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1.  Three-Dimensional Analysis of the Characteristics of the Femoral Canal Isthmus: An Anatomical Study 
BioMed Research International  2015;2015:459612.
Purpose. To establish a new approach for measuring and locating the femoral intramedullary canal isthmus in 3-dimensional (3D) space. Methods. Based on the computed tomography data from 204 Chinese patients, 3D models of the whole femur and the corresponding femoral isthmus tube were reconstructed using Mimics software (Materialise, Haasrode, Belgium). The anatomical parameters of the femur and the isthmus, including the femur length and radius, and the isthmus diameter and height, were measured accordingly. Results. The mean ratio of the isthmus height versus the femoral height was 55 ± 4.8%. The mean diameter of the isthmus was 10.49 ± 1.52 mm. The femoral length, the isthmus diameter, and the isthmus tube length were significantly larger in the male group. Significant correlations were observed between the femoral length and the isthmus diameter (r = 0.24, p < 0.01) and between the femoral length and the isthmus height (r = 0.6, p < 0.01). Stepwise linear regression analyses demonstrated that the femoral length and radius were the most important factors influencing the location and dimension of the femoral canal isthmus. Conclusion. The current study developed a new approach for measuring the femoral canal and for optimization of customer-specific femoral implants.
doi:10.1155/2015/459612
PMCID: PMC4475546  PMID: 26137483
2.  Experimental and clinical study of influence of high-frequency electric surgical knives on healing of abdominal incision 
AIM: To study the influence of high-frequency electric surgical knives on healing of abdominal incision.
METHODS: Two hundred and forty white rats were divided into 100, 102, 105, and 108 groups and rat models of abdominal operation were induced by using electric surgical knives and common lancets respectively. Then they were respectively given hypodermic injections of normal saline and 0.2 mL quantitative mixture of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa at a concentration of 102, 105 and 108. On the basis of the animal experiment, 220 patients undergoing abdominal operations (above type II) were randomly allocated into one of following three groups: electric knife (EK, 93 cases), electro-coagulation (EC, 55 cases) and control (72 cases). High-frequency electric surgical knives were used to dissect abdominal tissues and electro-coagulation for hemostasis in EK group. Common lancets and electro-coagulation were applied in EC group. Common lancets and tieing silk suture were used in the controls.
RESULTS: In all the groups except group 100, infection rate of incisional wounds made by electric surgical knives were remarkably higher than that with common lancets. Furthermore, there were significant differences in groups 102, 105, and 108 (P < 0.05), but not in group 100 (P > 0.05) between EK and EC groups. Clinical studies showed a delayed wound healing in 16 cases (17.20%) in EK, 11 cases (16.36%) in EC and 2 cases (2.86%) in the control groups. A significant difference between EK and the control groups (χ2 = 8.57, P < 0.01), and between EC and the control groups (χ2 = 5.66, P < 0.05) was observed, but not between EK and EC (χ2 = 0.017, P > 0.05).
CONCLUSION: High-frequency electric knives may remarkably delay abdominal incision healing. Its application should be minimized so as to reduce the possibility of postoperative complications.
doi:10.3748/wjg.v12.i25.4082
PMCID: PMC4087727  PMID: 16810765
High-frequency electric surgical knives; Abdominal incision; Healing; Infection
3.  γδ T cells recognize the insulin B:9-23 peptide antigen when it is dimerized through thiol oxidation* 
Molecular immunology  2014;60(2):116-128.
The insulin peptide B:9-23 is a natural antigen in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). In addition to αβ T cells and B cells, γδ T cells recognize the peptide and infiltrate the pancreatic islets where the peptide is produced within β cells. The peptide contains a cysteine in position 19 (Cys19), which is required for the γδ but not the αβ T cell response, and a tyrosine in position 16 (Tyr16), which is required for both. A peptide-specific mAb, tested along with the T cells, required neither of the two amino acids to bind the B:9-23 peptide. We found that γδ T cells require Cys19 because they recognize the peptide antigen in an oxidized state, in which the Cys19 thiols of two peptide molecules form a disulfide bond, creating a soluble homo-dimer. In contrast, αβ T cells recognize the peptide antigen as a reduced monomer, in complex with the MHCII molecule I-Ag7. Unlike the unstructured monomeric B:9-23 peptide, the γδ-stimulatory homo-dimer adopts a distinct secondary structure in solution, which differs from the secondary structure of the corresponding portion of the native insulin molecule. Tyr16 is required for this adopted structure of the dimerized insulin peptide as well as for the γδ response to it. This observation is consistent with the notion that γδ T cell recognition depends on the secondary structure of the dimerized insulin B:9-23 antigen.
doi:10.1016/j.molimm.2014.04.007
PMCID: PMC4091716  PMID: 24853397
Gamma delta T cells; T Cell Receptor; Insulin; Autoreactivity; Autoimmune diabetes; Oxidation
4.  Identification of Kv11.1 Isoform Switch as a Novel Pathogenic Mechanism of Long QT Syndrome 
Background
The KCNH2 gene encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier current in the heart. The relative expression of the full-length Kv11.1a isoform and the C-terminally truncated Kv11.1a-USO isoform plays an important role in regulation of channel function. The formation of C-terminal isoforms is determined by competition between the splicing and alternative polyadenylation of KCNH2 intron 9. It is not known whether changes in the relative expression of Kv11.1a and Kv11.1a-USO can cause long QT syndrome.
