Codonopsis pilosula polysaccharides (CPP) intervention alleviates sterigmatocystin (STC)-induced liver injury and gut microbiota dysbiosis.

Codonopsis pilosula polysaccharides (CPP), the main active ingredient of Codonopsis pilosula, has gained significant attention as a liver-protective agent. Previous studies have demonstrated that CPP could alleviate gut microbiota dysbiosis in colitis or obese mice. However, the effects of CPP on mycotoxin-induced liver injury and gut microbiota dysbiosis are still poorly understood. In this study, we aimed to investigate the protective effects of CPP on sterigmatocystin (STC)-induced liver injury, as well as its regulatory effects on gut microbiota. Our results revealed that CPP intervention significantly alleviated STC-induced liver injury, as evidenced by decreased liver index, reduced liver histopathological changes, and modulation of related molecular markers. Additionally, we found that CPP could alleviate liver injury by reducing liver inflammation and oxidative stress, inhibiting hepatocyte apoptosis, and regulating lipid metabolism. Notably, we also observed that CPP could alleviate STC-induced gut microbiota dysbiosis by modulating the diversity and richness of gut microbiota, suggesting that gut microbiota modulation may also serve as a mechanism for CPP-mediated remission of liver injury. In summary, our study not only provided a new theoretical basis for understanding the hepatotoxicity of STC and the protective effects of CPP against STC-induced liver injury, but also provided new perspectives for the application of CPP in the fields of food, healthcare products, and medicine.

Acute manipulation of Drd1 neurons in the prefrontal cortex bidirectionally regulates anxiety and depression-like behaviors.

BACKGROUND CONTEXT: The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety and depression. Manipulation of Drd1 neurons in the mPFC resulted in variable neuronal activity and, consequently, strikingly different behaviors. The acute regulation of anxiety- and depression-like behaviors by Drd1 neurons, a major neuronal subtype in the mPFC, has not yet been investigated. PURPOSE: The purpose of this study was to investigate whether acute manipulation of Drd1 neurons in the mPFC affects anxiety- and depression-like behaviors. STUDY DESIGN: Male Drd1-Cre mice were injected with an adeno-associated virus (AAV) expressing hM3DGq or hM4DGi. Clozapine-n-oxide (CNO, 1 mg/kg, i.p.) was injected 30 min before the behavioral tests. METHODS: Male Drd1-Cre mice were injected with AAV-Ef1α-DIO-hM4DGi-mCherry-WPRE-pA, AAV-Ef1α-DIO-hM3DGq-mCherry-WPRE-pA or AAV-Ef1α-DIO-mCherry-WPRE-pA. Three weeks later, whole-cell recordings after CNO (5 µM) were applied to the bath were used to validate the functional expression of hM4DGi and hM3DGq. Four groups of mice underwent all the behavioral tests, and after each of the tests, the mice were allowed to rest for 3-4 days. CNO (1 mg/kg) was injected intraperitoneally 30 min before the behavior test. Anxiety-like behaviors were evaluated by the open field test (OFT), the elevated plus maze test (EPMT), and the novelty-suppressed feeding test (NSFT). Depression-like behaviors were evaluated by the sucrose preference test (SPT) and force swimming test (FST). For all experiments, coronal sections of the targeted brain area were used to confirm virus expression. RESULTS: Whole-cell recordings from brain slices demonstrated that infusions of CNO (5 µM) into mPFC slices dramatically increased the firing activity of hM3DGq-mCherry+ neurons and abolished the firing activity of hM4DGi-mCherry+ neurons. Acute chemogenetic activation of Drd1 neurons in the mPFC increased the time spent in the central area in the OFT, increased the time spent in the open arms in the EMPT, decreased the latency to bite the food in the NSFT, increased the sucrose preference in the SPT, and decreased the immobility time in the FST. Acute chemogenetic inhibition of Drd1 neurons in the mPFC decreased the time spent in the central area in the OFT, decreased the time spent in the open arms in the EMPT, increased the latency to bite the food in the NSFT, decreased the sucrose preference in the SPT, and increased the immobility time in the FST. CONCLUSIONS: The present study showed that acute activation of Drd1 neurons in the mPFC produced rapid anxiolytic- and antidepressant-like effects, and acute inhibition had the opposite effect, revealing that Drd1 neurons in the mPFC bidirectionally regulate anxiety- and depression-like behaviors. CLINICAL SIGNIFICANCE: The findings of the present study regarding the acute effects of stimulating Drd1 neurons in the mPFC on anxiety and depression suggest that Drd1 neurons in the mPFC are a focus for the treatment of anxiety disorders and depression.

