The Impact of PCSK9 Gene Polymorphisms on Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are known to be associated with susceptibility to several cerebrovascular diseases, including ischemic stroke (IS). The aims of this study was to evaluate associations between PCSK9 gene polymorphisms and the risk of IS. Based on previous reports linking PCSK9 SNPs to plasma lipid levels and to atherosclerosis, and to inconsistencies in the reported associations between the SNPs, plasma lipid levels and IS risk, we choose the PCSK9 rs505151, rs529787, and rs17111503 to performe the association analysis. METHODS: Using multiple databases, all relevant case-control and cohort studies that matched our search criteria were collected. Quality assessment of included studies was performed using the Newcastle-Ottawa Scale. Demographic and genotype data were extracted from each study, and meta-analysis was performed using Stata/MP 17.0. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed and random effects models. RESULTS: A critical evaluation was conducted on ten case-control studies, involving a total of 2426 cases and 2424 controls. Pooled results from the allelic models indicated the PCSK9 rs505151 G allele (OR: 1.41, 95% CI: 1.06-1.87, p = 0.019, I2 = 53.9%) and the PCSK9 rs17111503 A allele (OR: 1.38, 95% CI: 1.22-1.55, p < 0.001, I2 = 43.5%) were significantly associated with IS. Study qualities ranged from moderate (n = 4) to good (n = 6). Begg's and Egger's tests results indicated there was no evidence of publication bias in the findings (p > 0.05). CONCLUSIONS: This meta-analysis demonstrated that G allele variant of PCSK9 rs505151 and A allele variant of PCSK9 rs17111503 were associated with an increased risk of IS. Based on our findings, these SNPs could serve as potential targets for the diagnosis and treatment of IS. The integration of information on genetic polymorphism into IS risk prediction model may be beneficial in routine clinical practice.

Neoadjuvant Immune Checkpoint Inhibition Improves Organ Preservation in T4bM0 Colorectal Cancer With Mismatch Repair Deficiency: A Retrospective Observational Study.

