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1.  Elimination of the male reproductive tract in the female embryo is actively promoted by COUP-TFII 
Science (New York, N.Y.)  2017;357(6352):717-720.
The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default, as the male reproductive tracts (Wolffian ducts) in the female degenerate due to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII in the Wolffian duct mesenchyme became intersex that contained both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced p-ERK signaling in Wolffian duct epithelium was responsible for the retention in an androgen-independent manner. These results support our hypothesis that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium crosstalk responsible for Wolffian duct maintenance.
doi:10.1126/science.aai9136
PMCID: PMC5713893  PMID: 28818950
2.  Balanced Fertilization Decreases Environmental Filtering on Soil Bacterial Community Assemblage in North China 
Although increasing evidences have emerged for responses of soil microorganisms to fertilizations, the knowledge regarding community assemblages that cause variations in composition is still lacking, as well as the possible feedback to soil fertility. Phylogenetic conservatism of species indicates their similar environmental preferences and/or function traits and phylogenetic signals further can infer community assemblages and influenced ecological processes. Here, we calculated the mean pairwise phylogenetic distance and nearest relative index, characterizing phylogenetic signal and the undergone ecological process to evaluate the community assembly of soil bacterial phylotypes in 20-year fertilized soils. The bacterial community assembly is structured by environmental filtering, regardless of fertilization regime. Soil phosphorous (P) availability imposes selection on community assemblage and influences their community turnover among fertilizations. When P nutrient lacks, the effect of environmental filtering becomes stronger, hence bacterial functional traits become more coherent; this process results into increased intraspecific interactions characterized by co-occurrence network analysis. In contrast, when P nutrient becomes abundant, the environmental selection is mitigated; function traits are evened. This process reduces intraspecific interactions and increases carbon sequestration efficiency, which is finally of great favor to the increases in soil fertility. This study has made the first attempt, at the bacterial level, to understand how fertilization affects agroecosystems. When more phylogenetic information on how nutrient cycling-related microbes respond to fertilization becomes available, the systematic knowledge will eventually provide guidance to optimal fertilization strategies.
doi:10.3389/fmicb.2017.02376
PMCID: PMC5716987
fertilization; soil microorganisms; phylogenetic diversity; ecological process; soil fertility
3.  Preoperative bathing with chlorhexidine reduces the incidence of surgical site infections after total knee arthroplasty 
Medicine  2017;96(47):e8321.
Supplemental Digital Content is available in the text
Abstract
Background:
Surgical site infection is a devastating postoperative complication, and the occurrence ranges from 1% to 2% after total knee arthroplasty (TKA). The efficacy of the preoperative use of chlorhexidine for reducing infection has been debated. This meta-analysis aimed to examine the efficacy of the use of chlorhexidine to prevent surgical site infections after TKA.
Methods:
In February 2017, a systematic literature review was conducted using the following electronic databases: PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, and the Google database. Data from randomized controlled trials (RCTs) and retrospective comparative study (RCS) that compared the use of chlorhexidine versus control washes to prep patients for TKA were retrieved. The primary endpoint was to compare the total incidence of infection with and without the use of chlorhexidine. The secondary outcomes were the incidence of infection in low-risk category patients, moderate-risk category patients, and high-risk category patients. After testing for publication bias and heterogeneity between studies, data were aggregated for random-effects modeling when necessary.
Results:
Four clinical trials that included 8787 patients (chlorhexidine group: n = 2615, control group: n = 6172) were ultimately included in the meta-analysis. Chlorhexidine was associated with a reduced total incidence of infection, corresponding to a reduction of 1.69% [risk ratio (RR) = 0.22; 95% confidence interval (95% CI) = 0.12–0.40; P = .000]. Similarly, chlorhexidine was associated with a reduction in the incidence of infection among patients in the moderate-risk category (RR, 0.18; 95% CI, 0.05–0.63; P = .007) and the high-risk category (RR, 0.13; 95% CI, 0.03–0.67; P = .014). There was no significant difference between the incidence of infection in low-risk category patients with chlorhexidine use compared with the use of control washes (RR, 0.60; 95% CI, 0.22–1.60; P = .330).
Conclusion:
The preoperative use of chlorhexidine could reduce the total incidence of infection and the incidence of infection in moderate-risk and high-risk category patients. The overall evidence and the number of included studies was limited; thus, a greater number of high-quality RCTs is still needed to further identify the effects of chlorhexidine on reducing the incidence of infection after TKA.
doi:10.1097/MD.0000000000008321
PMCID: PMC5708913
chlorhexidine; meta-analysis; total knee arthroplasty
4.  ORF7 of Varicella-Zoster Virus Is Required for Viral Cytoplasmic Envelopment in Differentiated Neuronal Cells 
Journal of Virology  2017;91(12):e00127-17.