Methods and Results
We identified a novel KCNH2 splice site mutation in a large family. The mutation, IVS9-2delA, is a deletion of the A in the AG dinucleotide of the 3′ acceptor site of intron 9. We designed an intron-containing full-length KCNH2 gene construct to study the effects of the mutation on the relative expression of Kv11.1a and Kv11.1a-USO at the mRNA, protein and functional levels. We found that this mutation disrupted normal splicing and resulted in exclusive polyadenylation of intron 9, leading to a switch from the functional Kv11.1a to the non-functional Kv11.1a-USO isoform in HEK293 cells and HL-1 cardiomyocytes. We also showed that IVS9-2delA caused isoform switch in the mutant allele of mRNA isolated from patient lymphocytes.
Conclusions
Our findings indicate that the IVS9-2delA mutation causes a switch in the expression of the functional Kv11.1a isoform to the non-functional Kv11.1a-USO isoform. Kv11.1 isoform switch represents a novel mechanism in the pathogenesis of long QT syndrome.
doi:10.1161/CIRCGENETICS.114.000586
PMCID: PMC4180443  PMID: 25028483
long QT syndrome; potassium channels
5.  The Electrocardiographic Manifestations of Arrhythmogenic Right Ventricular Dysplasia 
Current Cardiology Reviews  2014;10(3):237-245.
The ECG is abnormal in most patients with arrhythmogenic right ventricular dysplasia (ARVD). Right ventricular parietal block, reduced QRS amplitude, epsilon wave, T wave inversion in V1-3 and ventricular tachycardia in the morphology of left bundle branch block are the characteristic changes that reflect the underlying genetic predetermined pathology and pathoelectrophysiology. Recognizing the characteristic ECG changes in ARVD will be of help in making a correct diagnosis of this rare disease.
doi:10.2174/1573403X10666140514102928
PMCID: PMC4040875  PMID: 24827798
ECG; ARVD; desmosomal genes; ventricular tachyarrhythmia; SCD.
6.  Interleukin-18 genetic polymorphisms contribute differentially to the susceptibility to Crohn’s disease 
AIM: To investigate the correlation between interleukin-18 (IL-18) gene polymorphisms and the risk of developing Crohn’s disease (CD).
METHODS: The PubMed, CISCOM, CINAHL, Web of Science, EBSCO, Cochrane Library, MEDLINE, EMBASE and CBM databases were searched without any language restrictions using combinations of keywords relating to CD and IL-18 for relevant articles published before November 1st, 2013. Screening of the published studies retrieved from searches was based on our stringent inclusion and exclusion criteria and resulted in seven eligible studies for meta-analysis. A meta-analysis was conducted using a random-effects model with STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated.
RESULTS: Seven case-control studies, with a total of 1930 CD cases and 1930 healthy subjects, met our inclusion criteria. The results of our meta-analysis indicated that the IL-18 rs1946518 A>C and rs187238 G>C polymorphisms may correlate with an increased risk of CD under five genetic models (all P < 0.05). Furthermore, we observed positive associations between the IL-18 rs360718 A>C polymorphism and CD risk under three genetic models (C allele vs A allele: OR = 2.03, 95%CI: 1.20-3.43, P = 0.008; CC vs AA+AC: OR = 2.39, 95%CI: 1.2-4.43, P = 0.006; CC vs AC: OR = 2.31, 95%CI: 1.22-4.38, P = 0.010). However, such associations were not found for the IL-18 rs917997 C>T, codon 35 A>C and rs1946519 G>T polymorphisms (all P > 0.05). A subgroup analysis was conducted to investigate the effect of ethnicity on an individual’s susceptibility to CD. Our results revealed positive correlations between IL-18 genetic polymorphisms and an increased risk of CD among Asians and Africans (all P < 0.05), but not among Caucasians (all P > 0.05).
CONCLUSION: This meta-analysis indicated that the IL-18 rs1946518 A>C, rs187238 G>C and rs360718 A>C polymorphisms may contribute to susceptibility to CD, especially among Asians and Africans. These polymorphisms are known to reduce IL-18 mRNA and protein levels.
doi:10.3748/wjg.v21.i28.8711
PMCID: PMC4515852
Interleukin-18; Single nucleotide polymorphism; Crohn’s disease; Meta-analysis
7.  Randomized, Multicenter Study of Gefitinib Dose-escalation in Advanced Non-small-cell Lung Cancer Patients Achieved Stable Disease after One-month Gefitinib Treatment 
Scientific Reports  2015;5:10648.
