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1.  Crystallization and preliminary crystallographic analysis of a viral RNA-silencing suppressor encoded by Wuhan nodavirus  
A viral RNA-silencing suppressor encoded by Wuhan nodavirus has been overexpressed in Escherichia coli, purified and crystallized. Diffraction data were collected to 2.8 Å resolution.
Wuhan nodavirus (WhNV), which is a new member of the Nodaviridae family, encodes a viral protein, B2, that suppresses RNA silencing and host-cell RNA interference (RNAi)-mediated immunity. Although Flock House virus (FHV), another member of the Nodaviridae family, also produces a B2 protein with a similar function, the primary sequences of the B2 proteins from WhNV and FHV have no similarity. To gain a better understanding of the structural details and the mechanism of suppression of RNA silencing by WhNV B2 and to compare it with FHV B2, recombinant WhNV B2 protein has been overexpressed in Escherichia coli, purified and crystallized at 291 K using PEG 4000 as a precipitant. A 2.8 Å resolution data set has been collected from a single crystal at 100 K. This crystal belonged to space group P212121, with unit-cell parameters a = 27.3, b = 45.6, c = 133.9 Å, α = β = γ = 90°. Assuming the presence of two molecules in the asymmetric unit, the Matthews coefficient is 2.2 Å3 Da−1.
PMCID: PMC3792677  PMID: 24100569
Wuhan nodavirus; viral RNA-silencing suppressor
2.  Association of common SNP rs1136410 in PARP1 gene with the susceptibility to male infertility with oligospermia 
This study aims to explore possible associations between polymorphisms of common SNP rs1136410 and rS1805405 in PARP1 gene and male infertility with spermatogenesis impairment.
The polymorphic distributions of SNP rs1136410 and rS1805405 were investigated by polymerase chain reaction and restriction fragment length polymorphism analysis in a Chinese cohort including 371 infertile patients with idiopathic azoospermia or oligospermia and 231 controls.
Significant differences in the frequencies of allele and genotype of SNP rs1136410 were observed between patients with oligospermia and controls. The allele C (46.3 % vs. 36.4 %, P = 0.003) and genotype CC (22.6 % vs. 13.4 %, P = 0.014) significantly increased, whereas genotype TT (30 % vs. 40.7 %, P = 0.021) significantly decreased in patients with oligospermia compared with controls at this SNP locus.
These results indicated that genotype CC of SNP rs1136410 may increase the risk of oligosoermia and genotype TT of rs1136410 may have some protective effect from oligospermia, suggesting that the polymorphism of SNP rs1136410 in PARP1 gene may modify the susceptibility to male infertility with oligospermia.
PMCID: PMC4171409  PMID: 25106941
PARP1; Polymorphism; Spermatogenesis impairment; Male infertility; Oligospermia
3.  Chemoembolization alone vs combined chemoembolization and hepatic arterial infusion chemotherapy in inoperable hepatocellular carcinoma patients 
World Journal of Gastroenterology : WJG  2015;21(36):10443-10452.
AIM: To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis.
METHODS: Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups.
RESULTS: A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically.
CONCLUSION: Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.
PMCID: PMC4579891  PMID: 26420971
Chemoembolization; Hepatic arterial infusion chemotherapy; Oxaliplatin; Hepatocellular carcinoma
4.  Progressive Degeneration of Retinal and Superior Collicular Functions in Mice With Sustained Ocular Hypertension 
We investigated the progressive degeneration of retinal and superior collicular functions in a mouse model of sustained ocular hypertension.
Focal laser illumination and injection of polystyrene microbeads were used to induce chronic ocular hypertension. Retinal ganglion cell (RGC) loss was characterized by in vivo optical coherence tomography (OCT) and immunohistochemistry. Retinal dysfunction was also monitored by the full-field ERG. Retinal ganglion cell light responses were recorded using a 256-channel multielectrode array (MEA), and RGC subtypes were characterized by noncentered spike-triggered covariance (STC-NC) analysis. Single-unit extracellular recordings from superficial layers of the superior colliculus (SC) were performed to examine the receptive field (RF) properties of SC neurons.
The elevation of intraocular pressure (IOP) lasted 4 months in mice treated with a combination of laser photocoagulation and microbead injection. Progressive RGC loss and functional degeneration were confirmed in ocular hypertensive (OHT) mice. These mice had fewer visually responsive RGCs than controls. Using the STC-NC analysis, we classified RGCs into ON, OFF, and ON-OFF functional subtypes. We showed that ON and OFF RGCs were more susceptible to the IOP elevation than ON-OFF RGCs. Furthermore, SC neurons of OHT mice had weakened responses to visual stimulation and exhibited mismatched ON and OFF subfields and irregular RF structure.
