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Rockburst are often encountered in tunnel construction due to the complex geological conditions. To study the influence of unloading rate on rockburst, gneiss rockburst experiments were conducted under three groups of unloading rates. A high-speed photography system and acoustic emission (AE) system were used to monitor the entire process of rockburst process in real-time. The results show that the intensity of gneiss rockburst decreases with decrease of unloading rate, which is manifested as the reduction of AE energy and fragments ejection velocity. The mechanisms are proposed to explain this effect: (i) The reduction of unloading rate changes the crack propagation mechanism in the process of rockburst. This makes the rockbursts change from the tensile failure mechanism at high unloading rate to the tension-shear mixed failure mechanism at low unloading rate, and more energy released in the form of shear crack propagation. Then, less strain energy is converted into kinetic energy of fragments ejection. (ii) Less plate cracking degree of gneiss has taken shape due to decrease of unloading rate, resulting in the destruction of rockburst incubation process. The enlightenments of reducing the unloading rate for the project are also described quantitatively. The rockburst magnitude is reduced from the medium magnitude at the unloading rate of 0.1 MPa/s to the slight magnitude at the unloading rate of 0.025 MPa/s, which was judged by the ejection velocity.

Zearalenone (ZEN) has been shown to cause reproductive damage by inducing oxidative stress. Astaxanthin and L-carnitine are widely used to alleviate oxidative stress and promote sperm maturation. However, it remains uncertain whether they are effective in mitigating spermatogenesis disorders induced by ZEN. This study aimed to investigate the therapeutic efficacy and potential mechanisms of Vigor King (Vig), a compound preparation primarily consisting of astaxanthin and L-carnitine, in alleviating ZEN-induced spermatogenesis disorders. In the experiment, mice received continuous oral gavage of ZEN (80 μg/kg) for 35 days, accompanied by a rescue strategy with Vig (200 mg/kg). The results showed that Vig effectively reduced the negative impact on semen quality and improved the structural and functional abnormalities of the seminiferous epithelium caused by ZEN. Additionally, the accumulation of reactive oxygen species (ROS), DNA double-strand breaks, apoptosis, and autophagy abnormalities were all significantly ameliorated. Intriguingly, the GSK3β-dependent BTRC-NRF2 signaling pathway was found to play an important role in this process. Furthermore, testing of offspring indicated that Vig could extend its protective effects to the next generation, effectively combating the transgenerational toxic effects of ZEN. In summary, our research suggests that Vig supplementation holds considerable promise in alleviating spermatogenesis disorders induced by zearalenone.

Given the widespread occurrence of obesity, new strategies are urgently needed to prevent, halt and reverse this condition. We proposed a noninvasive neurostimulation tool, ultrasound deep brain stimulation (UDBS), which can specifically modulate the hypothalamus and effectively regulate food intake and body weight in mice. Fifteen-min UDBS of hypothalamus decreased 41.4% food intake within 2 hours. Prolonged 1-hour UDBS significantly decreased daily food intake lasting 4 days. UDBS also effectively restrained body weight gain in leptin-receptor knockout mice (Sham: 96.19%, UDBS: 58.61%). High-fat diet (HFD) mice treated with 4-week UDBS (15 min / 2 days) reduced 28.70% of the body weight compared to the Sham group. Meanwhile, UDBS significantly modulated glucose-lipid metabolism and decreased the body fat. The potential mechanism is that ultrasound actives pro-opiomelanocortin (POMC) neurons in the hypothalamus for reduction of food intake and body weight. These results provide a noninvasive tool for controlling food intake, enabling systematic treatment of obesity.

Numerous researches have reported on the regulatory network of liver regeneration induced by partial hepatectomy (PH). However, information on key molecules and/or signaling pathways regulating the termination stage of liver regeneration remains limited. In this study, we identify hepatic mitotic arrest deficient 1 (MAD1) as a crucial regulator of transforming growth factor β (TGF-β) in the hepatocyte to repress liver regeneration. MAD1 has a low expression level at the rapid proliferation phase but significantly increases at the termination phase of liver regeneration. We show that MAD1 deficiency accelerates hepatocyte proliferation and enhances mitochondrial biogenesis and respiratory. Mechanistically, MAD1 deficiency in hepatocytes enhances mitochondrial function and promotes hepatocyte proliferation by suppressing TGF-β signaling. Our study reveals MAD1 as a novel suppressor of hepatocyte proliferation, which may provide a new therapeutic target for the recovery of liver function after liver transplant and partial hepatectomy.

Underground space creation and energy extraction, which induce unloading on rock fractures, commonly occur in various rock engineering projects, and rock engineering projects are subjected to high temperatures with increasing depth. Fluid flow behavior of rock fractures is a critical issue in many subsurface rock engineering projects. Previous studies have extensively considered permeability evolution in rock fractures under loading phase, whereas changes in fracture permeability under unloading phase have not been fully understood. To examine the unloading-induced changes in fracture permeability under different temperatures, we performed water flow-through tests on fractured rock samples subjected to decreasing confining pressures and different temperatures. The experimental results show that the permeability of fracture increases with unloading of confining pressure but decreases with loading-unloading cycles. Temperature may affect fracture permeability when it is higher than a certain threshold. An empirical model of fracture hydraulic aperture including two material parameters of initial normal stiffness and maximum normal closure can well describe the permeability changes in rough rock fracture subjected to loading-unloading cycles and heating. A coupled thermo-mechanical model considering asperity damage is finally used to understand the influences of stress paths and temperatures on fracture permeability.

