Maladaptive Neuroplasticity in Corticospinal Tract after Ankle Sprain: Causal Links Established by Mendelian Randomization.

PURPOSE: It has been hypothesized that the corticospinal tract (CST) is involved in the neural origins underlying muscular deficits after an ankle sprain. Microstructural differences in the CST have been reported in patients with and without a history of ankle sprain, but the causal links between the CST and the injuries have not been verified. This study aimed to explore whether genetically predisposed ankle sprains would impair the integrity and organization of CST neurites, manifesting as reduced fractional anisotropy (FA) and increased orientation dispersion index (ODI). METHODS: Single-nucleotide polymorphisms (SNP) associated with ankle sprains were identified from genome-wide association studies (GWAS) in FinnGen based on hospital discharge records (7223 cases and 245,598 controls). Outcome statistics for CST microstructures were collected from the GWAS from diffusion-weighted-imaging outcomes in the UK Biobank (33,224 participants). Random-effect, inverse-variance weighted Mendelian randomization was used as the primary method. RESULTS: Eighteen SNP were selected as forming possible causal links between ankle sprains and CST structure; F value ranged from 755 to 1026. Ankle sprains were associated with a reduction in the FA of the right CST ( ß = -0.033, P = 0.0439), whereas no significant effects were observed on the left side ( ß = -0.029, 0.004; P = 0.0748). Ankle sprains significantly increased the ODI of the left CST ( ß = 0.053, P = 0.0036) and the right CST ( ß = 0.038, P = 0.0259). No significant pleiotropy or heterogeneity was observed in the analyses. CONCLUSIONS: A genetic predisposition to ankle sprains can lead to maladaptive neuroplasticity of the CST, manifesting as abnormally organized neurites.

Why are Women More Religious than Men? Do Risk Preferences and Genetic Risk Predispositions Explain the Gender Gap?

Risk preference theory argues that the gender gap in religiosity is caused by greater female risk aversion. Although widely debated, risk preference theory has been inadequately tested. Our study tests the theory directly with phenotypic and genetic risk preferences in three dimensions-general, impulsive, and sensation-seeking risk. Moreover, we examine whether the effect of different dimension of risk preference on the gender gap varies across different dimensions of religiosity. We find that general and impulsive risk preferences do not explain gender differences in religiosity, whereas sensation-seeking risk preference makes the gender gap in self-assessed religiousness and church attendance insignificant, but not belief in God, prayer, or importance of religion. Genetic risk preferences do not remove any of the gender gaps in religiosity, suggesting that the causal order is not from risk preference to religiosity. Evidence suggests that risk preferences are not a strong predictor for gender differences in religiosity.

Partition-based ultrahigh-dimensional variable screening.

Traditional variable selection methods are compromised by overlooking useful information on covariates with similar functionality or spatial proximity, and by treating each covariate independently. Leveraging prior grouping information on covariates, we propose partition-based screening methods for ultrahigh-dimensional variables in the framework of generalized linear models. We show that partition-based screening exhibits the sure screening property with a vanishing false selection rate, and we propose a data-driven partition screening framework with unavailable or unreliable prior knowledge on covariate grouping and investigate its theoretical properties. We consider two special cases: correlation-guided partitioning and spatial location- guided partitioning. In the absence of a single partition, we propose a theoretically justified strategy for combining statistics from various partitioning methods. The utility of the proposed methods is demonstrated via simulation and analysis of functional neuroimaging data.

Increased autophagic response in a population of metastatic breast cancer cells.

Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade.

Overexpression of microRNA-133b sensitizes non-small cell lung cancer cells to irradiation through the inhibition of glycolysis.

