The Embedding Problem for Markov Models of Nucleotide Substitution

Continuous-time Markov processes are often used to model the complex natural phenomenon of sequence evolution. To make the process of sequence evolution tractable, simplifying assumptions are often made about the sequence properties and the underlying process. The validity of one such assumption, time-homogeneity, has never been explored. Violations of this assumption can be found by identifying non-embeddability. A process is non-embeddable if it can not be embedded in a continuous time-homogeneous Markov process. In this study, non-embeddability was demonstrated to exist when modelling sequence evolution with Markov models. Evidence of non-embeddability was found primarily at the third codon position, possibly resulting from changes in mutation rate over time. Outgroup edges and those with a deeper time depth were found to have an increased probability of the underlying process being non-embeddable. Overall, low levels of non-embeddability were detected when examining individual edges of triads across a diverse set of alignments. Subsequent phylogenetic reconstruction analyses demonstrated that non-embeddability could impact on the correct prediction of phylogenies, but at extremely low levels. Despite the existence of non-embeddability, there is minimal evidence of violations of the local time homogeneity assumption and consequently the impact is likely to be minor.     

Estimation of Wheat Agronomic Parameters using New Spectral Indices

Crop agronomic parameters (leaf area index (LAI), nitrogen (N) uptake, total chlorophyll (Chl) content ) are very important for the prediction of crop growth. The objective of this experiment was to investigate whether the wheat LAI, N uptake, and total Chl content could be accurately predicted using spectral indices collected at different stages of wheat growth. Firstly, the product of the optimized soil-adjusted vegetation index and wheat biomass dry weight (OSAVI×BDW) were used to estimate LAI, N uptake, and total Chl content; secondly, BDW was replaced by spectral indices to establish new spectral indices (OSAVI×OSAVI, OSAVI×SIPI, OSAVI×CI_{red edge}, OSAVI×CI_{green mode} and OSAVI×EVI2); finally, we used the new spectral indices for estimating LAI, N uptake, and total Chl content. The results showed that the new spectral indices could be used to accurately estimate LAI, N uptake, and total Chl content. The highest R² and the lowest RMSEs were 0.711 and 0.78 (OSAVI×EVI2), 0.785 and 3.98 g/m² (OSAVI×CI_{red edge}) and 0.846 and 0.65 g/m² (OSAVI×CI_{red edge}) for LAI, nitrogen uptake and total Chl content, respectively. The new spectral indices performed better than the OSAVI alone, and the problems of a lack of sensitivity at earlier growth stages and saturation at later growth stages, which are typically associated with the OSAVI, were improved. The overall results indicated that this new spectral indices provided the best approximation for the estimation of agronomic indices for all growth stages of wheat.     

The Small GTPase RhoA Is Required for Proper Locomotor Circuit Assembly

The assembly of neuronal circuits during development requires the precise navigation of axons, which is controlled by attractive and repulsive guidance cues. In the developing spinal cord, ephrinB3 functions as a short-range repulsive cue that prevents EphA4 receptor-expressing corticospinal tract and spinal interneuron axons from crossing the midline, ensuring proper formation of locomotor circuits. Here we report that the small GTPase RhoA, a key regulator of cytoskeletal dynamics, is also required for ephrinB3/EphA4-dependent locomotor circuit formation. Deletion of RhoA from neural progenitor cells results in mice that exhibit a rabbit-like hopping gait, which phenocopies mice lacking ephrinB3 or EphA4. Consistent with this locomotor defect, we found that corticospinal tract axons and spinal interneuron projections from RhoA-deficient mice aberrantly cross the spinal cord midline. Furthermore, we determined that loss of RhoA blocks ephrinB3-induced growth cone collapse of cortical axons and disrupts ephrinB3 expression at the spinal cord midline. Collectively, our results demonstrate that RhoA is essential for the ephrinB3/EphA4-dependent assembly of cortical and spinal motor circuits that control normal locomotor behavior.     