Abstract Background Dysregulation of lipid metabolism is the most prominent metabolic alteration observed in obesity, cancer, and cardiovascular diseases. The present study aimed to explore the sex differences associated with lipid metabolism in urinary exosome proteins, and evaluate the correlation of urinary exosome proteins with serum lipid biomarkers. Methods The key enzymes regulating lipid metabolism in healthy adults were screened using urinary exosome data. Urinary exosomes were isolated from 120 healthy subjects and the expression of urinary proteins was assessed by Western blotting and ELISA. The correlation between urinary protein concentrations and the levels of serum lipid biomarkers was analyzed using correlation analysis. Results Three urinary exosome proteins, namely fatty acid synthase (FASN), phosphoenolpyruvate carboxykinase (PCK1), and ATP-citrate synthase (ACLY) were identified, and only FASN showed sex differences. Sex differences were also observed in the serum triglyceride (TG) levels. Healthy males had higher FASN levels than females, and a moderate positive correlation was found between FASN concentrations and serum TG levels in healthy males (r = 0.479, P

Abstract Oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases, both of which are important for the development of KSHV-related cancers. As one of the most abundant RNA modifications, N 6 -methyladenosine (m6A) and its related complexes regulate KSHV life cycle. However, the role of METTL16, a newly discovered RNA methyltransferase, in KSHV life cycle remains unknown. In this study, we have identified a suppressive role of METTL16 in KSHV lytic replication. METTL16 knockdown increased while METTL16 overexpression reduced KSHV lytic replication. METTL16 binding to and writing of m6A on MAT2A transcript are essential for its splicing, maturation and expression. As a rate-limiting enzyme in the methionine-S-adenosylmethionine (SAM) cycle, MAT2A catalyzes the conversion of L-methionine to SAM required for the transmethylation of protein, DNA and RNA, transamination of polyamines, and transsulfuration of cystathionine. Consequently, knockdown or chemical inhibition of MAT2A reduced intracellular SAM level and enhanced KSHV lytic replication. In contrast, SAM treatment was sufficient to inhibit KSHV lytic replication and reverse the effect of the enhanced KSHV lytic program caused by METTL16 or MAT2A knockdown. Mechanistically, METTL16 or MAT2A knockdown increased while SAM treatment decreased the intracellular reactive oxygen species level by altering glutathione level, which is essential for efficient KSHV lytic replication. These findings demonstrate that METTL16 suppresses KSHV lytic replication by modulating the SAM cycle to maintain intracellular SAM level and redox homeostasis, thus illustrating the linkage of KSHV life cycle with specific m6A modifications, and cellular metabolic and oxidative conditions.

Abstract. Background:. Measuring the health of the population is of great significance to the development of a region. We aimed to estimate the population, probability of death, and quality of life in western China. Methods:. We calculated the age-specific mortality rate and prevalence rate of diseases and injuries using the Full Population Database and the Home Page of Inpatient Medical Record. We used multiple interpolation methods to insert missing information from the death data and the model of Kannisto to adjust the mortality rate for elderly individuals. The age-specific prevalence rate of diseases and injuries was adjusted according to the standard ratio of age and methods of equal proportional allocation. Life expectancy was calculated by a life table, and the quality of life was estimated using the Sullivan method. Results:. The total population continued to increase in 2015 to 2019 in the Shaanxi Province, China. The mortality rate of children under five has improved, and the mortality rate of people over 65 is decreasing year by year. Life expectancy increased from 74.66 years in 2015 to 77.19 years in 2019. Even with the total risk of disease and injury, the health-adjusted life expectancy increased by 1.90 years within 5 years, and the number of unhealthy years significantly improved. Health-adjusted life expectancy increased by 1.75 years when only considered the ten major disease systems (tumors; endocrinology, nutrition and metabolism; mental and behavioral disorders; nervous system; sensory diseases; circulatory system; respiratory system; digestive system; genitourinary system; musculoskeletal system and connective tissue), and the number of unhealthy years increased slightly. Conclusions:. In the past five years, Shaanxi Province has made progress in improving life expectancy and controlling the development of chronic diseases. It is necessary to take specific preventive measures and improve the quality of basic public health services.

Efficient acquisition of crop leaf moisture information holds significant importance for agricultural production. This information provides farmers with accurate data foundations, enabling them to implement timely and effective irrigation management strategies, thereby maximizing crop growth efficiency and yield. In this study, unmanned aerial vehicle (UAV) multispectral technology was employed. Through two consecutive years of field experiments (2021–2022), soybean (Glycine max L.) leaf moisture data and corresponding UAV multispectral images were collected. Vegetation indices, canopy texture features, and randomly extracted texture indices in combination, which exhibited strong correlations with previous studies and crop parameters, were established. By analyzing the correlation between these parameters and soybean leaf moisture, parameters with significantly correlated coefficients (p < 0.05) were selected as input variables for the model (combination 1: vegetation indices; combination 2: texture features; combination 3: randomly extracted texture indices in combination; combination 4: combination of vegetation indices, texture features, and randomly extracted texture indices). Subsequently, extreme learning machine (ELM), extreme gradient boosting (XGBoost), and back propagation neural network (BPNN) were utilized to model the leaf moisture content. The results indicated that most vegetation indices exhibited higher correlation coefficients with soybean leaf moisture compared with texture features, while randomly extracted texture indices could enhance the correlation with soybean leaf moisture to some extent. RDTI, the random combination texture index, showed the highest correlation coefficient with leaf moisture at 0.683, with the texture combination being Variance1 and Correlation5. When combination 4 (combination of vegetation indices, texture features, and randomly extracted texture indices) was utilized as the input and the XGBoost model was employed for soybean leaf moisture monitoring, the highest level was achieved in this study. The coefficient of determination (R2) of the estimation model validation set reached 0.816, with a root-mean-square error (RMSE) of 1.404 and a mean relative error (MRE) of 1.934%. This study provides a foundation for UAV multispectral monitoring of soybean leaf moisture, offering valuable insights for rapid assessment of crop growth.