We demonstrated that the functional degeneration of RGCs is subtype-dependent and that the ON and OFF pathways from the retina to the SC were disrupted. Our study provides a foundation to investigate the mechanisms underlying the progressive vision loss in experimental glaucoma.
Sustained ocular hypertension induced progressive degeneration of retinal and superior collicular function in mice.
PMCID: PMC4365983  PMID: 25722210
ocular hypertension; retinal ganglion cells; superior colliculus; neural degeneration; multielectrode array
5.  Analysis of Pre-Analytic Factors Affecting the Success of Clinical Next-Generation Sequencing of Solid Organ Malignancies 
Cancers  2015;7(3):1699-1715.
Application of next-generation sequencing (NGS) technology to routine clinical practice has enabled characterization of personalized cancer genomes to identify patients likely to have a response to targeted therapy. The proper selection of tumor sample for downstream NGS based mutational analysis is critical to generate accurate results and to guide therapeutic intervention. However, multiple pre-analytic factors come into play in determining the success of NGS testing. In this review, we discuss pre-analytic requirements for AmpliSeq PCR-based sequencing using Ion Torrent Personal Genome Machine (PGM) (Life Technologies), a NGS sequencing platform that is often used by clinical laboratories for sequencing solid tumors because of its low input DNA requirement from formalin fixed and paraffin embedded tissue. The success of NGS mutational analysis is affected not only by the input DNA quantity but also by several other factors, including the specimen type, the DNA quality, and the tumor cellularity. Here, we review tissue requirements for solid tumor NGS based mutational analysis, including procedure types, tissue types, tumor volume and fraction, decalcification, and treatment effects.
PMCID: PMC4586792  PMID: 26343728
next-generation sequencing; targeted hotspot mutation analysis; pre-analytic factors; tissue qualification
6.  Protective effects of (-)-epigallocatechin-3-gallate against acetaminophen-induced liver injury in rats) 
BioMedicine  2015;5(3):15.
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant catechin with various biological activities found in tea. In this study, the effects of EGCG on the metabolism and toxicity of acetaminophen in rat liver were investigated. Male Sprague-Dawley rats were fed a controlled diet without or with EGCG (0.54 %, w/w) for 1 week and were then intraperitoneally injected with acetaminophen (1 g/kg body weight) and killed after 12 h. Concentrations of acetaminophen and its conjugates in plasma and liver were then determined. The cytochrome P450 (CYP) and phase II enzymes activities were also evaluated. Rats fed the EGCG diet had lower plasma alanine aminotransferase and aspartate aminotransferase activities, as indices of hepatotoxicity, after acetaminophen treatment. Morphological damage by acetaminophen was lower in rats fed the EGCG diet. In addition, EGCG significantly reduced hepatic activities of midazolam 1-hydroxylation (CYP3A), nitrophenol 6-hydroxylase (CYP2E1), UDP-glucurosyltransferase, and sulfotransferase. Finally, EGCG feeding reduced acetaminophen-glucuronate and acetaminophen-glutathione contents in plasma and liver. These results indicate that EGCG feeding may reduce the metabolism and toxicity of acetaminophen in rats.
PMCID: PMC4531855  PMID: 26264479
(-)-Epigallocatechin-3; gallate;; Acetaminophen; Cytochrome P450; Hepatotoxicity;; Rats
7.  GIT2 deficiency attenuates concanavalin A-induced hepatitis in mice 
FEBS Open Bio  2015;5:688-704.
•GIT2 depletion attenuates Con A-induced immunological hepatic injuries.•GIT2 depletion suppressed the activation and function of mouse CD4+ T cells.•GIT2 depletion suppressed liver infiltration by lymphoid cells after Con A treatment.•There were lower levels of proinflammatory cytokines in Git2−/− mice after Con A injection.
G protein-coupled receptor kinase interactor 2 (GIT2) is a signaling scaffold protein involved in regulation of cytoskeletal dynamics and the internalization of G protein-coupled receptors (GPCRs). The short-splice form of GIT2 is expressed in peripheral T cells and thymocytes. However, the functions of GIT2 in T cells have not yet been determined. We show that treatment with Con A in a model of polyclonal T-lymphocyte activation resulted in marked inhibitions in the intrahepatic infiltration of inflammatory cells, cytokine response and acute liver failure in Git2−/− mice. CD4+ T cells from Git2−/− mice showed significant impairment in proliferation, cytokine production and signal transduction upon TCR-stimulated activation. Our results suggested that GIT2 plays an important role in T-cell function in vivo and in vitro.
