs. 90.13 ± 4.78 pg/g), and tumor necrosis factor-α (91.99 ± 10.43 pg/g vs. 131.75 ± 17.89 pg/g) in mammary venous blood. The HC diet also increased the activity of myeloperoxidase (0.41 ± 0.05 U/g vs. 0.71 ± 0.11 U/g) and decreased the content of ATP (0.47 ± 0.10 µg/mL vs. 0.32 ± 0.11 µg/mL) in the mammary gland. In addition, phosphorylation of JNK (1.00 ± 0.21 vs. 2.84 ± 0.75), ERK (1.00 ± 0.20 vs. 1.53 ± 0.31), and p38 (1.00 ± 0.13 vs. 1.47 ± 0.41) and protein expression of IL-6 (1.00 ± 0.22 vs. 2.21 ± 0.27) and IL-8 (1.00 ± 0.17 vs. 1.96 ± 0.26) were enhanced in cows of the HC group, indicating that the mitogen-activated protein kinase (MAPK) signaling pathway was activated. Compared with the LC diet, the HC diet reduced the protein expression of mitochondrial biogenesis-related proteins PGC-1α (1.00 ± 0.17 vs. 0.55 ± 0.12), NRF1 (1.00 ± 0.17 vs. 0.60 ± 0.10), TFAM (1.00 ± 0.10 vs. 0.73 ± 0.09), and SIRTI (1.00 ± 0.44 vs. 0.40 ± 0.10). The HC diet promoted mitochondrial fission and inhibited mitochondrial fusion by reducing protein expression of MFN1 (1.00 ± 0.31 vs. 0.49 ± 0.09), MFN2 (1.00 ± 0.19 vs. 0.69 ± 0.13), and OPA1 (1.00 ± 0.08 vs. 0.72 ± 0.07), and by increasing that of DRP1 (1.00 ± 0.09 vs. 1.39 ± 0.10), MFF (1.00 ± 0.15 vs. 1.89 ± 0.12), and TTC1/FIS1 (1.00 ± 0.08 vs. 1.76 ± 0.14), leading to mitochondrial dysfunction. The HC diet increased mitochondrial permeability by upregulating the protein expression of VDAC1 (1.00 ± 0.42 vs. 1.90 ± 0.44), ANT (1.00 ± 0.22 vs. 1.27 ± 0.17), and CYPD (1.00 ± 0.41 vs. 1.82 ± 0.43). Taken together, these results indicated that feeding the HC diet induced mitochondrial damage via the MAPK signaling pathway in the mammary gland of dairy cows.

The association and prediction value of acylcarnitine on diabetic nephropathy in Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Acylcarnitines play a role in type 2 diabetes mellitus (T2DM), but the relationship between acylcarnitine and diabetic nephropathy was unclear. We aimed to explore the association of acylcarnitine metabolites with diabetic nephropathy and estimate the predictive value of acylcarnitine for diabetic nephropathy. METHODS: A total of 1032 (mean age: 57.24 ± 13.82) T2DM participants were derived from Liaoning Medical University First Affiliated Hospital. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Diabetic nephropathy was ascertained based on the medical records. Factor analysis was used to reduce the dimensions and extract factors of the 25 acylcarnitine metabolites. Logistic regression was used to estimate the relationship between factors extracted from the 25 acylcarnitine metabolites and diabetic nephropathy. Receiver operating characteristic curves were used to test the predictive values of acylcarnitine factors for diabetic nephropathy. RESULTS: Among all T2DM participants, 138 (13.37%) patients had diabetic nephropathy. Six factors were extracted from 25 acylcarnitines, which account for 69.42% of the total variance. In multi-adjusted logistic regression models, the odds ratio (OR, 95% confidence interval [CI]) of diabetic nephropathy on factor 1 (including butyrylcarnitine/glutaryl-carnitine/hexanoylcarnitine/octanoylcarnitine/decanoylcarnitine/lauroylcarnitine/tetradecenoylcarnitine), factor 2 (including propionylcarnitine/palmitoylcarnitine/hydroxypalmitoleyl-carnitine/octadecanoylcarnitine/arachidiccarnitine), and factor 3 (including tetradecanoyldiacylcarnitine/behenic carnitine/tetracosanoic carnitine/hexacosanoic carnitine) were 1.33 (95%CI 1.12-1.58), 0.76 (95%CI 0.62-0.93), and 1.24 (95%CI 1.05-1.47), respectively. The area under the curve for diabetic nephropathy prediction was significantly increased after the complement of factors 1, 2, and 3 in traditional factors model (P < 0.01). CONCLUSIONS: Some plasma acylcarnitine metabolites extracted in factors 1 and 3 were higher in diabetic nephropathy, while factor 2 was lower in diabetic nephropathy among T2DM patients. The addition of acylcarnitine to traditional factors model improved the predictive value for diabetic nephropathy.

