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26.  An alternative novel tool for DNA editing without target sequence limitation: the structure-guided nuclease 
Genome Biology  2016;17:186.
Engineered endonucleases are a powerful tool for editing DNA. However, sequence preferences may limit their application. We engineer a structure-guided endonuclease (SGN) composed of flap endonuclease-1 (FEN-1), which recognizes the 3′ flap structure, and the cleavage domain of Fok I (Fn1), which cleaves DNA strands. The SGN recognizes the target DNA on the basis of the 3′ flap structure formed between the target and the guide DNA (gDNA) and cut the target through its Fn1 dimerization. Our results show that the SGN, guided by a pair of gDNAs, cleaves transgenic reporter gene and endogenous genes in zebrafish embryonic genome.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1038-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-016-1038-5
PMCID: PMC5025552  PMID: 27634179
Structure-guided endonuclease; flap endonuclease-1 (FEN-1); Fok I; Guide DNA; DNA editing
27.  Continuous detection and genetic diversity of human rotavirus A in sewage in eastern China, 2013–2014 
Virology Journal  2016;13(1):153.
Background
Rotavirus is the leading viral agent for pediatric gastroenteritis. However, the case-based surveillance for rotavirus is limited in China, and its circulation in the environment is not well investigated.
Methods
From 2013 to 2014, rotavirus was detected in raw sewage samples of Jinan and Linyi by quantitative PCR (qPCR) and conventional reverse transcription PCR (RT-PCR). After sequenced and genotyped, sequences analysis was conducted.
Results
A total of 46 sewage samples were collected monthly for the detection of rotavirus, and rotavirus was positive in 43 samples (93.5 %, 43/46). By quantitative assessment, the concentrations of rotavirus in raw sewage ranged from 4.1 × 103 to 1.3 × 106 genome copies (GC)/L in Jinan, and from 1.5 × 103 to 3.0 × 105 GC/L in Linyi. A total of 318 sequences of 5 G-genotypes and 318 sequences of 5 P-genotypes were obtained. G9 (91.8 %, 292/318) and P[8] (56.0 %, 178/318) were the most common G- and P-genotype, respectively. Multiple transmission lineages were recognized in these genotypes. Interestingly, an intragenic recombination event between two G9 lineages was observed.
Conclusions
This study provided the first report of comprehensive environmental surveillance for rotavirus in China. The results suggest that the concentration of rotavirus in raw sewage was high, and multiple rotavirus transmission lineages continuously co-circulated in Shandong.
doi:10.1186/s12985-016-0609-0
PMCID: PMC5022235  PMID: 27623961
Rotavirus; Molecular epidemiology; Quantification; Sewage; China
28.  Transient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells 
Experimental neurology  2015;271:122-130.
Excitotoxicity plays a critical role in neurodegenerative disease. Cytosolic calcium overload and mitochondrial dysfunction are among the major mediators of high level glutamate-induced neuron death. Here, we show that the transient opening of mitochondrial permeability transition pore (tMPT) bridges cytosolic calcium signaling and mitochondrial dysfunction and mediates glutamate-induced neuron death. Incubation of the differentiated motor neuron-like NSC34D cells with glutamate (1 mM) acutely induces cytosolic calcium transient (30% increase). Glutamate also stimulates tMPT opening, as reflected by a 2-fold increase in the frequency of superoxide flash, a bursting superoxide production event in individual mitochondria coupled to tMPT opening. The glutamate-induced tMPT opening is attenuated by suppressing cytosolic calcium influx and abolished by inhibiting mitochondrial calcium uniporter (MCU) with Ru360 (100 µM) or MCU shRNA. Further, increased cytosolic calcium is sufficient to induce tMPT in a mitochondrial calcium dependent manner. Finally, chronic glutamate incubation (24 hr) persistently elevates the probability of tMPT opening, promotes oxidative stress and induces neuron death. Attenuating tMPT activity or inhibiting MCU protects NSC34D cells from glutamate-induced cell death. These results indicate that high level glutamate-induced neuron toxicity is mediated by tMPT, which connects increased cytosolic calcium signal to mitochondrial dysfunction.
doi:10.1016/j.expneurol.2015.05.010
PMCID: PMC4586369  PMID: 26024861
Glutamate; Excitotoxicity; Mitochondrial calcium uniporter; Transient mitochondrial permeability transition; Superoxide flashes; Neuron death
29.  Resting heart rate associates with one-year risk of major adverse cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention 
Experimental Biology and Medicine  2015;241(5):478-484.