PMCID: PMC4556731  PMID: 26380813
GIT2, G protein-coupled receptor kinase interactor 2; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; TCR, T cell receptor; Con A, concanavalin A; PMA, 4b-phorbol 12-myristate 13-acetate; GIT2; Hepatitis; Knock-out mice; Innate immunity; T cell activation
8.  Neuroinflammatory responses in diabetic retinopathy 
Diabetic retinopathy (DR) is a common complication of diabetes and has been recognized as a vascular dysfunction leading to blindness in working-age adults. It becomes increasingly clear that neural cells in retina play an important role in the pathogenesis of DR. Neural retina located at the back of the eye is part of the brain and a representative of the central nervous system. The neurosensory deficits seen in DR are related to inflammation and occur prior to the clinically identifiable vascular complications. The neural deficits are associated with abnormal reactions of retina glial cells and neurons in response to hyperglycemia. Improper activation of the innate immune system may also be an important contributor to the pathophysiology of DR. Therefore, DR manifests characteristics of both vasculopathy and chronic neuroinflammatory diseases. In this article, we attempt to provide an overview of the current understanding of inflammation in neural retina abnormalities in diabetes. Inhibition of neuroinflammation may represent a novel therapeutic strategy to the prevention of the progression of DR.
PMCID: PMC4527131  PMID: 26245868
Neural retina; Neuroinflammation; Diabetic retinopathy; Cytokine
9.  Immune efficacy of five novel recombinant Bordetella bronchiseptica proteins 
BMC Veterinary Research  2015;11:173.
The Gram-negative pathogen Bordetella bronchiseptica causes acute and chronic respiratory infection in a variety of animals. Currently, there is no vaccine to prevent these infections. To identify useful candidate antigens for such a vaccine, five B. bronchiseptica genes including amino acid ATP-binding cassette transporter substrate-binding protein (ABC), lipoprotein (PL), outer membrane porin protein (PPP), leu/ile/val-binding protein (BPP), and conserved hypothetical protein (CHP) were cloned and the recombinant proteins were expressed. The immune responses of mice to vaccination with individual recombinant proteins were measured.
Each of the tested recombinant proteins induced a high antibody titer. PPP and PL showed protective indices against challenges with B. bronchiseptica. The protection ratios were 62.5 and 50 %, respectively, compared with 12.5 % for control vaccinations. The protection ratios of ABC, BPP, and CHP were not significantly different from the controls. IgG-subtype and cytokine analysis demonstrated that PPP and PL can induce two immune responses: a humoral immune response and a cell-mediated immune response. The humoral immunity-mediated, Th2-type response dominated.
The identification of PPP and PL, which offer immune-protective potential, identifies them as candidates for the development of a diagnostic test or a vaccine for B. bronchiseptica.
PMCID: PMC4520013
Bordetella bronchiseptica; Recombinant proteins; Immune-protective protein; Subunit vaccine
10.  EGFR Modulates DNA Synthesis and Repair through Tyr Phosphorylation of Histone H4 
Developmental cell  2014;30(2):224-237.
Posttranslational modifications of histones play fundamental roles in many biological functions. Specifically, histone H4-K20 methylation is critical in DNA synthesis and repair. However, little is known about how these functions are regulated by the upstream stimuli. Here, we identify a tyrosine phosphorylation site at Y72 of histone H4, which facilitates recruitment of histone methyltransferases (HMTases), SET8 and SUV4-20H, to enhance its K20 methylation, thereby promoting DNA synthesis and repair. Phosphorylation-defective histone H4 mutant is deficient in K20 methylation, leading to reduced DNA synthesis, delayed cell cycle progression, and decreased DNA repair ability. Disrupting the interaction between epidermal growth factor receptor (EGFR) and histone H4 by Y72 peptide significantly reduced tumor growth. Furthermore, EGFR expression clinically correlates with histone H4-Y72 phosphorylation, H4-K20 mono-methylation, and the Ki-67 proliferation marker. These findings uncover a mechanism by which EGFR transduces signal to chromatin to regulate DNA synthesis and repair.
PMCID: PMC4149291  PMID: 25073158
11.  miR-32 functions as a tumor suppressor and directly targets SOX9 in human non-small cell lung cancer 
OncoTargets and therapy  2015;8:1773-1783.