Non-small cell lung cancer (NSCLC) accounts for 85% of all types of lung cancer and is the leading cause of world-wide cancer-associated mortalities. Radiation therapy has long been regarded as a fundamental therapeutic treatment strategy for NSCLC. However, alternative therapies for NSCLC remain insufficient, with the majority of cancers developing a high incidence of radioresistance. MicroRNAs (miRNAs/miRs) are endogenous oligonucleotide RNAs that serve an important role in carcinogenesis and tumor progression. In the present study, a novel function of miR-133b that is associated with the radiosensitivity of lung cancer cells is reported. miR-133 was downregulated in radioresistant lung cancer cells, which exhibited an elevated glycolysis rate when compared with radiosensitive cells. Additionally, it was observed that pyruvate kinase isoform M2 (PKM2) is a target of miR-133b, and that the expression of PKM2 is positively correlated with radioresistance. Finally, it was demonstrated that overexpression of miR-133b resensitizes radioresistant lung cancer cells through the inhibition of PKM2-mediated glycolysis. The current study may indicate a novel function of miR-133b, potentially aiding the development of anticancer therapeutics.

Globular adiponectin enhances invasion in human breast cancer cells.

Every year, a large number of women succumb to metastatic breast cancer due to a lack of curative approaches for this disease. Adiponectin (AdipoQ) is the most abundant of the adipocyte-secreted adipokines. In recent years, there has been an interest in the use of AdipoQ and AdipoQ receptor agonists as therapeutic agents for the treatment of breast cancer. However, while multiple epidemiological studies have previously indicated that low levels of circulating plasma AdipoQ portend poor prognosis in patients with breast cancer, recent studies have reported that elevated expression levels of AdipoQ in breast tissue are correlated with advanced stages of the disease. Thus, the aim of the present study was to clarify the mechanism by which AdipoQ in breast tissue acts directly on tumor cells to regulate the early steps of breast cancer metastasis. In the present study, the effects of different AdipoQ isoforms on the metastatic potential of human breast cancer cells were investigated. The results revealed that globular adiponectin (gAd) promoted invasive cell morphology and significantly increased the migration and invasion abilities of breast cancer cells, whereas full-length adiponectin (fAd) had no effect on these cells. Additionally, gAd, but not fAd, increased the expression levels of microtubule-associated protein 1 light chain 3 beta (LC3B)-II and intracellular LC3B puncta, which are indicators of autophagosome formation, thus suggesting autophagic induction by gAd. Furthermore, the inhibition of autophagic function by autophagy-related protein 7 knockdown attenuated the gAd-induced increase in invasiveness in breast cancer cells. Therefore, the results of the present study suggested that a specific AdipoQ isoform may enhance breast cancer invasion, possibly via autophagic induction. Understanding the roles of the different AdipoQ isoforms as microenvironmental regulatory molecules may aid the development of effective AdipoQ-based treatments for breast cancer.

Comparison of the clinical value of multi-band mucosectomy versus endoscopic mucosal resection for the treatment of patients with early-stage esophageal cancer.

The present study aimed to compare the clinical value of multi-band mucosectomy (MBM) versus endoscopic mucosal resection (EMR) for the treatment of patients with early-stage esophageal cancer. Between January 2011 and December 2012, 68 patients with early-stage esophageal cancer who underwent MBM and EMR were enrolled into the present study. The curative resection rate, duration of surgery, complications and follow-up records were retrospectively analyzed. Of the 68 patients included, 33 were treated with MBM and 35 with EMR. There was no significant difference in the rate of complete resection between the MBM and EMR groups (P>0.05). The mean duration of surgery in the MBM group was statistically lower than that in the EMR group (P<0.05). There was no statistically significant difference in the intraoperative and post-operative complications between the MBM and EMR groups (P>0.05). Esophageal cancer reoccurred in 2 patients treated with MBM and 1 patient treated with EMR during the follow-up period (range, 3-24 months). Overall, MBM can be considered a better surgical option for the management of patients with early-stage esophageal cancer, as it offers higher histological curative resection rates and improved safety. However, further studies and a larger follow-up period are required to confirm the long-term curative effect.

Clinicopathological features and prognosis of small gastrointestinal stromal tumors outside the stomach.