There is no consensus on the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC) and stable disease (SD) after gefitinib therapy. This randomized, open-label, multicenter study aimed to explore whether dose-escalation of gefitinib would improve response and survival in NSCLC patients who achieved SD after one-month of standard gefitinib dosage. Between May 2009 and January 2012, 466 patients were enrolled and 100 eligible patients were randomized (1:1) to receive either a higher dose (500 mg/d; H group) or to continue standard dose (250 mg/d; S group) of gefitinib. Objective response rate (ORR) was similar between the two groups (12.5% vs 12.5%, p = 1.000). There were no significant differences regarding progression-free survival (PFS) and overall survival (OS) between both arms (H group vs S group: median PFS, 5.30 months vs 6.23 months, p = 0.167; median OS, 13.70 months vs 18.87 months, p = 0.156). Therefore, dose-escalation of gefitinib does not confer a response or survival advantage in patients who achieve SD with one month of standard-dose gefitinib treatment.
doi:10.1038/srep10648
PMCID: PMC4516974  PMID: 26216071
8.  MAS-1 adjuvant immunotherapy generates robust Th2 type and regulatory immune responses providing long-term protection from diabetes in late-stage pre-diabetic NOD mice 
Autoimmunity  2014;47(5):341-350.
MAS-1, a nanoparticular, emulsion-based adjuvant, was evaluated for its ability to promote Th2 and regulatory immune responses and prevent type 1 diabetes progression when given alone or as antigen-specific immunotherapy (ASI) using insulin B chain (IBC; MER3101) and its analog B:9-23(19Ala) (MER3102). MAS-1 formulations were administered to NOD mice at age 9 and 13 weeks and followed through 52 weeks. MER3101 and MER3102 provided long-term protection with 60% and 73% of mice remaining diabetes-free at week 35, and 60% and 47% at week 52. MAS-1 adjuvant emulsion by itself also provided protection with 60% and 40% of mice diabetes-free at 35 and 52 weeks, respectively. Higher levels of interleukin (IL)-10 and IL-2 positive T cells were detected among splenocytes by week 15 in MER3101 and MER3102 immunized mice, whereas MAS-1 alone induced higher levels of IL-10-positive T cells. Diabetes-free 52-week-old mice expressed significant levels of antigen-specific IL-10-positive type 1 regulatory T cells and FoxP3-positive T cells when stimulated ex vivo with IBC. Antibodies targeting IBC and B:9-23(19Ala) induced by MER3101 and MER3102 were overwhelmingly Th2 type IgG1 and IgG2b isotypes. Splenocyte cultures from 52 week diabetes-free, MER3101-treated mice secreted significantly increased levels of IL-4 and IL-5 Th2 cytokines. Based on these pre-clinical results and its clinical safety profile, MAS-1 has the requisite qualities to be considered for use in prophylactic or early stage disease settings to augment ASI to prevent disease progression in type 1 diabetes.
doi:10.3109/08916934.2014.910768
PMCID: PMC4515961  PMID: 24783965
Autoimmune; diabetes; immunotherapy; insulin; NOD; Th2 type adjuvant; type 1
9.  Altered blood oxygen level-dependent signal variability in chronic post-traumatic stress disorder during symptom provocation 
Background
Recent research suggests that variability in brain signal provides important information about brain function in health and disease. However, it is unknown whether blood oxygen level-dependent (BOLD) signal variability is altered in post-traumatic stress disorder (PTSD). We aimed to identify the BOLD signal variability changes of PTSD patients during symptom provocation and compare the brain patterns of BOLD signal variability with those of brain activation.
Methods
Twelve PTSD patients and 14 age-matched controls, who all experienced a mining accident, underwent clinical assessment as well as fMRI scanning while viewing trauma-related and neutral pictures. BOLD signal variability and brain activation were respectively examined with standard deviation (SD) and general linear model analysis, and compared between the PTSD and control groups. Multiple regression analyses were conducted to explore the association between PTSD symptom severity and these two brain measures across all subjects as well as in the PTSD group.
Results
PTSD patients showed increased activation in the middle occipital gyrus compared with controls, and an inverse correlation was found between PTSD symptom severity and brain activation in the hippocampus and anterior cingulate cortex/medial prefrontal cortex. Brain variability analysis revealed increased SD in the insula, anterior cingulate cortex/medial prefrontal cortex, and vermis, and decreased SD in the parahippocapal gyrus, dorsolateral prefrontal cortex, somatosensory cortex, and striatum. Importantly, SD alterations in several regions were found in both traumatic and neutral conditions and were stratified by PTSD symptom severity.
Conclusion
BOLD signal variability may be a reliable and sensitive biomarker of PTSD, and combining brain activation and brain variability analysis may provide complementary insight into the neural basis of this disorder.
doi:10.2147/NDT.S87332
PMCID: PMC4517522
brain variability; general linear model; insula; functional magnetic resonance imaging
10.  Superiority of Minimally Invasive Oesophagectomy in Reducing In-Hospital Mortality of Patients with Resectable Oesophageal Cancer: A Meta-Analysis 
PLoS ONE  2015;10(7):e0132889.
Background
Compared with open oesophagectomy (OE), minimally invasive oesophagectomy (MIO) proves to have benefits in reducing the risk of pulmonary complications for patients with resectable oesophageal cancer. However, it is unknown whether MIO has superiority in reducing the occurrence of in-hospital mortality (IHM).
