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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.

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.

Abstract Background We evaluated the association between the I/D polymorphism in the ACE gene and lung cancer risk by performing a meta-analysis. Methods The heterogeneity in the study was tested using the Cochran χ2-based Q statistic test and I2 test, and then the random ratio or fixed effect was utilized to merge the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the strength of the association between ACE polymorphisms and susceptibility to lung cancer. Sensitivity analysis was also performed. Using funnel plot and Begg’s rank test, we investigated the publication bias. All statistical analyses were performed using Stata 12.0 and RevMan 5.3. Results A total of 4307 participants (2181 patients; 2126 controls) were included in the 12 case–control studies. No significant association was found between the ACE I/D polymorphism and lung cancer risk (II vs. ID + DD: OR = 1.22, 95% CI = 0.89–1.68; II + ID vs. DD: OR = 1.21, 95% CI = 0.90–1.63; I vs. D: OR = 1.15, 95% CI = 0.95–1.39). In the subgroup analysis by ethnicity, no significant association between the ACE I/D polymorphism and lung cancer risk was found among Asian and Caucasian populations for the comparisons of II vs. ID + DD, II + ID vs. DD, and I vs. D genetic models. Conclusion The ACE I/D polymorphism is not associated with the risk of lung cancer.

The smallest flying insects commonly possess bristled wings and use drag to provide flight forces. A bristled wing, with a wing area about 10% of that of a flat-plate wing, operating at the relevant Reynolds number of 5–15, produces a drag close to the plate wing. How this is done is not well understood. Here, detailed flows around each of the bristles are investigated numerically using simple model wings, and the following results are shown. (1) The drag production mechanism of the bristled wing is different from that of the plate wing: For the plate wing, the flow is blocked by the wing, giving a small positive pressure on the windward surface, and there exists a pair of weak vortices on the wing back, giving a small negative pressure on the leeward surface; the drag is due to the pressure forces (the frictional stress has almost no contribution). For the bristled wing, each bristle operates in a creeping flow and produces thick and strong shear layers. Strong viscous force generates a very large pressure difference between the windward and leeward surfaces of each bristle and very large frictional stress on the bristle surface, resulting in a large drag on each bristle, and the drag is equally contributed by the pressure and frictional forces. (2) Due to the flow-interference effect, when the bristle number reaches a certain value, a further increase in bristles has little effect on force production but has the disadvantage of increasing wing mass; this means that for a bristled wing of miniature insects, the distribution density of the bristles will not be too large, which agrees with observations.

Background/Aim: The prognosis of hepatocellular carcinoma (HCC) is very dismal and the targeted drugs of HCC are limited. Studies of HCC prognostic biomarkers have made little progress, though many new techniques such as high-throughput sequencing have been applied. FOS-like antigen 1 (FOSL1) is generally accepted as a proto-oncogene but its clinical significance in HCC has never been elucidated. Materials and Methods: In our study, we investigated the expression of FOSL1 in 114 paraffin-embedded HCC tissues, and detected FOSL1 mRNA levels in 20 pairs of fresh HCC tissues and their corresponding tumor adjacent tissues. The correlations between FOSL1 expression and clinicopathological factors were analyzed and the prognostic significance of FOSL1 was evaluated with univariate and multivariate analysis. Moreover, we detected the function of FOSL1 in HCC proliferation with experiments in vitro. Results: FOSL1 mRNAs in HCCs were significantly higher than those in tumor adjacent tissues. The percentage of high expression and low expression of FOSL1 accounted for 46% (53/114) and 54% (61/114), respectively. High expression of FOSL1 was significantly associated with larger tumor size (P = 0.021), hepatitis B virus infection (P = 0.014), advanced T stage (P = 0.014), and tumor necrosis metastasis stage (P = 0.014). Moreover, high expression of FOSL1 was significantly correlated with poor prognosis of HCC and could be identified as an independent prognostic biomarker of HCC (hazard ratio = 5.60, 95% confidence interval = 3.00–10.45, P < 0.001). With in vitro function assay, we demonstrated that FOSL1 played an essential role in HCC proliferation. Conclusions: High expression of FOSL1 is an independent risk factor of HCC predicting unfavorable prognosis, indicating that FOSL1 detection could stratify patients with high risk, and anti-FOSL1 therapy may be a promising way to treat HCC.

An amendment to this paper has been published and can be accessed via the original article.