ABSTRACT
Although a varicella-zoster virus (VZV) vaccine has been used for many years, the neuropathy caused by VZV infection is still a major health concern. Open reading frame 7 (ORF7) of VZV has been recognized as a neurotropic gene in vivo, but its neurovirulent role remains unclear. In the present study, we investigated the effect of ORF7 deletion on VZV replication cycle at virus entry, genome replication, gene expression, capsid assembly and cytoplasmic envelopment, and transcellular transmission in differentiated neural progenitor cells (dNPCs) and neuroblastoma SH-SY5Y (dSY5Y) cells. Our results demonstrate that the ORF7 protein is a component of the tegument layer of VZV virions. Deleting ORF7 did not affect viral entry, viral genome replication, or the expression of typical viral genes but clearly impacted cytoplasmic envelopment of VZV capsids, resulting in a dramatic increase of envelope-defective particles and a decrease in intact virions. The defect was more severe in differentiated neuronal cells of dNPCs and dSY5Y. ORF7 deletion also impaired transmission of ORF7-deficient virus among the neuronal cells. These results indicate that ORF7 is required for cytoplasmic envelopment of VZV capsids, virus transmission among neuronal cells, and probably the neuropathy induced by VZV infection.
IMPORTANCE The neurological damage caused by varicella-zoster virus (VZV) reactivation is commonly manifested as clinical problems. Thus, identifying viral neurovirulent genes and characterizing their functions are important for relieving VZV related neurological complications. ORF7 has been previously identified as a potential neurotropic gene, but its involvement in VZV replication is unclear. In this study, we found that ORF7 is required for VZV cytoplasmic envelopment in differentiated neuronal cells, and the envelopment deficiency caused by ORF7 deletion results in poor dissemination of VZV among neuronal cells. These findings imply that ORF7 plays a role in neuropathy, highlighting a potential strategy to develop a neurovirulence-attenuated vaccine against chickenpox and herpes zoster and providing a new target for intervention of neuropathy induced by VZV.
doi:10.1128/JVI.00127-17
PMCID: PMC5446663  PMID: 28356523
varicella-zoster virus; ORF7; differentiated neural progenitor cells; differentiated SH-SY5Y cells; cytoplasmic envelopment
5.  Logistic regression analysis of factors influencing the effectiveness of intensive sound masking therapy in patients with tinnitus 
BMJ Open  2017;7(11):e018050.
Objectives
To investigate factors influencing the effectiveness of intensive sound masking therapy on tinnitus using logistic regression analysis.
Design
The study used a retrospective cross-section analysis.
Participants
102 patients with tinnitus were recruited at the Sun Yat-sen Memorial Hospital of Sun Yat-sen University, China.
Intervention
Intensive sound masking therapy was used as an intervention approach for patients with tinnitus.
Primary and secondary outcome measures
Participants underwent audiological investigations and tinnitus pitch and loudness matching measurements, followed by intensive sound masking therapy. The Tinnitus Handicap Inventory (THI) was used as the outcome measure pre and post treatment. Multivariate logistic regression was performed to investigate the association of demographic and audiological factors with effective therapy.
Results
According to the THI score changes pre and post sound masking intervention, 51 participants were categorised into an effective group, the remaining 51 participants were placed in a non-effective group. Those in the effective group were significantly younger than those in the non-effective group (P=0.012). Significantly more participants had flat audiogram configurations in the effective group (P=0.04). Multivariable logistic regression analysis showed that age (OR=0.96, 95% CI 0.93 to 0.99, P=0.007), audiometric configuration (P=0.027) and THI score pre treatment (OR=1.04, 95% CI 1.02 to 1.07, P<0.001) were significantly associated with therapeutic effectiveness. Further analysis showed that patients with flat audiometric configurations were 5.45 times more likely to respond to intervention than those with high-frequency steeply sloping audiograms (OR=5.45, 95% CI 1.67 to 17.86, P=0.005).
Conclusion
Audiometric configuration, age and THI scores appear to be predictive of the effectiveness of sound masking treatment. Gender, tinnitus characteristics and hearing threshold measures do not seem to be related to treatment effectiveness. A further randomised control study is needed to provide evidence of the effectiveness of prognostic factors in tinnitus interventions.
doi:10.1136/bmjopen-2017-018050
PMCID: PMC5695311  PMID: 29146645
sound masking; tinnitus; audiometric configuration; prognostic factors
6.  Long noncoding RNA LINC00673 epigenetically suppresses KLF4 by interacting with EZH2 and DNMT1 in gastric cancer 
Oncotarget  2017;8(56):95542-95553.
Long non-coding RNAs (lncRNAs), a variety of transcripts without protein coding ability, have recently been reported to play vital roles in gastric cancer (GC) development and progression. However, the biological role of long non-coding RNA LINC00673 in GC is not fully known. In the study, we found that LINC00673 expression was dramatically higher in gastric cancer tissues compared with adjacent normal tissues, and positively associated with lymph node metastasis, distant metastasis and TNM stage in patients. Higher LINC00673 expression predicted poor disease-free survival (DFS) and overall survival (OS) in GC patients. By univariate and multivariate Cox analysis, the results confirmed that higher LINC00673 expression was an independent risk factor of prognosis in patients. Knockdown of endogenous LINC00673 significantly inhibited cell proliferation, colony formation number, cell migration and invasion in GC. Furthermore, knockdown of endogenous LINC00673 reduced the expression levels of PCNA, CyclinD1 and CDK2 in GC cells. RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) proved that LINC00673 suppressed KLF4 expression by interacting with EZH2 and DNMT1 in GC cells. Moreover, we confirmed that LINC00673 promoted cell proliferation and invasion by partly repressing KLF4 expression in GC. Taken together, these results indicated that LINC00673 may be a prognostic biomarker and therapeutic target for GC patients.