Objective
The objective of this meta-analysis was to explore the effect of MIO vs. OE on the occurrence of in-hospital mortality (IHM).
Data Sources
Sources such as Medline (through December 31, 2014), Embase (through December 31, 2014), Wiley Online Library (through December 31, 2014), and the Cochrane Library (through December 31, 2014) were searched.
Study Selection
Data of randomized and non-randomized clinical trials related to MIO versus OE were included.
Interventions
Eligible studies were those that reported patients who underwent MIO procedure. The control group included patients undergoing conventional OE.
Study Appraisal and Synthesis Methods
Fixed or random -effects models were used to calculate summary odds ratios (ORs) or relative risks (RRs) for quantification of associations. Heterogeneity among studies was evaluated by using Cochran’s Q and I2 statistics.
Results
A total of 48 studies involving 14,311 cases of resectable oesophageal cancer were included in the meta-analysis. Compared to patients undergoing OE, patients undergoing MIO had statistically reduced occurrence of IHM (OR=0.69, 95%CI =0.55 -0.86). Patients undergoing MIO also had significantly reduced incidence of pulmonary complications (PCs) (RR=0.73, 95%CI = 0.63-0.86), pulmonary embolism (PE) (OR=0.71, 95%CI= 0.51-0.99) and arrhythmia (OR=0.79, 95%CI = 0.68-0.92). Non-significant reductions were observed among the included studies in the occurrence of anastomotic leak (AL) (OR=0.93, 95%CI =0.78-1.11), or Gastric Tip Necrosis (GTN) (OR=0.89, 95%CI =0.54-1.49).
Limitation
Most of the included studies were non-randomized case-control studies, with a diversity of study designs, demographics of participants and surgical intervention.
Conclusions
Minimally invasive oesophagectomy (MIO) has superiority over open oesophagectomy (OE) in terms of the occurrence of in-hospital mortality (IHM) and should be the first-choice surgical procedure in esophageal surgery.
doi:10.1371/journal.pone.0132889
PMCID: PMC4509855  PMID: 26196135
11.  A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer 
PLoS ONE  2015;10(7):e0133803.
Background
Endothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC.
Methods
We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC. Meta-analysis was conducted by STATA version 12.0 software.
Results
Eight RCTs were identified, involving 6,065 patients. The results of direct comparison showed that compared with placebo, there was no statistically significant difference in the improvement of progression-free survival (PFS), overall survival (OS), time to disease progression (TTP), and total adverse events (AEs) with ET-A receptor antagonist treatment for CRPC. The results of ET-A receptor antagonists plus docetaxel versus docetaxel alone were similar. The indirect comparisons showed that there were no significant differences between zibotentan plus docetaxel versus atrasentan plus docetaxel when compared with docetaxel alone or zibotentan versus atrasenta compared with placebo in the improvement of PFS, OS, TTP, and total adverse events.
Conclusions
There were no significant benefits for ET-A receptor antagonists with or without docetaxel in the improvement of PFS, OS, TTP, and overall AEs. And there were no significant differences between zibotentan and atrasentan. Single-agent docetaxel should remain as one of the standard treatments.
doi:10.1371/journal.pone.0133803
PMCID: PMC4508042  PMID: 26192308
12.  Real-Time Tracking of Knee Adduction Moment in Patients with Knee Osteoarthritis 
Background
The external knee adduction moment (EKAM) is closely associated with the presence, progression, and severity of knee osteoarthritis (OA). However, there is a lack of convenient and practical method to estimate and track in real-time the EKAM of patients with knee OA for clinical evaluation and gait training, especially outside of gait laboratories.
New Method
A real-time EKAM estimation method was developed and applied to track and investigate the EKAM and other knee moments during stepping on an elliptical trainer in both healthy subjects and a patient with knee OA.
Results
Substantial changes were observed in the EKAM and other knee moments during stepping in the patient with knee OA.
Comparison with Existing Method(s)
This is the first study to develop and test feasibility of real-time tracking method of the EKAM on patients with knee OA using 3-D inverse dynamics.
Conclusions
The study provides us an accurate and practical method to evaluate in real-time the critical EKAM associated with knee OA, which is expected to help us to diagnose and evaluate patients with knee OA and provide the patients with real-time EKAM feedback rehabilitation training.
doi:10.1016/j.jneumeth.2013.12.001
PMCID: PMC4061264  PMID: 24361759
Knee adduction moment; knee osteoarthritis (OA); real-time estimation; biofeedback; diagnosis; outcome evaluation
13.  Changes in Olsen Phosphorus Concentration and Its Response to Phosphorus Balance in Black Soils under Different Long-Term Fertilization Patterns 
PLoS ONE  2015;10(7):e0131713.