BACKGROUND: Colorectal cancer with mismatch repair deficiency is usually less aggressive and associated with a lower risk of distant metastasis. Immune checkpoint inhibition, rather than traditional chemoradiotherapy, has shown great advantages in treating such patients. OBJECTIVE: This study aimed to verify the hypothesis that locally very advanced (T4b) colorectal cancer without distant metastases might present with higher probability of mismatch repair deficiency and be more sensitive to neoadjuvant immune checkpoint inhibition. DESIGN: This study was designed as a single-center retrospective observational study. SETTINGS: The study was conducted in a tertiary referral center in China. PATIENTS: The study included patients who were clinically diagnosed with T4bM0 colorectal cancer from 2008 to 2019. MAIN OUTCOME MEASURES: Clinicopathological characteristics, mismatch repair status, and survival outcomes of patients with mismatch repair deficiency were analyzed. RESULTS: A total of 268 patients were included. The incidence of patients with mismatch repair deficiency in the T4bM0 population was 27.6% (75/268), with 84.0% (63/75) in the colon and 16.0% (12/75) in the rectum. For tumors located in the proximal colon, 45.0% (50/111) exhibited mismatch repair deficiency, whereas the incidence of mismatch repair deficiency in sigmoid colon cancer and rectal cancer was only 15.9% (25/157). Neoadjuvant immune checkpoint inhibition significantly reduced the open surgery rate ( p = 0.000) and multivisceral resection rate ( p = 0.025). The pathological complete remission rate in the neoadjuvant immune checkpoint inhibition group was significantly higher than that in neoadjuvant chemoradiotherapy/chemotherapy group (70.0% vs 0%; p = 0.004). No tumor downstaging was observed after neoadjuvant chemotherapy. Neoadjuvant immune checkpoint inhibition provided significantly better disease-free survival ( p = 0.0078) and relatively longer overall survival ( p = 0.15) than other groups. LIMITATIONS: This study is limited by the possible selection bias and small sample size. CONCLUSIONS: Our data depicted the high incidence of mismatch repair deficiency in T4bM0 mismatch repair deficiency and the effectiveness of the neoadjuvant immune checkpoint inhibition group in organ preservation. Precision oncology requires identification of the protein status of mismatch repair at initial diagnosis to make a rational treatment decision for these patients. See Video Abstract at http://links.lww.com/DCR/B952 . LA INHIBICIN DEL PUNTO DE CONTROL INMUNITARIO NEOADYUVANTE MEJORA LA PRESERVACIN DE RGANOS EN EL CNCER COLORRECTAL TBM CON DEFICIENCIA DE REPARACIN DE ERRORES DE COINCIDENCIA UN ESTUDIO OBSERVACIONAL RETROSPECTIVO: ANTECEDENTES:Los pacientes con cáncer colorrectal con deficiencia en la reparación de desajustes suelen (dMMR) ser menos agresivos y se asocian con un menor riesgo de metástasis a distancia. La inhibición del punto de control inmunitario, en lugar de la quimiorradioterapia tradicional, ha mostrado grandes ventajas en el tratamiento de estos pacientes.OBJETIVO:Este estudio tuvo como objetivo verificar nuestra hipótesis de que el CCR localmente muy avanzado (T4b) sin metástasis a distancia podría presentarse con una mayor probabilidad de dMMR y ser más sensible a la inhibición del punto de control inmunitario neoadyuvante.DISEÑO:Este estudio fue diseñado como un estudio observacional retrospectivo de un solo centro.CONFIGURACIÓN:El estudio se realizó en un centro de referencia terciario en China.PACIENTES:Se incluyeron pacientes con diagnóstico clínico de CCR T4bM0 desde 2008 hasta 2019.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron las características clinicopatológicas, el estado de MMR y los resultados de supervivencia de los pacientes con dMMR.RESULTADOS:Se incluyeron un total de 268 pacientes. La incidencia de dMMR en la población T4bM0 fue del 27,6% (75/268), con un 84,0% (63/75) en colon y un 16,0% (12/75) en recto. Para los tumores ubicados en el colon proximal, el 45,0% (50/111) exhibió dMMR, mientras que la incidencia de dMMR en el cáncer de colon sigmoideo y el cáncer de recto fue solo del 15,9% (25/157). La inhibición del punto de control inmunitario neoadyuvante redujo significativamente la cirugía abierta y la tasa de resección multivisceral ( p = 0,000 y p = 0,025, respectivamente). La tasa de PCR en el grupo de inhibición del punto de control inmunitario neoadyuvante fue significativamente mayor que en el grupo de quimiorradioterapia/quimioterapia neoadyuvante (70,0% frente a 0%, p = 0,004). No se observó reducción del estadio del tumor después de la quimioterapia neoadyuvante. La inhibición del punto de control inmunitario neoadyuvante proporcionó una supervivencia sin enfermedad significativamente mejor ( p = 0,0078) y una supervivencia general relativamente más larga ( p = 0,15) que otros grupos.LIMITACIONES:Este estudio está limitado por el posible sesgo de selección y el pequeño tamaño de la muestra.CONCLUSIONES:Nuestros datos representan la alta incidencia de dMMR en T4bM0 CRC y la eficacia del grupo de inhibición del punto de control inmunitario neoadyuvante en la preservación de órganos. La oncología de precisión requiere la identificación del estado de la proteína MMR en el diagnóstico inicial para tomar una decisión de tratamiento racional para estos pacientes especiales. Consulte el Video Resumen en http://links.lww.com/DCR/B952 . (Traducción-Dr. Yesenia Rojas-Khalil ).

Extracellular vesicles: a rising star for therapeutics and drug delivery.

Extracellular vesicles (EVs) are nano-sized, natural, cell-derived vesicles that contain the same nucleic acids, proteins, and lipids as their source cells. Thus, they can serve as natural carriers for therapeutic agents and drugs, and have many advantages over conventional nanocarriers, including their low immunogenicity, good biocompatibility, natural blood-brain barrier penetration, and capacity for gene delivery. This review first introduces the classification of EVs and then discusses several currently popular methods for isolating and purifying EVs, EVs-mediated drug delivery, and the functionalization of EVs as carriers. Thereby, it provides new avenues for the development of EVs-based therapeutic strategies in different fields of medicine. Finally, it highlights some challenges and future perspectives with regard to the clinical application of EVs.

[Exploration on mechanism of Polygalae Radix and Acori Tatarinowii Rhizoma in treating Alzheimer's disease based on network pharmacology and experimental verification].