The Prognostic Value of the Combination of the Prognostic Nutritional Index and the Lymphocyte:Monocyte Ratio for the Prediction of Patients with Muscle-Invasive Bladder Cancer.

OBJECTIVE: To explore the efficacy of combining the prognostic nutritional index (PNI) and the lymphocyte:monocyte ratio (LMR) for patients with muscle-invasive bladder cancer (MIBC). METHODS: Of 172 patients who were diagnosed with MIBC in our hospital, 94 were eligible for the study. The clinical data of the 94 patients with MIBC were collected. The patients were divided according to the optimal cut-off values for the preoperative PNI and LMR into a low-PNI subgroup (PNI <44.15, 52 patients), a high-PNI subgroup (PNI ≥44.15, 42 patients), a low-LMR subgroup (LMR <2.98, 50 patients) and a high-LMR subgroup (LMR ≥2.98, 44 patients). The area under the receiver operating characteristic (ROC) curve (AUC) was used to analyse the efficacy of the PNI and the LMR in predicting the prognosis of patients with MIBC. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for patients with MIBC. Kaplan-Meier (K‒M) survival analysis was used for overall survival (OS) analysis to explore the ability of the PNI combined with the LMR to predict the prognosis of patients with MIBC. RESULTS: The optimal cut-off values for the preoperative PNI and the preoperative LMR were 44.15 and 2.98, respectively, on the basis of ROC curves. ROC curve analysis revealed that the PNI (AUC = 0.720, sensitivity 65.9%, specificity 74.50%, Youden index 0.399) and the LMR (AUC = 0.724, sensitivity 65.9%, specificity 70.0%, Youden index 0.395) both had good prognostic efficacy for patients with MIBC. The results of univariate and multivariate logistic regression analyses showed that preoperative PNI <44.15 was an independent risk factor for OS in patients with MIBC (p = 0.027). Based on K‒M survival curve analysis, patients with PNI <44.15 and LMR <2.98 had the shortest OS (p = 0.00002). CONCLUSIONS: Low preoperative PNI and LMR values are indicative of poor prognosis in patients with MIBC. The efficacy of their combination was better than that of the factors independently.

Fabrication of Large-Area Silicon Spherical Microlens Arrays by Thermal Reflow and ICP Etching.

In this paper, we proposed an efficient and high-precision process for fabricating large-area microlens arrays using thermal reflow combined with ICP etching. When the temperature rises above the glass transition temperature, the polymer cylinder will reflow into a smooth hemisphere due to the surface tension effect. The dimensional differences generated after reflow can be corrected using etching selectivity in the following ICP etching process, which transfers the microstructure on the photoresist to the substrate. The volume variation before and after reflow, as well as the effect of etching selectivity using process parameters, such as RF power and gas flow, were explored. Due to the surface tension effect and the simultaneous molding of all microlens units, machining a 3.84 × 3.84 mm2 silicon microlens array required only 3 min of reflow and 15 min of ICP etching with an extremely low average surface roughness Sa of 1.2 nm.

H2AK119ub1 differentially fine-tunes gene expression by modulating canonical PRC1- and H1-dependent chromatin compaction.