The Olsen phosphorus (P) concentration of a soil is a key index that can be used to evaluate the P supply capacity of the soil and to estimate the optimal P fertilization rate. A study of the relationship between the soil Olsen P concentration and the P balance (P input minus P output) and their variations among different fertilization patterns will help to provide useful information for proper management of P fertilization. In this paper, the two investigated long-term experiments were established on black soils in the northeast region of China. Six fertilization treatments were selected: (1) unfertilized (CK); (2) nitrogen only (N); (3) nitrogen and potassium (NK); (4) nitrogen and phosphorus (NP); (5) nitrogen, phosphorus, and potassium (NPK); and (6) nitrogen, phosphorus, potassium and manure (NPKM). The results showed that the average Olsen P concentrations in the black soils at Gongzhuling and Harbin (16- and 31-year study periods, respectively), decreased by 0.49 and 0.56 mg kg-1 a-1, respectively, without P addition and increased by 3.17 and 1.78 mg kg-1 a-1, respectively, with P fertilization. The changes in soil Olsen P concentrations were significantly (P<0.05) correlated with the P balances at both sites except for the NP and NPK treatments at Gongzhuling. Under an average deficit of 100 kg ha-1 P, the soil Olsen P concentration at both sites decreased by 1.36~3.35 mg kg-1 in the treatments without P addition and increased by 4.80~16.04 mg kg-1 in the treatments with 100 kg ha-1 of P accumulation. In addition, the changes in Olsen P concentrations in the soil with 100 kg ha-1of P balance were significantly correlated with the P activation coefficient (PAC, percentage of Olsen P to total P, r=0.99, P<0.01) and soil organic matter content (r=0.91, P<0.01). A low pH was related to large changes of Olsen P by 1 kg ha-1 of P balance. These results indicated that soil organic matter and pH have important effects on the change in soil Olsen P by 1 kg ha-1 of P balance.
doi:10.1371/journal.pone.0131713
PMCID: PMC4503644  PMID: 26177293
14.  Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion 
Scientific Reports  2015;5:12079.
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0–3), but not the late stage after rUCCAO (day 4–32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.
doi:10.1038/srep12079
PMCID: PMC4502604  PMID: 26174710
15.  Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic–Ischemic Brain Damage in Neonatal Rats 
PLoS ONE  2015;10(7):e0132998.
c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage.
doi:10.1371/journal.pone.0132998
PMCID: PMC4501737  PMID: 26171786
16.  Phylogeny and differentiation of the St genome in Elymus L. sensu lato (Triticeae; Poaceae) based on one nuclear DNA and two chloroplast genes 
BMC Plant Biology  2015;15:179.
Background
Hybridization and polyploidization can be major mechanisms for plant evolution and speciation. Thus, the process of polyploidization and evolutionary history of polyploids is of widespread interest. The species in Elymus L. sensu lato are allopolyploids that share a common St genome from Pseudoroegneria in different combinations with H, Y, P, and W genomes. But how the St genome evolved in the Elymus s. l. during the hybridization and polyploidization events remains unclear. We used nuclear and chloroplast DNA-based phylogenetic analyses to shed some light on this process.
Results
The Maximum likelihood (ML) tree based on nuclear ribosomal internal transcribed spacer region (nrITS) data showed that the Pseudoroegneria, Hordeum and Agropyron species served as the St, H and P genome diploid ancestors, respectively, for the Elymus s. l. polyploids. The ML tree for the chloroplast genes (matK and the intergenic region of trnH-psbA) suggests that the Pseudoroegneria served as the maternal donor of the St genome for Elymus s. l. Furthermore, it suggested that Pseudoroegneria species from Central Asia and Europe were more ancient than those from North America. The molecular evolution in the St genome appeared to be non-random following the polyploidy event with a departure from the equilibrium neutral model due to a genetic bottleneck caused by recent polyploidization.
Conclusion
Our results suggest the ancient common maternal ancestral genome in Elymus s. l. is the St genome from Pseudoroegneria. The evolutionary differentiation of the St genome in Elymus s. l. after rise of this group may have multiple causes, including hybridization and polyploidization. They also suggest that E. tangutorum should be treated as C. dahurica var. tangutorum, and E. breviaristatus should be transferred into Campeiostachys. We hypothesized that the Elymus s. l. species origined in Central Asia and Europe, then spread to North America. Further study of intraspecific variation may help us evaluate our phylogenetic results in greater detail and with more certainty.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0517-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-015-0517-2
PMCID: PMC4499217  PMID: 26164196
Elymus s. l.; St genome; nr DNA; Chloroplast gene; Phylogeny; Molecular evolution
17.  Hepatitis E Virus Produced from Cell Culture Has a Lipid Envelope 
PLoS ONE  2015;10(7):e0132503.