This study aimed to explore the action targets and mechanisms of Polygala tenuifolia and Acorus tatarinowii in treating Alzheimer's disease(AD) based on network pharmacology, molecular docking, and animal tests. The AD-related targets were collec-ted from GeneCard and the main active ingredients and targets of P. tenuifolia and A. tatarinowii from the TCMSP. Cytoscape was applied to construct the "Chinese herb-active ingredient-target-disease" network, followed by the construction of protein-protein interaction(PPI) network using STRING. GO biological function and KEGG pathway enrichment analysis was performed by DAVID and Metascape. The main active components of P. tenuifolia and A. tatarinowii and their potential core targets were docking using AutoDock Vina. The effects of P. tenuifolia and A. tatarinowii on the cognitive function were verified in mice with scopolamine(SCOP)-induced cognitive impairment. A total of seven active ingredients including kaempferol, onjixanthone Ⅰ, and marmesin and 56 potential targets of P. tenuifolia and A. tatarinowii were screened out, with the core targets covering AKT1, PTGS2, TNF, and NF-κB inflammation pathway mainly involved. The results of molecular docking also showed that the main active components of P. tenuifolia and A. tatarinowii stably bond to the core targets predicted by network pharmacology. The new object recognition experiment suggested that P. tenuifolia and A. tatarinowii improved the learning and memory abilities of mice after SCOP induction. As revealed by pathological section observation and relevant kit assay, P. tenuifolia and A. tatarinowii reduced the damage of central cholinergic neurons and enhanced the antioxidant ability of SCOP-induced mice. Western blot confirmed that P. tenuifolia and A. tatarinowii down-regulated the protein expression levels of TLR4, NF-κB, and related inflammatory factors(TNF-α, IL-1ß, and IL-6). All these have suggested that P. tenuifolia and A. tatarinowii inhibits AD via multiple components, multiple targets, and multiple pathways, which has provided an experimental basis for the clinical application of P. tenuifolia and A. tatarinowii for the treatment of AD.

From Esters to Ketones via a Photoredox-Assisted Reductive Acyl Cross-Coupling Strategy.

A method was developed for ketone synthesis via a photoredox-assisted reductive acyl cross-coupling (PARAC) using a nickel/photoredox dual-catalyzed cross-electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°-alkyl 2-pyridyl esters can act as acyl electrophiles while N-(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°-radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°-3°, 3°-2°, and aryl-3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0 /NiI /NiIII pathway for ketone formation.

Current Status of Endovascular Treatment for Acute Large Vessel Occlusion in China: A Real-World Nationwide Registry.

BACKGROUND AND PURPOSE: The benefit of endovascular treatment (EVT) for large vessel occlusion in clinical practice in developing countries like China needs to be confirmed. The aim of the study was to determine whether the benefit of EVT for acute ischemic stroke in randomized trials could be generalized to clinical practice in Chinese population. METHODS: We conducted a prospective registry of EVT at 111 centers in China. Patients with acute ischemic stroke caused by imaging-confirmed intracranial large vessel occlusion and receiving EVT were included. The primary outcome was functional independence at 90 days defined as a modified Rankin Scale score of 0 to 2. Outcomes of specific subgroups in the anterior circulation were reported and logistic regression was performed to predict the primary outcome. RESULTS: Among the 1793 enrolled patients, 1396 (77.9%) had anterior circulation large vessel occlusion (median age, 66 [56-73] years) and 397 (22.1%) had posterior circulation large vessel occlusion (median age, 64 [55-72] years). Functional independence at 90 days was reached in 45% and 44% in anterior and posterior circulation groups, respectively. For anterior circulation population, underlying intracranial atherosclerotic disease was identified in 29% of patients, with higher functional independence at 90 days (52% versus 44%; P=0.0122) than patients without intracranial atherosclerotic disease. In the anterior circulation population, after adjusting for baseline characteristics, procedure details, and early outcomes, the independent predictors for functional independence at 90 days were age <66 years (odds ratio [OR], 1.733 [95% CI, 1.213-2.476]), time from onset to puncture >6 hours (OR, 1.536 [95% CI, 1.065-2.216]), local anesthesia (OR, 2.194 [95% CI, 1.325-3.633]), final modified Thrombolysis in Cerebral Infarction 2b/3 (OR, 2.052 [95% CI, 1.085-3.878]), puncture-to-reperfusion time ≤1.5 hours (OR, 1.628 [95% CI, 1.098-2.413]), and National Institutes of Health Stroke Scale score 24 hours after the procedure <11 (OR, 9.126 [95% CI, 6.222-13.385]). CONCLUSIONS: Despite distinct characteristics in the Chinese population, favorable outcome of EVT can be achieved in clinical practice in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03370939.

