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Background Calpains are a family of calcium-dependent thiol proteases that participate in a wide variety of biological activities. In our recent study, calpain is increased in the sera of scleroderma or systemic sclerosis (SSc). However, the role of calpain in interstitial lung disease (ILD) has not been reported. ILD is a severe complication of SSc, which is the leading cause of death in SSc. The pathogenesis of SSc-related ILD remains incompletely understood. This study investigated the role of myeloid cell calpain in SSc-related ILD. Methods A novel line of mice with myeloid cell-specific deletion of Capns1 ( Capns1-ko ) was created. SSc-related ILD was induced in Capns1-ko mice and their wild-type littermates by injection 0.l mL of bleomycin (0.4 mg/mL) for 4 weeks. In a separate experiment, a pharmacological inhibitor of calpain PD150606 (Biomol, USA, 3 mg/kg/day, i.p.) daily for 30 days was given to mice after bleomycin injection on daily basis. At the end of the experiment, the animals were killed, skin and lung tissues were collected for the following analysis. Inflammation, fibrosis and calpain activity and cytokines were assessed by histological examinations and ELISA, and immunohistochemical analyses, western blot analysis and Flow cytometry analysis. Results Calpain activities increased in SSc-mouse lungs. Both deletion of Capns1 and administration of PD150606 attenuated dermal sclerosis as evidenced by a reduction of skin thickness and reduced interstitial fibrosis and inflammation in bleomycin model of SSc mice. These effects of reduced calpain expression or activity were associated with prevention of macrophage polarization toward M1 phenotype and consequent reduced production of pro-inflammatory cytokines including TNF-α, IL-12 and IL-23 in lung tissues of Capns1-ko mice with bleomycin model of SSc. Furthermore, inhibition of calpain correlated with an increase in the protein levels of PI3K and phosphorylated AKT1 in lung tissues of the bleomycin model of SSc mice. Conclusions This study for the first time demonstrates that the role of myeloid cell calpain may be promotion of macrophage M1 polarization and pro-inflammatory responses related PI3K/AKT1 signaling. Thus, myeloid cell calpain may be a potential therapeutic target for bleomycin model of SSc-related ILD.

Background Global fertility declines have become an inevitable trend, and many countries are adopting policies to drive fertility increases. Fertility intention plays an important role in predicting fertility behavior. The Chinese government has recently issued the ‘three-child’ policy, and there is still little research on the third birth intention of the childbearing-age population. Therefore, the aim of this study is to investigate the prevalence and related reasons of third birth intention in the childbearing-age population in mainland China, and analyze the sociodemographic differences. Method A cross-sectional survey was conducted in mainland China from June to July 2021. A total of 15,332 childbearing-age participants responded and completed the Fertility Intention Questionnaire online through the Wenjuanxing Platform. Data were explored and analyzed by SPSS (version 22.0) software. Descriptive statistics were used to describe the current situation and reasons of third birth intention. Binary logistic regression analysis was applied to assess the influencing factors in the sociodemographic level. Results The mean age of the participants was 32.9 ± 5.94 years. Only 12.2% of participants reported having third birth intention. The subjective norm of having both son and daughter (22.0%) and busy at work (29.2%) accounted for the largest proportion in the reasons of acceptance and rejection, respectively. Age has negative impact on third birth intention ( OR  = 0.960). Men were 2.209 times more likely to have three children than women ( P  < 0.001). With the improvement of education and family monthly income, the birth intention shows a downward trend. Compared with Han nationalities, first marriage and city residents, the ethnic minorities, remarriage and rural residents have stronger birth intention (all P  < 0.05). And individuals with two existing children are inclined to have the third child ( OR  = 1.839). Conclusion The third birth intention in the childbearing-age population in China is still low after the announcement of the three-child policy. It is necessary to create a favorable fertility context for childbearing-age group with high level of third birth intention, like younger, male, minority, remarriage, with lower education and family monthly income, living in rural and two existing children. Furthermore, removing barriers for those unintended is also prominent to ensure the impetus of policy.