A high-concentrate diet induces inflammatory injury via regulating Ca2+/CaMKKß-mediated autophagy in mammary gland tissue of dairy cows.

Introduction: Calmodulin-dependent protein kinase ß (CaMKKß) is closely related to Ca2+ concentration. An increase in Ca2+ concentration in the cytoplasm activates CaMKKß, and activated CaMKKß affects the activities of AMPK and mTOR and induces autophagy. A high-concentrate diet leads to Ca2+ disorder in mammary gland tissue. Objectives: Therefore, this study mainly investigated the induction of mammary gland tissue autophagy by a high-concentrate diet and the specific mechanism of lipopolysaccharide (LPS)-induced autophagy in bovine mammary epithelial cells (BMECs). Material and Methods: Twelve mid-lactation Holstein dairy cows were fed with a 40% concentrate diet (LC) and a 60% concentrate diet (HC) for 3 weeks. At the end of the trial, rumen fluid, lacteal vein blood, and mammary gland tissue were collected. The results showed that the HC diet significantly decreased rumen fluid pH, with a pH lower than 5.6 for more than 3 h, indicating successfully induction of subacute rumen acidosis (SARA). The mechanism of LPS-induced autophagy in BMECs was studied in vitro. First, the cells were divided into a Ctrl group and LPS group to study the effects of LPS on the concentration of Ca2+ and autophagy in BMECs. Then, cells were pretreated with an AMPK inhibitor (compound C) or CaMKKß inhibitor (STO-609) to investigate whether the CaMKKß-AMPK signaling pathway is involved in LPS-induced BMEC autophagy. Results: The HC diet increased the concentration of Ca2+ in mammary gland tissue and pro-inflammatory factors in plasma. The HC diet also significantly increased the expression of CaMKKß, AMPK, and autophagy-related proteins, resulting in mammary gland tissue injury. In vitro cell experiments showed that LPS increased intracellular Ca2+ concentration and upregulated protein expression of CaMKKß, AMPK, and autophagy-related proteins. Compound C pretreatment decreased the expression of proteins related to autophagy and inflammation. In addition, STO-609 pretreatment not only reversed LPS-induced BMECs autophagy but also inhibited the protein expression of AMPK, thereby alleviating the inflammatory response in BMECs. These results suggest that inhibition of the Ca2+/CaMKKß-AMPK signaling pathway reduces LPS-induced autophagy, thereby alleviating inflammatory injury of BMECs. Conclusion: Therefore, SARA may increase the expression of CaMKKß by increasing Ca2+ levels and activate autophagy through the AMPK signaling pathway, thereby inducing inflammatory injury in mammary gland tissue of dairy cows.

Newton-Raphson Meets Sparsity: Sparse Learning Via a Novel Penalty and a Fast Solver.