The microstructure and property of Al-Si alloy improved by the Sc-microalloying and Y2O3 nano-particles.

The effect of Sc-microalloying and Y2O3 nano-particles on the microstructure and mechanical properties of as-cast Al-5.5Si alloy is studied by means of optical microscopy, transmission electron microscopy, hardness test and tensile test. The influence of annealing treatment on the microstructure and properties of the Al-Si alloys is also investigated as well. The results show that the addition of Sc and Y2O3 nano-particles could significantly improve the mechanical property of the Al-Si alloy. The ultimate tensile strength and yield strength of Al-Si-Sc/Y2O3 alloy are improved by around 45 and 71%, respectively, when compared to that of the Al-Si alloy. The effect of the nanosized particles (precipitated and added) on strengthening and deformation of Al-Si alloy is analyzed and discussed in detail. The results of annealing treatment indicate that the change in mechanical property of the Al-Si-Sc alloy during annealing treatment is mainly associated with the precipitation of the secondary Si phase.

Selective 1,2-Aryl-Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis.

A highly chemo- and regioselective intermolecular 1,2-aryl-aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three-component conjunctive cross-coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α-silyl amines could be transferred to α-amino radicals by photo-induced single electron transfer step. The radical addition/cross-coupling cascade reaction proceeds under mild, base-free and redox-neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α-aryl substituted γ-amino acid derivatives motifs.

Effect of short-term blood pressure variability on functional outcome after intra-arterial treatment in acute stroke patients with large-vessel occlusion.

BACKGROUND: Endovascular treatment (EVT) is advocated for acute ischaemic stroke with large-vessel occlusion (LVO), but perioperative periods are challenging. This study investigated the relationship between post-EVT short-term blood pressure variability (BPV) and early outcomes in LVO patients. METHODS: We retrospectively reviewed 72 LVO patients undergoing EVT between June 2015 and June 2018. Hourly systolic and diastolic blood pressures (SBP and DBP, respectively) were recorded in the first 24 h post-EVT. BPV were evaluated as standard deviation (SD), coefficient of variation (CV), and successive variation (SV) separately for SBP and DBP. Functional independence at 3 months was defined as a modified Rankin Scale (mRS) score of 0-2. RESULTS: For 58.3% patients with favorable outcomes, the median National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT scores on admission were 14 and 8, respectively. The maximum SBP ([154.3 ± 16.8] vs. [163.5 ± 15.6], P = 0.02), systolic CV ([8. 8% ± 2.0%] vs. [11.0% ± 1.8], P < 0.001), SV ([11.4 ± 2.3] vs. [14.6 ± 2.0], P < 0.001), and SD ([10.5 ± 2.4] vs. [13.8 ± 3.9], P < 0.001) were lower in patients with favorable outcomes. On multivariable logistic regression analysis, systolic SV (OR: 4.273, 95% CI: 1.030 to 17.727, P = 0.045) independently predicted unfavorable prognosis. The area under the curve was 0.868 (95% CI: 0.781 to 0.955, P < 0.001), and sensitivity and specificity were 93.3% and 73.8%, respectively, showing excellent predictive value for 3-month poor-outcomes. CONCLUSIONS: Decreased systolic SV following intra-arterial therapies result in favorable outcomes at 3 months. Systolic SV may be a novel predictor of functional prognosis in LVO patients.

Clustering of unhealthy lifestyle behaviours and associations with perceived and actual weight status among primary school children in China: A nationally representative cross-sectional study.

