TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress of hepatocytes plays a causative role in non-alcoholic fatty liver disease (NAFLD). Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. Whether ER stress regulates HNF4α expression remains unknown. The aim of this study was to delineate the machinery of HNF4α protein degradation and explore a therapeutic strategy based on protecting HNF4α stability during NAFLD progression. METHODS: Correlation of HNF4α and tribbles homologue 3 (TRIB3), an ER stress sensor, was evaluated in human and mouse NAFLD tissues. RNA-sequencing, mass spectrometry analysis, co-immunoprecipitation, in vivo and in vitro ubiquitination assays were used to elucidate the mechanisms of TRIB3-mediated HNF4α degradation. Molecular docking and co-immunoprecipitation analyses were performed to identify a cell-penetrating peptide that ablates the TRIB3-HNF4α interaction. RESULTS: TRIB3 directly interacts with HNF4α and mediates ER stress-induced HNF4α degradation. TRIB3 recruits tripartite motif containing 8 (TRIM8) to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470. Abrogating the degradation of HNF4α attenuated the effect of TRIB3 on a diet-induced NAFLD model. Moreover, the TRIB3 gain-of-function variant p.Q84R is associated with NAFLD progression in patients, and induces lower HNF4α levels and more severe hepatic steatosis in mice. Importantly, disrupting the TRIB3-HNF4α interaction using a cell-penetrating peptide restores HNF4α levels and ameliorates NAFLD progression in mice. CONCLUSIONS: Our findings unravel the machinery of HNF4α protein degradation and indicate that targeting TRIB3-TRIM8 E3 complex-mediated HNF4α polyubiquitination may be an ideal strategy for NAFLD therapy. IMPACT AND IMPLICATIONS: Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. However, the mechanism of HNF4α protein degradation remains unknown. Herein, we reveal that TRIB3-TRIM8 E3 ligase complex is responsible for HNF4α degradation during NAFLD. Inhibiting the TRIB3-HNF4α interaction effectively stabilized HNF4α protein levels and transcription factor activity in the liver and ameliorated TRIB3-mediated NAFLD progression. Our findings demonstrate that disturbing the TRIM8-TRIB3-HNF4α interaction may provide a novel approach to treat NAFLD and even other liver diseases by stabilizing the HNF4α protein.

Effect of age and sex on hematological and biochemical parameters in Chinese rhesus monkeys (Macaca mulatta) anesthetized with ketamine.

OBJECTIVE: Rhesus monkeys are increasingly used in biomedical research, which makes their hematological and biochemical parameters increasingly important in preclinical research. Since age and sex can influence blood parameters, establishing reference intervals for such parameters based on age and sex becomes along with identifying the effect of age and sex on those parameters. METHODS: A total of 1385 healthy Chinese rhesus monkeys (548 males and 837 females) anesthetized with ketamine were selected and segregated by age (six groups) and sex. A total of 21 hematological and 26 biochemical parameters were measured, and the effects of age and sex were analyzed. RESULTS: We established baseline indices for hematological and biochemical parameters based on age and sex, separately, and observed significant impacts of age, sex, and age-sex interactions on blood parameters. Among different age groups, significant differences were found in WBC, NEUT%, LYM%, EO%, LYM#, EO#, MCV, RDW-CV, PLT, MPV, PDW, PCT, TP, Alb, GLB, A/G, ALT, AST, ALP, TBIL, GGT, BUN, Cre, GLU, CK, TRIG, LDL, HCY, IL-6 FOL, Vit B12, VIT D-T, PTH, and AMH. Additionally, significant differences were observed in RBC, HGB, HCT, MPV, Alb, BUN, Cre, GLU, CHOL, TRIG, HDL, LDL, HCY, and VIT D-T between the two sexes. An age-sex interaction exerted a significant effect on WBC, NEUT#, MCV, MCHC, PDW, GLB, ALP, Cre, CHOL, TRIG, HDL, LDL, HCY, IL-6, Vit B12, VIT D-T. However, neither age, sex, and age-sex interactions exerted significant effects on MO%, MOMO#, MCH, RDW-SD, CRP, and CT. CONCLUSION: Our study investigated the blood parameters of rhesus monkeys to provide a reference basis for rhesus monkey-related scientific experimental research.