In machine learning and statistics, the penalized regression methods are the main tools for variable selection (or feature selection) in high-dimensional sparse data analysis. Due to the nonsmoothness of the associated thresholding operators of commonly used penalties such as the least absolute shrinkage and selection operator (LASSO), the smoothly clipped absolute deviation (SCAD), and the minimax concave penalty (MCP), the classical Newton-Raphson algorithm cannot be used. In this article, we propose a cubic Hermite interpolation penalty (CHIP) with a smoothing thresholding operator. Theoretically, we establish the nonasymptotic estimation error bounds for the global minimizer of the CHIP penalized high-dimensional linear regression. Moreover, we show that the estimated support coincides with the target support with a high probability. We derive the Karush-Kuhn-Tucker (KKT) condition for the CHIP penalized estimator and then develop a support detection-based Newton-Raphson (SDNR) algorithm to solve it. Simulation studies demonstrate that the proposed method performs well in a wide range of finite sample situations. We also illustrate the application of our method with a real data example.

Effects of dietary disodium fumarate supplementation on muscle quality, chemical composition, oxidative stress and lipid metabolism of Hu sheep induced by high concentrate diet.

Long-term feeding of high-concentrate (HC) diet causes the decrease of rumen pH, and induces subacute rumen acidosis (SARA), which results in metabolic disorders in sheep. This not only reduces animal performance, but also increases the risk of oxidative stress and inflammatory reaction. Disodium fumarate can improve the rumen buffering capacity and increase rumen pH. This experiment was conducted to investigate the effects of high concentrate diet on muscle quality, chemical composition, oxidative damage and lipid metabolism of Hu sheep, and the regulating effect of disodium fumarate. The results showed that HC diet induced SARA by reducing rumen pH value, thus causing oxidative stress and lipid metabolism disorder in longissimus lumborum (LL) muscle of Hu sheep, which also reduced meat quality by increasing shear force, drip loss, cooking loss, chewiness and hardness, and reducing the contents of crude fat and crude protein in LL muscle. However, disodium fumarate can improve meat quality of SARA Hu sheep by regulating rumen pH, inhibiting muscle oxidative stress and promoting lipid metabolism.

iE-DAP Induced Inflammatory Response and Tight Junction Disruption in Bovine Mammary Epithelial Cells via NOD1-Dependent NF-κB and MLCK Signaling Pathway.

γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), a bacterial cell wall component, can trigger an inflammatory response. A mammary inflammatory response causes tight junction (TJ) dysfunction. This study aimed to explore the effects and involved mechanisms of iE-DAP-induced inflammatory response on the TJ integrity in bovine mammary epithelial cells (BMECs). The results showed that iE-DAP-induced inflammatory response and TJ disruption was associated with increased expression levels of inflammatory cytokines and decreased gene expression of ZO-1 and Occludin, as well as a reduction in transepithelial electrical resistance and elevation in paracellular dextran passage. While MLCK inhibitor ML-7 reversed the TJ disruption induced by iE-DAP. NF-κB inhibitor BAY 11-7085 hindered the activation of NF-κB and MLCK signaling pathways, the inflammatory response and TJ disruption induced by iE-DAP. NOD1-specific shRNA also inhibited the activation of the NOD1/NF-κB signaling pathway and reversed the inflammatory response and TJ injury in iE-DAP-treated BMECs. Above results suggest that iE-DAP activated the NF-κB and MLCK signaling pathway in NOD1-dependent manner, which promoted the transcription of inflammatory cytokines and altered the expression and distribution of tight junction proteins, finally caused inflammatory response and TJ disruption. This study might provide theoretical basis and scientific support for the prevention and treatment of mastitis.

Assessing Healthy Aging Score and Its Association With All-Cause Mortality: Findings From the China Health and Retirement Longitudinal Study.