Few studies have focused on clustering of unhealthy lifestyle behaviours among primary school children and potential associations with perceived and actual weight status. An index was constructed from adding up 13 unhealthy behaviours measured by survey responses. Multilevel linear regressions were used to analyse associations between child personal characteristics, perceived and actual weight status with the unhealthy lifestyle index among 11,157 children in primary schools across China. Parental and area factors were also taken into account, including education, weight status, physical activity, urban/rural and area socioeconomic circumstances. The unhealthy lifestyle index normally distributed, with 84.5% of children reporting between 2 and 6 unhealthy behaviours. Boys reported more unhealthy behaviours compared with girls (coefficient 0.32, 95%CI 0.26 to 0.37) and children in urban areas had fewer unhealthy behaviours than their rural counterparts (-0.29, 95%CI -0.56 to -0.03). An interaction revealed stronger 'protective' effects of living in cities for girls than boys, which were not explained by differences in child overweight/obesity. More unhealthy behaviours were characteristic of children in more affluent areas, and of those born to mothers and/or fathers with lower educational attainment. Children who perceived themselves as overweight or underweight both scored higher on the unhealthy lifestyle index. Unhealthy behaviours that could increase the risk of childhood obesity are common among Chinese primary school children, particularly among boys in cities, those in more affluent areas and with parents with lower education. There was no effect of actual weight status on number of unhealthy behaviours. Perceived, but not actual weight status, was also a significant correlate of unhealthy behaviours. Clustering of unhealthy lifestyle behaviours that could increase the risk of childhood obesity are common among Chinese primary school children, particularly among boys in cities, those in more affluent areas and with parents with lower education. Perceived, but not actual weight status, was also a significant correlate of unhealthy lifestyle. This has important implications for public health because understanding clustering of unhealthy lifestyle behaviours can be used to assist in the development of targeted obesity prevention initiatives.

Pharmacokinetic and Pharmacodynamic Properties of Rosmarinic Acid in Rat Cholestatic Liver Injury.

The objective of this study was to evaluate the hepatoprotective and metabolic effects of rosmarinic acid (RA) in rats. RA [100 mg/kg body weight (BW)] was intragastrically (i.g.) administered to Sprague-Dawley (SD) rats once a day for seven consecutive days. The rats were then i.g. administered α-naphthylisothiocyanate (ANIT) (80 mg/kg once on the 5th day) to induce acute intrahepatic cholestasis after the last administration of RA. Blood samples were collected at different time points (0.083 h, 0.17 h, 0.33 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 20 h) after administration, and the levels of RA were estimated by HPLC. Plasma and bile biochemical analysis, bile flow rate, and liver histopathology were measured to evaluate the hepatoprotective effect of RA. The PK-PD curves showed obviously clockwise (AST and ALT) or anticlockwise (TBA, TBIL). Pretreatment with RA at different doses significantly restrained ANIT-induced pathological changes in bile rate, TBA, TBIL, ALT, AST (p < 0.05 or p < 0.01). The relationship between RA concentration and its hepatoprotective effects on acute cholestasis responses was assessed by PK-PD modeling.

Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia, hyperlipidemia and hypertension in a rat model of the metabolic syndrome.

BACKGROUND: Modified Lingguizhugan Decoction (MLD) came from famous Chinese medicine Linggui Zhugan Decoction. The MLD is used for the treatment of metabolic syndrome in the clinical setting. Our study focuses on the comprehensive treatment of MLD incorporated with dietary restriction and exercise in a rat model of the metabolic syndrome (MS). METHODS: Rats were divided into five groups: control group (Cont), high-fat diet group (HFD), high-fat diet incorporated with dietary restriction group (HFD-DR), exercise incorporated with dietary restriction group (HFD-DR-Ex) and MLD incorporated with dietary restriction and exercise group (HFD-DR-Ex-MLD). Treatments were conducted for 1 week after feeding high-fat diet for 12 weeks. The effects of treatments on high fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance in rats of MS were examined. In addition, the tumor necrosis factor-α (TNF-α), leptin and protein kinase B (PKB) in rats serum and liver were also examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: After a week's intervention by dietary restriction, dietary restriction incorporated with exercise or MLD, compared with HFD rats, the relative weight of liver and fat, levels of triglyceride, total cholesterol, low-density lipoprotein, free fatty acid, aspartate aminotransferase, glutamic-pyruvic transaminase and alkaline phosphatase, insulin, were significantly decreased (p < 0.05 or 0.01). This treatment also inhibited abnormal increases of TNF-α, leptin and PKB in serum and liver. CONCLUSION: MLD incorporated with dietary restriction and exercise treatment exhibit effects in alleviating high-fat diet-induced obesity, hyperglycemia, hyperlipidemia, hypertension, hepatic injury and insulin resistance, which are possibly due to the down-regulation of TNF-α, leptin and PKB.

The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage.