doi:10.18632/oncotarget.20980
PMCID: PMC5707041
long noncoding RNA; LINC00673; DNMT1; EZH2; KLF4
7.  Effects of transthoracic device closure on ventricular septal defects and reasons for conversion to open-heart surgery: A meta-analysis 
Scientific Reports  2017;7:12219.
Transthoracic device closure (TTDC) is thought to be a promising technology for the repair of ventricular septal defects (VSDs). However, there is considerable controversy regarding the efficacy and safety of TTDC. The present study aimed to compare the benefits and safety of TTDC with those of conventional open-heart surgery (COHS) and analyze the associated factors causing complications, conversion to COHS and reoperation. Electronic database searches were conducted in PubMed, EMBASE, Cochrane Library, Clinicaltrials.gov and several Chinese databases. A total of 5 randomized controlled trials (RCTs), 7 cohort studies, 13 case-control studies, 129 case series and 13 case reports were included. Compared to COHS, TTDC exhibited superior efficacy with a significantly lower risk of post-operative arrhythmia; however, no significant differences in other outcomes were identified. Meta-regression analysis showed that perimembranous VSDs (pmVSDs), a smaller VSD, a smaller occluder, and a median or subxiphoid approach lowered the relative risk of several post-operative complications, conversion to COHS and reoperation. The current evidence indicates that TTDC is associated with a lower risk of post-operative arrhythmia and is not associated with an increased risk of complications. PmVSDs, a smaller VSD and occluder, and a median or subxiphoid approach correlate with better outcomes when using TTDC.
doi:10.1038/s41598-017-12500-6
PMCID: PMC5610181  PMID: 28939836
8.  Diagnosis of cobalamin C deficiency with renal abnormality from onset in a Chinese child by next generation sequencing: A case report 
The aim of the present study was to present the diagnosis and treatment course of a patient with cobalamin C deficiency (cblC) hospitalized with renal function abnormality from the onset. A female, 7-year-old patient who presented with a cough and progressive dyspnea for 1 day was admitted to the Children's Hospital of Nanjing Medical University (Nanjing, China). A routine clinical examination was performed, including physical examination, routine blood and urine tests, blood gas analysis, computed tomography scans of the head, chest and abdomen, electrocardiogram, echocardiography and abdominal ultrasonography. In addition, laboratory tests were performed, including tests for viral infection and markers of autoimmunity, humoral immunity, myocardial enzymes and tumors. Tandem mass analysis and renal biopsy were conducted. Next generation sequencing (NGS) was performed to identify mutated genes, and structural investigation was conducted to identify the key residue mutations in the patient. Routine clinical examination revealed that the patient had multiple organ failure, indicating the presence of metabolic disease. Tandem mass analysis and renal biopsy also indicated that the patient had methylmalonic acidemia (MMA) and thrombotic microangiopathy combined with focal renal cortical necrosis. Furthermore, next-generation sequencing identified the presence of two heterozygous mutations in the MMA cblC type with homocystinuria (MMACHC) gene. Structural analysis demonstrated that the two mutations were in key components of the MMACHC protein. The patient was finally diagnosed with cblC according to the results obtained. In conclusion, NGS may aid in the diagnosis and therapeutic management of cblC with renal abnormality from the onset in children.
doi:10.3892/etm.2017.4970
PMCID: PMC5639280
cobalamin C; methylmalonic acidemia; homocystinuria; renal failure
9.  A new species of Scutellaria (Scutellarioideae, Lamiaceae) from Sichuan Province in southwest China 
PeerJ  2017;5:e3624.
Scutellaria wuana, a new species discovered from a xeric valley in Muli County of Sichuan Province in southwest China, is described and illustrated. Morphologically, the new species shares similarities with S. mairei, but can be readily distinguished by a suite of morphological characters including a white-pubescent erect stem, conspicuous leaf petioles, and a yellow corolla with a trapeziform lower-middle lip lobe. The habitat and distribution of S. wuana are also distinctive. The position of the new species within Scutellaria is examined in a phylogenetic context using the nuclear ribosomal internal and external transcribed spacers. Additionally, we examine leaf epidermal and pollen grain micromorphology of the new species and putative relatives.
doi:10.7717/peerj.3624
PMCID: PMC5550825
China; Endemisim; Morphology; Scutellaria; SEM observation; Taxonomy
10.  A CONSORT-compliant prospective randomized controlled trial: radiation dose reducing in computed tomography using an additional lateral scout view combined with automatic tube current modulation 
Medicine  2017;96(30):e7324.