Energy expenditure is a critical characteristic in evaluating the flight performance of flying insects. To investigate how the energy cost of small-sized insects varies with flight speed, we measured the detailed wing and body kinematics in the full speed range of fruitflies and computed the aerodynamic forces and power requirements of the flies. As flight speed increases, the body angle decreases and the stroke plane angle increases; the wingbeat frequency only changes slightly; the geometrical angle of attack in the middle upstroke increases; the stroke amplitude first decreases and then increases. The mechanical power of the fruitflies at all flight speeds is dominated by aerodynamic power (inertial power is very small), and the magnitude of aerodynamic power in upstroke increases significantly at high flight speeds due to the increase of the drag and the flapping velocity of the wing. The specific power (power required for flight divided by insect weigh) changes little when the advance ratio is below about 0.45 and afterwards increases sharply. That is, the specific power varies with flight speed according to a J-shaped curve, unlike those of aircrafts, birds and large-sized insects which vary with flight speed according to a U-shaped curve.

Most of the previous studies on Weis-Fogh clap-fling mechanism have focused on the vortex structures and velocity fields. Detailed pressure distribution results are provided for the first time in this study to reveal the differences between the full and the partial clap-fling motions. The two motions are studied by numerically solving the Navier–Stokes equations in moving overset grids. The Reynolds number is set to 20, relevant to the tiny flying insects. The following has been shown: (1) During the clap phase, the wings clap together and create a high pressure region in the closing gap between wings, greatly increasing the positive pressure on the lower surface of wing, while pressure on the upper surface is almost unchanged by the interaction; during the fling phase, the wings fling apart and create a low pressure region in the opening gap between wings, greatly increasing the suction pressure on the upper surface of wing, while pressure on the lower surface is almost unchanged by the interaction; (2) The interference effect between wings is most severe at the end of clap phase and the start of the fling phase: two sharp force peaks (8–9 times larger than that of the one-winged case) are generated. But the total force peaks are manifested mostly as drag and barely as lift of the wing, owing to the vertical orientation of the wing section; (3) The wing–wing interaction effect in the partial clap-fling case is much weaker than that in the full clap-fling case, avoiding the generation of huge drag. Compared with a single wing flapping with the same motion, mean lift in the partial case is enhanced by 12% without suffering any efficiency degradation, indicating that partial clap-fling is a more practical choice for tiny insects to employ.

In the present paper, the controlled flight of fruitflies after voluntary takeoff is studied. Wing and body kinematics of the insects after takeoff are measured using high-speed video techniques, and the aerodynamic force and moment are calculated by the computational fluid dynamics method based on the measured data. How the control moments are generated is analyzed by correlating the computed moments with the wing kinematics. A fruit-fly has a large pitch-up angular velocity owing to the takeoff jump and the fly controls its body attitude by producing pitching moments. It is found that the pitching moment is produced by changes in both the aerodynamic force and the moment arm. The change in the aerodynamic force is mainly due to the change in angle of attack. The change in the moment arm is mainly due to the change in the mean stroke angle and deviation angle, and the deviation angle plays a more important role than the mean stroke angle in changing the moment arm (note that change in deviation angle implies variation in the position of the aerodynamic stroke plane with respect to the anatomical stroke plane). This is unlike the case of fruitflies correcting pitch perturbations in steady free flight, where they produce pitching moment mainly by changes in mean stroke angle.

BACKGROUND: MtDNA haplogroups could have important implication for understanding of the relationship between the mutations of the mitochondrial genome and diseases. Distribution of a variety of diseases among these haplogroups showed that some of the mitochondrial haplogroups are predisposed to disease. To examine the susceptibility of mtDNA haplogroups to ROU, we sequenced the mtDNA HV1, HV2 and HV3 in Chinese ROU. METHODOLOGY/PRINCIPAL FINDINGS: MtDNA haplogroups were analyzed in the 249 cases of ROU patients and the 237 cases of healthy controls respectively by means of primer extension analysis and DNA sequencing. Haplogroups G1 and H were found significantly more abundant in ROU patients than in healthy persons, while haplogroups D5 and R showed a trend toward a higher frequency in control as compared to those in patients. The distribution of C-stretch sequences polymorphism in mtDNA HV1, HV2 and HV3 regions was found in diversity. CONCLUSIONS/SIGNIFICANCE: For the first time, the relationship of mtDNA haplogroups and ROU in Chinese was investigated. Our results indicated that mtDNA haplogroups G1 and H might constitute a risk factor for ROU, which possibly increasing the susceptibility of ROU. Meanwhile, haplogroups D5 and R were indicated as protective factors for ROU. The polymorphisms of C-stretch sequences might being unstable and influence the mtDNA replication fidelity.