The study was to access the association between resting heart rate (RHR) and one-year risk of major adverse cardiovascular events (MACE) in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI). Patients with ACS after PCI (n = 808) were prospectively followed-up for MACE. RHR was obtained from electrocardiogram. MACE was defined as a composite of cardiac death, nonfatal recurrent myocardial infarction, ischemic-driven revascularization, and ischemic stroke. The association between RHR and one-year risk of MACE was assessed using Cox proportional hazards regression model. Compared with patients with RHR >76 bpm, the adjusted hazard ratio (AHR) was 0.51 (95% confidence intervals [CI]: 0.23–1.14; P = 0.100) for patients with RHR < 61 bpm, and 0.44 (95%CI: 0.23–0.85; P = 0.014) for those with RHR 61–76 bpm. For patients with RHR ≥ 61 bpm, an increase of 10 bpm in RHR was associated with an increase by 38.0% in the risk of MACE (AHR: 1.38; 95% CI: 1.04–1.83; P = 0.026). ACS patients after PCI with RHR >76 bpm were at higher risk of MACE during one-year follow-up compared with patients with RHR 61–76 bpm. An elevated RHR ≥ 61 bpm was associated with increased risk of one-year MACE in ACS patients.
doi:10.1177/1535370215617563
PMCID: PMC4950480  PMID: 26585407
Resting heart rate; acute coronary syndrome; percutaneous coronary intervention; major adverse cardiovascular events
30.  Effect of Xinyue capsules on patients with coronary heart disease after percutaneous coronary intervention: study protocol for a randomized controlled trial 
Trials  2016;17:412.
Background
The risk of cardiovascular events remains high in patients with coronary heart disease (CHD) after successful percutaneous coronary intervention (PCI). Panax quinquefolius saponin, a major component of Xinyue capsule, has been used to treat patients with CHD. The aim of this study is to evaluate the efficacy and safety of Xinyue capsules in patients with CHD after PCI.
Methods/design
This study is a multicenter, placebo-controlled, double-blind, randomized controlled clinical trial. A total of 1100 participants are randomly allocated to two groups: the intervention group and a placebo group. The intervention group receives Xinyue capsules plus conventional treatment, and the placebo group receives placebo capsules plus conventional treatment. The patients receive either Xinyue or placebo capsules three times daily (1.8 g/day) for up to 24 weeks. The primary outcome measure is the time from randomization to the first occurrence of major adverse cardiovascular events. The secondary outcome measure is the time from randomization to the first occurrence of stroke, pulmonary embolism, and peripheral vascular events, as well as death due to any cause. All outcome measures will be assessed at 12, 24, 36, and 48 weeks after randomization. Adverse events will be monitored during the trial.
Discussion
The aim of this study is to evaluate the effects of Xinyue capsules on patients with CHD after interventional treatment. The results of this trial will provide critical evidence regarding Chinese herbal medicine treatment for CHD.
Trial registration
Chinese Clinical Trials Registry identifier ChiCTR-IPR-14005475. Registered on 10 November 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1531-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-016-1531-x
PMCID: PMC4991005  PMID: 27538952
Xinyue capsule; Coronary heart disease; Randomized controlled trial
31.  A parameter estimation algorithm for LFM/BPSK hybrid modulated signal intercepted by Nyquist folding receiver 
Nyquist folding receiver (NYFR) is a novel ultra-wideband receiver architecture which can realize wideband receiving with a small amount of equipment. Linear frequency modulated/binary phase shift keying (LFM/BPSK) hybrid modulated signal is a novel kind of low probability interception signal with wide bandwidth. The NYFR is an effective architecture to intercept the LFM/BPSK signal and the LFM/BPSK signal intercepted by the NYFR will add the local oscillator modulation. A parameter estimation algorithm for the NYFR output signal is proposed. According to the NYFR prior information, the chirp singular value ratio spectrum is proposed to estimate the chirp rate. Then, based on the output self-characteristic, matching component function is designed to estimate Nyquist zone (NZ) index. Finally, matching code and subspace method are employed to estimate the phase change points and code length. Compared with the existing methods, the proposed algorithm has a better performance. It also has no need to construct a multi-channel structure, which means the computational complexity for the NZ index estimation is small. The simulation results demonstrate the efficacy of the proposed algorithm.
doi:10.1186/s13634-016-0387-2
PMCID: PMC4990610  PMID: 27594883
Nyquist folding receiver; LFM/BPSK hybrid modulated signal; Parameter estimation; Signal characteristics
32.  Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer 
Oncology Letters  2016;12(4):2880-2885.