Abstract
Background:
Radiation exposure has been a hot point in research field of computed tomography (CT). Recently, automated tube current modulation (ATCM) has emerged as an important technique to reduce radiation exposure. Many studies have shown that the difference in scout view would affect modulation. This prospective randomized controlled study is aimed to investigate the impact of an additional lateral scout view on radiation dose and image quality in CT using ACTM.
Methods:
Combined with ATCM (Care Dose 4D) on multidetector CT, 2 thoracic phantom CT image series were acquired in which planning was conducted with either an anteroposterior (AP) or an AP-lateral scout view. Also, 410 patients underwent thoracic CT examinations using Care Dose 4D modulation and were randomized to either a scan planned with an AP-lateral scout or a single AP scout. Effects of the different scout views on applied effective milliampere seconds (mAs), volume CT dose index (CTDIvol) and dose–length–product (DLP) were analyzed. The quality of patient CT images was also assessed. Data were analyzed using independent t tests and linear correlation analysis.
Results:
Compared with AP groups, the mean CTDIvol (phantom, 0.89 ± 0.08 vs 1.36 ± 0.26 mGy, P < .001; in patients, 1.12 [0.96, 1.34] vs 2.16 [1.66, 2.64] mGy, P < .001) and DLP (in phantom, 26 [23.25, 28] vs 40 [34.25, 48] mGy×cm, P < .001; in patients, 41 [33, 41] vs 77 [60.5, 99.5] mGy×cm, P < .001) were significantly reduced by approximately 50% in AP-lateral scout view group. With the AP-lateral topogram, the radiation dose on different off-center positions was essentially equal (CTDIvol: 0.76–0.99 mGy; DLP: 22–28 mGy×cm effective dose: 0.31–0. 39 mSv). For image quality, contrast-to-noise ratio and signal-to-noise ratio values in the AP group were similar to those of AP-lateral scout view group.
Conclusion:
AP combined with an additional lateral scout view using ACTM can significantly reduce the radiation dose without compromising image quality in chest screening CT.
doi:10.1097/MD.0000000000007324
PMCID: PMC5627806  PMID: 28746180
computed tomography; quality control; radiation dose; thorax
11.  Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase 
PLoS Pathogens  2017;13(7):e1006542.
Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of Notch signaling, the transcriptional regulator Hairy and Enhancer of Split 1 (Hes1) is essential for governing NPC fate and fetal brain development. In the present study, we report that HCMV infection downregulates Hes1 protein levels in infected NPCs. The HCMV 72-kDa immediate-early 1 protein (IE1) is involved in Hes1 degradation by assembling a ubiquitination complex and promoting Hes1 ubiquitination as a potential E3 ubiquitin ligase, followed by proteasomal degradation of Hes1. Sp100A, an important component of PML nuclear bodies, is identified to be another target of IE1-mediated ubiquitination. A C-terminal acidic region in IE1, spanning amino acids 451 to 475, is required for IE1/Hes1 physical interaction and IE1-mediated Hes1 ubiquitination, but is dispensable for IE1/Sp100A interaction and ubiquitination. Our study suggests a novel mechanism linking downregulation of Hes1 protein to neurodevelopmental disorders caused by HCMV infection. Our findings also complement the current knowledge of herpesviruses by identifying IE1 as the first potential HCMV-encoded E3 ubiquitin ligase.
Author summary
Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children, but the underlying pathogenesis of this infection remains unclear. Hes1, an important effector of Notch signaling, governs the fate of neural progenitor cells (NPCs) and fetal brain development. Here we demonstrate that: (1) HCMV infection results in loss of Hes1 protein in NPCs; (2) the HCMV immediate-early 1 protein (IE1) mediates Hes1 protein downregulation through direct interaction, which requires amino acids 451–475; (3) IE1 assembles a Hes1 ubiquitination complex and mediates Hes1 ubiquitination; and (4) IE1 also assembles an Sp100A ubiquitination complex and mediates Sp100A ubiquitination, but does not require amino acids 451–475. These results suggest that HCMV IE1 is a potential E3 ubiquitin ligase. Downregulation of Hes1 by HCMV infection and IE1 implies a novel mechanism linking Hes1 depletion to virus-induced neuropathogenesis.
doi:10.1371/journal.ppat.1006542
PMCID: PMC5549770  PMID: 28750047
12.  Comparing yield and relative costs of WHO TB screening algorithms in selected risk groups among people aged 65 years and over in China, 2013 
PLoS ONE  2017;12(6):e0176581.
Objective
To calculate the yield and cost per diagnosed tuberculosis (TB) case for three World Health Organization screening algorithms and one using the Chinese National TB program (NTP) TB suspect definitions, using data from a TB prevalence survey of people aged 65 years and over in China, 2013.
Methods
This was an analytic study using data from the above survey. Risk groups were defined and the prevalence of new TB cases in each group calculated. Costs of each screening component were used to give indicative costs per case detected. Yield, number needed to screen (NNS) and cost per case were used to assess the algorithms.