The aim of the present study was to assess the clinicopathological features and prognostic factors of primary small gastrointestinal stromal tumors (GISTs) outside the stomach. The clinical data, clinicopathological features and prognostic factors of 20 patients with a pathologically-confirmed diagnosis of non-gastric GIST that were treated at Liaoning Cancer Hospital & Institute between July 2006 and December 2013 were retrospectively analyzed. In total, 15 patients were male and 5 were female, with a median age of 58 years (range, 44-82 years). A change in bowel habits was the original symptom of rectal small GISTs in 6 out of 8 patients, while patients with small GISTs in other locations demonstrated no overt symptoms and the lesions were detected by systematic examinations of other diseases or abdominal surgical procedures performed on other organs. In total, 19 patients out of the total 20 patients underwent surgery, and 1 patient with rectal GIST received continuous oral imatinib mesylate (400 mg once a day) instead of undergoing surgery. The mean diameter of tumors was 1.55±0.54 cm (range, 0.3-2.0 cm) and the median was 1.70 cm. The pathomorphology of the lesions was mainly spindle cell, and immunohistochemistry revealed the expression rate of cluster of differentiation (CD)117, CD34 and discovered on GIST-1 were 85, 80 and 70%. According to the mitosis index, small rectal GISTs were more frequent compared with other positions (P<0.05), while the frequency of small GISTs >1 cm in size was not significantly different from the frequency of small GISTs ≤1 cm in size (P=0.995). All 20 patients were followed up, with a median follow-up duration of 49.5 months (range, 10.5-94.4 months). At the end of the follow-up period, tumor recurrence occurred in 5 patients and 1 patient succumbed following progression. According to the analysis of the tumor sites, the RFS time of patients with small rectal GISTs was significantly different than the RFS time in patients with small GISTs in other positions. The clinical symptoms of non-gastric small GISTs were not evident and were challenging to detect. Small GISTs, regardless of size, possessed malignant potential and once detected, GISTs should be surgically resected. Lesions located in the rectum demonstrated an increased degree of malignancy and were more likely to recur. The tumor size and Ki67 index could not be considered as prognostic factors of non-gastric small GISTs.

Covariance-enhanced discriminant analysis.

Linear discriminant analysis has been widely used to characterize or separate multiple classes via linear combinations of features. However, the high dimensionality of features from modern biological experiments defies traditional discriminant analysis techniques. Possible interfeature correlations present additional challenges and are often underused in modelling. In this paper, by incorporating possible interfeature correlations, we propose a covariance-enhanced discriminant analysis method that simultaneously and consistently selects informative features and identifies the corresponding discriminable classes. Under mild regularity conditions, we show that the method can achieve consistent parameter estimation and model selection, and can attain an asymptotically optimal misclassification rate. Extensive simulations have verified the utility of the method, which we apply to a renal transplantation trial.

Selection of latent variables for multiple mixed-outcome models.

Latent variable models have been widely used for modeling the dependence structure of multiple outcomes data. However, the formulation of a latent variable model is often unknown a priori, the misspecification will distort the dependence structure and lead to unreliable model inference. Moreover, multiple outcomes with varying types present enormous analytical challenges. In this paper, we present a class of general latent variable models that can accommodate mixed types of outcomes. We propose a novel selection approach that simultaneously selects latent variables and estimates parameters. We show that the proposed estimator is consistent, asymptotically normal and has the oracle property. The practical utility of the methods is confirmed via simulations as well as an application to the analysis of the World Values Survey, a global research project that explores peoples' values and beliefs and the social and personal characteristics that might influence them.

Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke.

Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen-glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1ß and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1ß and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells in vivo in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.

The helicase-like domain of plant potexvirus replicase participates in formation of RNA 5' cap structure by exhibiting RNA 5'-triphosphatase activity.

Open reading frame 1 (ORF1) of potexviruses encodes a viral replicase comprising three functional domains: a capping enzyme at the N terminus, a putative helicase in the middle, and a polymerase at the C terminus. To verify the enzymatic activities associated with the putative helicase domain, the corresponding cDNA fragment from bamboo mosaic virus (BaMV) was cloned into vector pET32 and the protein was expressed in Escherichia coli and purified by metal affinity chromatography. An activity assay confirmed that the putative helicase domain has nucleoside triphosphatase activity. We found that it also possesses an RNA 5'-triphosphatase activity that specifically removes the gamma phosphate from the 5' end of RNA. Both enzymatic activities were abolished by the mutation of the nucleoside triphosphate-binding motif (GKS), suggesting that they have a common catalytic site. A typical m(7)GpppG cap structure was formed at the 5' end of the RNA substrate when the substrate was treated sequentially with the putative helicase domain and the N-terminal capping enzyme, indicating that the putative helicase domain is truly involved in the process of cap formation by exhibiting its RNA 5'-triphosphatase activity.