Ursolic acid is a type of pentacyclic triterpene compound with multiple pharmacological activities including cancer resistance, protection from liver injury, antisepsis, anti-inflammation and antiviral activity. The present study aimed to investigate the anticancer effect of ursolic acid. Ursolic acid activates cell apoptosis and its pro-apoptotic mechanism remains to be fully elucidated. Cell Counting kit-8 assays, flow cytometric analysis and analysis of caspase-3 and caspase-9 activity were used to estimate the anticancer effect of ursolic acid on DU145 prostate cancer cells. The protein expression of cytochrome c, rho-associated protein kinase (ROCK), phosphatase and tensin homolog (PTEN) and cofilin-1 were examined using western blot analysis. In the present study, ursolic acid significantly suppressed cell growth and induced apoptosis, as well as increasing caspase-3 and caspase-9 activities of DU145 cells. Furthermore, cytoplasmic and mitochondrial cytochrome c protein expression was significantly activated and suppressed, respectively, by ursolic acid. Ursolic acid significantly suppressed the ROCK/PTEN signaling pathway and inhibited cofilin-1 protein expression in DU145 cells. The results of the present study indicate that the anticancer effect of ursolic acid activates cell apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer.
doi:10.3892/ol.2016.5015
PMCID: PMC5038386  PMID: 27698874
ursolic acid; prostate cancer; cytochrome c; rho-associated protein kinase/phosphatase and tensin homolog; cofilin-1
33.  A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation 
Scientific Reports  2016;6:31379.
Physiological processes such as metabolism, cell apoptosis and immune responses, must be strictly regulated to maintain their homeostasis and achieve their normal physiological functions. The speed with which bio-molecular homeostatic regulation occurs directly determines the ability of an organism to adapt to conditional changes. To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes was constructed using DNA origami nanotechnology. This nano-fingers device functioned in linked open and closed phases using two types of DNA tweezers, which were covalently coupled with aptamers that captured specific molecules when the tweezer arms were sufficiently close. Via this specific interaction mechanism, certain physiological processes could be simultaneously regulated from two directions by capturing one biofactor and releasing the other to enhance the regulatory capacity of the device. To validate the universal application of this device, regulation of the homeostasis of the blood coagulant thrombin was attempted using the nano-fingers device. It was successfully demonstrated that this nano-fingers device achieved coagulation buffering upon the input of fuel DNA. This nano-device could also be utilized to regulate the homeostasis of other types of bio-molecules.
doi:10.1038/srep31379
PMCID: PMC4979213  PMID: 27506964
34.  TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells 
Scientific Reports  2016;6:30904.
Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
doi:10.1038/srep30904
PMCID: PMC4971483  PMID: 27485764
35.  De Novo Transcriptome Analysis of Differential Functional Gene Expression in Largemouth Bass (Micropterus salmoides) after Challenge with Nocardia seriolae 
Largemouth bass (Micropterus salmoides) are common hosts of an epizootic bacterial infection by Nocardia seriolae. We conducted transcriptome profiling of M. salmoides to understand the host immune response to N. seriolae infection, using the Illumina sequencing platform. De novo assembly of paired-end reads yielded 47,881 unigenes, the total length, average length, N50, and GC content of which were 49,734,288, 1038, 1983 bp, and 45.94%, respectively. Annotation was performed by comparison against non-redundant protein sequence (NR), non-redundant nucleotide (NT), Swiss-Prot, Clusters of Orthologous Groups (COG), Kyoto Encyclopaedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Interpro databases, yielding 28,964 (NR: 60.49%), 36,686 (NT: 76.62%), 24,830 (Swissprot: 51.86%), 8913 (COG: 18.61%), 20,329 (KEGG: 42.46%), 835 (GO: 1.74%), and 22,194 (Interpro: 46.35%) unigenes. Additionally, 8913 unigenes were classified into 25 Clusters of Orthologous Groups (KOGs) categories, and 20,329 unigenes were assigned to 244 specific signalling pathways. RNA-Seq by Expectation Maximization (RSEM) and PossionDis were used to determine significantly differentially expressed genes (False Discovery Rate (FDR) < 0.05) and we found that 1384 were upregulated genes and 1542 were downregulated genes, and further confirmed their regulations using reverse transcription quantitative PCR (RT-qPCR). Altogether, these results provide information on immune mechanisms induced during bacterial infection in largemouth bass, which may facilitate the prevention of nocardiosis.
doi:10.3390/ijms17081315
PMCID: PMC5000712  PMID: 27529219
Illumina paired-end sequencing; immune response; largemouth bass (Micropterus salmoides); Nocardia seriolae; transcriptome
36.  Crucial roles of the Arp2/3 complex during mammalian corticogenesis 
Development (Cambridge, England)  2016;143(15):2741-2752.