Findings
The prevalence survey identified 172 new TB cases in 34,250 participants. Prevalence varied greatly in different groups, from 131/100,000 to 4651/ 100,000. Two groups were chosen to compare the algorithms. The medium-risk group (living in a rural area: men, or previous TB case, or close contact or a BMI <18.5, or tobacco user) had appreciably higher cost per case (USD 221, 298 and 963) in the three algorithms than the high-risk group (all previous TB cases, all close contacts). (USD 72, 108 and 309) but detected two to four times more TB cases in the population. Using a Chest x-ray as the initial screening tool in the medium risk group cost the most (USD 963), and detected 67% of all the new cases. Using the NTP definition of TB suspects made little difference.
Conclusions
To “End TB”, many more TB cases have to be identified. Screening only the highest risk groups identified under 14% of the undetected cases,. To “End TB”, medium risk groups will need to be screened. Using a CXR for initial screening results in a much higher yield, at what should be an acceptable cost.
doi:10.1371/journal.pone.0176581
PMCID: PMC5464530  PMID: 28594824
13.  Crystal structure of a multi-domain human smoothened receptor in complex with a super stabilizing ligand 
Nature Communications  2017;8:15383.
The Smoothened receptor (SMO) belongs to the Class Frizzled of the G protein-coupled receptor (GPCR) superfamily, constituting a key component of the Hedgehog signalling pathway. Here we report the crystal structure of the multi-domain human SMO, bound and stabilized by a designed tool ligand TC114, using an X-ray free-electron laser source at 2.9 Å. The structure reveals a precise arrangement of three distinct domains: a seven-transmembrane helices domain (TMD), a hinge domain (HD) and an intact extracellular cysteine-rich domain (CRD). This architecture enables allosteric interactions between the domains that are important for ligand recognition and receptor activation. By combining the structural data, molecular dynamics simulation, and hydrogen-deuterium-exchange analysis, we demonstrate that transmembrane helix VI, extracellular loop 3 and the HD play a central role in transmitting the signal employing a unique GPCR activation mechanism, distinct from other multi-domain GPCRs.
Smoothened receptors (SMO) play a key role in the Hedgehog signalling pathway. Here the authors present the structure of a multi-domain human SMO with a rationally designed stabilizing ligand bound in the transmembrane domain of the receptor, and propose a model for SMO activation.
doi:10.1038/ncomms15383
PMCID: PMC5442369  PMID: 28513578
14.  Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129 
Background
Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer.
Methods
Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing. Among them, H129-G4 was obtained by inserting binary tandemly connected GFP cassettes into the H129 genome, and H129-ΔTK-tdT was obtained by deleting the thymidine kinase (TK) gene and adding tdTomato coding gene to the H129 genome. Then the obtained viral tracers were tested in vitro and in vivo for the tracing capacity.
Results
H129-G4 is capable of transmitting through multiple synapses, labeling the neurons by green florescent protein, and visualizing the morphological details of the labeled neurons. H129-ΔTK-tdT neither replicates nor spreads in neurons alone, but transmits to and labels the postsynaptic neurons with tdTomato in the presence of complementary expressed TK from a helper virus. H129-ΔTK-tdT is also capable to map the direct projectome of the specific neuron type in the given brain regions in Cre transgenic mice. In the tested brain regions where circuits are well known, the H129-ΔTK-tdT tracing patterns are consistent with the previous results.
Conclusions
With the assistance of the helper virus complimentarily expressing TK, H129-ΔTK-tdT replicates in the initially infected neuron, transmits anterogradely through one synapse, and labeled the postsynaptic neurons with tdTomato. The H129-ΔTK-tdT anterograde monosynaptic tracing system offers a useful tool for mapping the direct output in neuronal circuitry. H129-G4 is an anterograde multisynaptic tracer with a labeling signal strong enough to display the details of neuron morphology.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-017-0179-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13024-017-0179-7
PMCID: PMC5427628  PMID: 28499404
Herpes simplex virus type 1 (HSV-1); H129 strain; Anterograde; Neuronal tracer; H129; ΔTK; tdT; Monosynaptic; H129-G4; Multisynaptic
15.  Port-Site Metastases and Chimney Effect of B-Ultrasound-Guided and Laparoscopically-Assisted Hyperthermic Intraperitoneal Perfusion Chemotherapy 
Yonsei Medical Journal  2017;58(3):497-504.
Purpose
CO2 leakage along the trocar (chimney effect) has been proposed to be an important factor underlying port-site metastasis after laparoscopic surgery. This study aimed to test this hypothesis by comparing the incidence of port-site metastasis between B-ultrasound-guided and laparoscopically-assisted hyperthermic intraperitoneal perfusion chemotherapy (HIPPC).
Materials and Methods
Sixty-two patients with malignant ascites induced by gastrointestinal or ovarian cancer were divided into two groups to receive either B-ultrasound-guided or laparoscopically-assisted HIPPC. Clinical efficacy was assessed from the objective remission rate (ORR), the Karnofsky Performance Status (KPS) score, and overall survival. The incidence of port-site metastasis was compared between the two groups.