The metal ion hypothesis of Alzheimer's disease and the anti-neuroinflammatory effect of metal chelators.

Alzheimer's disease (AD), characterized by the ß-amyloid protein (Aß) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aß monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aß deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aß but also directly bind to Aß and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aß dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.

Deletion of Sox9 in the liver leads to hepatic cystogenesis in mice by transcriptionally downregulating Sec63.

Hepatic cysts are found in heterogeneous disorders with different pathogeneses, of which simple hepatic cysts and polycystic liver diseases are two major types. The process of hepatic cytogenesis for these two diseases is caused by defects in remodelling of the ductal plate during biliary tract development, which is called ductal plate malformation. SOX9 is a transcription factor participating in the process of bile duct development, and thus, its dysregulation may play important roles in hepatic cystogenesis. SEC63 encodes an endoplasmic reticulum membrane protein that is mutated in human autosomal dominant polycystic liver disease. However, the transcriptional regulation of SEC63 is largely unknown. In the present study, a liver-specific Sox9 knockout (Sox9LKO ) mouse was generated to investigate the roles and underlying mechanism of SOX9 in hepatic cystogenesis. We found that hepatic cysts began to be observed in Sox9LKO mice at 6 months of age. The number and size of cysts increased with age in Sox9LKO mice. In addition, the characteristics of hepatic cytogenesis, including the activation of proliferation, absence of primary cilium, and disorder of polarity in biliary epithelial cells, were detected in the livers of Sox9LKO mice. RNAi silencing of SOX9 in human intrahepatic biliary epithelial cells (HIBEpic) resulted in increased proliferation and reduced formation of the primary cilium. Moreover, Sec63 was downregulated in primary biliary epithelial cells from Sox9LKO mice and SEC63 in HIBEpic transfected with siSOX9. Chromatin immunoprecipitation assays and luciferase reporter assays further demonstrated that SOX9 transcriptionally regulated the expression of SEC63 in biliary epithelial cells. Importantly, the overexpression of SEC63 in HIBEpic partially reversed the effects of SOX9 depletion on the formation of primary cilia and cell proliferation. These findings highlight the biological significance of SOX9 in hepatic cytogenesis and elucidate a novel molecular mechanism underlying hepatic cytogenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Bioinformatic Analysis of Exosomal MicroRNAs of Cerebrospinal Fluid in Ischemic Stroke Rats After Physical Exercise.

Physical exercise is beneficial to the structural and functional recovery of post-ischemic stroke, but its molecular mechanism remains obscure. Herein, we aimed to explore the underlying mechanism of exercise-induced neuroprotection from the perspective of microRNAs (miRNAs). Adult male Sprague-Dawley (SD) rats were randomly distributed into 4 groups, i.e., the physical exercise group with the transient middle cerebral artery occlusion (tMCAO) surgery (PE-IS, n = 28); the physical exercise group without tMCAO surgery (PE, n = 6); the sedentary group with tMCAO surgery (Sed-IS, n = 28); and the sedentary group without tMCAO surgery (Sed, n = 6). Notably, rats in the PE-IS and PE groups were subjected to a running exercise for 28 days while rats in the Sed-IS and Sed groups received no exercise training. After long-term exercise, exosomal miRNAs of cerebrospinal fluid (CSF) were analyzed using high-throughput sequencing. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed for the differentially expressed miRNAs. Physical exercise improved the neurological function and attenuated the lesion expansion after stroke. In total, 41 differentially expressed miRNAs were screened for the GO and KEGG analysis. GO enriched terms were associated with the central nervous system, including cellular response to retinoic acid, vagus nerve morphogenesis, cellular response to hypoxia, dendritic cell chemotaxis, cell differentiation, and regulation of neuron death. Besides, these differentially expressed miRNAs were linked to the pathophysiological process of stroke, including axon guidance, NF-kappa B signaling pathway, thiamine metabolism, and MAPK signaling pathway according to KEGG analysis. In summary, exercise training significantly alleviated the neurological damage at both functional and structural levels. Moreover, the differentially expressed miRNAs regulating multiple signal pathways were potentially involved in the neuroprotective effects of physical exercise. Therefore, these miRNAs altered by physical exercise might represent the therapeutic strategy for cerebral ischemia.