Shuanghuanglian injection (SHLI) has been widely used for administration with cephalosporin in China for long time. The objective of this study was to evaluate the pharmacological properties and biochemical changes of cefepime combined with SHLI. The SD rats included were received either an intravenous (iv. 4 mL/kg) dose of normal saline, or intravenous (iv. 0.74, 0.37, 0.185 g/kg, respectively) doses of SHLI once daily for 7 days. After last administration, cefepime (0.41 g/kg) was intravenous injected to the animals. The serum and urine samples were acquired and stored at 4 °C. They were used for quantitative determination of urea nitrogen (BUN), creatinine (CRE), urine protein, alkaline phosphatase (ALP) and N-acetyl-B-d-glucosaminidase (NAG). At different time points, the levels of cefepime in rat plasma were estimated for pharmacokinetic measures by HPLC. Aspirin was selected as internal standard (IS). The results showed that there were positive effects by increasing the total amount of CRE, BUN, NAG and urine protein (p < 0.01 or <0.05) and decreasing the levels of ALP (especially the high dose group of SHLI with cefepime) (p < 0.01). Besides, the pharmacokinetic results indicated that cefepime was distributed as non-compartment model after intravenous administration. Compared with the corresponding values for the compounds given alone, the area under the blood drug concentration time curve (AUC0-t and AUC0-∞) was better increased in middle- and high-dose groups (pall < 0.01), the mean residence time (MRT) of cefepime was larger (pall < 0.01) and the total clearance (CL) was lower at different levels. The results mean that the duration and concentration of cefepime could be prolonged and the clearance reduced while in combination with SHLI. Furthermore, the cefepime in the three tested doses caused changes of renal tubular epithelial cells while the severity of changes mainly dependent on the specific doses. In conclusion, the results above-mentioned suggest a possible contribution of drug combination in the nephrotoxicity and biochemical alterations especially at high doses. Further, monitoring measures for the renal functions are warranted to evaluate during the combination of these two drugs.

Structural insights into the unusually strong ATPase activity of the AAA domain of the Caenorhabditis elegans fidgetin-like 1 (FIGL-1) protein.

The FIGL-1 (fidgetin like-1) protein is a homolog of fidgetin, a protein whose mutation leads to multiple developmental defects. The FIGL-1 protein contains an AAA (ATPase associated with various activities) domain and belongs to the AAA superfamily. However, the biological functions and developmental implications of this protein remain unknown. Here, we show that the AAA domain of the Caenorhabditis elegans FIGL-1 protein (CeFIGL-1-AAA), in clear contrast to homologous AAA domains, has an unusually high ATPase activity and forms a hexamer in solution. By determining the crystal structure of CeFIGL-1-AAA, we found that the loop linking helices α9 and α10 folds into the short helix α9a, which has an acidic surface and interacts with a positively charged surface of the neighboring subunit. Disruption of this charge interaction by mutagenesis diminishes both the ATPase activity and oligomerization capacity of the protein. Interestingly, the acidic residues in helix α9a of CeFIGL-1-AAA are not conserved in other homologous AAA domains that have relatively low ATPase activities. These results demonstrate that the sequence of CeFIGL-1-AAA has adapted to establish an intersubunit charge interaction, which contributes to its strong oligomerization and ATPase activity. These unique properties of CeFIGL-1-AAA distinguish it from other homologous proteins, suggesting that CeFIGL-1 may have a distinct biological function.

Association of children's eating behaviors with parental education, and teachers' health awareness, attitudes and behaviors: a national school-based survey in China.

BACKGROUND: In China, childhood obesity is a growing health issue. Eating behaviors among children can be influenced by both the family and school environment. We examine the association between these environments and eating habits among children. METHODS: A total of 11 270 fourth to sixth grade school children, 11 270 of their fathers or mothers, and 1348 teachers from 48 schools were sampled using a multistage cluster random sampling method. Questionnaires collected information on eating behaviors among children, non-communicable chronic disease (NCD)-related health knowledge and behaviors among teachers, and education levels among parents. Mixed effect logistic regression models were used to describe the key associations between eating behaviors among children and teacher and parental characteristics. RESULTS: Health awareness, positive health attitudes, never-smoking and regular-exercise among teachers was positively associated with healthy eating behaviors among their students (having breakfast, vegetables and dairy products every day; P < 0.05), and negatively associated with the unhealthy behaviors (daily intake of fried foods and desserts and sugary beverages; P < 0.05). More than one parent having a high school level or above was positively related to healthy eating behaviors among their children (P < 0.05), but its associations with high-calorie eating habits were negative in urban and positive in rural areas (P < 0.05). CONCLUSIONS: School-based interventions which target health-related awareness, attitude and behaviors among school teachers may help improve school-aged children's eating behaviors. Parental education levels may help guide efforts to target children at higher risk of unhealthy eating habits.