Results
Patients in the B-ultrasound (n=32) and laparoscopy (n=30) groups were comparable in terms of age, sex, primary disease type, volume of ascites, and free cancer cell (FCC)-positive ascites. After HIPPC, there were no significant differences between the B-ultrasound and laparoscopy groups in the KPS score change, ORR, and median survival time. The incidence of port-site metastasis after HIPPC was not significantly different between the B-ultrasound (3 of 32, 9.36%) and laparoscopy (3 of 30, 10%) groups, but significantly different among pancreatic, gastric, ovarian, and colorectal cancer (33.33, 15.79, 10.00, and 0.00%, p<0.001).
Conclusion
The chimney effect may not be the key reason for port-site metastasis after laparoscopy. Other factors may play a role, including the local microenvironment at the trocar site and the delivery of viable FCCs (from the tumor or malignant ascites) to the trauma site during laparoscopic surgery.
doi:10.3349/ymj.2017.58.3.497
PMCID: PMC5368133  PMID: 28332353
Chimney effect; laparoscopy; B-ultrasound; HIPPC; port-site metastasis
16.  Full Chloroplast Genome Assembly of 11 Diverse Watermelon Accessions 
doi:10.3389/fgene.2017.00046
PMCID: PMC5394170
chloroplast genome; watermelon; genome assembly; annotation; cucurbitaceae
17.  A prediction model for lymph node metastases using pathologic features in patients intraoperatively diagnosed as stage I non-small cell lung cancer 
BMC Cancer  2017;17:267.
Background
There is little information on which pattern should be chosen to perform lymph node dissection for stage I non-small-cell lung cancer. This study aimed to develop a model for predicting lymph node metastasis using pathologic features of patients intraoperatively diagnosed as stage I non-small-cell lung cancer.
Methods
We collected pathology data from 284 patients intraoperatively diagnosed as stage I non-small-cell lung cancer who underwent lobectomy with complete lymph node dissection from 2013 through 2014, assessing various factors for an association with metastasis to lymph nodes (age, gender, pathology, tumour location, tumour differentiation, tumour size, pleural invasion, bronchus invasion, multicentric invasion and angiolymphatic invasion). After analysing these variables, we developed a multivariable logistic model to estimate risk of metastasis to lymph nodes.
Results
Univariate logistic regression identified tumour size >2.65 cm (p < 0.001), tumour differentiation (p < 0.001), pleural invasion (p = 0.034) and bronchus invasion (p < 0.001) to be risk factors significantly associated with the presence of metastatic lymph nodes. On multivariable analysis, only tumour size >2.65 cm (p < 0.001), tumour differentiation (p = 0.006) and bronchus invasion (p = 0.017) were independent predictors for lymph node metastasis. We developed a model based on these three pathologic factors that determined that the risk of metastasis ranged from 3% to 44% for patients intraoperatively diagnosed as stage I non-small-cell lung cancer. By applying the model, we found that the values ŷ > 0.80, 0.43 < ŷ ≤ 0.80, ŷ ≤ 0.43 plus tumour size >2 cm and ŷ ≤0.43 plus tumour size ≤2 cm yielded positive lymph node metastasis predictive values of 44%, 18%, 14% and 0%, respectively.
Conclusions
A non-invasive prediction model including tumour size, tumour differentiation and bronchus invasion may be useful to give thoracic surgeons recommendations on lymph node dissection for patients intraoperatively diagnosed as Stage I non-small cell lung cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-017-3273-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-017-3273-x
PMCID: PMC5390383  PMID: 28407802
Non-small-cell lung cancer; Lymph node; Metastasis; Multivariable logistic model
18.  Updated association of tea consumption and bone mineral density 
Medicine  2017;96(12):e6437.
Abstract
Background:
Current studies evaluating the association of tea consumption and bone mineral density (BMD) have yielded inconsistent findings. Therefore, we conducted a meta-analysis to assess the relationship between tea consumption and BMD.
Methods:
The PubMed, Embase, and Cochrane Library databases were comprehensively searched, and a meta-analysis performed of all observational studies assessing the association of tea consumption and BMD. Forest plots were used to illustrate the results graphically. The Q-test and I2 statistic were employed to evaluate between-study heterogeneity. Potential publication bias was assessed by the funnel plot.
Results:
Four cohort, 1 case–control, and 8 cross-sectional studies including a total of 12,635 cases were included. Tea consumption was shown to prevent bone loss [odds ratio (OR): 0.66; 95% confidence interval (CI), 0.47–0.94; P = 0.02], yielding higher mineral densities in several bones, including the lumbar spine [standardized mean difference (SMD): 0.19; 95% CI, 0.08–0.31; P = 0.001], hip (SMD: 0.19; 95% CI, 0.05–0.34; P = 0.01), femoral neck [mean difference (MD): 0.01; 95% CI, 0.00–0.02; P = 0.04], Ward triangle (MD: 0.02; 95% CI, 0.01–0.04; P = 0.001), and greater trochanter (MD: 0.03; 95% CI, 0.02–0.04; P < 0.00001), than the non-tea consumption group.