Autophagic Protein Beclin 1 Serves as an Independent Positive Prognostic Biomarker for Non-Small Cell Lung Cancer

Beclin 1, a key regulator of autophagy, has been found to be aberrantly expressed in a variety of human malignancies. Herein, we employed immunohistochemistry (IHC) to detect the protein expression of Beclin 1 in non-small cell lung cancer (NSCLC) and paired normal adjacent lung tissues, and analyzed its clinicopathological/prognostic significance in NSCLC. Receiver operating characteristic (ROC) curve analysis was utilized to determine a cutoff point (>2 VS. ≤2) for Beclin 1 expression in a training set (n = 105). For validation, the ROC-derived cutoff value was subjected to analysis of the association of Beclin 1 with patients’ clinical characteristics and outcome in a testing set (n = 111) and the overall patient cohort (n = 216). Our data showed that Beclin 1 was significantly lower in NSCLC tissues compared with the adjacent normal tissues, negatively associating with tumor recurrence rate (65.8% VS 32.3%; p < 0.001). In the testing set and the overall patient cohort, low expression of Beclin 1 showed significantly inferior overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) compared to high expression of Beclin 1. In the testing set and the overall patient cohort, the median duration of OS for patients with high and low expression of Beclin 1 was 108 VS. 24.5 months (p < 0.001) and 108 VS. 28 months (p < 0.001), respectively. Furthermore, low expression of Beclin 1 was also a poor prognostic factor within each stage of NSCLC patients. Multivariate analysis identified that Beclin 1 was an independent prognostic factor for NSCLC. Our findings in the present study provided evidence that Beclin 1 may thus emerge as an independent prognostic biomarker in this tumor entity in the future.     

Tumor Necrosis Factor Alpha rs1800629 Polymorphism and Risk of Cervical Lesions: A Meta-Analysis

Background

Tumor necrosis factor- alpha (TNF-α) is an inflammatory cytokine which may play important role on the immune response may control the progression of cervical lesions. There is a possible association between TNF-α rs1800629 G/A polymorphism and cervical lesions, but previous studies report conflicting results. We performed a meta-analysis to comprehensively assess the association between TNF-α rs1800629 polymorphism and cervical lesions risk.

Methods

Literature searches of Pubmed, Embase, Web of Science, and Wanfang databases were performed for all publications on the association between TNF-α rs1800629 polymorphism and cervical lesions through December 15, 2012. The pooled odds ratios (ORs) with their 95% confidence interval (95%CIs) were calculated to assess the strength of the association.

Results

Twenty individual case-control studies from 19 publications with a total of 4,146 cases and 4,731 controls were finally included into the meta-analysis. Overall, TNF-α rs1800629 polymorphism was significantly associated with increased risk of cervical lesions under two main genetic comparison models (For A versus G: OR 1.22, 95%CI 1.04–1.44, P = 0.017; for AA versus GG: OR 1.32, 95%CI 1.02–1.71, P = 0.034). Subgroup analysis by ethnicity further showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical lesions in Caucasians but not in Asians. Subgroup analysis by the types of cervical lesions showed that there was a significant association between TNF-α rs1800629 polymorphism and increased risk of cervical cancer (For A versus G: OR 1.24, 95%CI 1.05–1.47, P = 0.011; for AA versus GG: OR 1.31, 95%CI 1.01–1.70, P = 0.043; for AA/GA versus GG: OR 1.25, 95%CI 1.01–1.54, P = 0.039).

Conclusion

The meta-analysis suggests that TNF-α rs1800629 polymorphism is associated with increased risk of cervical lesions, especially in Caucasians.     

The Dual Effect of Cannabinoid Receptor-1 Deficiency on the Murine Postoperative Ileus

Introduction

Intestinal inflammatory responses play a critical role in the pathogenesis of postoperative ileus (POI). As cannabinoid receptor-1 (CB1) is involved in inhibiting gastrointestinal (GI) motility and anti-inflammation, we aimed to explore its contribution to POI.

Methods

Experimental POI was induced in adult female CB1-deficient (CB1–/–) mice and wild-type littermates (C57BL/6N) by standardized small bowel manipulation. Twenty-four hours after surgery, GI transit was assessed by charcoal transport. FITC avidin, F4/80, and myeloperoxidase immunohistochemistry techniques were used to evaluate the inflammatory response in the muscularis of ileum and colon. Expressions of p38MAPK and its phosphorylated form (pp38) in the intestine were determined. Plasma levels of proinflammatory cytokines and chemokines were measured by ELISA as well.

