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Abstract Exercise is usually regarded to have short-term beneficial effects on immune health. Here we show that early-life regular exercise exerts long-term beneficial effects on inflammatory immunity. Swimming training for 3 months in male mice starting from 1-month-old curbs cytokine response and mitigates sepsis when exposed to lipopolysaccharide challenge, even after an 11-month interval of detraining. Metabolomics analysis of serum and liver identifies pipecolic acid, a non-encoded amino acid, as a pivotal metabolite responding to early-life regular exercise. Importantly, pipecolic acid reduces inflammatory cytokines in bone marrow-derived macrophages and alleviates sepsis via inhibiting mTOR complex 1 signaling. Moreover, early-life exercise increases histone 3 lysine 4 trimethylation at the promoter of Crym in the liver, an enzyme responsible for catalyzing pipecolic acid production. Liver-specific knockdown of Crym in adult mice abolishes this early exercise-induced protective effects. Our findings demonstrate that early-life regular exercise enhances anti-inflammatory immunity during middle-aged phase in male mice via epigenetic immunometabolic modulation, in which hepatic pipecolic acid production has a pivotal function.

Abstract Objective The aim of this study was to establish a nomogram graph model to accurately predict the venous thromboembolism (VTE) risk probability in the general population with lung cancer. Methods Based on data from patients with lung cancer in Chongqing University Cancer Hospital of China, the independent risk factors of VTE were identified by the logistic univariable and multivariable analysis and were integrated to construct a nomogram, which was validated internally. The predictive effectiveness of the nomogram was evaluated by the receiver operating characteristic curve (ROC) and calibration curve. Results A total of 3398 lung cancer patients were included for analysis. The nomogram incorporated eleven independent VTE risk factors including karnofsky performance scale (KPS), stage of cancer, varicosity, chronic obstructive pulmonary disease (COPD), central venous catheter (CVC), albumin, prothrombin time (PT), leukocyte counts, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), dexamethasone, and bevacizumab. The C-index of the nomogram model was 0.843 and 0.791 in the training and validation cohort, respectively, demonstrating good discriminative power. The calibration plots of the nomogram revealed excellent agreement between the predicted and actual probabilities. Conclusions We established and validated a novel nomogram for predicting the risk of VTE in patients with lung cancer. The nomogram model could precisely estimate the VTE risk of individual lung cancer patients and identify high-risk patients who are in need of a specific anticoagulation treatment strategy.

Bacterial wilt, caused by Ralstonia solanacearum, one of the most destructive phytopathogens, leads to significant annual crop yield losses. Type III effectors (T3Es) mainly contribute to the virulence of R. solanacearum, usually by targeting immune-related proteins. Here, we clarified the effect of a novel E3 ubiquitin ligase (NEL) T3E, RipAW, from R. solanacearum on pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and further explored its action mechanism. In the susceptible host Arabidopsis thaliana, we monitored the expression of PTI marker genes, flg22-induced ROS burst, and callose deposition in RipAW- and RipAWC177A-transgenic plants. Our results demonstrated that RipAW suppressed host PTI in an NEL-dependent manner. By Split-Luciferase Complementation, Bimolecular Fluorescent Complimentary, and Co-Immunoprecipitation assays, we further showed that RipAW associated with three crucial components of the immune receptor complex, namely FLS2, XLG2, and BIK1. Furthermore, RipAW elevated the ubiquitination levels of FLS2, XLG2, and BIK1, accelerating their degradation via the 26S proteasome pathway. Additionally, co-expression of FLS2, XLG2, or BIK1 with RipAW partially but significantly restored the RipAW-suppressed ROS burst, confirming the involvement of the immune receptor complex in RipAW-regulated PTI. Overall, our results indicate that RipAW impairs host PTI by disrupting the immune receptor complex. Our findings provide new insights into the virulence mechanism of R. solanacearum.

Abstract The smallest insects fly with bristled wings at very low Reynolds numbers (Re) and use the drag of the wings to provide the weight-supporting force and thrust. Previous studies used two-dimensional (2-D) models to study the aerodynamic force and the detailed flow field of the bristled wings, neglecting the three-dimensional (3-D) effect caused by the finite span. At high Re, the 3-D effect is known to decrease the aerodynamic force on a body, compared with the 2-D case. However, the bristled wing operates at very low Re, for which the 3-D effect is unknown. Here, a 3-D model of the bristled wing is constructed to numerically investigate the detailed flow field and the aerodynamic force of the wing. Our findings are as follows: The 3-D effect at low Re increases the drag of the bristled wing compared with that of the corresponding 2-D wing, which is contrary to that of the high-Re case. The drag increase is limited to the tip region of the bristles and could be explained by the increase of the flow velocity around the tip region. The spanwise length of the drag-increasing region (measuring from the wing tip) is about 0.23 chord length and does not vary as the wing aspect ratio increases. The amount of the drag increment in the tip region does not vary as the wing aspect ratio increases either, leading to the decrease of the drag coefficient with increasing aspect ratio.

