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2.  Older Adults with Amnestic Mild Cognitive Impairment Exhibit Exacerbated Gait Slowing under Dual-Task Challenges 
Current Alzheimer research  2014;11(5):494-500.
With age, performance of motor tasks becomes more reliant on cognitive resources to compensate for the structural and functional declines in the motor control regions in the brain. We hypothesized that participants with amnestic mild cognitive impairment (aMCI) are more prone to motor dysfunctions than cognitively normal older adults under dual-task conditions where competitive demands challenge cognitive functions while performing a motor task simultaneously.
Sixteen aMCI participants (females=9, age=64±5yrs, clinical dementia rating score=0.5) and 10 age- and education-matched cognitively normal adults (females=5, age=62±6yrs) participated. Using a 10-meter-walk test (10MW), gait velocity was recorded at baseline and under 4 different dual-task (DT) conditions designed to challenge working memory, executive function, and episodic memory. Specifically, DT1: verbal fluency; DT2: 5-digit backward span; DT3: serial-7 subtraction; and DT4: 3-item delayed recall. Physical function was measured by Timed Up-and-Go (TUG), simple reaction time (RT) to a free-falling yardstick, and functional reach (FR).
No difference was found in physical functions, aerobic fitness, and exercise cardiopulmonary responses between aMCI participants and controls. However, aMCI participants showed more pronounced gait slowing from baseline when compared to the controls (p<0.05; p=0.001; p<0.001; p<0.001, respectively).
Our finding supports the theory of shared resource of motor and cognitive control. Participants with aMCI manifested more gait slowing than cognitively-normal older adults under DT conditions, with the largest differences during tests of working and episodic memory. The outcome of dual-task assessment shows promise as a potential marker for detection of aMCI and early Alzheimer disease.
PMCID: PMC4082490  PMID: 24801217
Dual-task; early detection; gait; mild cognitive impairment; motor control
3.  Overlapping functions of ABC transporters in topotecan disposition as determined in gene knockout mouse models 
Molecular cancer therapeutics  2013;12(7):1343-1355.
It is established that efflux transporters of the ABC superfamily can affect the pharmacokinetics (PKs) of drugs through mechanisms pertaining to drug absorption, elimination and distribution. To characterize the role of multiple transporters in topotecan's PKs, total (lactone+carboxylate) and lactone forms were measured by LC/MS/MS in plasma, bile, urine and feces following IV administration at doses of 1 mg/kg and 4 mg/kg to eight mouse strains; C57BL/6 (WT), Abcb1−/−, Abcc2−/−, Abcc4−/−, Abcg2−/−, Abcc2;Abcb1−/−, Abcc2;Abcg2−/−, Abcc4;Abcg2−/−. Compared with WT mice and at both dose levels, the plasma areas under the curve (AUC) for topotecan lactone were not significantly different in the Abcc2−/−, Abcc4−/−, Abcb1−/− strains, whereas significant differences were found in Abcg2−/−, Abcc2;Abcb1−/− (only at the high dose), Abcc4;Abcg2−/− and Abcc2;Abcg2−/− mice and ranged from 2.1-fold to 3.3-fold higher. Consistent with these changes, the fecal and biliary excretion of topotecan was reduced, while renal elimination was elevated in Abcg2−/− based strains. Similarly, the Abcc2;Abcb1−/− strain also had elevated renal elimination and reduced fecal excretion of topotecan lactone, this was more pronounced at the 4 mg/kg dose level, suggesting possible saturation of Abcg2. The Abcc4 transporter was found not to be a major determinant of topotecan PKs. It is concluded that Abcg2 has the most significant effect on topotecan elimination, whereas both Abcb1 and Abcc2 have overlapping functions with Abcg2. As such it is relevant to examine how polymorphisms in these transporters influence topotecan activity in patients and whether coadministration of transport modulators could positively affect efficacy without increasing toxicity.