The absence of a productive cell culture system hampered detailed analysis of the structure and protein composition of the hepatitis E virion. In this study, hepatitis E virus from a robust HEV cell culture system and from the feces of infected monkeys at the peak of virus excretion was purified by ultra-centrifugation. The common feature of the two samples after ultracentrifugation was that the ORF2 protein mainly remained in the top fractions. The ORF2 protein from cell culture system was glycosylated, with an apparent molecular weight of 88 kDa, and was not infectious in PLC/PRF/5 cells. The ORF2 protein in this fraction can bind to and protect HEV RNA from digestion by RNase A. The RNA-ORF2 product has a similar sedimentation coefficient to the virus from feces. The viral RNA in the cell culture supernatant was mainly in the fraction of 1.15g/cm3 but that from the feces was mainly in the fraction of 1.21 g/cm3. Both were infectious in PLC/PRF/5 cells. And the fraction in the middle of the gradient (1.06g/cm3) from the cell culture supernatant,but not that from the feces, also has ORF2 protein and HEV RNA but was not infectious in PLC/PRF/5.The infectious RNA-rich fraction from the cell culture contained ORF3 protein and lipid but the corresponding fraction from feces had no lipid and little ORF3 protein. The lipid on the surface of the virus has no effect on its binding to cells but the ORF3 protein interferes with binding. The result suggests that most of the secreted ORF2 protein is not associated with HEV RNA and that hepatitis E virus produced in cell culture differs in structure from the virus found in feces in that it has a lipid envelope.
doi:10.1371/journal.pone.0132503
PMCID: PMC4498737  PMID: 26161670
18.  MicroRNA Expression Profile in Penile Cancer Revealed by Next-Generation Small RNA Sequencing 
PLoS ONE  2015;10(7):e0131336.
Penile cancer (PeCa) is a relatively rare tumor entity but possesses higher morbidity and mortality rates especially in developing countries. To date, the concrete pathogenic signaling pathways and core machineries involved in tumorigenesis and progression of PeCa remain to be elucidated. Several studies suggested miRNAs, which modulate gene expression at posttranscriptional level, were frequently mis-regulated and aberrantly expressed in human cancers. However, the miRNA profile in human PeCa has not been reported before. In this present study, the miRNA profile was obtained from 10 fresh penile cancerous tissues and matched adjacent non-cancerous tissues via next-generation sequencing. As a result, a total of 751 and 806 annotated miRNAs were identified in normal and cancerous penile tissues, respectively. Among which, 56 miRNAs with significantly different expression levels between paired tissues were identified. Subsequently, several annotated miRNAs were selected randomly and validated using quantitative real-time PCR. Compared with the previous publications regarding to the altered miRNAs expression in various cancers and especially genitourinary (prostate, bladder, kidney, testis) cancers, the most majority of deregulated miRNAs showed the similar expression pattern in penile cancer. Moreover, the bioinformatics analyses suggested that the putative target genes of differentially expressed miRNAs between cancerous and matched normal penile tissues were tightly associated with cell junction, proliferation, growth as well as genomic instability and so on, by modulating Wnt, MAPK, p53, PI3K-Akt, Notch and TGF-β signaling pathways, which were all well-established to participate in cancer initiation and progression. Our work presents a global view of the differentially expressed miRNAs and potentially regulatory networks of their target genes for clarifying the pathogenic transformation of normal penis to PeCa, which research resource also provides new insights into future investigations aimed to explore the in-depth mechanisms of miRNAs and other small RNAs including piRNAs in penile carcinogenesis regulation and effective target-specific theragnosis.
doi:10.1371/journal.pone.0131336
PMCID: PMC4497725  PMID: 26158897
19.  Forward genetic screen for auxin-deficient mutants by cytokinin 
Scientific Reports  2015;5:11923.
Identification of mutants with impairments in auxin biosynthesis and dynamics by forward genetic screening is hindered by the complexity, redundancy and necessity of the pathways involved. Furthermore, although a few auxin-deficient mutants have been recently identified by screening for altered responses to shade, ethylene, N-1-naphthylphthalamic acid (NPA) or cytokinin (CK), there is still a lack of robust markers for systematically isolating such mutants. We hypothesized that a potentially suitable phenotypic marker is root curling induced by CK, as observed in the auxin biosynthesis mutant CK-induced root curling 1 / tryptophan aminotransferase of Arabidopsis 1 (ckrc1/taa1). Phenotypic observations, genetic analyses and biochemical complementation tests of Arabidopsis seedlings displaying the trait in large-scale genetic screens showed that it can facilitate isolation of mutants with perturbations in auxin biosynthesis, transport and signaling. However, unlike transport/signaling mutants, the curled (or wavy) root phenotypes of auxin-deficient mutants were significantly induced by CKs and could be rescued by exogenous auxins. Mutants allelic to several known auxin biosynthesis mutants were re-isolated, but several new classes of auxin-deficient mutants were also isolated. The findings show that CK-induced root curling provides an effective marker for discovering genes involved in auxin biosynthesis or homeostasis.
doi:10.1038/srep11923
PMCID: PMC4491711  PMID: 26143750
20.  Timing of Antibiotic Prophylaxis in Elective Caesarean Delivery: A Multi-Center Randomized Controlled Trial and Meta-Analysis 
PLoS ONE  2015;10(7):e0129434.
Objective
To compare the effectiveness of antibiotic prophylaxis before skin incision with that after umbilical cord clamping in elective caesarean delivery.
Methods
We conducted a randomized open-label controlled trial with two parallel arms at three hospitals in western China. Participants meeting the inclusion criteria received antibiotics 30-60 minutes before skin incision while others received antibiotics after umbilical cords clamping. For the meta-analysis, studies were identified from the database of PUBMED, Cochrane Library and EMbase and assessed using the Cochrane risk of bias tool.