MicroRNA-32 (miR-32) is dysregulated in certain human malignancies and correlates with tumor progression. However, its expression and function in non-small cell lung cancer (NSCLC) remain unclear. Thus, the aim of this study was to explore the effects of miR-32 expression on NSCLC tumorigenesis and development.
Using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR), we detected miR-32 expression in NSCLC cell lines and primary tumor tissues. The association of miR-32 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-32 expression on the biological behavior of NSCLC cells were investigated. Finally, the potential regulatory effect of miR-32 on SOX9 expression was confirmed.
miR-32 expression levels were significantly downregulated in NSCLC compared with the corresponding noncancerous lung tissues (P<0.001). In addition, decreased miR-32 expression was significantly associated with lymph node metastasis (P=0.002), advanced tumor/nodes/metastasis (TNM) classification stages (P<0.001), and shorter overall survival (P<0.001). Multivariate regression analysis corroborated that downregulated miR-32 expression was an independent unfavorable prognostic factor for NSCLC patients. In vitro studies demonstrated that miR-32 overexpression reduced A549 cell proliferation, migration, and invasion, and promoted apoptosis. Furthermore, SOX9 was confirmed as a direct target of miR-32, using a luciferase reporter assay.
These findings indicate that miR-32 may act as a tumor suppressor in NSCLC and could serve as a novel therapeutic agent for miR-based therapy.
PMCID: PMC4516199
prognosis; proliferation; apoptosis; invasion; migration
12.  The Prognostic Impact of Preoperative and Postoperative Chemoradiation in Clinical Stage II and III Esophageal Squamous Cell Carcinomas 
Medicine  2015;94(25):e1002.
While preoperative chemoradiation followed by surgery (pre-OP CRT) has been widely applied in the treatment of patients with esophageal cancer, some studies have shown a survival benefit of postoperative chemoradiation (post-OP CRT). The optimal combination of multimodality therapy and the sequence of surgery and chemoradiation for esophageal cancer remain to be investigated.
A total of 1385 patients with clinical stage II and III esophageal squamous cell carcinoma (ESCC) were included. On the basis of the sequence of surgery and chemoradiation, the patients were grouped as follows: preoperative chemoradiation followed by surgery (pre-OP CRT+S), surgery alone (S), and surgery followed by postoperative chemoradiation (S+post-OP CRT). Propensity score matching analysis was used to identify 78 well-balanced patients in each group for outcome comparison.
In all, 753, 339, and 293 patients were in the pre-OP CRT+S, S, and S+post-OP CRT groups, respectively. Before matching, no differences were observed in the overall survival among the patients in these 3 groups (P = 0.422). After matching, both the pre-OP CRT+S and S+post-OP CRT groups were significantly associated with a better survival compared with the S group (pre-OP CRT+S vs. S: P < 0.001; S+post-OP CRT vs. S: P = 0.005). In contrast, the survival was similar between the pre-OP CRT+S and S+post-OP CRT groups (P = 0.544). In the subgroup analysis, patients with clinical T3/4 stage tumors or those with a tumor size greater than 5 cm were more likely to demonstrate an overall survival benefit from pre-OP CRT compared with post-OP CRT.
Both pre-OP CRT and post-OP CRT demonstrated a survival benefit compared with surgery alone, which indicates the importance of trimodality therapy in patients with clinical stage II/III ESCC. However, no survival difference was observed among patients in the pre-OP CRT+S and S+post-OP CRT groups, which suggests that the sequence of surgery and chemoradiation may be irrelevant to the outcome.
PMCID: PMC4504557  PMID: 26107665
13.  Acoustic Radiation Force Impulse Technology in the Differential Diagnosis of Solid Breast Masses with Different Sizes: Which Features Are Most Efficient? 
BioMed Research International  2015;2015:410560.
Purpose. To evaluate diagnostic performance of acoustic radiation force impulse (ARFI) technology for solid breast masses with different sizes and determine which features are most efficient. Materials and Methods. 271 solid breast masses in 242 women were examined with ARFI, and their shear wave velocities (SWVs), Virtual Touch tissue imaging (VTI) patterns, and area ratios (ARs) were measured and compared with their histopathological outcomes. Receiver operating characteristic curves (ROC) were calculated to assess diagnostic performance of ARFI for small masses (6–14 mm) and big masses (15–30 mm). Results. SWV of mass was shown to be positively associated with mass size (P < 0.001). For small masses, area under ROC (Az) of AR was larger than that of SWV (P < 0.001) and VTI pattern (P < 0.001); no significant difference was found between Az of SWV and that of VTI pattern (P = 0.906). For big masses, Az of VTI pattern was less than that of SWV (P = 0.008) and AR (P = 0.002); no significant difference was identified between Az of SWV and that of AR (P = 0.584). Conclusions. For big masses, SWV and AR are both efficient measures; nevertheless, for small masses, AR seems to be the best feature.