Coverage of smoking cessation treatment by union health and welfare funds.

OBJECTIVES: This study determined the level of insurance coverage for smoking cessation treatment and factors associated with coverage among health and welfare funds affiliated with a large labor union. METHODS: A self-administered written survey was mailed to fund and union officials. Analyses were conducted by chi2 tests. RESULTS: Twenty-nine percent of funds provided coverage for some type of smoking cessation treatment, with the odds of coverage significantly increased among funds whose administrators reported having received members' requests for smoking cessation treatment in the past year (odds ratio = 4.9, P = .05). CONCLUSIONS: Coverage for smoking cessation services is low, comparable to coverage offered by other health insurers. Interventions with union members and fund officials are needed to provide union members with access to affordable and effective smoking cessation treatments.

Characterization of the AdoMet-dependent guanylyltransferase activity that is associated with the N terminus of bamboo mosaic virus replicase.

Bamboo mosaic virus (BaMV), a member of the potexvirus group, infects primarily members of the Bambusoideae. Open reading frame 1 (ORF1) of BaMV encodes a 155-kDa polypeptide that has long been postulated to be a replicase involved in the replication and formation of the cap structure at the 5' end of the viral genome. To identify and characterize the enzymatic activities associated with the N-terminal domain of the BaMV ORF1 protein, the intact replicase and two C-terminally truncated proteins were expressed in Saccharomyces cerevisiae. All three versions of BaMV ORF1 proteins could be radiolabeled by [alpha-(32)P]GTP, which is a characteristic of guanylyltransferase activity. The presence of S-adenosylmethionine (AdoMet) was essential for this enzymatic activity. Thin-layer chromatography analysis suggests that the radiolabeled moiety linked to the N-terminal domain of the BaMV ORF1 protein is m(7)GMP. The N-terminal domain also exhibited methyltransferase activity that catalyzes the transfer of the [(3)H]methyl group from AdoMet to GTP or guanylylimidodiphosphate. Therefore, during cap structure formation in BaMV, methylation of GTP may occur prior to transguanylation as for alphaviruses and brome mosaic virus. This study establishes the association of RNA capping activity with the N-terminal domain of the replicase of potexviruses and further supports the idea that the reaction sequence of RNA capping is conserved throughout the alphavirus-like superfamily of RNA viruses.

Identification and characterization of the Escherichia coli-expressed RNA-dependent RNA polymerase of bamboo mosaic virus.

Bamboo mosaic virus (BaMV), a member of the potexvirus group, infects primarily members of the Bambusoideae. The open reading frame 1 (ORF1) of BaMV encodes a 155-kDa polypeptide that was postulated to be involved in the replication and the formation of cap structure at the 5' end of the viral genome. To characterize the activities associated with the 155-kDa viral protein, it was expressed in Escherichia coli BL21(DE3) cells with thioredoxin, hexahistidine, and S. Tag fused consecutively at its amino terminus, and the fusion protein was purified by metal affinity chromatography. Several RNA fragments, prepared by in vitro transcription, were tested as substrates for the RNA-dependent RNA polymerase (RdRp) activity. Among them, the expressed fusion enzyme was able to generate a 32P-labeled RNA product when 3'-end RNA fragments of the positive strand or negative strand of BaMV were included in the assay mixture. Dot hybridization assay revealed that the reaction products are complementary to their RNA substrates. Taken together, the evidence suggests that the 155-kDa protein encoded by ORF1 of BaMV has an RdRp activity and should be involved in the replication of BaMV. Mutational analyses demonstrate the importance of the GDD motif in the polymerase activity, and deletion studies suggest that the polymerase activity resides in the carboxyl terminus of the 155-kDa viral protein.