The polarity and organization of radial glial cells (RGCs), which serve as both stem cells and scaffolds for neuronal migration, are crucial for cortical development. However, the cytoskeletal mechanisms that drive radial glial outgrowth and maintain RGC polarity remain poorly understood. Here, we show that the Arp2/3 complex – the unique actin nucleator that produces branched actin networks – plays essential roles in RGC polarity and morphogenesis. Disruption of the Arp2/3 complex in murine RGCs retards process outgrowth toward the basal surface and impairs apical polarity and adherens junctions. Whereas the former is correlated with an abnormal actin-based leading edge, the latter is consistent with blockage in membrane trafficking. These defects result in altered cell fate, disrupted cortical lamination and abnormal angiogenesis. In addition, we present evidence that the Arp2/3 complex is a cell-autonomous regulator of neuronal migration. Our data suggest that Arp2/3-mediated actin assembly might be particularly important for neuronal cell motility in a soft or poorly adhesive matrix environment.
Summary: During mouse cortical development, the Arp2/3 actin branching complex regulates process formation and the maintenance of radial glial cell polarity, as well as affecting neuronal migration.
doi:10.1242/dev.130542
PMCID: PMC5004905  PMID: 27385014
Arp2/3 complex; Actin; Cortical development; Neurogenesis; Neuronal migration; Radial glia; Mouse
37.  Quality of life and related factors of nursing home residents in Singapore 
Background
Litter is known about the well-being of nursing home (NH) residents in Singapore. This study aimed to identify predictors of self-reported quality of life (QOL) of NH residents in Singapore.
Methods
In face-to-face interviews, trained medical students assessed each consenting resident recruited from 6 local NHs using a modified Minnesota QOL questionnaire, and rating scales and questions assessing independence, cognitive function, depression, and communication. Predictors of residents’ QOL in five aspects (comfort, dignity, food enjoyment, autonomy, and security) were identified using the censored least absolute deviations (CLAD) models.
Results
A total of 375 residents completed the interviews. A higher score on comfort was negatively associated with major depression while a higher score on dignity was positively associated with no difficulty in communication with staff. Higher scores in food enjoyment were negatively associated with major depression and poorer cognitive function. Higher scores in autonomy were negatively associated with major depression, greater dependence, and difficulty in communication with staff. A higher score on security were negatively associated with major depression.
Conclusion
It appears that depression and difficulty in communication with staff are the two main modifiable risk factors of poor quality of life of local NH residents.
doi:10.1186/s12955-016-0503-x
PMCID: PMC4964280  PMID: 27464566
Quality of life; Nursing home; Risk factors; Singapore
38.  Appraisal of clinical practice guidelines for management of paediatric type 2 diabetes mellitus using the AGREE II instrument: a systematic review protocol 
Systematic Reviews  2016;5:111.
Background
The prevalence of type 2 diabetes mellitus (T2DM) in children and adolescents is increasing. This has spurred the development and publication of clinical practice guidelines (CPGs) for the management of paediatric T2DM. Given the long-term complications of T2DM, optimal management is important to prevent or delay these complications. However, the quality of published CPGs has not yet been empirically evaluated.
Our objective is to systematically appraise all published CPGs for the management of T2DM in children and adolescents.
Methods
We will identify all published CPGs that address T2DM in children and adolescents through MEDLINE, Embase, CINAHL, Trip, and the National Guideline Clearinghouse and will screen diabetes and paediatric societies and associations’ websites. Search records will be screened in duplicate for inclusion. Grey literature will be covered by systematically searching publications of all relevant diabetes societies and associations and other health organizations for CPGs that meet our inclusion criteria. CPGs deemed eligible for inclusion will be retrieved. Quality assessment will be conducted using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool by a team of four appraisers. Scaled scores of the AGREE II will be used to gauge the overall quality of CPGs.
Discussion
The results of this review will be disseminated through presentations at local, national, and international conferences and publication in a peer-reviewed journal. The results of this review can help improve the reporting of future guidelines, inform decisions of policy-makers to endorse CPGs, and affect the choice of guideline use in clinical practice.
Systematic review registration
PROSPERO CRD42016034187
doi:10.1186/s13643-016-0288-3
PMCID: PMC4944246  PMID: 27412255
39.  Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer 
Oncotarget  2016;7(27):42585-42597.
Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERβ exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERβ, but not ERα, that dictates ERβ transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERβ activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERβ, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERβ-specific agonists such as S-equol enhance ERβ phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERβ activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERβ tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERβ signaling is an attractive target for anticancer treatment.
doi:10.18632/oncotarget.10018
PMCID: PMC5173158  PMID: 27323858
tyrosine phosphorylation; ERβ; ubiquitination; antitumor activity; protein turnover
40.  The Relationship between C-Reactive Protein Level and Discharge Outcome in Patients with Acute Ischemic Stroke 
Previous studies showed that C-reactive protein (CRP), an inflammatory marker, was associated with stroke severity and long-term outcome. However, the relationship between the acute-phase CRP level and discharge outcome has received little attention. We prospectively studied 301 patients with acute ischemic stroke (over a period of two weeks) from two hospital stroke wards and one rehabilitation department in Henan, China. Patients’ demographic and clinical data were collected and evaluated at admission. Poor discharge outcome was assessed in patients at discharge using the Modified Rankin Scale (MRS > 2). Multivariate logistic regression analysis was performed to determine the risk factors of poor discharge outcome after adjusting for potential confounders. Poor discharge outcome was observed in 78 patients (25.9%). Univariate analyses showed that factors significantly influencing poor discharge outcome were age, residence, recurrent acute ischemic stroke, coronary heart disease, the National Institutes of Health Stroke Scale (NIHSS) score at admission, non-lacunar stroke, time from onset of stroke to admission, CRP, TBIL (total bilirubin), direct bilirubin (DBIL), ALB (albumin), FIB (fibrinogen) and D-dimer (p < 0.05). After adjusting for age, residence, recurrent ischemic stroke, coronary heart disease, NIHSS score at admission, lacunar stroke, time from onset of stroke to admission, CRP, TBIL, DBIL, ALB, FIB and D-dimer, multivariate logistic regression analyses revealed that poor outcome at discharge was associated with recurrent acute ischemic stroke (OR, 2.115; 95% CI, 1.094–4.087), non-lacunar stroke (OR, 2.943; 95% CI, 1.436–6.032), DBIL (OR, 1.795; 95% CI, 1.311–2.458), and CRP (OR, 4.890; 95% CI, 3.063–7.808). In conclusion, the CRP level measured at admission was found to be an independent predictor of poor outcome at discharge. Recurrent acute ischemic stroke, non-lacunar stroke and DBIL were also significantly associated with discharge outcome in acute ischemic stroke.
doi:10.3390/ijerph13070636
PMCID: PMC4962177  PMID: 27355961
acute ischemic stroke; C-reactive protein; recurrence; discharge outcome
41.  Smg6/Est1 licenses embryonic stem cell differentiation via nonsense-mediated mRNA decay 
The EMBO Journal  2015;34(12):1630-1647.
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of Smg6 is compatible with embryonic stem cell (ESC) proliferation despite the absence of telomere maintenance and functional NMD. Differentiation of Smg6-deficient ESCs is blocked due to sustained expression of pluripotency genes, normally repressed by NMD, and forced down-regulation of one such target, c-Myc, relieves the differentiation block. Smg6-null embryonic fibroblasts are viable as well, but are refractory to cellular reprograming into induced pluripotent stem cells (iPSCs). Finally, depletion of all major NMD factors compromises ESC differentiation, thus identifying NMD as a licensing factor for the switch of cell identity in the process of stem cell differentiation and somatic cell reprograming.
doi:10.15252/embj.201489947
PMCID: PMC4475398  PMID: 25770585
cell reprograming; ESC differentiation; NMD; Smg6/Est1; telomere
42.  MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy 
Scientific Reports  2016;6:27589.
Melanocortin therapy by using adrenocorticotropic hormone (ACTH) or non-steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in experimental glomerular diseases and induces remission of nephrotic syndrome in patients with diverse glomerulopathies, even those resistant to steroids. The underlying mechanism remains elusive, but the role of melanocortin 1 receptor (MC1R) has been implicated and was examined here. Four patients with congenital red hair color and nephrotic syndrome caused by idiopathic membranous nephropathy or focal segmental glomerulosclerosis were confirmed by gene sequencing to bear dominant-negative MC1R mutations. Despite prior corticosteroid resistance, all patients responded to ACTH monotherapy and ultimately achieved clinical remission, inferring a steroidogenic-independent and MC1R-dispensable anti-proteinuric effect of melanocortin signaling. In confirmatory animal studies, the protective effect of [Nle4, D-Phe7]-α-melanocyte stimulating hormone (NDP-MSH), a potent non-steroidogenic pan-melanocortin receptor agonist, on the lipopolysaccharide elicited podocytopathy was completely preserved in MC1R-null mice, marked by reduced albuminuria and diminished histologic signs of podocyte injury. Moreover, in complementary in vitro studies, NDP-MSH attenuated the lipopolysaccharide elicited apoptosis, hypermotility and impairment of filtration barrier function equally in primary podocytes derived from MC1R-null and wild-type mice. Collectively, our findings suggest that melanocortin therapy confers a proteinuria reducing and podoprotective effect in proteinuric glomerulopathies via MC1R-independent mechanisms.