Results
Four hundred and ten patients were randomized to receive antibiotics before skin incision (n = 205) or after umbilical cords clamping (n = 205). There was no difference in the incidence of postpartum endometritis (RR = 0.34, 95% CI 0.04 to 3.24), wound infection (RR = 3.06, 95% CI 0.13 to 74.69) and total puerperal morbidity (RR = 1.02, 95% CI 0.47 to 2.22). No increase in the incidence of neonatal sepsis (RR = 0.34, 95% CI 0.04 to 3.24), septic workup (RR = 0.41, 95% CI 0.08 to 2.07), or intermediate NICU admission (RR = 0.73, 95% CI 0.24 to 2.26) was observed. The meta-analysis involving nine RCTs showed that no statistically significant difference was found in terms of the risk of postpartum endometritis (RR = 0.73, 95% CI 0.39, 1.36), wound infection (RR = 0.80, 95%CI 0.55, 1.17), or puerperal morbidity (RR = 0.89, 95% CI 0.70, 1.13). No increase in the incidence of neonatal sepsis (RR = 0.65, 95% CI 0.35 to 1.20), septic workup (RR = 0.88, 95% CI 0.50 to 1.54), or intermediate NICU admission (RR = 0.91, 95% CI 0.70 to 1.18) was observed.
Conclusion
For elective caesarean delivery, the effects of antibiotic prophylaxis before skin incision and after umbilical cord clamping were equal. Both antibiotic prophylaxis before skin incision and that after umbilical cord clamping were recommended for elective caesarean delivery. The outcome of further studies should address both maternal and neonatal infectious morbidity as well as long-term neonatal follow up.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TRC-11001853
doi:10.1371/journal.pone.0129434
PMCID: PMC4492889  PMID: 26148063
21.  QoL analyses from INFORM study, a phase III study of gefitinib versus placebo as maintenance therapy in advanced NSCLC 
Scientific Reports  2015;5:11934.
This report aimed to provide the full results of QoL assessment in INFORM study. QoL was assessed by FACT-L questionnaire. QoL improvement ratio in gefitinib arm was higher than placebo arm (FACT-L: 46% vs. 22%, p < 0.001; TOI: 41% vs. 18%, p < 0.001; LCS: 46% vs. 22%, p < 0.001). Gefitinib prolonged time-to-worsening of QoL (FACT-L: 2.8 m vs 1.4 m, p = 0.019; TOI: 3.5 m vs 1.4 m, p = 0.006; LCS: 2.8 vs 1.4 m, p = 0.028). Patients with an improvement in QoL had longer PFS (FACT-L: 9.4 m vs. 2.8 m vs. 2.7 m, P < 0.001; TOI: 9.9 m vs. 2.8 m vs. 2.1 m, P < 0.001; LCS: 9.4 m vs. 2.9 m vs. 2.1 m, P < 0.001) and OS (FACT-L: 25.4 m vs. 19.9 m vs. 14.4 m, P = 0.003; TOI: 25.7 m vs. 19.0 m vs. 12.7 m, P = 0.002; LCS: 25.4 m vs. 19.3 m vs. 14.7 m, P = 0.004) compared with patients with stable or worsened QoL. Furthermore, in patients with good QoL at baseline, the treatment of gefitinib couldn’t improve OS compared to placebo, whereas patients with low QoL experienced marginal significant improvement in OS (20.6 m vs 14.4, p = 0.051). Our study indicated that gefitinib could improve patients’ QoL, confirmed the prognostic value of QoL changes during treatment, and implied patients with low QoL at baseline may be the potential population which will gain OS benefit from maintenance EGFR-TKI therapy.
doi:10.1038/srep11934
PMCID: PMC4490396  PMID: 26137916
22.  Auditory cortex controls sound-driven innate defense behaviour through corticofugal projections to inferior colliculus 
Nature Communications  2015;6:7224.
Defense against environmental threats is essential for animal survival. However, the neural circuits responsible for transforming unconditioned sensory stimuli and generating defensive behaviours remain largely unclear. Here, we show that corticofugal neurons in the auditory cortex (ACx) targeting the inferior colliculus (IC) mediate an innate, sound-induced flight behaviour. Optogenetic activation of these neurons, or their projection terminals in the IC, is sufficient for initiating flight responses, while the inhibition of these projections reduces sound-induced flight responses. Corticocollicular axons monosynaptically innervate neurons in the cortex of the IC (ICx), and optogenetic activation of the projections from the ICx to the dorsal periaqueductal gray is sufficient for provoking flight behaviours. Our results suggest that ACx can both amplify innate acoustic-motor responses and directly drive flight behaviours in the absence of sound input through corticocollicular projections to ICx. Such corticofugal control may be a general feature of innate defense circuits across sensory modalities.
Defense against environmental threats is essential for survival, yet the neural circuits mediating innate defensive behaviours are not completely understood. Here the authors demonstrate that descending projections from the auditory cortex to the midbrain mediate innate, sound-evoked flight behaviour.
doi:10.1038/ncomms8224
PMCID: PMC4467028  PMID: 26068082
23.  Multi-parameter assessment of platelet inhibition and its stability during aspirin and clopidogrel therapy 
Thrombosis research  2014;134(1):96-104.