Conclusion:
This meta-analysis provided a potential trend that tea consumption might be beneficial for BMD, especially in the lumbar spine, hip, femoral neck, Ward triangle, and greater trochanter, which might help prevent bone loss.
doi:10.1097/MD.0000000000006437
PMCID: PMC5371490  PMID: 28328853
bone mineral density; meta-analysis; osteoporosis; tea consumption
19.  An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes 
Scientific Reports  2017;7:44120.
In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist MK-801 or GluN1 knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia.
doi:10.1038/srep44120
PMCID: PMC5356012  PMID: 28303894
20.  Quantum Dots for Wide Color Gamut Displays from Photoluminescence to Electroluminescence 
Monodisperse quantum dots (QDs) were prepared by low-temperature process. The remarkable narrow emission peak of the QDs helps the liquid crystal displays (LCD) and electroluminescence displays (QD light-emitting diode, QLED) to generate wide color gamut performance. The range of the color gamut for QD light-converting device (QLCD) is controlled by both the QDs and color filters (CFs) in LCD, and for QLED, the optimized color gamut is dominated by QD materials.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-017-1907-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s11671-017-1907-1
PMCID: PMC5328897  PMID: 28249368
Quantum dots (QDs); Quantum dot light-converting device (QLCD); Color filter (CF); Quantum dot light-emitting diode (QLED); Wide color gamut; Solution process
21.  Comparative profiling of hepatopancreas transcriptomes in satiated and starving Pomacea canaliculata 
BMC Genetics  2017;18:18.
Background
Although Pomacea canaliculata is native to South and Central America, it has become one of the most abundant invasive species worldwide and causes extensive damage to agriculture and horticulture. Conventional physical and chemical techniques have been used to eliminate P. canaliculata, but the effects are not ideal. Therefore, it is important to devise a new method based on a greater understanding of the biology of P. canaliculata. However, the molecular mechanisms underlying digestion and absorption in P. canaliculata are not well understood due to the lack of available genomic information for this species, particularly for digestive enzyme genes.
Results
In the present study, hepatopancreas transcriptome sequencing produced over 223 million high-quality reads, and a global de novo assembly generated a total of 87,766 unique transcripts (unigenes), of which 19,942 (22.7%) had significant similarities to proteins in the UniProt database. In addition, 296,675 annotated sequences were associated with Gene Ontology (GO) terms. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed for the unique unigenes, and 262 pathways (p-value < 10−5) in P. canaliculata were found to be predominantly related to plant consumption and coarse fiber digestion and absorption. These transcripts were classified into four large categories: hydrolase, transferase, isomerase and cytochrome P450. The Reads Per Kilobase of transcript per Million mapped reads (RPKM) analysis showed that there were 523 down-regulated unigenes and 406 up-regulated unigenes in the starving apple snails compared with the satiated apple snails. Several important genes are associated with digestion and absorption in plants: endo-beta-1, 4-glucanase, xylanase, cellulase, cellulase EGX1, cellulase EGX3 and G-type lysozyme genes were identified. The qRT-PCR results confirmed that the expression patterns of these genes (except for the longipain gene) were consistent with the RNA-Seq results.
Conclusions
Our results provide a more comprehensive understanding of the molecular genes associated with hepatopancreas functioning. Differentially expressed genes corresponding to critical metabolic pathways were detected in the transcriptome of starving apple snails compared with satiated apple snails. In addition to the cellulase gene, other genes were identified that may be important factors in plant matter metabolism in P. canaliculata, and this information has the potential to expedite the study of digestive physiology in apple snails.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-017-0485-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-017-0485-7
PMCID: PMC5322654  PMID: 28228093
Pomacea canaliculata; Hepatopancreas, Transcriptome; Digestion
22.  Gastric Juice-Based Real-Time PCR for Tailored Helicobacter Pylori Treatment: A Practical Approach 
A gastric juice-based real-time polymerase chain reaction (PCR) assay was established to identify Helicobacter pylori infection, clarithromycin susceptibility and human CYP2C19 genotypes and to guide the choice of proton pump inhibitor (PPI), clarithromycin and amoxicillin treatment for tailored H. pylori eradication therapy. From January 2013 to November 2014, 178 consecutive dyspeptic patients were enrolled for collection of gastric biopsy samples and gastric juice by endoscopy at the Peking University Third Hospital; 105 and 73 H. pylori-positive and -negative patients, respectively, were included in this study. H. pylori infection was defined as samples with both a strongly positive rapid urease test (RUT) and positive H. pylori histology. A series of primers and probes were distributed into four reactions for identifying the H. pylori cagH gene coupled with an internal control (Rnase P gene), A2142G and A2143G mutants of the H. pylori 23S rRNA gene, and single-nucleotide polymorphisms (SNPs) G681A of CYP2C19*2 and G636A of CYP2C19*3. The E-test and DNA sequencing were used to evaluate the H. pylori clarithromycin susceptibility phenotype and genotype. The SNPs CYP2C19*2 and CYP2C19*3 were also evaluated by nucleotide sequencing. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this gastric juice-based real-time PCR assay were evaluated by comparing with the same measures obtained through gastric biopsy-based PCR and culture. The H. pylori diagnostic sensitivities of the culture, PCR, and gastric biopsy- and gastric juice-based real-time PCR assays were 90.48% (95/105), 92.38% (97/105), 97.14% (102/105) and 100% (105/105), respectively; the specificities of the above methods were all 100%. Higher false-negative rates were found among the gastric biopsy samples assessed by culture (10.48%, 11/105), PCR (7.62%, 8/105) and real-time PCR (2.86%, 3/105) than in gastric juice by real-time PCR. Regarding clarithromycin susceptibility, a concordance of 82.98% (78/94) and discordance of 17.02% (16/94) were observed among the different methods, discrepancies that mainly represent differences between the H. pylori clarithromycin susceptibility phenotype and genotype. Three coinfections of susceptible and resistant strains were detected, with resistant-to-susceptible ratios of 1.16, 3.44, and 8.26. The CYP2C19 genotyping results from gastric juice by real-time PCR were completely in accordance with those obtained from biopsy samples by conventional PCR. This gastric juice-based real-time PCR assay is a more accurate method for detecting H. pylori infection, clarithromycin susceptibility and CYP2C19 polymorphisms. The method may be employed to inform the choice of proton pump inhibitor (PPI), clarithromycin and amoxicillin treatment for tailored H. pylori eradication therapy.