doi:10.1038/srep27589
PMCID: PMC4897792  PMID: 27270328
43.  The Combination of DGT Technique and Traditional Chemical Methods for Evaluation of Cadmium Bioavailability in Contaminated Soils with Organic Amendment 
Organic amendments have been proposed as a means of remediation for Cd-contaminated soils. However, understanding the inhibitory effects of organic materials on metal immobilization requires further research. In this study colza cake, a typical organic amendment material, was investigated in order to elucidate the ability of this material to reduce toxicity of Cd-contaminated soil. Available concentrations of Cd in soils were measured using an in situ diffusive gradients in thin films (DGT) technique in combination with traditional chemical methods, such as HOAc (aqua regia), EDTA (ethylene diamine tetraacetic acid), NaOAc (sodium acetate), CaCl2, and labile Cd in pore water. These results were applied to predict the Cd bioavailability after the addition of colza cake to Cd-contaminated soil. Two commonly grown cash crops, wheat and maize, were selected for Cd accumulation studies, and were found to be sensitive to Cd bioavailability. Results showed that the addition of colza cake may inhibit the growth of wheat and maize. Furthermore, the addition of increasing colza cake doses led to decreasing shoot and root biomass accumulation. However, increasing colza cake doses did lead to the reduction of Cd accumulation in plant tissues, as indicated by the decreasing Cd concentrations in shoots and roots. The labile concentration of Cd obtained by DGT measurements and the traditional chemical extraction methods, showed the clear decrease of Cd with the addition of increasing colza cake doses. All indicators showed significant positive correlations (p < 0.01) with the accumulation of Cd in plant tissues, however, all of the methods could not reflect plant growth status. Additionally, the capability of Cd to change from solid phase to become available in a soil solution decreased with increasing colza cake doses. This was reflected by the decreases in the ratio (R) value of CDGT to Csol. Our study suggests that the sharp decrease in R values could not only reflect the extremely low capability of labile Cd to be released from its solid phase, but may also be applied to evaluate the abnormal growth of the plants.
doi:10.3390/ijerph13060595
PMCID: PMC4924052  PMID: 27314376
organic amendment; colza cake; cadmium bioavailability; DGT extraction; extraction method; plant
44.  Dosimetric study for cervix carcinoma treatment using intensity modulated radiation therapy (IMRT) compensation based on 3D intracavitary brachytherapy technique 
Purpose
Intensity modulated radiation therapy (IMRT) compensation based on 3D high-dose-rate (HDR) intracavitary brachytherapy (ICBT) boost technique (ICBT + IMRT) has been used in our hospital for advanced cervix carcinoma patients. The purpose of this study was to compare the dosimetric results of the four different boost techniques (the conventional 2D HDR intracavitary brachytherapy [CICBT], 3D optimized HDR intracavitary brachytherapy [OICBT], and IMRT-alone with the applicator in situ).
Material and methods
For 30 patients with locally advanced cervical carcinoma, after the completion of external beam radiotherapy (EBRT) for whole pelvic irradiation 45 Gy/25 fractions, five fractions of ICBT + IMRT boost with 6 Gy/fractions for high risk clinical target volume (HRCTV), and 5 Gy/fractions for intermediate risk clinical target volume (IRCTV) were applied. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were acquired using an in situ CT/MRI-compatible applicator. The gross tumor volume (GTV), the high/intermediate-risk clinical target volume (HRCTV/IRCTV), bladder, rectum, and sigmoid were contoured by CT scans.
Results
For ICBT + IMRT plan, values of D90, D100 of HRCTV, D90, D100, and V100 of IRCTV significantly increased (p < 0.05) in comparison to OICBT and CICBT. The D2cc values for bladder, rectum, and sigmoid were significantly lower than that of CICBT and IMRT alone. In all patients, the mean rectum V60 Gy values generated from ICBT + IMRT and OICBT techniques were very similar but for bladder and sigmoid, the V60 Gy values generated from ICBT + IMRT were higher than that of OICBT. For the ICBT + IMRT plan, the standard deviations (SD) of D90 and D2cc were found to be lower than other three treatment plans.