Polycomb repressive complex 1 (PRC1) is a key transcriptional regulator in development via modulating chromatin structure and catalyzing histone H2A ubiquitination at Lys119 (H2AK119ub1). H2AK119ub1 is one of the most abundant histone modifications in mammalian cells. However, the function of H2AK119ub1 in polycomb-mediated gene silencing remains debated. In this study, we reveal that H2AK119ub1 has two distinct roles in gene expression, through differentially modulating chromatin compaction mediated by canonical PRC1 and the linker histone H1. Interestingly, we find that H2AK119ub1 plays a positive role in transcription through interfering with the binding of canonical PRC1 to nucleosomes and therefore counteracting chromatin condensation. Conversely, we demonstrate that H2AK119ub1 facilitates H1-dependent chromatin condensation and enhances the silencing of developmental genes in mouse embryonic stem cells, suggesting that H1 may be one of several possible pathways for H2AK119ub1 in repressing transcription. These results provide insights and molecular mechanisms by which H2AK119ub1 differentially fine-tunes developmental gene expression.

IFN-λ drives distinct lung immune landscape changes and antiviral responses in human metapneumovirus infection.

Human metapneumovirus (HMPV) is a primary cause of acute respiratory infection, yet there are no approved vaccines or antiviral therapies for HMPV. Early host responses to HMPV are poorly characterized, and further understanding could identify important antiviral pathways. Type III interferon (IFN-λ) displays potent antiviral activity against respiratory viruses and is being investigated for therapeutic use. However, its role in HMPV infection remains largely unknown. Here, we show that IFN-λ is highly upregulated during HMPV infection in vitro in human and mouse airway epithelial cells and in vivo in mice. We found through several immunological and molecular assays that type II alveolar cells are the primary producers of IFN-λ. Using mouse models, we show that IFN-λ limits lung HMPV replication and restricts virus spread from upper to lower airways but does not contribute to clinical disease. Moreover, we show that IFN-λ signaling is predominantly mediated by CD45- non-immune cells. Mice lacking IFN-λ signaling showed diminished loss of ciliated epithelial cells and decreased recruitment of lung macrophages in early HMPV infection along with higher inflammatory cytokine and interferon-stimulated gene expression, suggesting that IFN-λ may maintain immunomodulatory responses. Administration of IFN-λ for prophylaxis or post-infection treatment in mice reduced viral load without inflammation-driven weight loss or clinical disease. These data offer clinical promise for IFN-λ in HMPV treatment. IMPORTANCE: Human metapneumovirus (HMPV) is a common respiratory pathogen and often contributes to severe disease, particularly in children, immunocompromised people, and the elderly. There are currently no licensed HMPV antiviral treatments or vaccines. Here, we report novel roles of host factor IFN-λ in HMPV disease that highlight therapeutic potential. We show that IFN-λ promotes lung antiviral responses by restricting lung HMPV replication and spread from upper to lower airways but does so without inducing lung immunopathology. Our data uncover recruitment of lung macrophages, regulation of ciliated epithelial cells, and modulation of inflammatory cytokines and interferon-stimulated genes as likely contributors. Moreover, we found these roles to be distinct and non-redundant, as they are not observed with knockout of, or treatment with, type I IFN. These data elucidate unique antiviral functions of IFN-λ and suggest IFN-λ augmentation as a promising therapeutic for treating HMPV disease and promoting effective vaccine responses.

Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans.

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1+ T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans.

The Prognostic Value of the Combination of the Prognostic Nutritional Index and the Lymphocyte: Monocyte Ratio for the Prediction of Patients with Muscle-Invasive Bladder Cancer