Toxicity of Evodiae fructus on rat liver mitochondria: the role of oxidative stress and mitochondrial permeability transition.

Evodiae fructus (EF) has been used in China for thousands of years as an analgesic, antiemetic, anti-inflammatory and antidiarrheal drug. EF is a toxic drug and causes hepatotoxicity in humans. Although recent chronic toxicity studies performed on aqueous extract of EF has revealed that it can produce obvious cumulative hepatotoxicity, the mechanism behind this toxicity is still uncertain. In the present study, we investigated the influence of EF on oxidative stress, mitochondrial permeability transition, adenosine triphosphate (ATP), and cytochrome C release of hepatic mitochondria. Rats were divided into four groups and fed distilled water, 6, 12, 24 g/kg of aqueous extract of EF daily for 15 days. Evodiamine, rutaecarpine and evodine were quantified in the aqueous extract by high performance liquid chromatography with ultraviolet detection (HPLC/UV). The results showed that aqueous extract of EF could significantly (p < 0.05) decrease MnSOD levels to 56.50%, 46.77% and 19.67% of control group, GSH level was decreased to 74.24%, 53.97% and 47.91% of control group and MDA level was increased to 131.55%, 134.34% and 150.81% of control group in the 6, 12 and 24 g/kg groups, respectively; extract also induced mitochondria swelling, vacuolation, MPT pore opening and a significant decrease (p < 0.05) in mitochondrial potential, while ATP levels were significant decreased (p < 0.05) to 65.24%, 38.08% and 34.59% of control group in the 6, 12 and 24 g/kg groups, respectively, resulting in ATP depletion and CytC release, finally trigger cell death signaling, which are the partial hepatotoxicity mechanisms of EF.

Differential expression of serum miR-126, miR-141 and miR-21 as novel biomarkers for early detection of liver metastasis in colorectal cancer.

OBJECTIVE: MicroRNAs (miRNAs) have potential as diagnostic biomarkers in cancer. Evaluation of the association between miRNA expression patterns and early detection of liver metastasis in colorectal cancer (CRC) has not been reported. METHODS: We investigated the expression of metastasis-associated miRs-31, 335, 206, 141, 126, 200b, 200c, 21, Let7a, Let7b and Let7c in localized, liver-metastatic and other organ-metastatic CRC (OM-CRC). Expressions of target miRNAs in serum were evaluated in 116 consecutive localized CRC (L-CRC), 72 synchronous liver-metastatic CRC (SLM-CRC) and 36 other OM-CRC by quantitative real-time PCR. RESULTS: Seven of 11 tested miRNAs could be detected from serum. Four miRNAs, miR-126, Let-7a, miR-141 and miR-21 were identified as metastasis-associated miRNAs. Compared with L-CRC, significant up-regulated expression was observed for miR-141 and miR-21 in SLM-CRC and OM-CRC, down-regulated expression was observed for miR-126 in SLM-CRC and OM-CRC, and up-regulated expression of Let-7a in OM-CRC. The receiver operating characteristic (ROC) curve showed serum miR-126 had a cut-off [log10 relative quantity (log10 (RQ))=-0.2005] with 77.78% sensitivity and 68.97% specificity with an area under curve (AUC) of 0.7564, miR-141 had a cut-off (log10 (RQ)=-0.2285) with 86.11% sensitivity and 76.11% specificity with an AUC of 0.8279, and miR-21 had a cut-off (log10 (RQ)=-0.1310) with 73.61% sensitivity and 66.38% specificity with an AUC of 0.7479. CONCLUSIONS: We identified liver metastasis-associated miRNAs, suggesting serum miR-126, miR-141 and miR-21 may be novel biomarkers for clinical diagnosis of early stage liver-metastatic CRC.

Penalized robust learning for optimal treatment regimes with heterogeneous individualized treatment effects.