Conclusions
The ICBT + IMRT technique not only provides good target coverage but also maintains low doses (D2cc) to the OAR. ICBT + IMRT is an optional technique to boost parametrial region or tumor of large size and irregular shape when intracavitary/interstitial brachytherapy cannot be used.
doi:10.5114/jcb.2016.60590
PMCID: PMC4965499  PMID: 27504132
brachytherapy; cervical cancer; cervix carcinoma; dosimetry; IMRT
45.  Cyclin E Deregulation Promotes Loss of Specific Genomic Regions 
Current biology : CB  2015;25(10):1327-1333.
Summary
Cell cycle progression is regulated by the cyclin-dependent kinase (Cdk) family of protein kinases, so named because their activation depends on association with regulatory subunits known as cyclins [1]. Cyclin E normally accumulates at the G1/S boundary, where it promotes S phase entry and progression by activating Cdk2. In normal cells, cyclin E/Cdk2 activity is associated with DNA replication-related functions [2]. However, deregulation of cyclin E leads to inefficient assembly of pre-replication complexes [3], replication stress [4], and chromosome instability [5]. In malignant cells, cyclin E is frequently overexpressed, correlating with decreased survival in breast cancer patients [6, 7]. Transgenic mice deregulated for cyclin E in the mammary epithelia develop carcinoma [8], confirming that cyclin E is an oncoprotein. However, it remains unknown how cyclin E-mediated replication stress promotes genomic instability during carcinogenesis. Here we show that deregulation of cyclin E causes human mammary epithelial cells to enter into mitosis with short unreplicated genomic segments at a small number of specific loci, leading to anaphase anomalies and ultimately deletions. Incompletely replicated regions are preferentially located at late-replicating domains, fragile sites and breakpoints, including the mixed-lineage leukemia breakpoint cluster region (MLL BCR). Furthermore, these regions are characterized by a paucity of replication origins or unusual DNA structures. Analysis of a large set of breast tumors shows a significant correlation between cyclin E amplification and deletions at a number of the genomic loci identified in our study. Our results demonstrate how oncogene-induced replication stress contributes to genomic instability in human cancer.
doi:10.1016/j.cub.2015.03.022
PMCID: PMC4439338  PMID: 25959964
46.  The mitochondrial genome of the land snail Cernuella virgata (Da Costa, 1778): the first complete sequence in the family Hygromiidae (Pulmonata, Stylommatophora) 
ZooKeys  2016;55-69.
The land snail Cernuella virgata (da Costa, 1778) is widely considered as a pest to be quarantined in most countries. In this study, the complete mitochondrial genome of Cernuella virgata is published. The mitochondrial genome has a length of 14,147 bp a DNA base composition of 29.07% A, 36.88% T, 15.59% C and 18.46% G, encoding 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes and two ribosomal RNA (rRNA) genes. The complete nucleotide composition was biased toward adenine and thymine, A+T accounting for 69.80%. Nine PCGs and 14 tRNA genes are encoded on the J strand, and the other four PCGs and eight tRNA genes are encoded on the N strand. The genome also includes 16 intergenic spacers. All PCGs start strictly with ATN, and have conventional stop codons (TAA and TAG). All tRNAs fold into the classic cloverleaf structure, except tRNAArg, tRNASer(UCN), tRNASer(AGN) and tRNAPro. The first three lack the dihydrouridine arm while the last lacks the TψC arm. There are 502 bp long noncoding regions and 418bp long gene overlaps in the whole mitochondrial genome, accounting for 3.54% and 2.95% of the total length respectively. Phylogenetic analyses based on the sequences of the protein coding genes revealed a sister group relationship between the Hygromiidae and the Helicidae.
doi:10.3897/zookeys.589.7637
PMCID: PMC4926662  PMID: 27408534
DNA sequencing; phylogeny; plant quarantine; secondary structure; white snail
47.  Structure and transformation of tactoids in cellulose nanocrystal suspensions 
Nature Communications  2016;7:11515.