The porous architectures of oxygen cathodes are highly desired for high-capacity lithium–oxygen batteries (LOBs) to support cathodic catalysts and provide accommodation for discharge products. However, controllable porosity is still a challenge for laminated cathodes with cathode materials and binders, since polymer binders usually shield the active sites of catalysts and block the pores of cathodes. In addition, polymer binders such as poly(vinylidene fluoride) (PVDF) are not stable under the nucleophilic attack of intermediate product superoxide radicals in the oxygen electrochemical environment. The parasitic reactions and blocking effect of binders deteriorate and then quickly shut down the operation of LOBs. Herein, the present work proposes a binder-free three-dimensional (3D) porous graphene (PG) cathode for LOBs, which is prepared by the self-assembly and the chemical reduction of GO with triblock copolymer soft templates (Pluronic F127). The interconnected mesoporous architecture of resultant 3D PG cathodes achieved an ultrahigh capacity of 10,300 mAh g−1 for LOBs. Further, the cathodic catalysts ruthenium (Ru) and manganese dioxide (MnO2) were, respectively, loaded onto the inner surface of PG cathodes to lower the polarization and enhance the cycling performance of LOBs. This work provides an effective way to fabricate free-standing 3D porous oxygen cathodes for high-performance LOBs.

All-inorganic cesium copper halide nanocrystals have attracted extensive attention due to their cost-effectiveness, low toxicity, and rich luminescence properties. However, controlling the synthesis of these nanocrystals to achieve a precise composition and high luminous efficiency remains a challenge that limits their future application. Herein, we report the effect of oleylammonium iodide on the synthesis of copper halide nanocrystals to control the composition and phase and modulate their photoluminescence (PL) quantum yields (QYs). For CsCu2I3, the PL peak is centered at 560 nm with a PLQY of 47.3%, while the PL peak of Cs3Cu2I5 is located at 440 nm with an unprecedently high PLQY of 95.3%. Furthermore, the intermediate-state CsCu2I3/Cs3Cu2I5 heterostructure shows white light emission with a PLQY of 66.4%, chromaticity coordinates of (0.3176, 0.3306), a high color rendering index (CRI) of 90, and a correlated color temperature (CCT) of 6234 K, indicating that it is promising for single-component white-light-emitting applications. The nanocrystals reported in this study have excellent luminescence properties, low toxicity, and superior stability, so they are more suitable for future light-emitting applications.

Objective To investigate the status and influencing factors of falls among the elderly in a community in Beijing, and provide reference for the prevention of falls in community. Methods Convenience sampling method was used to investigate 509 elderly residents over 60 years old in a community in Beijing, and logistic regression was used to analyze the risk factors of falls. Results The fall rate of the elderly in the community of Beijing was 26. 72%(136/509). Logistic regression results showed that age(OR=1. 93), abnormal gait(OR=6. 44), abnormal balance(OR=11. 20), urinary/stool incontinence(OR=4. 57), dizziness and vertigo(OR-2. 27), visual impairment(OR=1. 97), history of stroke(OR=3. 02) and arrhythmia(OR=2. 77) were the risk factors for falling of the elderly in the community. Conclusion The fall rate of the elderly in this community in Beijing is high, so the elderly with advanced age, abnormal gait, abnormal balance, urinary/fecal incontinence, dizziness, dizziness, visual impairment, stroke history, arrhythmia should be strengthened to reduce the fall rate of the elderly and the adverse consequences of falling, improve the quality of life of the elderly. (目的 调查北京社区老年人跌倒现状, 并探讨其影响因素, 为社区跌倒预防工作提供参考依据。方法 采用便利抽样法, 对509名60岁以上的社区老年居民进行调查, 采用logistic回归分析跌倒的危险因素。结果 北京某社区老年人的跌倒率为26. 72%(136/509), Logistic回归结果显示, 年龄(OR=1. 93)、步态异常(OR=6. 44)、平衡异常(OR=11. 20)、尿/便失禁(OR=4. 57)、头晕眩晕(OR=2. 27)、视力障碍(OR=1. 97)、脑卒中史(OR=3. 02)、心律失常(OR=2. 77)是社区老年人跌倒的危险因素。结论 北京市该社区老年人跌倒率较高, 对于高龄、步态异常、平衡异常、尿/便失禁、头晕眩晕、视力障碍、有脑卒中史、心律失常的老年人应加强防护, 以降低老年人的跌倒率及跌倒后不良后果, 提高老年人的生活质量。)

Hepatic miR-182-5p is identified as a key regulator of liver regeneration by stimulating Cyp7a1-mediated cholic acid production in hepatocytes and activating hedgehog (Hh) signaling, consequently increasing cell proliferation.