The growing popularity of personalized medicine motivates people to explore individualized treatment regimes according to heterogeneous characteristics of the patients. For the large-scale data analysis, however, the data are collected at different times and different locations, i.e. subjects are usually from a heterogeneous population, which causes that the optimal treatment regimes also vary for patients across different subgroups. In this paper, we mainly focus on the estimation of optimal treatment regimes for subjects come from a heterogeneous population with high-dimensional data. We first remove the main effects of the covariates for each subgroup to eliminate non-ignorable residual confounding. Based on the centralized outcome, we propose a penalized robust learning that estimates the coefficient matrix of the interactions between covariates and treatment by penalizing pairwise differences of the coefficients of any two subgroups for the same covariate, which can automatically identify the latent complex structure of the coefficient matrix with heterogeneous and homogeneous columns. At the same time, the penalized robust learning can also select the important variables that truly contribute to the individualized treatment decisions with commonly used sparsity structure penalty. Extensive simulation studies show that our proposed method outperforms current popular methods, and it is further illustrated in the real analysis of the Tamoxifen breast cancer data.

Meniscal Allograft versus Synthetic Graft in Treatment Outcomes of Meniscus Repair: A Mini-review and Meta-analysis.

Meniscal injuries are highly correlated with osteoarthritis (OA) onset and progression. Although meniscal allograft transplantation (MAT) is a therapeutic option to restore meniscal anatomy, a shortage of donor material and the donor-derived infectious risk may be concerns in clinics. This review summarizes the literature reporting meniscus repair status in preclinical models and clinical practice using allografts or synthetic grafts. The advantages and limitations of biodegradable polymer-based meniscal scaffolds, applied in preclinical studies, are discussed. Then, the long-term treatment outcomes of patients with allografts or commercial synthetic scaffolds are compared. A total of 47 studies are included in our network meta-analysis. Compared with the meniscal allografts, the commercial synthetic products significantly improved clinical treatment outcomes in terms of the Knee Injury and Osteoarthritis Outcome Score (KOOS), Visual Analog Scale (VAS) scores, and Lysholm scores. In addition, development strategies for the next generation of novel synthetic scaffolds are proposed through optimization of structural design and fabrication, and selection of cell sources, external stimuli, and active ingredients. This review may inspire researchers and surgeons to design and fabricate clinic-orientated grafts with improved treatment outcomes.

A magnesium screw with optimized geometry exhibits improved corrosion resistance and favors bone fracture healing.

Stress-induced corrosion impairs the mechanical integrity of magnesium (Mg) and its alloys as potential orthopedic implants. Although there has been extensive work reporting the effects of stress on Mg corrosion in vitro, the geometric design principles of the Mg-based orthopedic devices still remain largely unknown. In this work, a numerical simulation model mimicking fractured bone fixation and surgical animal models were applied to investigate the effects of the geometric design of Mg screws on the stress distribution and the stress-induced degradation behavior. Finite element (FE) analysis was used for calculation of stress concentrations around the Mg screws, with different thread type, thread pitch, and thread width. Afterward, the Mg screws of the pre-optimization and post-optimization groups exhibiting the highest and lowest stress concentrations, respectively, were implanted in the fractured distal femora and back subcutaneous tissue of rabbits. Encouragingly, there was a significant difference between the pre-optimization and the post-optimization groups in the degradation rate of the stressed screw parts located around the fracture line. Interestingly, there was no significant difference between the two groups in the degradation rate of the non-stressed screw parts. Consistently, the Mg screw post-optimization exhibited a significantly lower degradation rate than that pre-optimization in the back subcutaneous implantation model, which generated stress in the whole screw body. The alteration in geometric design did not affect the corrosion rate of the Mg screws in an immersion test without load applied. Importantly, an accelerated new bone formation with less fibrous encapsulation around the screws was observed in the Mg group post-optimization relative to the Mg group pre-optimization and the poly (lactic acid) group. Geometry optimization may be a promising strategy to reduce stress-induced corrosion in Mg-based orthopedic devices. STATEMENT OF SIGNIFICANCE: Stress concentrations influence corrosion characteristics of magnesium (Mg)-based implants. The geometric design parameters, including thread type, thread pitch, and thread width of the Mg screws, were optimized through finite element analysis to reduce stress concentrations in a fractured model. The Mg screws with triangular thread type, 2.25 mm pitch, and 0.3 mm thread width, exhibiting the lowest maximum von Mises stress, showed a significant decrease in the volume loss relative to the Mg screws pre-optimization. Compared with the Mg screw pre-optimization and the poly(lactic acid) screw, the Mg screw post-optimization favored new bone formation while inhibiting fibrous encapsulation. Collectively, optimization in the geometric design is a promising approach to reduce stress-induced corrosion in Mg-based implants.