Setaria italica (foxtail millet), a founder crop of East Asian agriculture, is a model plant for C4 photosynthesis and developing approaches to adaptive breeding across multiple climates. Here we established the Setaria pan-genome by assembling 110 representative genomes from a worldwide collection. The pan-genome is composed of 73,528 gene families, of which 23.8%, 42.9%, 29.4% and 3.9% are core, soft core, dispensable and private genes, respectively; 202,884 nonredundant structural variants were also detected. The characterization of pan-genomic variants suggests their importance during foxtail millet domestication and improvement, as exemplified by the identification of the yield gene SiGW3 , where a 366-bp presence/absence promoter variant accompanies gene expression variation. We developed a graph-based genome and performed large-scale genetic studies for 68 traits across 13 environments, identifying potential genes for millet improvement at different geographic sites. These can be used in marker-assisted breeding, genomic selection and genome editing to accelerate crop improvement under different climatic conditions. Setaria pan-genome constructed using genome assemblies of 110 representative accessions and variation analyses provides insights into foxtail millet domestication and the genetic basis for crop improvement.

Forests acting as carbon storage and sequestration play an essential role in the global nutrient cycle, in which fungi are active participants. The forests cover almost all regions from the boreal, temperate to the subtropical and tropical forests. The relative proportion of carbon sequestrated in forest soil varies from approximately 85% of the terrestrial carbon pool in boreal forests to 60% in temperate forests and to 50% in tropical rainforests. Fungi as decomposers of organic matter and root-associated mediators of belowground carbon transport and respiration are the key drivers of the carbon cycle in forests. For example, saprophytic fungi can degrade soil organic matter to release carbon into the soil, whereas symbiotic fungi could form symbiosis with plants, through which plant and fungi can benefit each other with nutrient flow. Given the importance of fungi in the ecological environment, this paper summarizes the importance of soil fungi in terms of fungal diversity and function in forest ecosystems.

Enterovirus 71 (EV71) is an important cause of hand, foot, and mouth disease, especially in China. In this phase 3 trial involving 10,077 infants and children in China, an EV71 vaccine provided protection against EV71-associated disease. Enterovirus 71 (EV71), an enterovirus that is not associated with poliomyelitis, was one of the major causative agents of outbreaks of hand, foot, and mouth disease or herpangina in Europe, 1 – 3 Australia, 4 , 5 and Japan 6 , 7 between 1972 and 1988, and it has been implicated in a series of outbreaks across the Asia–Pacific region since the 1990s. 8 – 11 The largest Asia–Pacific epidemic occurred in China in 2008, when approximately 490,000 infections and 126 deaths in infants and young children were reported. 12 The vast majority of severe cases and fatal cases occurred in children younger than 3 years of age. EV71 . . .

G-protein-signaling modulator 1 ( GPSM1 ) exhibits strong genetic association with Type 2 diabetes (T2D) and Body Mass Index in population studies. However, how GPSM1 carries out such control and in which types of cells are poorly understood. Here, we demonstrate that myeloid GPSM1 promotes metabolic inflammation to accelerate T2D and obesity development. Mice with myeloid-specific GPSM1 ablation are protected against high fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis via repression of adipose tissue pro-inflammatory states. Mechanistically, GPSM1 deficiency mainly promotes TNFAIP3 transcription via the Gα i3 /cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-κB signaling in macrophages. In addition, we identify a small-molecule compound, AN-465/42243987, which suppresses the pro-inflammatory phenotype by inhibiting GPSM1 function, which could make it a candidate for metabolic therapy. Furthermore, GPSM1 expression is upregulated in visceral fat of individuals with obesity and is correlated with clinical metabolic traits. Overall, our findings identify macrophage GPSM1 as a link between metabolic inflammation and systemic homeostasis. G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.

Glioblastoma (GBM) is the most common and malignant cancer of the central nervous system, and radiotherapy is widely applied in GBM treatment; however, the sensitivity to radiotherapy varies in different patients. To solve this clinical dilemma, a radiosensitivity prediction signature was constructed in the present study based on genomic methylation. In total, 1044 primary GBM samples with clinical and methylation microarray data were involved in this study. LASSO-COX, GSVA, Kaplan–Meier survival curve analysis, and COX regression were performed for the construction and verification of predictive models. The R programming language was used as the main tool for statistical analysis and graphical work. Via the integration analysis of methylation and the survival data of primary GBM, a novel prognostic and radiosensitivity prediction signature was constructed. This signature was found to be stable in prognosis prediction in the TCGA and CGGA databases. The possible mechanism was also explored, and it was found that this signature is closely related to DNA repair functions. Most importantly, this signature could predict whether GBM patients could benefit from radiotherapy. In summary, a radiosensitivity prediction signature for GBM patients based on five methylated probes was constructed, and presents great potential for clinical application.