ABSTRACT Mitogen-activated protein kinases (MAPKs) play critical roles in the induction of numerous cytokines, chemokines, and inflammatory mediators that mobilize the immune system to counter pathogenic infections. Dual-specificity phosphatase 1 (DUSP1) is a member of the dual-specificity phosphatases that inactivates MAPKs through a negative-feedback mechanism. Here, we report that in response to viral and bacterial infections, not only the DUSP1 transcript but also its N6-methyladenosine (m6A) levels rapidly increase together with that of the m6A reader protein YTHDF2, resulting in enhanced YTHDF2-mediated DUSP1 transcript degradation. The knockdown of DUSP1 promotes p38 and Jun N-terminal kinase (JNK) phosphorylation and activation, thus increasing the expression of innate immune response genes, including the interleukin-1β (IL-1β), colony-stimulating factor 3 (CSF3), transglutaminase 2 (TGM2), and proto-oncogene tyrosine-protein kinase Src (SRC) genes. Similarly, the knockdown of the m6A eraser ALKBH5 increases the DUSP1 transcript m6A level, resulting in accelerated transcript degradation, the activation of p38 and JNK, and the enhanced expression of IL-1β, CSF3, TGM2, and SRC. These results demonstrate that m6A and the reader protein YTHDF2 orchestrate optimal innate immune responses during viral and bacterial infections by downregulating the expression of a negative regulator, DUSP1, of the p38 and JNK pathways that are central to innate immune responses against pathogenic infections. IMPORTANCE Innate immunity is central to controlling pathogenic infections and maintaining the homeostasis of the host. In this study, we have revealed a novel mechanism regulating innate immune responses during viral and bacterial infections. We have found that N6-methyladenosine (m6A) and the reader protein YTHDF2 regulate dual-specificity phosphatase 1, a negative regulator of the mitogen-activated protein kinases p38 and JNK, to maximize innate immune responses during viral and bacterial infections. These results provide novel insights into the mechanism regulating innate immunity, which could help in the development of novel approaches for controlling pathogenic infections.

Abstract N 6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification influencing all aspects of mRNA biology. While m6A modifications during numerous viral infections have been described, the role of m6A in innate immune response remains unclear. Here, we examined cellular m6A epitranscriptomes during infections of Pseudomonas aeruginosa and herpes simplex virus type 1 (HSV-1), and lipopolysaccharide (LPS) stimulation to identify m6A-regulated innate immune response genes. We showed that a significant portion of cellular genes including many innate immune response genes underwent m6A modifications in 5'UTR and 3'UTR. We identified common and distinct m6A-modified genes under different stimulating conditions. Significantly, the expression of a subset of innate immune response genes was positively correlated with m6A level. Importantly, we identified genes that had significant enrichments of m6A peaks during P. aeruginosa infection following knockdown of m6A “eraser” ALKBH5, confirming the regulation of these genes by m6A and ALKBH5. Among them, we confirmed the association of m6A modification with gene expression in immune response genes TNFAIP3, IFIT1, IFIT2 and IFIH1. Taken together, our results revealed the vital role of m6A in regulating innate immunity against bacterial and viral infections. These works also provided rich resources for the scientific community.

Body temperature plays a critical role in rehabilitation, and numerous studies proved that the regulation of body temperature contributes to the sensorimotor recovery of patients with brain diseases such as stroke. The hypothalamus plays a key role in thermoregulation. Ultrasound deep brain stimulation (UDBS) can noninvasively modulate deep brain nuclei and have potential applications in the treatment of Parkinson’s disease, Alzheimer’s disease, and depression, among others. The purpose of this study was to investigate whether ultrasound stimulation of the hypothalamus could regulate body temperature in free-moving mice. Results showed that thermoregulation was related to ultrasonic parameters (pulse repetition frequency (PRF), duty cycle, total time, and acoustic pressure). UDBS of the preoptic area of the anterior hypothalamus at 500 Hz PRF could significantly reduce body temperature ( $\text{T}\,\,= -0.25\,\,\pm \,\,0.073\,\,^{\circ }\text{C}$ at t = 5 min, $\text{T}\,\,= -0.51\,\,\pm \,\,0.19\,\,^{\circ }\text{C}$ at t = 10 min, $\text{T}\,\,= -0.84\,\,\pm \,\,0.27\,\,^{\circ }\text{C}$ at t = 15 min). Meanwhile, UDBS of the dorsomedial hypothalamus at 10 Hz PRF triggered a significant increase in body temperature ( $\text{T}\,\,=0.5\,\,\pm \,\,0.077\,\,^{\circ }\text{C}$ at t = 5 min, $\text{T}\,\,=1.16\,\,\pm \,\,0.23\,\,^{\circ }\text{C}$ at t = 10 min). These results suggest that UDBS, as a noninvasive neuromodulation tool, may play a key role in the future clinical treatment of malignant hyperthermia and hypothermia.