doi:10.7150/ijms.18996
PMCID: PMC5479129
gastric juice; real-time PCR; tailored H. pylori eradication.
23.  Epiregulin Promotes Lung Metastasis of Salivary Adenoid Cystic Carcinoma 
Theranostics  2017;7(15):3700-3714.
Salivary adenoid cystic carcinoma (SACC) is a peculiar malignant tumor, characterized by its slow but inexorable growth, with a high incidence of lung metastasis and poor prognosis. Here, we show the upregulated expression of EGFR ligand epiregulin in a subset of SACC cells correlates with lung metastasis and unfavorable outcome in patients with SACC. We found that upregulation of epiregulin in SACC cells induced epithelial-mesenchymal transition by regulating GLI1/E-cadherin. Elevated epiregulin increased the expression of pro-angiogenic factors, such as VEGFA, bFGF, and IL-8. We also show that epiregulin can be delivered via exosomes and was enriched in exosomes derived from epiregulin-overexpressing SACC cells. Furthermore, treating immunodeficient mice with these epiregulin-enriched exosomes greatly enhanced SACC metastasis to lung. These epiregulin-enriched exosomes significantly enhanced angiogenesis in the neighboring tumor microenvironment and increased vascular permeability in the pre-metastatic lung microenvironment in vivo. Therefore, epiregulin, as well as epiregulin-containing exosomes, may be a novel target for controlling SACC lung metastasis.
doi:10.7150/thno.19712
PMCID: PMC5667342
adenoid cystic cacinoma; epiregulin; lung metastasis; exosomes; pre-metastatic niche
24.  Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species 
Oncotarget  2016;7(52):86211-86224.
Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.
doi:10.18632/oncotarget.13367
PMCID: PMC5349908  PMID: 27863415
ent-kaurene diterpenoid derivative; esophageal squamous cell carcinoma; ROS; mitochondrion; Bax
25.  Genetically-mediated Grey and White Matter Alteration in Normal 
Elderly Individuals with the CLU-C Allele Gene 
Current Alzheimer Research  2016;13(11):1302-1310.
Abstract: Background
Several genome-wide association studies have found that the rs11136000 polymorphism of the C allele (CLU-C) is associated with the risk for developing late-onset Alzheimer’s disease (LOAD). However, the effects of the CLU-C/C genotype on brain structure, including gray and white matter, are not adequately understood.
Objectives
We aimed to clarify the gray matter and white matter integrity changes in non-demented ageing individuals with the AD risk gene of the rs11136000 polymorphism of the C allele (CLU-C) and the correlation with cognitive performance.
Methods
Voxel-based analysis was used to compare the differences in high-resolution structural T1 and diffusion tensor imaging data between 31 CLU-C/C and 15 non-CLU-C/C carriers in non-demented older adults.
Results
Compared to non-CLU-C/C carriers, CLU-C homozygotes showed a reduced gray matter concentration (GMC) in the left parahippocampal gyrus, right middle frontal and temporal middle gyri, increased GMC in the left middle frontal and right fusiform gyri and increased gray matter volume (GMV) in the left middle frontal gyrus (P < 0.001). Decreased fractional anisotropy (FA) in the sub-gyral white matter of the left external capsule and left anterior cingulate and increased FA in the sub-gyral white matter of the left temporal lobe were also found in CLU-C/C genotype carriers. Moreover, the FA value in the left external capsule correlated with several cognitive measures.
Conclusion
Our findings provide further evidence for the CLU risk variant as a candidate gene for AD and may serve as a pre-clinical neuroimaging phenotype of late-onset AD.
doi:10.2174/1567205013666160703180531
PMCID: PMC5112753  PMID: 27396407
Aging; Alzheimer’s disease; clusterin (CLU); diffusion tensor imaging; neuroimaging; voxel-based morphometry

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