Introduction
Poor response to antiplatelet drugs is associated with adverse outcomes. We assessed platelet inhibition and its stability and tested correlation and agreement between platelet function assays.
Methods
Peripheral blood from 58 patients on both aspirin and clopidogrel who underwent percutaneous coronary intervention (PCI) was collected at hospital discharge (visit-1) and at 30–90 days (visit-2). Platelet function was measured using light transmission aggregometry (LTA-AA and LTA-ADP), VerifyNow (Aspirin; ARU and P2Y12; PRU), ex vivo TxB2, urinary 11dhTxB2, and VASP (PRI) assays. Data were analyzed as continuous, quartiles and binary. Patients were defined as aspirin poor responder (PR) with ARU ≥550, LTA-AA maximum ≥20%, TxB2 ≥1 ng/mL or 11dhTxB2 ≥1,500 pg/mg of creatinine and as clopidogrel PR with PRU ≥240, PRU ≥208, LTA-ADP maximum ≥40%, PRI ≥50%, or PRI ≥66%.
Results
Aspirin PR was 3–33% and clopidogrel PR was 10–35% in visit-1. LTA-AA, 11dhTxB2, and all clopidogrel-response measures showed correlation and agreement between visit-1 and visit-2. The highest agreement between two visits was revealed by PRU ≥240 and PRI ≥66% (PRU-κ=0.7, 95% CI=0.47, 0.93; PRI-κ=0.69, 95% CI=0.42, 0.95, p-values<0.001). Comparison of platelet function assays in a single visit (Visit-1) revealed a poor correlation between LTA-AA and 11dhTxB2 assays and no agreement among aspirin-response assays. The highest correlation and agreement were obtained between VerifyNow P2Y12 and VASP assays (rho=0.7, p-value<0.001 and PRU ≥208-PRI-κ=0.41–0.42, 95% CI=0.13, 0.69, p-values<0.001).
Conclusions
Platelet inhibition is stable during aspirin and clopidogrel treatment. Clopidogrel-response assays correlate and agree with each other better than aspirin-response assays.
doi:10.1016/j.thromres.2014.04.023
PMCID: PMC4097303  PMID: 24852729
Aspirin; cardiovascular diseases; clopidogrel; drug resistance; percutaneous coronary intervention; platelet function assay
24.  Impaired Development and Competitive Refinement of the Cortical Frequency Map in Tumor Necrosis Factor-α-Deficient Mice 
Cerebral Cortex (New York, NY)  2013;24(7):1956-1965.
Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.
doi:10.1093/cercor/bht053
PMCID: PMC4110455  PMID: 23448874
auditory cortex; development; homeostatic plasticity; plasticity; tumor necrosis factor
25.  Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in Duchenne muscular dystrophy 
Cardiovascular Research  2014;103(1):60-71.
Aims
To determine whether altered beta-adrenergic responses contribute to early cardiac dysfunction in mdx (X-linked muscular dystrophy) mice, an animal model for human Duchenne muscular dystrophy.
Methods and results
Replacement fibrosis in mdx hearts gradually increased with age, suggesting a gradual loss of cardiomyocytes. Echocardiography and intra-left ventricular haemodynamic measurements detected baseline cardiac dysfunction in mdx mice at ≥8 months. However, a reduction of cardiac beta-adrenergic response to isoproterenol (ISO) was already present in mdx mice at 4 months. Ventricular myocytes (VMs) isolated from 4- and 8-month-old mdx mice had greater baseline contractile function {fractional shortening, [Ca2+]i, and sarcoplasmic reticulum (SR) Ca2+ content} and ICa-L than age-matched control VMs and than myocytes isolated from 2-month-old mdx mice. ISO increased myocyte function in the VMs of 4- and 8-month-old mdx mice to the same level as in age-matched control VMs. In the VMs of 12-month-old mdx mice, ISO failed to increase myocyte function to the level in VMs of 12-month-old control mice and could not further increaseICa-L. No differences were observed in the expression of Cav1.2α1c, Cav1.2β1, Cav1.2β2, sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and the Na+/Ca2+ exchanger. In contrast, total ryanodine receptor 2 (RyR2) and basal phosphorylation of RyR2, phospholamban, and Cav1.2α1c were found to be increased in hearts of 4-month-old mdx mice; baseline protein kinase A activity was also increased. After ISO treatment, phosphorylation levels were the same in mdx and control hearts. VMs of 4-month-old mdx mice had reduced beta1-adrenergic receptor (β1-AR) density and beta-adrenergic sensitivity.
Conclusion
In young mdx mice, the myocyte increases its contractile function to compensate for myocyte loss. However, these myocytes with enhanced baseline function have reduced potential for stimulation, decreased β1-AR density/sensitivity, leading to blunted cardiac beta-adrenergic response.
doi:10.1093/cvr/cvu119
PMCID: PMC4133593  PMID: 24812281
Duchenne muscular dystrophy; Heart; Beta-adrenergic response; Myocyte contraction; Calcium

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