Neuromyelitis optica spectrum disorder: pregnancy-related attack and predictive risk factors.

OBJECTIVES: To investigate the influence of pregnancy on patients with neuromyelitis optica spectrum disorder (NMOSD) and to identify risk factors that predict pregnancy-related attack. METHODS: From January 2015 to April 2019, 418 female patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records and identified 110 patients with 136 informative pregnancies, of whom 83 were aquaporin-4 antibody (AQP4-ab)-positive and 21 were myelin oligodendrocyte glycoprotein-antibody-positive. Pregnancy-related attack was defined as an attack that occurred during pregnancy or within 1 year after delivery/abortion. We compared annualised relapse rate (ARR) during 12 months before pregnancy with that during every trimester of pregnancy and after delivery/abortion. Multivariate analyses were used to explore the independent risk factors involved and a nomogram was generated for the prediction of pregnancy-related attack. Thirty-five female patients from 3 other centres formed an external cohort to validate this nomogram. RESULTS: ARR increased significantly during the first trimester after delivery (p<0.001) or abortion (p=0.019) compared with that before pregnancy. Independent risk factors predicting pregnancy-related attack included age at delivery/abortion (20-26.5, p=0.018; 26.5-33, p=0.001), AQP4-ab titre (≥1:100, p=0.049) and inadequate treatment during pregnancy and postpartum period (p=0.004). The concordance index of nomogram was 0.87 and 0.77 using bootstrap resampling in internal and external validation. CONCLUSIONS: The first trimester post partum is a high-risk period for NMOSD recurrence. Patients with younger age, higher AQP4-ab titre and inadequate treatment are at higher risk for pregnancy-related attack.

UPLC-QTOF/MS-Based Metabolomics Reveals the Protective Mechanism of Hydrogen on Mice with Ischemic Stroke.

As a reductive gas, hydrogen plays an antioxidant role by selectively scavenging oxygen free radicals. It has been reported that hydrogen has protective effects against nerve damage caused by ischemia-reperfusion in stroke, but the specific mechanism is still unclear. Therefore, this study aims to investigate the protective effects of hydrogen on stroke-induced ischemia-reperfusion injury and its detailed mechanism. Two weeks after the inhalation of high concentrations (66.7%) of hydrogen, middle cerebral artery occlusion (MCAO) was induced in mice using the thread occlusion technique to establish an animal model of the focal cerebral ischemia-reperfusion. Then, a metabolomics analysis of mouse cerebral cortex tissues was first performed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) to study the metabolic changes and protective mechanisms of hydrogen on stroke ischemia-reperfusion injury. According to the metabolomic profiling of cortex tissues, 29 different endogenous metabolites were screened, including palmitoyl-L-carnitine, citric acid, glutathione, taurine, acetyl-L-carnitine, N-acetylaspartylglutamic acid (NAAG), L-aspartic acid, lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE). Through pathway analysis, the metabolic pathways were concentrate on the glutathione pathway and the taurine pathway, mitochondrial energy metabolism and phospholipid metabolism that related to the oxidative stress process. This result reveals that hydrogen may protect against ischemic stroke by reducing oxidative stress during ischemia-reperfusion, thereby protecting nerve cells from reactive oxygen species(ROS).

Updated Hourly Emissions Factors for Chinese Power Plants Showing the Impact of Widespread Ultralow Emissions Technology Deployment.

Nationwide severe air pollution has prompted China to mandate the adoption of ultralow emissions (ULE) control technologies at all of its coal-fired power plants by 2020. This process has accelerated greatly since 2014 and, combined with operational adjustments related to overcapacity, has reduced the emissions of nitrogen oxides (NO x), sulfur dioxide (SO2), and particulate matter (PM). Yet the quantitative understanding of ULE benefits is poor. Using detailed emissions data from 38 units at 17 power plants, corresponding to 10 combinations of ULE technologies representative of the Chinese power sector, we show that emissions factors for NO x, SO2, and PM are up to 1-2 orders of magnitude lower after ULE retrofitting. The effectiveness in cutting emissions shows a large spread across the various ULE technology combinations, providing an opportunity to choose the most efficient, economically viable technology (or a combination of technologies) in the future. The temporal variations in emissions at hourly resolution reveal the effects of power plant load on emissions, an increasingly important factor given that power plants are not operated at full capacity. These data will be useful in efforts to understand the evolving state of air quality in China and can also provide a basis for benchmarking state-of-the-art air pollution control equipment globally.