Cellulose nanocrystals obtained from natural sources are of great interest for many applications. In water, cellulose nanocrystals form a liquid crystalline phase whose hierarchical structure is retained in solid films after drying. Although tactoids, one of the most primitive components of liquid crystals, are thought to have a significant role in the evolution of this phase, they have evaded structural study of their internal organization. Here we report the capture of cellulose nanocrystal tactoids in a polymer matrix. This method allows us to visualize, for the first time, the arrangement of cellulose nanocrystals within individual tactoids by electron microscopy. Furthermore, we can follow the structural evolution of the liquid crystalline phase from tactoids to iridescent-layered films. Our insights into the early nucleation events of cellulose nanocrystals give important information about the growth of cholesteric liquid crystalline phases, especially for cellulose nanocrystals, and are crucial for preparing photonics-quality films.
Cellulose nanocrystals suspensions self-assemble into cholesteric liquid crystalline droplets, namely tactoids, which then condense into helical structures upon drying. Here, Wang et al. capture the structural evolution of this nucleation process by trapping and protecting tactoids in a polymer matrix.
doi:10.1038/ncomms11515
PMCID: PMC4857480  PMID: 27143197
48.  A regularized multivariate regression approach for eQTL analysis 
Statistics in biosciences  2013;7(1):129-146.
Expression quantitative trait loci (eQTLs) are genomic loci that regulate expression levels of mRNAs or proteins. Understanding these regulatory provides important clues to biological pathways that underlie diseases. In this paper, we propose a new statistical method, GroupRemMap, for identifying eQTLs. We model the relationship between gene expression and single nucleotide variants (SNVs) through multivariate linear regression models, in which gene expression levels are responses and SNV genotypes are predictors. To handle the high-dimensionality as well as to incorporate the intrinsic group structure of SNVs, we introduce a new regularization scheme to (1) control the overall sparsity of the model; (2) encourage the group selection of SNVs from the same gene; and (3) facilitate the detection of trans-hub-eQTLs. We apply the proposed method to the colorectal and breast cancer data sets from The Cancer Genome Atlas (TCGA), and identify several biologically interesting eQTLs. These findings may provide insight into biological processes associated with cancers and generate hypotheses for future studies.
doi:10.1007/s12561-013-9106-9
PMCID: PMC4465818  PMID: 26085849
GroupRemMap; remMap; eQTL Analysis; Regularization; Multivariate Linear Regression
49.  H-Type Hypertension and C Reactive Protein in Recurrence of Ischemic Stroke 
Hypertension with high homocysteine (HHcy) (H-type hypertension) and C reactive protein (CRP) can increase the incidence of ischemic stroke. However, it is not clear whether recurrent ischemic stroke (RIS) is related to H-type hypertension and CRP. The present study investigated the correlation of H-type hypertension and CRP level with RIS. Totally, 987 consecutive patients with acute ischemic stroke were recruited in a teaching hospital in Henan province, China during March 2014 to March 2015. The demographic and clinical characteristics and blood biochemical parameters of patients were analyzed. Elevated levels of CRP and homocysteine (Hcy) were defined as >8.2 mg/L and 10 μmol/L, respectively. Among the 987 patients, 234 were RIS. Thirty-eight percent of RIS patients had elevated CRP level and 91.5% of RIS patients had HHcy. In multivariate analysis, adjusted odds ratio (OR) of RIS in patients aged ≥60 years was 1.576 (95% CI: 1.125–2.207), in male patients 1.935 (95% CI: 1.385–2.704), in patients with diabetes 1.463 (95% CI: 1.037–2.064), CRP levels 1.013 (95% CI: 1.006–1.019), simple hypertension 3.370 (95% CI: 1.15–10.183), and H-type hypertension 2.990 (95% CI: 1.176–7.600). RIS was associated with older age, male, diabetes, H-type hypertension and CRP. Controlling H-type hypertension and CRP level may reduce the risk of RIS.
doi:10.3390/ijerph13050477
PMCID: PMC4881102  PMID: 27164124
C reactive protein; H-type hypertension; recurrence ischemic stroke
50.  An Intracranial Gliosis Mimicking Neoplasm: A Dilemma 
Iranian Journal of Radiology  2016;13(2):e16785.
Intracranial gliosis has no typical clinical signals or imaging characteristics. Therefore, it can be easily misdiagnosed as neoplasm. Hereby, we report a unique case of gliosis that grew outward from the surface of the brain. MRI depicted its signal and enhancement pattern similar to the cerebral gray matter. The diagnosis was confirmed by pathology and immunohistochemistry. Although it was difficult to reach a diagnosis, correlating its origin, growing pattern and MR features and knowing that gliosis can present this way may help in differentiating it from other diseases.
doi:10.5812/iranjradiol.16785
PMCID: PMC5040098  PMID: 27703653
Gliosis; Pathology; Magnetic Resonance Imaging (MRI); Neoplasm

Results 26-50 (332)