Objective: To explore the efficacy of combining the prognostic nutritional index (PNI) and the lymphocyte:monocyte ratio (LMR) for patients with muscle-invasive bladder cancer (MIBC). Methods: Of 172 patients who were diagnosed with MIBC in our hospital, 94 were eligible for the study. The clinical data of the 94 patients with MIBC were collected. The patients were divided according to the optimal cut-off values for the preoperative PNI and LMR into a low-PNI subgroup (PNI <44.15, 52 patients), a high-PNI subgroup (PNI ≥44.15, 42 patients), a low-LMR subgroup (LMR <2.98, 50 patients) and a high-LMR subgroup (LMR ≥2.98, 44 patients). The area under the receiver operating characteristic (ROC) curve (AUC) was used to analyse the efficacy of the PNI and the LMR in predicting the prognosis of patients with MIBC. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for patients with MIBC. Kaplan–Meier (K‒M) survival analysis was used for overall survival (OS) analysis to explore the ability of the PNI combined with the LMR to predict the prognosis of patients with MIBC. Results: The optimal cut-off values for the preoperative PNI and the preoperative LMR were 44.15 and 2.98, respectively, on the basis of ROC curves. ROC curve analysis revealed that the PNI (AUC = 0.720, sensitivity 65.9%, specificity 74.50%, Youden index 0.399) and the LMR (AUC = 0.724, sensitivity 65.9%, specificity 70.0%, Youden index 0.395) both had good prognostic efficacy for patients with MIBC. The results of univariate and multivariate logistic regression analyses showed that preoperative PNI <44.15 was an independent risk factor for OS in patients with MIBC (p = 0.027). Based on K‒M survival curve analysis, patients with PNI <44.15 and LMR <2.98 had the shortest OS (p = 0.00002). Conclusions: Low preoperative PNI and LMR values are indicative of poor prognosis in patients with MIBC...(AU)

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.

SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.

A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.

Biomechanical behaviour of a novel bone cement screw in the minimally invasive treatment of Kummell's disease: a finite element study.

OBJECTIVE: To investigate and evaluate the biomechanical behaviour of a novel bone cement screw in the minimally invasive treatment of Kummell's disease (KD) by finite element (FE) analysis. METHODS: A validated finite element model of healthy adult thoracolumbar vertebrae T12-L2 was given the osteoporotic material properties and the part of the middle bone tissue of the L1 vertebral body was removed to make it wedge-shaped. Based on these, FE model of KD was established. The FE model of KD was repaired and treated with three options: pure percutaneous vertebroplasty (Model A), novel unilateral cement screw placement (Model B), novel bilateral cement screw placement (Model C). Range of motion (ROM), maximum Von-Mises stress of T12 inferior endplate and bone cement, relative displacement of bone cement, and stress distribution of bone cement screws of three postoperative models and intact model in flexion and extension, as well as lateral bending and rotation were analyzed and compared. RESULTS: The relative displacements of bone cement of Model B and C were similar in all actions studied, and both were smaller than that of Model A. The minimum value of relative displacement of bone cement is 0.0733 mm in the right axial rotation of Model B. The maximum Von-Mises stress in T12 lower endplate and bone cement was in Model C. The maximum Von-Mises stress of bone cement screws in Model C was less than that in Model B, and it was the most substantial in right axial rotation, which is 34%. There was no substantial difference in ROM of the three models. CONCLUSION: The novel bone cement screw can effectively reduce the relative displacement of bone cement by improving the stability of local cement. Among them, novel unilateral cement screw placement can obtain better fixation effect, and the impact on the biomechanical environment of vertebral body is less than that of novel bilateral cement screw placement, which provides a reference for minimally invasive treatment of KD in clinical practice.

Dietary soybean lecithin promoted growth performance and feeding in juvenile Chinese perch (Siniperca chuatsi) could be by optimizing glucolipid metabolism.