Potential Application Prospects of Biomolecule-Modified Two-Dimensional Chiral Nanomaterials in Biomedicine.

Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.

Prediction of 6-month poststroke spasticity in patients with acute first-ever stroke by machine learning.

OBJECTIVE: Poststroke spasticity (PSS) reduces arm function and leads to low levels of independence. This study suggested applying machine learning (ML) from routinely available data to support the clinical management of PSS. DESIGN: 172 patients with acute first-ever stroke were included in this prospective cohort study. Twenty clinical information and rehabilitation assessments were obtained to train various ML algorithms for predicting 6-month PSS defined by a modified Ashworth scale (MAS) score ≥ 1. Factors significantly relevant were also defined. RESULTS: The study results indicated that multivariate adaptive regression spline (area under the curve (AUC) value: 0.916; 95% confidence interval (CI): 0.906-0.923), adaptive boosting (AUC: 0.962; 95% CI: 0.952-0.973), random forest (RF) (AUC: 0.975; 95% CI: 0.968-0.981), support vector machine (SVM) (AUC: 0.980; 95% CI: 0.970-0.989) outperformed the traditional logistic model (AUC: 0.897; 95% CI: 0.884-0.910) (P < 0.05). Among all of the algorithms, the RF and SVM models outperformed the others (P < 0.05). FMA score, days in hospital, age, stroke location, and paretic side were the most important features. CONCLUSION: These findings suggest that ML algorithms can help augment clinical decision-making processes for the assessment of PSS occurrence, which may enhance the efficacy of management for patients with PSS in the future.

The application of demographic characteristics of Ectropis grisescens (Lepidoptera: Geometridae) in pest risk assessment of IPM.

Ectropis grisescens Warren is one of the most important pests of tea plants. In this study, data on the development, survival, and fecundity of E. grisescens were collected at 15, 22, and 32 °C and analyzed by using the age-stage, two-sex life table. At 15 °C, the duration of the preadult period of E. grisescens was significantly prolonged (81.06 days), with high mortality (69.0%), and the proportion of emerged female adults was extremely low (7.0%). At 32 °C, the preadult period was significantly shortened (29.12 days), with high preadult mortality (74.0%), and a low proportion of emerged female adults (15.0%). At 22 °C, with low preadult mortality (24.0%), and a high proportion of emerged female adults (26.0%). The overall effects of the shorter preadult duration, higher preadult survival rate, higher proportion of emerged female adults, higher fecundity (F = 350.88 eggs/♀), and higher net reproductive rate (R0 = 91.23 offspring/individual) at 22 °C resulted in the highest values of the intrinsic rate of increase (r = 0.1054 days-1) and finite rate of increase (λ = 1.1112 days-1). Computer simulation showed that E. grisescens populations can increase much faster at 22 °C than at 15 and 32 °C. The weighted population size and cumulative weighted insect-days provided the dynamics necessary for estimating the damage potential of E. grisescens in devising economical pest management programs. Our results demonstrate that populations of E. grisescens were able to develop at a broad range of temperatures and adapt to the high temperatures. These finding can be utilized to improve the management of E. grisescens.

Comparison of the effect of tea shoots during different seasons in Arma chinensis (Hemiptera: Pentatomidae) reared on Ectropis grisescens (Lepidoptera: Geometridae) pupae.

In this study, we compared the growth, development, and fecundity of Arma chinensis (Fallou) reared on pupae of the geometrid Ectropis grisescens Warren fed on tea shoots during different seasons of the year. The raw data on life history were analyzed using the age-stage, 2-sex life table. When reared on spring or winter geometrid pupae, the duration of the immature stage of A. chinensis was significantly longer than in those produced during the summer or autumn. The survival rate of immature A. chinensis reared on autumn geometrid pupae was significantly lower compared to other treatments. Reproductive diapause was observed in adult A. chinensis reared on winter geometrid pupae. The adult preoviposition period (APOP), total preoviposition period (TPOP), and total longevity were significantly longer in A. chinensis reared on winter pupae than in the other treatments. The fecundity of A. chinensis reared on spring geometrid pupae was significantly lower than in the other treatments. The higher intrinsic rate of increase of the A. chinensis reared on summer pupae (r = 0.0966 day-1) and autumn pupae (r = 0.0983 day-1) resulted in higher fecundity, shorter immature duration, and shorter TPOP compared to the winter and spring populations. These findings can be utilized to enhance and sustain biological control of E. grisescens in tea plantations.

Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial.

The combination of immune-checkpoint blockade with chemotherapy for the first-line treatment of advanced triple-negative breast cancer (TNBC) has generated mixed results. TORCHLIGHT is a randomized, double-blinded phase 3 trial evaluating the efficacy and safety of first-line toripalimab and nab-paclitaxel (nab-P) (n = 353; experimental arm) versus placebo and nab-P (n = 178; control arm) for the treatment of women with metastatic or recurrent TNBC. The primary end point was progression-free survival (PFS) assessed by a blinded independent central review in the PD-L1-positive and intention-to-treat populations. The secondary end points included overall survival and safety. Overall, 200 and 100 patients, in the toripalimab and placebo arm respectively had PD-L1-positive TNBC. At the prespecified interim analysis, a statistically significant improvement in PFS assessed by a blinded independent central review was demonstrated in the experimental arm in the PD-L1-positive population (median PFS 8.4 versus 5.6 months; hazard ratio (HR) = 0.65, 95% confidence interval (CI) 0.470-0.906, P = 0.0102). The median overall survival was 32.8 versus 19.5 months (HR = 0.62, 95% CI 0.414-0.914, P = 0.0148). Similar incidences of treatment-emergent adverse events (AEs) (99.2% versus 98.9%), grade ≥3 treatment-emergent AEs (56.4% versus 54.3%) and fatal AEs (0.6% versus 3.4%) occurred in the experimental and control arms. The addition of toripalimab to nab-P provided a significant improvement in PFS for PD-L1-positive patients with metastatic or recurrent TNBC with an acceptable safety profile. ClinicalTrial.gov identifier NCT03777579 .

Developing the theoretical model of Chinese physical education teachers' health communication competence: based on grounded theory.

Background: Physical education teachers' health communication competence is a key factor in health promotion. Although health communication is a multidisciplinary field, medical practitioners are the primary focus of health communication research, whereas physical education teachers are marginalized. Therefore, this study proposes a theoretical model of health communication competence for physical education teachers. Methods: This qualitative research utilized interviews as the primary data collection method. Purposeful sampling was employed to select participants, including university teachers, primary and secondary school teachers, and health education professionals from diverse regions of China. A total of 31 participants were interviewed through two focus groups (N = 15) and individual semi-structured interviews (N = 16). Grounded theory was used to analyze and code the collected interview materials. Results: The health communication competence of physical education teachers consisted of three main categories, 10 subcategories, 30 concepts, and 240 statement labels. The three main categories were as follows: (i) foundations of health communication knowledge and skills (this category encompassed three subcategories, namely sport and health knowledge reserve, health beliefs, and health behaviors); (ii) health communication perception competence (this category included two subcategories, namely health risk and crisis perception competence and communication audience perception competence); and (iii) practical competence of health communication (this category consisted of five subcategories, namely language expression competence, organizational and design competence, utilization of new media tools competence, communication content selection and processing competence, and professional skills). Conclusion: The theoretical model of health communication competence in this study provides a foundation for the involvement of physical education teachers in health communication work. It can serve as a reference for the development of both pre-service health education courses and in-service training systems for physical education teachers. Future research can expand the sample size and geographic coverage to further validate the applicability of the findings. Additionally, investigating the factors influencing the formation of the identified competencies is recommended.

Correlation of N30 somatosensory evoked potentials with spasticity and neurological function after stroke: A cross-sectional study.