Synthetic lethality is a proven effective antitumor strategy that has attracted great attention. Large-scale screening has revealed many synthetic lethal genetic phenotypes, and relevant small-molecule drugs have also been implemented in clinical practice. Increasing evidence suggests that CDKs, constituting a kinase family predominantly involved in cell cycle control, are synthetic lethal factors when combined with certain oncogenes, such as MYC, TP53, and RAS, which facilitate numerous antitumor treatment options based on CDK-related synthetic lethality. In this review, we focus on the synthetic lethal phenotype and mechanism related to CDKs and summarize the preclinical and clinical discoveries of CDK inhibitors to explore the prospect of CDK inhibitors as antitumor compounds for strategic synthesis lethality in the future.

Abstract Nucleocytoplasmic transport of signaling modulators is essential for regulating cellular responses to extracellular stimulation and stress, as well as pathogen infection. Exportin 1 (XPO1), also known as chromosomal maintenance 1 (CRM1), mediates nuclear export of proteins, rRNAs, snRNAs, and some mRNAs. In this study, we have identified an essential role of XPO1 in regulating Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication during primary infection of primary human umbilical vein endothelial cells. Treatment with an XPO1 inhibitor KPT-8602 and short hairpin RNA (shRNA)-mediated knockdown of XPO1 reduced KSHV lytic replication but had no effect on KSHV entry and trafficking. XPO1 inhibition induced retention of autophagy adaptor protein p62 (SQSTM1) in the nucleus, which enhanced activation of TBK1 and IRF3. As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.

BackgroundThe electron beams produced by laser plasma acceleration have excellent quality for pulse lengths of the order of fs. Due to the existence of a strong laser field, there are difficulties in direct applications, and more applications need to transmit the electron beams to the application terminal. The energy spread leads to the generation of energy chirp of the electron beam in the transmission.PurposeThis study aims to explore the design of the beam optics to compress the pulse length and keep it on the fs scale.MethodsAn achromatic beamline consisting of bending magnets and quadrupole magnets was designed to compress the pulse length of electron beams. Critical parameters of an achromatic beamline were given by a derived formula. Transformation matrix was employed to investigate the differences of the pulse lengths in achromatic transmission and non-achromatic transmission. The pulse lengths of electron beams with different energies were scanned with different deflection angles (0.3 rad, 0.6 rad, 0.9 rad) and deflection radii (0.15 m, 0.25 m, 0.35 m) to study the influence of beamline parameters. Finally, the magnetic field gradients of the quadrupole lens were adjusted to realize the compression of electron beams with different energies in a beamline.ResultsComparing to non-achromatic transmission, the pulse lengths of electrons with the same energy and different initial divergence angles can be compressed effectively in the achromatic beamline. The larger the deflection angle or the deflection radius, the longer the pulse duration of the electron beam with higher energy (>25 MeV). By adjusting the magnetic field gradients of the quadrupole lens, the pulse lengths can be reduced from more than 100 fs to around 20 fs at higher energies.ConclusionsUsing a fixed-size achromatic beamline, combined with magnetic field strength adjustment, the pulse lengths of electron beams with different energies can be kept on the order of fs after transmission.

BackgroundMultimorbidity has an effect on life expectancy, while its effect on healthy life years is unclear. This study aims to investigate the associations between healthy life years lost due to multimorbidity and living risk.MethodsThe participants of The China Health and Retirement Longitudinal Study (CHARLS) were assessed at four visits between 2011 (baseline) and 2018. At baseline, 13,949 individuals were administered surveys. A combined score based on seven health-related factors was calculated, and the participants were classified into 3 groups based on living risk. We used the adjusted Cox regression methods to examine the associations between living risk groups and multimorbidity. We estimated the healthy life years lost due to multimorbidity using the Sullivan method.ResultsA total of 9,091 adults aged 45 years or older (mean age of 59.55 ± 9.50 years with one disease, 52.60% women) were analyzed in the CHARLS. The probability of no multimorbidity over 7 years decreased from 0.9947 to 0.9697 in the low-risk group, whereas the probability of multimorbidity in low living risk was lower than that of high living risk, ranging from HR 1.253 (95% CI.992–1.581; P = 0.058) to 1.431 (1.05–1.949; P = 0.023) in sex, and ranging from HR 1.340 (95% CI 1.106–1.623; P = 0.003) to 2.002 (1.058–3.787; P = 0.033) in area. At 45 years, the healthy life years lost in men was

A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5′-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p–induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

Evidence in animals suggests that deep brain stimulation or optogenetics can be used for recovery from disorders of consciousness (DOC). However, these treatments require invasive procedures. This report presents a noninvasive strategy to stimulate central nervous system neurons selectively for recovery from DOC in mice. Through the delivery of ultrasound energy to the ventral tegmental area, mice were aroused from an unconscious, anaesthetized state in this study, and this process was controlled by adjusting the ultrasound parameters. The mice in the sham group under isoflurane-induced, continuous, steady-state general anaesthesia did not regain their righting reflex. On insonation, the emergence time from inhaled isoflurane anaesthesia decreased (sham: 13.63±0.53 min, ultrasound: 1.5±0.19 min, p

The expression of G2 and S phase-expressed-1 (GTSE1) was upregulated in human cancer. However, its expression and roles in lung cancer have not been identified yet. In our study, we reported that GTSE1 expression was statistically higher in lung tissues than in the adjacent noncancerous tissues which might be a consequence of hypomethylation of the GTSE1 promoter. The upregulated expression of GTSE1 mRNA predicted the poorer survival of the lung patients. Ectopic expression of GTSE1 in lung cancer cells significantly increased while knockdown of GTSE1 decreased cell proliferation, cell migration, and cell invasion in H460 and A549 cells. Furthermore, knockdown of GTSE1 regulated the cell cycle and promoted cell apoptosis in H460 and A549 cells. Finally, we presented that GTSE1 was able to activate AKT/mTOR signaling in H460 and A549 cells. In conclusion, these results indicated that the overexpressed GTSE1 was involved in the progress of lung cancer by promoting proliferation migration and invasion and inhibiting apoptosis of lung cancer cells via activating AKT/mTOR signaling.