To explore the potential benefits of dietary phospholipids (PLs) in fish glucose metabolism and to promote feed culture of Chinese perch (Siniperca chuatsi), we set up six diets to feed Chinese perch (initial mean body weight 37.01 ± 0.20 g) for 86 days, including: Control diet (CT), 1% (SL1), 2% (SL2), 3% (SL3), 4% (SL4) soybean lecithin (SL) and 2% (KO2) krill oil (KO) supplemental diets (in triplicate, 20 fish each). Our study found that the SL2 significantly improved the weight gain rate and special growth rate, but the KO2 did not. In addition, the SL2 diet significantly improved feed intake, which is consistent with the mRNA levels of appetite-related genes (npy, agrp, leptin A). Additionally, in the CT and SL-added groups, leptin A expression levels were nearly synchronized with serum glucose levels. Besides, the SL2 significantly upregulated expression levels of glut2, gk, cs, fas and downregulated g6pase in the liver, suggesting that it may enhance glucose uptake, aerobic oxidation, and conversion to fatty acids. The SL2 also maintained the hepatic crude lipid content unchanged compared to the CT, possibly by significantly down-regulating the mRNA level of hepatic lipase gene (hl), and by elevating serum low-density lipoprotein (LDL) level and intraperitoneal fat ratio in significance. Moreover, the serum high-density lipoprotein levels were significantly increased by PL supplementation, and the SL2 further significantly increased serum total cholesterol and LDL levels, suggesting that dietary PLs promote lipid absorption and transport. Furthermore, dietary SL at 1% level could enhance non-specific immune capacity, with serum total protein level being markedly higher than that in the CT group. In conclusion, it is speculated that the promotion of glucose utilization and appetite by 2% dietary SL could be linked. We suggest a 1.91% supplementation of SL in the diet for the best growth performance in juvenile Chinese perch.

A CYP78As-small grain4-coat protein complex â ¡ pathway promotes grain size in rice.

CYP78A, a cytochrome P450 subfamily that includes rice (Oryza sativa L.) BIG GRAIN2 (BG2, CYP78A13) and Arabidopsis thaliana KLUH (KLU, CYP78A5), generate an unknown mobile growth signal (referred to as a CYP78A-derived signal) that increases grain (seed) size. However, the mechanism by which the CYP78A pathway increases grain size remains elusive. Here, we characterized a rice small grain mutant, small grain4 (smg4), with smaller grains than its wild type due to restricted cell expansion and cell proliferation in spikelet hulls. SMG4 encodes a multidrug and toxic compound extrusion (MATE) transporter. Loss of function of SMG4 causes smaller grains while overexpressing SMG4 results in larger grains. SMG4 is mainly localized to endoplasmic reticulum (ER) exit sites (ERESs) and partially localized to the ER and Golgi. Biochemically, SMG4 interacts with coat protein complex Ⅱ (COPⅡ) components (Sar1, Sec23, and Sec24) and CYP78As (BG2, GRAIN LENGTH 3.2 [GL3.2], and BG2-LIKE 1 [BG2L1]). Genetically, SMG4 acts, at least in part, in a common pathway with Sar1 and CYP78As to regulate grain size. In summary, our findings reveal a CYP78As-SMG4-COPⅡ regulatory pathway for grain size in rice, thus providing new insights into the molecular and genetic regulatory mechanism of grain size.

The treatment of tuberculosis in the upper thoracic spine using the small incision technique through the third rib.

Background: The complex anatomical structure of the upper thoracic spine makes it challenging to achieve surgical exposure, resulting in significant surgical risks and difficulties. Posterior surgery alone fails to adequately address and reconstruct upper thoracic lesions due to limited exposure. While the anterior approach offers advantages in fully exposing the anterior thoracic lesions, the surgical procedure itself is highly intricate. Although there exist various anterior approaches for the upper thoracic spine, the incidence of upper thoracic spine lesions is relatively low. Consequently, there are limited reports on the treatment and reconstruction of upper thoracic spine lesions using the third rib small incision approach in the context of upper thoracic tuberculosis. Methods: We collected data from four patients with upper thoracic tuberculosis who were admitted to our department between July 2017 and November 2022. The treatment for upper thoracic tuberculosis involved utilizing the third rib small incision approach, which included two cases of thoracic 3-4 vertebral tuberculosis, one case of thoracic 4 vertebral tuberculosis, and one case of thoracic 5 vertebral tuberculosis. Among the patients, three were positioned in the left lateral position, while one was positioned in the right lateral position. Prior to admission, all four patients received a two-week course of oral medication, consisting of isoniazid, rifampicin, pyrazinamide, and ethambutol. After the surgical procedure, they continued receiving anti-tuberculosis treatment for a duration of 12 months. Results: The average duration of the surgical procedure was 150 min, with an average blood loss of 500 ml. One patient exhibited symptoms of brachial plexus injury, which gradually improved after careful observation. All patients experienced primary wound healing, and no complications such as pulmonary infection, respiratory failure, or other adverse events were observed. Additionally, one patient showed elevated transaminase levels, leading to a modification in the anti-tuberculosis drug regimen from quadruple therapy to triple therapy. Conclusion: The treatment of upper thoracic tuberculosis through the third rib small incision technique is a very good surgical approach, which has the advantages of safety and effectiveness.

Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection.

BACKGROUND: Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses. RESULTS: Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1-/- recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7- TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection. CONCLUSIONS: This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.

Activity of the new OSBP inhibitor Y18501 against Pseudoperonospora cubensis and its application for the control of cucumber downy mildew.

Y18501 is a new oxysterol-binding protein inhibitor (OSBPI) with a similar structure to oxathiapiprolin. Y18501 showed strong inhibitory activities against Phytophthora spp. and Pseudoperonospora cubensis, with EC50 ranging from 0.0005 to 0.0046 µg/mL. It also had good control efficacy on cucumber downy mildew (CDM) in the green house and in the field, and could effectively inhibit different development stages of P. cubensis, especially for sporangiophore production, sporangial production, mycelium extension, and elongation of germ tube. In addition, Y18501 showed excellent protective and curative activities against P. cubensis. It also had acropetal systemic mobility in the cucumber leaves, and could be taken up and translocated to the upper leaves more effectively from the lower leaves than from the roots. Y18501 had poorer permeability in cucumber leaves compared to oxathiapiprolin. The simultaneous application of Y18501 and chlorothalonil could significantly promote the inhibition of P. cubensis.

The contribution of cultural identity to subjective well-being in collectivist countries: a study in the context of contemporary Chinese culture.

Introduction: Though the important effect of cultural identity on subjective well-being is widely acknowledged, the details of how different cultures' unique features influence well-being remain to be revealed. To address this issue in the context of Chinese culture, the present study investigates whether and how the prominent features of Chinese culture-collectivism and red culture-shape Chinese people's subjective well-being. Methods: The Red Cultural Identity Scale, Subjective Well-Being Scale, Collectivism Scale, and Perspective-Taking Scale were used to assess 1,045 Chinese residents. Results: The results showed that red cultural identity positively predicted participants' subjective well-being through the mediated role of collectivism. Furthermore, perspective-taking was found to moderate the mediating effect of collectivism. Discussion: These results demonstrate that the way cultural identity predicts subjective well-being is highly correlated to specific cultural features, e.g., the opinion of values, which was significant in practice with a cross-cultural background.

Gut microbiota and intervertebral disc degeneration: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Although previous studies have suggested a close association between gut microbiota (GM) and intervertebral disc degeneration (IVDD), the causal relationship between them remains unclear. Hence, we thoroughly investigate their causal relationship by means of a two-sample Mendelian randomization (MR) study, aiming to determine the impact of gut microbiota on the risk of developing intervertebral disc degeneration. METHODS: Summary data from genome-wide association studies of GM (the MiBioGen) and IVDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS: We identified nine gut microbial taxa that were causally associated with IVDD (P < 0.05). Following the Benjamini-Hochberg corrected test, the association between the phylum Bacteroidetes and a higher risk of IVDD remained significant (IVW FDR-corrected P = 0.0365). The results of the Cochrane Q test did not indicate heterogeneity (P > 0.05). Additionally, both the MR-Egger intercept test and the MR-PRESSO global test revealed that our results were not influenced by horizontal pleiotropy (P > 0.05). Furthermore, the leave-one-out analysis substantiated the reliability of the causal relationship. In the reverse analysis, no evidence was found to suggest that IVDD has an impact on the gut microbiota. CONCLUSION: Our results validate the potential causal impact of particular GM taxa on IVDD, thus providing fresh insights into the gut microbiota-mediated mechanism of IVDD and laying the groundwork for further research into targeted preventive measures.