OBJECTIVE: To test whether the presence of N30 somatosensory evoked potentials, generated from the supplementary motor area and premotor cortex, correlate with post-stroke spasticity, motor deficits, or motor recovery stage. DESIGN: A cross-sectional study. PATIENTS: A total of 43 patients with stroke hospitalized at Maoming People's Hospital, Maoming, China. METHODS: Forty-three stroke patients underwent neurofunctional tests, including Modified Ashworth Scale (MAS), Brunnstrom stage, manual muscle test and neurophysiological tests, including N30 somatosensory evoked potentials, N20 somatosensory evoked potentials, motor evoked potentials, H-reflex. The results were compared between groups. Correlation and regression analyses were performed as well. RESULTS: Patients with absence of N30 somatosensory evoked potential exhibited stronger flexor carpi radialis muscle spasticity (r = -0.50, p < 0.05) and worse motor function (r = 0.57, p < 0.05) than patients with presence of N30 somatosensory evoked potential. The generalized linear model (GLM) including both N30 somatosensory evoked potentials and motor evoked potentials (Akaike Information Criterion (AIC) = 121.99) better reflected the recovery stage of the affected proximal upper limb than the models including N30 somatosensory evoked potentials (AIC = 125.06) or motor evoked potentials alone (AIC = 127.45). CONCLUSION: N30 somatosensory evoked potential status correlates with the degrees of spasticity and motor function of stroke patients. The results showed that N30 somatosensory evoked potentials hold promise as a biomarker for the development of spasticity and the recovery of proximal limbs.

Possible mechanism of betel-quid-extract-induced expression of matrix metalloproteinase-2.

BACKGROUND/PURPOSE: Betel quid extract (BQE) has been demonstrated to induce matrix metalloproteinase (MMP)-2 expression. This study aimed to establish the possible mechanism involved in this event. METHODS: Western blotting, reverse-transcription polymerase chain reaction, and gelatin zymography were used to study the expression level of MMP-2. LY294002, PD98059, U0126, N-acetyl-L-cysteine, SB203580, SP600125, and Bay 11-7082 were used to pretreat OECM-1 cells before BQE treatment and MMP-2 detection. RESULTS: OECM-1 cells were subjected to short-term (10 minutes) or long-term (24 hours) BQE treatment (designated as SBT and LBT, respectively), and we found that both treatments increased MMP-2 protein and extracellular signal-regulated kinase (ERK) phosphorylation levels in a concentration- and time-dependent manner. LBT also increased MMP-2 mRNA level. LBT-induced MMP-2 secretion was not inhibited by PD98059 (up to 50 µM) when ERK was effectively blocked, but was attenuated by LY294002 (0-10 µM) in a concentration-dependent manner. This LBT effect was inhibited strongly by SB203580 (10 µM), SP600125 (10 µM), and Bay 11-7082 (10 µM) and mildly by N-acetyl-L-cysteine (5 mM), but not by U0126 (10 µM). CONCLUSION: Both SBT and LBT upregulate MMP-2 expression, and LBT-induced MMP-2 expression might be mediated by phosphoinositide 3-kinase, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-κB, and to a lesser extent, by reactive oxygen species, rather than by ERK.

LncRNA-ATB Promotes Cisplatin Resistance in Lung Adenocarcinoma Cells by Targeting the miR-200a/ß-Catenin Pathway.

INTRODUCTION: Lung adenocarcinoma (LUAD), which is associated with high morbidity and mortality, is prone to cisplatin resistance, resulting in poor patient prognosis. Long non-coding RNAs (lncRNAs) have complex biological functions in a variety of tumors. Elucidating the underlying molecular mechanisms between lncRNA and cisplatin resistance in LUAD is expected to enable identification of new targets for drug development. METHODS: Cell proliferation was measured by CCK-8 assay and cell apoptosis was detected using flow cytometry analysis. Luciferase reporter assay was conducted to determine the interaction between lncRNA and MicroRNA. Gene expression was evaluated by Real-Time Quantitative Reverse Transcription Polymerase Chain Reaction and Western blot analysis. RESULTS: Long non-coding RNA activated by TGF-ß (lncRNA-ATB) was shown to be significantly up-regulated in A549 cells resistant to cisplatin/cis-dichlorodiammineplatinum (II) (cis-DDP) (A549/CDDP cells), compared with corresponding levels in parental A549 cells. Overexpression of lncRNA-ATB significantly elevated cisplatin resistance in LUAD cell lines (A549 and H1975 cells), and this was associated with activation of apoptosis-related genes. Conversely, silencing of lncRNA-ATB decreased cisplatin resistance in LUAD cells. Mechanistically, lncRNA-ATB increased expression of ß-catenin by directly binding to MicroRNA-200a (miR-200a), thereby promoting cell survival and cisplatin resistance. Transfection with a miR-200a mimic or treatment with the ß-catenin downstream pathway inhibitor IWR-1 could reverse the phenotypes induced by lncRNA-ATB overexpression. CONCLUSION: In summary, this study revealed that lncRNA-ATB is dramatically up-regulated in cisplatin-resistant LUAD cell lines, and that lncRNA-ATB facilitates cell survival by targeting the miR-200a/ß-catenin pathway in these cells.