Summary: Ultrasound stimulation has recently emerged as a non-invasive method for modulating brain activity in animal and human studies with healthy subjects. Whether brain diseases such as Alzheimer's disease, epilepsy, and depression can be treated using ultrasound stimulation still needs to be explored. Recent studies have reported that ultrasound stimulation suppressed epileptic seizures in a rodent model of epilepsy. These findings raise the crucial question of whether ultrasound stimulation can inhibit seizures in non-human primates with epilepsy. Here, we addressed this critical question. We confirmed that ultrasound stimulation significantly reduced the frequency of seizures in acute epileptic monkeys. Furthermore, the results showed that the number and duration of seizures were reduced, whereas the inter-seizure interval was increased after ultrasound stimulation. Besides, no significant brain tissue damage was observed by T2-weighted MR imaging. Our results are of great importance for future clinical applications of ultrasound neuromodulation in patients with epilepsy.

Objective. To study the expression, biological function, and mechanism of FKBP4 in non-small-cell lung cancer (NSCLC). Methods. First of all, the expression of FKBP4 in NSCLC tissues and cell lines was detected by qRT-PCR; then, the effects of FKBP4 on proliferation, apoptosis, migration, and invasion of NSCLC were studied by CCK-8 assays, flow cytometry assays, wound-healing assays, and Transwell assays. After that, tumor xenografts were used to explore the effect of FKBP4 on NSCLC tumor growth in vivo, and the phosphorylation of Akt and mTOR was measured by western blot. Results. FKBP4 was highly expressed in NSCLC tissues and cells, and its expression was closely related to NSCLC tumor size, lymph node metastasis, and patient prognosis. In vitro, FKBP4 can promote NSCLC cell proliferation, migration, and invasion and inhibit NSCLC cell apoptosis. In vivo, FKBP4 can promote NSCLC tumor growth. Furthermore, FKBP4 can promote Akt and mTOR phosphorylation and activate the Akt/mTOR signaling pathway and an mTOR inhibitor can neutralize the functions of FKBP4 in NSCLC cells. Conclusion. FKBP4 serves as an oncogene to promote malignant processes in NSCLC, and it has the potential to be used as a biological marker and therapeutic target for NSCLC.

Abstract Background Limited evidences were reported about the risk of pre-pregnancy hair dye use or irregular menstruation with abnormal birth weight during pregnancy, and their joint effects were also unknown. The aim of our study was to explore whether the pre-pregnancy exposure of hair dye and irregular menstruation were associated with the risk of abnormal birth weight. Methods We conducted a nested case-control study from a prospective cohort of 6203 pregnant women. Low birth weight study included 315 mother-infant pairs (105 LBW cases and 210 matched controls), and macrosomia study included 381 mother-infant pairs (127 macrosomia cases and 254 matched controls). Meanwhile, lifestyle information including hair dying custom and menstrual history were collected by face-to-face questionnaires and birth outcomes were extracted from the medical records. The logistic regressions models were used to analyze the join effect of irregular menstruation and hair dye use. Results Pre-pregnancy hair dye use was associated with increased risk of LBW (adjusted OR = 1.71, 95% CI: 1.01–2.92, P = 0.048). Irregular menstruation had high risk of LBW (adjusted OR = 2.79, 95% CI: 1.53–5.09, P = 0.001) and macrosomia (adjusted OR = 1.93, 95% CI: 1.09–3.44, P = 0.023). Additionally, in the LBW study, women who used hair dye with pre-pregnancy BMI

The objective of this article is to review the current status of the bacteria-virus interplay in Kaposi’s sarcoma-associated herpesvirus (KSHV) infection and KSHV-driven cancers. KSHV is the etiological agent of several cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma. Due to immunosuppression, patients with KSHV are at an increased risk for bacterial infections. Moreover, among patients coinfected by HIV and KSHV, patients with KS have distinct oral microbiota compared to non-KS patients. Bacterial biomarkers associated with KSHV-driven cancers can provide insights in discerning the mechanisms of KSHV-induced oncogenesis. For example, pathogen-associated molecular patterns and bacterial products of certain bacterial species can regulate the expression of KSHV lytic and latent genes, thereby affecting viral replication and dissemination. In addition, infection with distinct opportunistic bacterial species have been associated with increased cell proliferation and tumorigenesis in KSHV-induced cancers through activation of pro-survival and -mitogenic cell signaling pathways. By elucidating the various mechanisms in which bacteria affect KSHV-associated pathogenesis, we will be able to pinpoint therapeutic targets for KSHV infection and KSHV-related cancers.