Background/Objectives: This study aimed to develop an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for quantifying amantadine (AMA) in rat plasma and to investigate its pharmacokinetics under simulated high-altitude hypoxia, contrasting its behavior with that of its structural analog memantine (MEM). Methods: The method entailed using memantine (MEM) as an internal standard. Sample preparation involved protein precipitation, followed by gradient elution with detection via positive electrospray ionization and selective reaction monitoring (SRM). The method validation complied with the International Conference on Harmonization (ICH) M10 guidelines. Pharmacokinetic studies were conducted in rats exposed to either low altitude (1500 m) or simulated high altitude (6500 m) after a single oral dose of AMA (10 mg/kg). Results: The assay demonstrated linearity from 5 to 1000 µg/L, with accuracy, precision, recovery, and stability all meeting the respective acceptance criteria. Hypoxia did not significantly alter systemic exposure to AMA, as measured by parameters such as the area under the concentration–time curve (AUC), maximum concentration (Cmax), and apparent clearance (CLz/F). However, hypoxia prolonged the elimination half-life by 55% and increased the variance in the mean residence time. This finding contrasts sharply with our previous results on MEM under identical hypoxic conditions, which showed a 72.15% increase in AUC and a 41.99% decrease in CLz/F. Conclusions: A robust UPLC-MS/MS method for quantifying AMA was successfully established. AMA exhibits unique pharmacokinetic resilience to acute hypoxia, characterized by increased variability in elimination without changes in overall exposure. This profile starkly differs from the heightened exposure and reduced clearance observed for drugs like MEM, which are predominantly cleared by hepatic metabolism (under the studied conditions). These findings are consistent with the concept that a drug’s primary elimination pathway (renal excretion vs. hepatic metabolism) critically determines its pharmacokinetic susceptibility to hypoxic stress.

To investigate the effects of low-level auricular vagus nerve stimulation (LL-aVNS) on blood pressure and heart rate in patients with paroxysmal atrial fibrillation. A total of 22 patients with paroxysmal atrial fibrillation diagnosed in Fuzhou First General Hospital Affiliated with Fujian Medical University from September 2021 to December 2022 were selected and given LL-aVNS treatment based on the original unchanged drug treatment for 4 weeks. The systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate maximum (HRmax), heart rate minimum (HRmin), left ventricular ejection fraction (LVEF), left atrial diameter (LAD), Atrial Fibrillation Severity Scale (AFSS) symptom subscale, and Memorial Symptom Assessment Scale-Heart Failure (MSAS-HF) before and after the treatment were observed and compared. In addition, adverse effects of the LL-aVNS procedure and 6-month follow-up were recorded. SBP, DBP, and HRmin were lower after the treatment than before the treatment ( < 0.05); AFSS symptom subscale scores and MSAS-HF scores after the treatment were lower before the treatment ( < 0.05); itching of the skin was observed in one case during the course of LL-aVNS; and two patients were hospitalized for acute exacerbation of chronic heart failure between 4 months and 6 months after the treatment. LL-aVNS in patients with paroxysmal atrial fibrillation can assist in controlling blood pressure and heart rate, effectively relieving symptoms, and the treatment process is safe and feasible.

Volvariella volvacea endoglucanase EG1 was used to treat bleached softwood kraft pulp (BSKP) and hardwood pulp (BHKP) to improve the refinability and physical strength, as well as to reduce vessel picking in Eucalyptus pulp. The results indicated that BSKP was treated with an enzyme dosage of 3 U/g for 2 h at 12,000 refining revolutions, which increased the tensile index from 71.4 N·m/g to 86.7 N·m/g. For BHKP, treatment with 10 U/g of EG1 for 2 h at 15,000 refining revolutions improved the tensile index from the control of 47.7 N·m/g to 56.9 N·m/g. Vessel-removed and vessel-enriched fractions of Eucalyptus pulp were obtained by screening and treated with EG1, respectively. It was found that EG1-assisted refining increased the physical strength and surface strength of both pulp fractions, and the latter improved even more, with increases of 22.4% and 160%, respectively.