Background and Objectives: To construct a comprehensive healthy aging score (HAS) and explore its association with all-cause mortality and its potential interactions with other demographics on mortality. Research Design and Methods: This study included 5,409 participants aged ≥60 years from the China Health and Retirement Longitudinal Study. An HAS was constructed based on three dimensions of healthy aging including intrinsic capacity (IC), environmental support (ES), and chronic disease (CD), which were assessed at baseline, and categorized by tertiles (poor, moderate, and high). Participants were followed up biennially for all-cause mortality through the death registration or family interview from 2011 to 2018. Data were analyzed using Cox regression, Laplace regression, and receiver-operating characteristic analysis. Results: During 7 years of follow-up, 877 (16.21%) participants died. An HAS was constructed based on the cognition, mobility, and instrumental activity of daily living in the IC dimension; housing in the ES dimension; and hypertension, diabetes, chronic lung disease, stroke, and cancer in the CD dimension, which was associated with death. HAS seems a good predictor of all-cause mortality, with an area under the curve of 0.749. The hazard ratios and 95% confidence intervals for all-cause mortality related to moderate and poor HAS (vs high HAS) were 1.26 (1.01-1.56) and 2.38 (1.94-2.91), respectively. The median survival time was 2.46 years shorter in participants with poor HAS than those with high HAS. There were significant additive interactions of HAS with age, sex, and marital status on death. Discussion and Implications: Poor HAS may increase mortality and shorten survival, especially among older, male, and single adults.

Comparison of survival benefit between salvage surgery after conversion therapy versus surgery alone for hepatocellular carcinoma with portal vein tumor thrombosis: a propensity score analysis.

BACKGROUND: Salvage surgery after conversion therapy with a combination of tyrosine kinase inhibitor and anti-programmed death-1 antibody has shown improved survival benefits in patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). We aimed to compare the survival benefits in a retrospective cohort of patients with HCC with PVTT who underwent salvage surgery after conversion therapy and surgery alone. METHODS: From January 2015 to October 2021, we selected patients diagnosed with HCC with PVTT who underwent liver resection at Chinese PLA General Hospital. The primary endpoint in the comparison of survival benefits between conversion therapy and surgery-alone groups was recurrence-free survival. Propensity score matching was applied to reduce any potential bias in the study. RESULTS: The 6-, 12-, and 24-month recurrence-free survival rates in the conversion and surgery alone groups were 80.3% vs 36.5%, 65.4% vs 29.4%, and 56% vs 21%, respectively. On multivariable Cox regression analyses, conversion therapy significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone. CONCLUSIONS: For patients with HCC with PVTT, surgery after conversion therapy is in relationship with increased survival in comparison with surgery alone.

Disodium Fumarate Alleviates Endoplasmic Reticulum Stress, Mitochondrial Damage, and Oxidative Stress Induced by the High-Concentrate Diet in the Mammary Gland Tissue of Hu Sheep.

The long-term feeding of the high-concentrate diet (HC) reduced rumen pH and induced subacute rumen acidosis (SARA), leading to mammary gland tissue damage among ruminants. Disodium fumarate enhanced rumen bufferation and alleviated a decrease in rumen pH induced by the HC diet. Therefore, the purpose of this study was to investigate whether disodium fumarate could alleviate endoplasmic reticulum (ER) stress, mitochondrial damage, and oxidative stress induced by the high-concentrate diet in the mammary gland tissue of Hu sheep. In this study, 18 Hu sheep in mid-lactation were randomly divided into three groups: one fed with a low-concentrate diet (LC) diet, one fed with a HC diet, and one fed with a HC diet with disodium fumarate (AHC). Each sheep was given an additional 10 g of disodium fumarate/day. The experiment lasted for eight weeks. After the experiment, rumen fluid, blood, and mammary gland tissue were collected. The results show that, compared with the LC diet, the HC diet could reduce rumen pH, and the pH below 5.6 was more than 3 h, and the LPS content of blood and rumen fluid in HC the diet was significantly higher than in the LC diet. This indicates that the HC diet induced SARA in Hu sheep. However, the supplementation of disodium fumarate in the HC diet increased the rumen pH and decreased the content of LPS in blood and rumen fluid. Compared with the LC diet, the HC diet increased Ca2+ content in mammary gland tissue. However, the AHC diet decreased Ca2+ content. The HC diet induced ER stress in mammary gland tissue by increasing the mRNA and protein expressions of GRP78, CHOP, PERK, ATF6, and IRE1α. The HC diet also activated the IP3R-VDAC1-MCU channel and lead to mitochondrial damage by inhibiting mitochondrial fusion and promoting mitochondrial division, while disodium fumarate could alleviate these changes. In addition, disodium fumarate alleviated oxidative stress induced by the HC diet by activating Nrf2 signaling and reducing ROS production in mammary gland tissue. In conclusion, the supplementation of disodium fumarate at a daily dose of 10 g/sheep enhanced rumen bufferation by maintaining the ruminal pH above 6 and reduced LPS concentration in ruminal fluid and blood. This reaction avoided the negative effect observed by non-supplemented sheep that were fed with a high-concentrate diet involving endoplasmic reticulum stress, oxidative stress, and mitochondrial damage in the mammary gland tissue of Hu sheep.