PMCID: PMC4519539  PMID: 26258138
14.  Clinical Neuropathological Analysis of 10 Cases of Cerebral Amyloid Angiopathy-Related Cerebral Lobar Hemorrhage 
The clinical and pathological characteristics of 10 cases of cerebral amyloid angiopathy (CAA)-related cerebral lobar hemorrhage (CLH) that was diagnosed at autopsy were investigated to facilitate the diagnosis of this condition.
The clinical characteristics of 10 cases of CAA-related CLH were retrospectively reviewed, and a neuropathological examination was performed on autopsy samples.
The 10 cases included two with a single lobar hemorrhage and eight with multifocal lobar hemorrhages. In all of the cases, the hemorrhage bled into the subarachnoid space. Pathological examinations of the 10 cases revealed microaneurysms in two, double barrel-like changes in four, multifocal arteriolar clusters in five, obliterative onion skin-like intimal changes in four, fibrinoid necrosis of the vessels in seven, neurofibrillary tangles in eight, and senile plaques in five cases.
CAA-related CLHs were located primarily in the parietal, temporal, and occipital lobes. These hemorrhages normally consisted of multiple repeated CLHs that frequently bled into the subarachnoid space. CAA-associated microvascular lesions may be the pathological factor underlying CLH.
PMCID: PMC4534736  PMID: 26279810
Cerebral amyloid angiopathy; Cerebral lobar hemorrhage; Neuropathology
15.  Cryptococcal infection of the femoral bone similar with pathologic features of vascular tumors: a case report and review of literature 
A rare case is presented of a 62-year-old man with primary isolated cryptococcal femoral osteomyelitis. Magnetic resonance imaging (MRI) revealed osteolytic destruction of his left femur. Biopsy was performed firstly. Under microscope, the lesion was compose of numerous large mononuclear cells, scattered multinucleated giant cells, a few lymphocytes and neutrophils, necrosis with serious artificial deformation. By immunohistochemistry (IHC), only CD31 and CD68 were positive, while CK, CK8/18, EMA, P63, CK7, CK20, PSAP, PSA, CD34 negative. It was considered a low grade vascularsarcoma, but not confirmed. Then the operation was done. Surgical specimen showed a lot of red-sphere materials in most cells cytoplasm. The Gomorra methenamine silver staining and PAS revealed the mucopolysaccharide-containing capsule of the Cryptococcus. Laboratory culture of lesion liquid grew a kind of yeast at 37°C. Cryptococcal femoral osteomyelitis was diagnosed at last. The patient is good now after the thorough debridement and anti-fungal treatment.
PMCID: PMC4555760  PMID: 26339432
Femur; cryptococcus; osteomyelitis; cryptococcosis
16.  Sex-Related Responses of Populus cathayana Shoots and Roots to AM Fungi and Drought Stress 
PLoS ONE  2015;10(6):e0128841.
We investigated the impact of drought and arbuscular mycorrhizal (AM) fungi on the morphological structure and physiological function of shoots and roots of male and female seedlings of the dioecious plant Populus cathayana Rehder. Pot-grown seedlings were subjected to well watered or water-limiting conditions (drought) and were grown in soil that was either inoculated or not inoculated with the AM fungus Rhizophagus intraradices. No significant differences were found in the infection rates between the two sexes. Drought decreased root and shoot growth, biomass and root morphological characteristics, whereas superoxide radical (O2–) and hydrogen peroxide content, peroxidase (POD) activity, malondialdehyde (MDA) concentration and proline content were significantly enhanced in both sexes. Male plants that formed an AM fungal symbiosis showed a significant increase in shoot and root morphological growth, increased proline content of leaves and roots, and increased POD activity in roots under both watering regimes; however, MDA concentration in the roots decreased. By contrast, AM fungi either had no effect or a slight negative effect on the shoot and root growth of female plants, with lower root biomass, total biomass and root/shoot ration under drought. In females, MDA concentration increased in leaves and roots under both watering regimes, and the proline content and POD activity of roots increased under drought conditions; however, POD activity significantly decreased under well-watered conditions. These findings suggest that AM fungi enhanced the tolerance of male plants to drought by improving shoot and root growth, biomass and the antioxidant system. Further investigation is needed to unravel the complex effects of AM fungi on the growth and antioxidant system of female plants.