Results

POI was characterized by decreased GI transit (p<0.01) and accompanied by a marked intestinal and systematic inflammatory response in wild-type and CB1–/– mice. Increased numbers of inflammatory cells, including macrophages, neutrophils, and mast cells were observed in the muscularis of ileum and colon (p<0.01, or p<0.05). Plasma levels of interleukin-6 (IL-6), cytokine-induced neutrophil chemoattractant-1 (CINC-1/KC), and monocyte chemoattractant protein-1 (MCP-1) were elevated (p<0.01, or p<0.05). Expression of p38 and pp38 increased in the intestine (p<0.01, or p<0.05). CB1–/– mice showed an increased inflammatory response during POI, especially the systemic inflammatory markers, such as IL-6, KC, CINC1, and pp38 expression were increased as compared to those in WT mice (p<0.05).

Conclusions

Intestinal motility was inhibited during POI. In this condition, inhibition of motility did not seem to be altered by the absence of CB1 receptors, however, an increased inflammatory response was observed in CB1–/– mice. Hence, CB1 receptor activation rather than inhibition may reduce the inflammatory response in POI, which has a remote potential to relate into reduced inhibition of intestinal motility during POI.     

Epidemiology and Risk Factors of Cervical Spine Injury during Heating Season in the Patients with Cervical Trauma: A Cross-Sectional Study

Purpose

The purpose of this study was to describe the epidemiology of cervical spine injury in the patients with cervical trauma and analyze its associated risk factors during the special heating season in North China.

Methods

This cross-sectional study investigated predictors for cervical spine injury in cervical trauma patients using retrospectively collected data of Hebei Provincial Orthopaedic Hospital from 11/2011 to 02/2012, and 11/2012 to 02/2013. Binary logistic regression analysis was used to determine risk factors for cervical fractures/dislocations or cord injury.

Results

A total of 106 patients were admitted into this study. Of all, 34 patients (32.1%) were treated from 11/2011 to 02/2012 and 72 patients (67.9%) from 11/2012 to 02/2013. The mean age was 41.9±13.3 years old; 85 patients (80.2%) were male and 82 (77.4%) from rural areas. Eighty patients (75.5%) were caused by fall including 45 (42.5%) by severe fall (>2 m). Sixty-five patients (61.3%) of all suffered injuries to other body regions and 32 (30.2%) got head injury. Thirty-one patients (29.2%) sustained cervical cord injury with cervical fractures/dislocations. Twenty-six (83.9%) of cervical cord injury patients were from rural areas and 24 (77.4%) of those resulted from fall including 15 (48.4%) from severe fall (>2 m). Logistic regression displayed that age (OR, 1.47; 95% CI, 1.05–2.07), head injury (OR, 5.63; 95% CI, 2.23–14.26), were risk factors for cervical cord injury and snowing (OR, 8.25; 95% CI, 2.26–30.15) was a risk factor for cervical spine injury due to severe fall (>2 m).

Conclusions

The elder male patients and patients with head trauma are high-risk population for cervical cord injury. As a seasonal factor, snowing during heating season is of note a risk factor for cervical spine injury resulting from severe fall (>2 m) in the patients with cervical trauma in North China.     

Select Dietary Phytochemicals Function as Inhibitors of COX-1 but Not COX-2

Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors. Many active dietary factors are reported to suppress carcinogenesis by targeting COX-2. A major question was accordingly raised: why has the lifelong use of phytochemicals that likely inhibit COX-2 presumably not been associated with adverse cardiovascular side effects. To answer this question, we selected a library of dietary-derived phytochemicals and evaluated their potential cardiovascular toxicity in human umbilical vein endothelial cells. Our data indicated that the possibility of cardiovascular toxicity of these dietary phytochemicals was low. Further mechanistic studies revealed that the actions of these phytochemicals were similar to aspirin in that they mainly inhibited COX-1 rather than COX-2, especially at low doses.