Effects of Exosomes on Neurological Function Recovery for Ischemic Stroke in Pre-clinical Studies: A Meta-analysis.

Background: Exosomes, especially stem cell-derived exosomes, have been widely studied in pre-clinical research of ischemic stroke. However, their pooled effects remain inconclusive. Methods: Relevant literature concerning the effects of exosomes on neurological performance in a rodent model of ischemic stroke was identified via searching electronic databases, including PubMed, Embase, and Web of Science. The primary outcomes included neurological function scores (NFS) and infarct volume (IV), and the secondary outcomes were several pro-inflammatory factors and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells. Subgroup analyses regarding several factors potentially influencing the effects of exosomes on NFS and IV were also conducted. Results: We identified 21 experiments from 18 studies in the meta-analysis. Pooled analyses showed the positive and significant effects of exosomes on NFS (standardized mean difference -2.79; 95% confidence interval -3.81 to -1.76) and IV (standardized mean difference -3.16; 95% confidence interval -4.18 to -2.15). Our data revealed that the effects of exosomes on neurological outcomes in rodent stroke models might be related to routes of administration and exosomes sources. In addition, there was significant attenuation in pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α and interleukin-1ß, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells when undergoing exosomes treatment. Conclusion: Cell-derived exosomes treatment demonstrated statistically significant improvements in structural and neurological function recovery in animal models of ischemic stroke. Our results also provide relatively robust evidence supporting cell-derived exosomes as a promising therapy to promote neurological recovery in stroke individuals.

Variation among 532 genomes unveils the origin and evolutionary history of a global insect herbivore.

The diamondback moth, Plutella xylostella is a cosmopolitan pest that has evolved resistance to all classes of insecticide, and costs the world economy an estimated US $4-5 billion annually. We analyse patterns of variation among 532 P. xylostella genomes, representing a worldwide sample of 114 populations. We find evidence that suggests South America is the geographical area of origin of this species, challenging earlier hypotheses of an Old-World origin. Our analysis indicates that Plutella xylostella has experienced three major expansions across the world, mainly facilitated by European colonization and global trade. We identify genomic signatures of selection in genes related to metabolic and signaling pathways that could be evidence of environmental adaptation. This evolutionary history of P. xylostella provides insights into transoceanic movements that have enabled it to become a worldwide pest.

The impact of cover crops on the predatory mite Anystis baccarum (Acari, Anystidae) and the leafhopper pest Empoasca onukii (Hemiptera, Cicadellidae) in a tea plantation.

BACKGROUND: Empoasca onukii, the tea green leafhopper, is a key pest of tea whose control often requires the extensive use of insecticides. As a predator of the tea green leafhopper, the mite Anystis baccarum is a potential biological control agent worldwide, though little is known about how intercropping cover crops can impact its suppressing effect on E. onukii. Therefore, we conducted a field experiment to investigate how the relationship of the abundance of the predatory mite and its leafhopper prey is influenced by two different cover crops and a manually weeded inter-row treatment as a contrast to naturally growing vegetation in a tea plantation in China. RESULTS: The abundance of A. baccarum was significantly higher in tea canopies of intercropped treatments than in canopies over natural ground cover. Litter samples showed higher abundances of A. baccarum when tea was intercropped with Paspalum notatum than with natural ground cover in the first year of treatment. The abundance of E. onukii in tea canopies was higher over the bare ground treatment in the first year but the opposite was observed in the second year. CONCLUSIONS: Results suggest that the abundance of A. baccarum in a tea plantation is influenced by intercropping and it can affect its leafhopper prey, albeit with varying levels of suppression. For informing biological control and suppression of pests, long-term experiments are needed to investigate the interactions of both pest and predator with cover crop treatments. © 2019 Society of Chemical Industry.