PMCID: PMC4478039  PMID: 26102587
17.  Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase 
PLoS ONE  2015;10(6):e0130062.
The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2’-O positions of the viral RNA cap, using S-adenosyl-L-methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition.
PMCID: PMC4476580  PMID: 26098995
18.  Speech function of the oropharyngeal isthmus: A modeling study 
A finite element method (FEM) based numerical model of upper airway structures (jaw, tongue, maxilla, soft palate) was implemented to observe interactions between the soft palate and tongue, and in particular to distinguish the contributions of individual muscles in producing speech-relevant constrictions of the oropharyngeal isthmus (OPI), or “uvular” region of the oral tract. Simulations revealed a sphincter-like general operation for the OPI, particularly with regard to the function of the palatoglossus muscle. Further, as has been observed with the lips, the OPI can be controlled by multiple distinct muscular mechanisms, each reliably producing a different sized opening and robust to activation noise, suggestive of a modular view of speech motor control. As off-midline structures of the OPI are difficult to observe during speech production, biomechanical simulation offers a promising approach to studying these structures.
PMCID: PMC4451102  PMID: 26046008
19.  FSH regulates fat accumulation and redistribution in aging through the Gαi/Ca2+/CREB pathway 
Aging Cell  2015;14(3):409-420.
Increased fat mass and fat redistribution are commonly observed in aging populations worldwide. Although decreased circulating levels of sex hormones, androgens and oestrogens have been observed, the exact mechanism of fat accumulation and redistribution during aging remains obscure. In this study, the receptor of follicle-stimulating hormone (FSH), a gonadotropin that increases sharply and persistently with aging in both males and females, is functionally expressed in human and mouse fat tissues and adipocytes. Follicle-stimulating hormone was found to promote lipid biosynthesis and lipid droplet formation; FSH could also alter the secretion of leptin and adiponectin, but not hyperplasia, in vitro and in vivo. The effects of FSH are mediated by FSH receptors coupled to the Gαi protein; as a result, Ca2+ influx is stimulated, cAMP-response-element-binding protein is phosphorylated, and an array of genes involved in lipid biosynthesis is activated. The present findings depict the potential of FSH receptor-mediated lipodystrophy of adipose tissues in aging. Our results also reveal the mechanism of fat accumulation and redistribution during aging of males and females.
PMCID: PMC4406670  PMID: 25754247
ageing; ca2+; endocrinology; mouse models; signal transduction; signalling
20.  Predictors of ICU Admission and Outcomes 1 Year Post-Admission in Persons with IBD: A Population-based Study 
Inflammatory Bowel Diseases  2015;21(6):1341-1347.
Article first published online 3 April 2015.
Supplemental Digital Content is Available in the Text.
To determine predictors of intensive care unit (ICU) admission and to assess health care utilization (HCU) post-ICU admission among persons with inflammatory bowel disease (IBD).
We matched a population-based database of Manitobans with IBD to a general population cohort on age, sex, and region of residence and linked these cohorts to a population-based ICU database. We compared the incidence rates of ICU admission among prevalent IBD cases according to HCU in the year before admission using generalized linear models adjusting for age, sex, socioeconomic status, region, and comorbidity. Among incident cases of IBD who survived their first ICU admission, we compared HCU with matched controls who survived ICU admission.
Risk factors for ICU admission from the year before admission included cumulative corticosteroid use (incidence rate ratio, 1.006 per 100 mg of prednisone; 95% confidence interval, 1.004–1.008) and IBD-related surgery (incidence rate ratio, 2.79; 95% confidence interval, 1.99–3.92). Use of immunomodulatory therapies within 1 year, or surgery for IBD beyond 1 year prior, were not associated with ICU admission. In those who used corticosteroids and immunomodulatory medications in the year before ICU admission, the use of immunomodulatory medications conferred a 30% risk reduction in ICU admission (incidence rate ratio, 0.70; 95% confidence interval, 0.50–0.97). Persons with IBD who survived ICU admission had higher HCU in the year following ICU discharge than controls.
Corticosteroid use and surgery within the year are associated with ICU admission in IBD while immunomodulatory therapy is not. Surviving ICU admission is associated with high HCU in the year post-ICU discharge.