ABSTRACT The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, among which the cancer-vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) screening in a unique model of matched primary and oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV)-transformed cells and identified genes that were growth promoting and growth suppressive for both types of cells, among which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by small interfering RNA (siRNA) knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells and in cell lines of other cancers, including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation, but the mechanisms of p53 activation differed among the different types of cancer cells. p53 activation depended on the formation of promyelocytic leukemia (PML) nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken the data together, we have identified novel growth-promoting and growth-suppressive genes of primary and cancer cells and have demonstrated that XPO1 is a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML- and p62-dependent mechanism of p53 activation in some types of cancer cells. IMPORTANCE Using a model of oncogenic virus KSHV-driven cellular transformation of primary cells, we have performed a genome-wide CRISPR-Cas9 screening to identify vulnerable genes of cancer cells. This screening is unique in that this virus-induced oncogenesis model does not depend on any cellular genetic alterations and has matched primary and KSHV-transformed cells, which are not available for similar screenings in other types of cancer. We have identified genes that are both growth promoting and growth suppressive in primary and transformed cells, some of which could represent novel proto-oncogenes and tumor suppressors. In particular, we have demonstrated that the exportin XPO1 is a critical factor for the survival of transformed cells. Using a XPO1 inhibitor (KPT-8602) and siRNA-mediated knockdown, we have confirmed the essential role of XPO1 in cell proliferation and in growth transformation of KSHV-transformed cells, as well as of gastric and liver cancer cells. XPO1 inhibition induces cell cycle arrest by activating p53, but the mechanisms of p53 activation differed among different types of cancer cells. p53 activation is dependent on the formation of PML nuclear bodies in gastric and liver cancer cells. Mechanistically, XPO1 inhibition induces relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. These results illustrate that XPO1 is a vulnerable target of cancer cells and reveal a novel mechanism for blocking cancer cell proliferation by XPO1 inhibition as well as a novel PML- and p62-mediated mechanism of p53 activation in some types of cancer cells.

Currently, there is no available biomarker for lung cancer diagnosis. Here we recruited 844 lung cancer patients and 620 healthy participants from six hospitals. A total of four serum proteins was identified and subsequently assessed in the training and validation cohorts. The concentrations of four serum proteins were found to be significantly higher in lung cancer patients compared with healthy participants. The area under the curve (AUC) for the 4-biomarker were 0.86 in the training cohort, and 0.87 in the validation cohort. The classification improved to a corrected AUC of 0.90 and 0.89 respectively following addition of sex, age and smoking status. Similar results were observed for early-stage lung cancer. Remarkably, in a blinded test with a suspicious pulmonary nodule, the adjusted prediction model correctly discriminated the patients with 86.96% sensitivity and 98.25% specificity. These results demonstrated the 4-biomarker panel improved lung cancer prediction beyond that of known risk factors. Moreover, the biomarkers were valuable in differentiating benign nodules which will remain indolent from those that are likely to progress and therefore might serve as an adjuvant diagnosis tool for LDCT scanning.

This paper introduces a new way to analyze mixtures of inflammable gases with a single catalytic sensor. The analysis technology was based on a new finding that an electric field on the catalytic sensor can change the output sensitivity of the sensor. The analysis of mixed inflammable gases results from processing the output signals obtained by adjusting the electric field parameter of the catalytic sensor. For the signal process, we designed a group of equations based on the heat balance of catalytic sensor expressing the relationship between the output signals and the concentration of gases. With these equations and the outputs of different electric fields, the gas concentration in a mixture could be calculated. In experiments, a mixture of methane, butane and ethane was analyzed by this new method, and the results showed that the concentration of each gas in the mixture could be detected with a single catalytic sensor, and the maximum relative error was less than 5%.

To complement traditional antivirals, natural compounds that act via host targets and present high barriers to resistance are of increasing interest. In the work reported here, we detected that homoharringtonine (HHT) presents effective antiviral activity. HHT completely inhibited infections of vesicular stomatitis virus (VSV), Newcastle disease virus (NDV), and porcine epidemic diarrhea virus (PEDV) at concentrations of 50, 100, and 500 nM in cell cultures, respectively. Treatment with HHT at doses of 0.05 or 0.2 mg/kg significantly reduced viral load and relieved severe symptoms in PEDV- or NDV-infected animals. HHT treatment, however, moderately inhibited avian influenza virus (AIV) infection, suggesting its potent antiviral action is restricted to a number of classes of RNA viruses. In this study, we also observed that HHT actively inhibited herpes simplex virus type 1 (HSV-1) replication with a 50% inhibitory concentration (IC50) of 139 nM; the treatment with HHT at 1000 nM led to reductions of three orders of magnitude. Moreover, HHT antagonized the phosphorylation level of endogenous and exogenous eukaryotic initiation factor 4E (p-eIF4E), which might regulate the selective translation of specific messenger RNA (mRNA). HHT provides a starting point for further progress toward the clinical development of broad-spectrum antivirals.

Background and objective Magnetic fluid hyperthermia (MFH) is a method of heat therapy using nanometer techniques and hyperthermia. It has the advantage of high specificity of targeting. The aim of this study is to detect the effects of MFH induced by an alternating magnetic field on human being carcinoma A549 cells in vitro. Methods A human adenocarcinoma cell line A549 was cultured with various concentrations of ferroferric oxide (Fe3O4) magnetic fluid (1.5-6.0) mg/mL and exposed to an alternative magnetic field (AMF) for 30 min. And then the optical density (OD) of viable cell, cytotocixity index, growth curve of cells, morphologic changes of cell, cell cycle and aposptosis were measured. Results The proliferation of the A549 cells were remarkably inhibited, the OD value of viable cells decreased and cytotoxity index (CI) increased; Apoptosis of the A549 cells were observed to have cell shrinkage, chromatin condensation, margination, unclear fragmentation and intact cell membrane by light and electron microscopy; The cells were inhibited in the stage S. Conclusion MFH induced by AMF could inhibit the proliferation, which promotes apoptosis and arrest at S stage of the A549 cells.