Association of lifespan reproductive duration with depression in Swedish twins: The role of hormone replacement therapy.

OBJECTIVE: To examine the association between reproductive duration and postmenopausal depression (taking the use of hormone replacement therapy [HRT] into account). METHODS: In this population-based cohort study, 11 320 postmenopausal women (mean age 63.6 years) were followed for up to 18 years. Reproductive duration was categorized into three groups: short (≤34 years), average (35-39 years), and long (≥40 years). Depression was ascertained from the Sweden National Patient Registry. RESULTS: During the follow up, 593 (5.24%) women developed depression. In the multi-adjusted generalized estimating equation model, the odds ratios (ORs) of depression were 1.28 (95% confidence interval [CI] 1.05-1.55) and 1.25 (95% CI 1.01-1.55) for women with short and long reproductive durations, respectively, compared with those women with average reproductive duration. Women with a non-typical reproductive duration (≤34 or ≥40 years) who received HRT were at a higher risk of depression (OR 1.82, 95% CI 1.42-2.33). There was a significant additive interaction between non-typical reproductive duration and the use of HRT on depression (attributable proportion 0.26, 95% CI 0.03-0.50). CONCLUSION: Women with a short or long reproductive duration, especially those with a history of HRT use, have a higher risk of depression after menopause compared with those with an average reproductive duration.

Hyperuricemia as an effect modifier of the association between metabolic phenotypes and nonalcoholic fatty liver disease in Chinese population.

BACKGROUND: Different metabolic phenotypes may be related to nonalcoholic fatty liver disease (NAFLD), but such association whether modified by serum uric acid levels is unknown. We examined the association between different metabolic phenotypes and NAFLD and further explore whether hyperuricemia could modify this association. METHODS: A total of 2959 participants (mean age: 55.02 years) with medical checkups were recruited from Tianjin Medical University General Hospital. Participants were categorized into four groups according to their BMI levels and metabolically healthy status: metabolically healthy normal weight (MHNW), metabolically healthy overweight or obese (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy overweight or obese (MUO). Blood samples (including serum uric acid) were collected from participants after an overnight fast. NAFLD was diagnosed based on abdominal ultrasonography scanning. Data were analyzed using logistic regression models and the interaction effect model. RESULTS: The prevalence of NAFLD in MHNW, MHO, MUNW, and MUO groups was 9.9% (7.9-12.0%), 42.8% (39.5-46.1%), 36.5% (31.2-41.9%), and 69.7% (66.8-72.6%), respectively. In multi-adjusted logistic models, the ORs (95% CIs) of NAFLD were 5.32 (4.01-7.04) for participants with MHO, 4.51 (3.17-6.40) for those with MUNW, and 13.68 (10.23-18.30) for those with MUO compared to those with MHNW. In the stratified analysis by uric acid levels, the prevalence of NAFLD was significantly higher in participants with MHO, MUNW, and MUO in the hyperuricemia group than those in the normal uric acid group, and the interaction effect of metabolic phenotypes and uric acid on NAFLD was statistical significant (P < 0.05). CONCLUSIONS: MHO, MUNW, and MUO were associated with higher prevalence of NAFLD. Serum uric acid levels may modify the association between metabolically phenotypes and NAFLD.