PMCID: PMC4450906  PMID: 25989339
critical illness; critical care; population-based; inflammatory bowel disease; Crohn's disease; ulcerative colitis; health care utilization
21.  The CYP51F1 Gene of Leptographium qinlingensis: Sequence Characteristic, Phylogeny and Transcript Levels 
Leptographium qinlingensis is a fungal associate of the Chinese white pine beetle (Dendroctonus armandi) and a pathogen of the Chinese white pine (Pinus armandi) that must overcome the terpenoid oleoresin defenses of host trees. L. qinlingensis responds to monoterpene flow with abundant mechanisms that include export and the use of these compounds as a carbon source. As one of the fungal cytochrome P450 proteins (CYPs), which play important roles in general metabolism, CYP51 (lanosterol 14-α demethylase) can catalyze the biosynthesis of ergosterol and is a target for antifungal drug. We have identified an L. qinlingensis CYP51F1 gene, and the phylogenetic analysis shows the highest homology with the 14-α-demethylase sequence from Grosmannia clavigera (a fungal associate of Dendroctonus ponderosae). The transcription level of CYP51F1 following treatment with terpenes and pine phloem extracts was upregulated, while using monoterpenes as the only carbon source led to the downregulation of CYP5F1 expression. The homology modeling structure of CYP51F1 is similar to the structure of the lanosterol 14-α demethylase protein of Saccharomyces cerevisiae YJM789, which has an N-terminal membrane helix 1 (MH1) and transmembrane helix 1 (TMH1). The minimal inhibitory concentrations (MIC) of terpenoid and azole fungicides (itraconazole (ITC)) and the docking of terpenoid molecules, lanosterol and ITC in the protein structure suggested that CYP51F1 may be inhibited by terpenoid molecules by competitive binding with azole fungicides.
PMCID: PMC4490426  PMID: 26016505
Leptographium qinlingensis; lanosterol 14-α demethylase; terpenoid; homology modeling; molecule docking
22.  Novel gemini cationic lipids with carbamate groups for gene delivery 
To obtain efficient non-viral vectors, a series of Gemini cationic lipids with carbamate linkers between headgroups and hydrophobic tails were synthesized. They have the hydrocarbon chains of 12, 14, 16 and 18 carbon atoms as tails, designated as G12, G14, G16 and G18, respectively. These Gemini cationic lipids were prepared into cationic liposomes for the study of the physicochemical properties and gene delivery. The DNA-bonding ability of these Gemini cationic liposomes was much better than their mono-head counterparts (designated as M12, M14, M16 and M18, respectively). In the same series of liposomes, bonding ability declined with an increase in tail length. They were tested for their gene-transferring capabilities in Hep-2 and A549 cells. They showed higher transfection efficiency than their mono-head counterparts and were comparable or superior in transfection efficiency and cytotoxicity to the commercial liposomes, DOTAP and Lipofectamine 2000. Our results convincingly demonstrate that the gene-transferring capabilities of these cationic lipids depended on hydrocarbon chain length. Gene transfection efficiency was maximal at a chain length of 14, as G14 can silence about 80 % of luciferase in A549 cells. Cell uptake results indicate that Gemini lipid delivery systems could be internalised by cells very efficiently. Thus, the Gemini cationic lipids could be used as synthetic non-viral gene delivery carriers for further study.
PMCID: PMC4100725  PMID: 25045521
23.  Subtype-dependent Morphological and Functional Degeneration of Retinal Ganglion Cells in Mouse Models of Experimental Glaucoma 
Journal of nature and science  2015;1(5):e103-.
In this short review, Puyang and her colleagues compared the results from three laboratories on the dendritic and functional degeneration of retinal ganglion cells (RGCs) in mouse models of experimental glaucoma [1–4]. Acute or chronic ocular hypertension was induced in mice, and different techniques were applied to identify RGC types. The dendritic alternations of RGCs were examined following the induction of ocular hypertension, and their light response properties were characterized by the multi-electrode array (MEA) recording. These studies support the notion that the morphological and functional degeneration of RGCs are subtype-dependent in experimental glaucoma.
PMCID: PMC4437223  PMID: 26000339
Retinal Ganglion Cells (RGCs); Experimental Glaucoma; Dendritic Degeneration; Multi-Electrode Array (MEA)
24.  Biological Significance of Photoreceptor Photocycle Length: VIVID Photocycle Governs the Dynamic VIVID-White Collar Complex Pool Mediating Photo-adaptation and Response to Changes in Light Intensity 
PLoS Genetics  2015;11(5):e1005215.