NOP53 is a tumor suppressor protein located in the nucleolus and is translocated to the cytoplasm during infection by vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1), as shown in our previous study. Cytoplasmic NOP53 interacts with the retinoic acid-inducible gene I (RIG-I) to remove its K63-linked ubiquitination, leading to attenuation of type I interferon IFN-β. In the present study, we found no obvious translocation of NOP53 in infection by a mutant virus lacking ICP4 (HSV-1/d120, replication inadequate). Blocking cytoplasmic translocation of NOP53 by the deletion of its nuclear export sequence (NES) abrogated its ability to support viral replication. These results demonstrated that NOP53 redistribution is related to viral replication. It is interesting that treatment with poly (I:C) or RIG-I-N (a constitutively-active variant) directly induced NOP53 cytoplasmic translocation. To better assess the function of cytoplasmic NOP53 in viral replication, the NOP53-derived protein N3-T, which contains a human immunodeficiency virus (HIV)-derived cell-penetrating Tat peptide at the C-terminal region of N3 (residues 330–432), was constructed and expressed. The recombinant N3-T protein formed trimers, attenuated the expression of IFN-β and IFN-stimulated genes, as well as decreased the phosphorylation level of interferon regulatory factor 3 (IRF3). Furthermore, N3-T promoted the efficient replication of enveloped and non-enveloped DNA and RNA viruses belonging to 5 families. Our findings expand the understanding of the mechanism by which viruses utilize the nucleolar protein NOP53 for optimal viral replication.

Lung cancer is the leading cause of cancer-related deaths for both men and women. Early diagnosis of lung cancer has a 5-year survival rate of 48.8%, however, nearly 35% of stage I patients relapses after surgical resection, thus portending a poor prognosis. Therefore, detecting lung cancer in early stage and further identifying the high-risk patients would allow the opportunity to provide adjuvant therapy and possibly increase survival. There is considerable evidence that the immune system produces an autoantibody response to neoplastic cells. The detection of such autoantibodies has been shown to have diagnostic and prognostic value. Here we took advantage of the high-throughput Luminex technique to multiplex a total of 14 tumor-associated autoantigens to detect the autoantibody from the patients sera. The 14 antigens were expressed by in vitro transcription/translation system with HaloTag at N-terminus. The fusion proteins were then covalently immobilized onto the Luminex microspheres conjugated by the halo-link ligand, thus eliminating the protein purification procedure. Sera samples from cancer patients and healthy controls were interacted with the microsphere-antigen complex to measure the autoantibodies. We have developed a quick multiplex detection system for measuring autoantibody signature from patient sera with minimal cross-reaction. A panel of seven autoantibody biomarkers has generated an AUC>80% in distinguishing the lung cancers from healthy controls. This study is the first report by combining Luminex platform and HaloTag technology to detect humoral immune response in cancer patients. Due to the flexibility of the Luminex technology, this approach can be applied to others conditions such as infectious, neurological, and metabolic diseases. One can envision that this multiplex Luminex system as well as the panel of seven biomarkers could be used to screen the high-risk population with subsequent CT test based on the blood test result.

The plastic penetration condition and biting-in condition of a radial conical ring rolling process with a closed die structure on the top and bottom of driven roll, simplified as RCRRCDS, were established. The reasonable value range of mandrel feed rate in rolling process was deduced. A coupled thermomechanical 3D FE model of RCRRCDS process was established. The changing laws of equivalent plastic strain (PEEQ) and temperature distributions with rolling time were investigated. The effects of ring’s outer radius growth rate and rolls sizes on the uniformities of PEEQ and temperature distributions, average rolling force, and average rolling moment were studied. The results indicate that the PEEQ at the inner layer and outer layer of rolled ring are larger than that at the middle layer of ring; the temperatures at the “obtuse angle zone” of ring’s cross-section are higher than those at “acute angle zone”; the temperature at the central part of ring is higher than that at the middle part of ring’s outer surfaces. As the ring’s outer radius growth rate increases at its reasonable value ranges, the uniformities of PEEQ and temperature distributions increase. Finally, the optimal values of the ring’s outer radius growth rate and rolls sizes were obtained.

With the wide application of the OSCE in the field of pharmacy, the development of e-assessment in OSCE is a predictable trend. However, the feasibility of its practical application and the acceptance of examiners who are accustomed to using traditional paper-based methods are worthy of being discussed. The e-assessment system (EAS) was constructed in this study and used in the examination process. Examiner satisfaction and changes in acceptance of EAS were evaluated. Examiners showed high recognition for the advantages of EAS in data processing, but EAS obviously made the examiner more nervous than the paper-based method. After repeated use of the e-OSCE system, the examiner's satisfaction and acceptance significantly improved, which showed that there was a certain correlation between examiner's familiarity with the assessment method and their acceptance. Besides, EAS has great advantages over traditional paper-based methods, and it is feasible in clinical practice examination of pharmacy education.