Abstract Most of the smallest flying insects use bristled wings. It was observed that during the second half of their upstroke, the left and right wings become parallel and close to each other at the back, and move upward at zero angle of attack. In this period, the wings may produce drag (negative vertical force) and side forces which tend to push two wings apart. Here we study the aerodynamic forces and flows of two simplified bristled wings experiencing such a motion, compared with the case of membrane wings (flat-plate wings), to see if there is any advantage in using the bristled wings. The method of computational fluid dynamics is used in the study. The results are as follows. In the motion of two bristled wings, the drag acting on each wing is 40% smaller than the case of a single bristled wing conducting the same motion, and only a very small side force is produced. But in the case of the flat-plate wings, although there is similar drag reduction, the side force on each wing is larger than that of the bristled wing by an order of magnitude (the underlying physical reason is discussed in the paper). Thus, if the smallest insects use membrane wings, their flight muscles need to overcome large side forces in order to maintain the intended motion for less negative lift, whereas using bristled wings do not have this problem. Therefore, the adoption of bristled wings can be beneficial during upward movement of the wings near the end of the upstroke, which may be one reason why most of the smallest insects adopt them.

Summary Musk is a precious raw material and ingredient in Chinese traditional medicine. The production of unqualified musk has become a puzzling problem in forest musk deer (FMD) breeding. However, what the essential differences between so‐called unqualified musk and mature qualified musk have not yet been elucidated. In this study, 12 musk samples were collected and separated into two groups according to their external properties. One group is white or black cream‐like secretion with sour or unpleasant odour (MM); the other group is brown or blackish brown solid secretion with pleasant fragrance (DM). Next‐generation sequencing and gas chromatography‐mass spectrometry were used to explore the essential differences between the DM and MM groups in microbial and chemical compositions. The results indicate that the DM group has more heterogenous microbial structure but simpler relationships among microbial communities. LEfSe analysis showed that 14 taxa at the genus level could be used to distinguish the DM and MM groups and Bacillus, Paracoccus, tenoteophomonas, Mycobacterium and Leuconostoc were more abundant in the DM group (P

A new ent-abietane diterpenoid, named Euphejolkinolide A (1), was isolated from the whole plant of Euphorbia peplus L. Its structure, including absolute configurations, was determined by spectroscopic analyses and was corroborated by single-crystal X-ray diffraction analysis. This new compound was assessed for its activity to induce lysosome biogenesis through Lyso-Tracker Red staining, in which compound 1 could significantly induce lysosome biogenesis. In addition, quantitative real-time PCR (qRT-PCR) analysis demonstrated a direct correlation between the observed lysosome biogenesis and the transcriptional activation of the lysosomal genes after treatment with the compound 1. Moreover, compound 1 promoted autophagic flux by upregulating LC3-II and downregulating SQSTM1 in both human microglia cells and U251 cells, which is required for cellular homeostasis. Further results suggested 1 induced lysosome biogenesis and autophagy which was mediated by TFEB (transcription factor EB). The structure activity relationships (SAR) analysis suggested that the carbony1 at C-7 in 1 might be a key active group. Overall, the current data suggested that 1 could be a potential compound for lysosome disorder therapy by induction of autophagy.

Studies have revealed that non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations has a high incidence of brain metastases (BMs). However, the association between EGFR mutations and BMs remains unknown. This review summarizes detailed information about the incidence of BMs, clinical and imaging characteristics of BMs, brain surveillance strategies, influence of treatments on BMs, prognosis after BMs, and differences in EGFR mutations between paired primary tumors and BMs in EGFR-mutated NSCLC. The prognostic results demonstrate that patients with mutated EGFR have a higher incidence of BMs, EGFR tyrosine kinase inhibitors (EGFR-TKIs) (afatinib and osimertinib) delay the development of BMs, and patients with mutated EGFR with synchronous or early BMs have better overall survival after BMs than those with wild-type EGFR. The EGFR mutation status of BM sites is not always in accordance with the primary tumors, which indicates that there is heterogeneity in EGFR gene status between paired primary tumors and BMs. However, the EGFR gene status of the primary site can largely represent that of BM sites. Among patients developing synchronous BMs, patients with mutated EGFR are less likely to have central nervous system (CNS) symptoms than patients with wild-type EGFR. However, the possibility of neuro-symptoms is high in patients with metachronous BMs. Patients with mutated EGFR tend to have multiple BMs as compared to patients with wild-type EGFR. Regarding very early-stage NSCLC patients without neuro-symptoms, regular neuroimaging follow-up is not recommended. Among advanced NSCLC patients with EGFR mutation, liberal brain imaging follow-up in the first several years showed more advantages in terms of cost.

RING-finger-type ubiquitin E3 ligase Constitutively Photomorphogenic 1 (COP1) and floral integrators such as FLOWERING LOCUS T (FT), TWIN SISTER OF FT (TSF) and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) have been identified as regulators of stomatal movement. However, little is known about their roles and relationship in dark-induced stomatal closure. Here, we demonstrated that COP1 is required for dark-induced stomatal closure using cop1 mutant. The cop1 mutant closed stomata in response to exogenous nitric oxide (NO) but not hydrogen peroxide (H2O2), and H2O2 but not NO accumulated in cop1 in darkness, further indicating that COP1 acts downstream of H2O2 and upstream of NO in dark-induced stomatal closure. Expression of FT, TSF and SOC1 in wild-type (WT) plants decreased significantly with dark duration time, but this process was blocked in cop1. Furthermore, ft, tsf, and soc1 mutants accumulated NO and closed stomata faster than WT plants in response to darkness. Altogether, our results indicate that COP1 transduces H2O2 signaling, promotes NO accumulation in guard cells by suppressing FT, TSF and SOC1 expression, and consequently leads to stomatal closure in darkness. These findings add new insights into the mechanisms of dark-induced stomatal closure.