Most organisms on earth sense light through the use of chromophore-bearing photoreceptive proteins with distinct and characteristic photocycle lengths, yet the biological significance of this adduct decay length is neither understood nor has been tested. In the filamentous fungus Neurospora crassa VIVID (VVD) is a critical player in the process of photoadaptation, the attenuation of light-induced responses and the ability to maintain photosensitivity in response to changing light intensities. Detailed in vitro analysis of the photochemistry of the blue light sensing, FAD binding, LOV domain of VVD has revealed residues around the site of photo-adduct formation that influence the stability of the adduct state (light state), that is, altering the photocycle length. We have examined the biological significance of VVD photocycle length to photoadaptation and report that a double substitution mutant (vvdI74VI85V), previously shown to have a very fast light to dark state reversion in vitro, shows significantly reduced interaction with the White Collar Complex (WCC) resulting in a substantial photoadaptation defect. This reduced interaction impacts photoreceptor transcription factor WHITE COLLAR-1 (WC-1) protein stability when N. crassa is exposed to light: The fast-reverting mutant VVD is unable to form a dynamic VVD-WCC pool of the size required for photoadaptation as assayed both by attenuation of gene expression and the ability to respond to increasing light intensity. Additionally, transcription of the clock gene frequency (frq) is sensitive to changing light intensity in a wild-type strain but not in the fast photo-reversion mutant indicating that the establishment of this dynamic VVD-WCC pool is essential in general photobiology and circadian biology. Thus, VVD photocycle length appears sculpted to establish a VVD-WCC reservoir of sufficient size to sustain photoadaptation while maintaining sensitivity to changing light intensity. The great diversity in photocycle kinetics among photoreceptors may be viewed as reflecting adaptive responses to specific and salient tasks required by organisms to respond to different photic environments.
Author Summary
Sensing light from the environment using a variety of photoreceptors is of great adaptive significance for most eukaryotes. A key feature of photoreceptors is the photocycle length, the time taken to decay from the initial signaling light state back to the receptive dark state; however, the significance of photocycle length, or adduct decay length, has not been tested in a biological setting. The photocycle length is determined by the chemical environment of the active site where a photon absorbing chromophore forms an adduct with a conserved amino acid. There is clear evidence of evolutionary selection for a particular photocycle length even between photoreceptors containing the same prototypic light-sensing domains suggesting functional relevance. Using defined in vitro mutations that change the photocycle length of the VIVID (VVD) protein over 4 orders of magnitude we were able to ascribe a pivotal role of the native photochemistry of the protein in its function as a photoreceptor in the light and circadian biology of Neurospora crassa. This study links in vitro photochemical studies with in vivo function and provides evidence that the true evolutionary and functional significance of native photochemistry of photoreceptors can be enhanced by studying photocycle mutants in their native systems.
PMCID: PMC4433212  PMID: 25978382
25.  Effects of Emergency Cervical Cerclage on Pregnancy Outcome: A Retrospective Study of 158 Cases 
The aim of this study was to evaluate the effectiveness and safety of emergency cervical cerclage in women with advanced cervical dilatation and bulging of fetal membranes. The study included 158 women who underwent emergency cervical cerclage because of cervix dilatation and protruding membranes in mid-trimester at Sun Yat-sen Memorial Hospital of Sun Yat-sen University. Pregnancy outcomes and pregnancy outcome related to clinical features were analyzed retrospectively. Analysis revealed that the placement of emergency cerclage led to the delivery of live infants with a success rate of 82.28%. The mean interval between cerclage and delivery was 52.16.±26.62 days, with a mean gestation at delivery of 30.3±4.7 weeks and a mean birth weight of 1934.69±570.37 g. No severe maternal complications such as maternal death, hematosepsis, and hysterorrhexis occurred after the operation. Two women (1.25%) had laceration of the cervix, 1 woman (0.61%) suffered pulmonary edema, and 2 women (1.25%) developed deep vein thrombosis (DVT). There were significant correlations between the pregnancy outcome and risk factors, including any presenting symptoms, cervical dilatation, postoperative white blood cell count, and C-reactive protein (CRP) value. No significant difference was found in women with good vs. poor outcome in terms of maternal age and obstetric histories. Emergency cervical cerclage is effective in prolonging pregnancy and improving neonatal outcome in women with cervical incompetence. It should be considered a viable option for women with a dilated cervix in mid-trimester.
PMCID: PMC4444177  PMID: 25975832
C-Reactive Protein; Obstetric Labor, Premature; Uterine Cervical Incompetence

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