PMCID: PMC3707957  PMID: 23635651
4.  Time-Varying Modeling of Cerebral Hemodynamics 
The scientific and clinical importance of cerebral hemodynamics has generated considerable interest in their quantitative understanding via computational modeling. In particular, two aspects of cerebral hemodynamics, Cerebral Flow Autoregulation (CFA) and CO2 Vasomotor Reactivity (CVR), have attracted much attention because they are implicated in many important clinical conditions and pathologies (orthostatic intolerance, syncope, hypertension, stroke, vascular dementia, MCI, Alzheimer’s disease and other neurodegenerative diseases with cerebrovascular components). Both CFA and CVR are dynamic physiological processes by which cerebral blood flow is regulated in response to fluctuations in cerebral perfusion pressure and blood CO2 tension. Several modeling studies to date have analyzed beat-to-beat hemodynamic data in order to advance our quantitative understanding of CFA-CVR dynamics. A confounding factor in these studies is the fact that the dynamics of the CFA-CVR processes appear to vary with time (i.e. changes in cerebrovascular characteristics) due to neural, endocrine and metabolic effects. This paper seeks to address this issue by tracking the changes in linear time-invariant models obtained from short successive segments of data from 10 healthy human subjects. The results suggest that systemic variations exist but have stationary statistics and, therefore, the use of time-invariant modeling yields “time-averaged models” of physiological and clinical utility.
PMCID: PMC4059681  PMID: 24184697
cerebral hemodynamics; cerebral flow autoregulation; CO2 vasomotor reactivity; time-varying modeling
5.  Prevalence and clinical characteristics of lower limb atherosclerotic lesions in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study 
The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes.
A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes.
After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients.
The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.
PMCID: PMC4054910  PMID: 24926320
Type 1 diabetes; Ketosis-onset diabetes; Type 2 diabetes; Lower limb arteries; Atherosclerosis
6.  1-Deacet­oxy-1-oxocaesalmin 
The title compound, C24H30O7, is a diterpenoid isolated from the seeds of Caesalpinia minax. It consists of two cyclo­hexane rings (A and B), one unsaturated six-membered ring (C) and one furan ring (D). The stereochemistry of the ring junctures is A/B trans and B/C trans. Rings A and B have normal chair conformations while C adopts a twisted half-chair conformation due to fusion to the furan ring which is planar [r.m.s. deviation = 0.0009 (2) Å]. In the crystal, hydroxyl O—H⋯Ocarbon­yl hydrogen bonds link the mol­ecules into a chain structure extending along the a-axis direction.
PMCID: PMC4051044  PMID: 24940245
7.  Urine real-time polymerase chain reaction detection for children virus pneumonia with acute human cytomegalovirus infection 
BMC Infectious Diseases  2014;14:245.
Human cytomegalovirus (HCMV) is an important pathogen of viral pneumonia in children. The diagnosis of acute HCMV infection is complicated and difficult.
Clinical and laboratory data of 6063 hospitalized children with respiratory infection and 509 with respiratory virus infection alone were retrospectively analyzed. Urine and respiratory specimens of 186 hospitalized children with pneumonia were also prospectively collected. Real-time polymerase chain reaction (PCR) and a chemiluminescent assay were used to detect HCMV DNA copy number, the pp65 gene, and HCMV IgM.
The patients with respiratory virus infection alone and those with pulmonary HCMV infection (n = 422) were mostly children aged <6 months old (82.91%, 422/509). The accuracy of urine HCMV DNA (82.32%) was higher than that of HCMV IgM (67.78%), indicating that PCR of urine samples is suitable for determining pediatric acute pulmonary HCMV infection. There was no significant difference in detecting HCMV DNA or the pp65 gene between urinary and respiratory specimens (P > 0.05) in 186 pediatric pneumonia cases. The accuracy of the pp65 gene measured in urine for determining acute pulmonary HCMV infection was the highest (93.01%).
Our study shows a novel method for investigating acute pulmonary HCMV infection in children by using real-time PCR and non-invasive samples. This study also highlights the superiority and potential use of the pp65 gene as an important target for the diagnosis of acute pulmonary HCMV infection.
PMCID: PMC4024271  PMID: 24884393
Human cytomegalovirus; Children; Pneumonia; Urine sample; pp65 gene
8.  Electroacupuncture Ameliorates Acute Lung Injury through Promoting Gastrointestinal Motility in Rats with Acute Pancreatitis 
Objective. Gastrointestinal disfunction and acute lung injury (ALI) were common in acute pancreatitis (AP). The effect of electro-acupuncture (EA) on gastrointestinal motility and ALI in rats with AP was investigated to verify the theory of “lung and large intestine are interior exteriorly related” in traditional Chinese medicine. Methods. Male Sprague-Dawley rats were randomly divided into the normal group, model group, and EA group. AP model was established by three injections of 20% L-arginine at 1 h intervals. EA were applied to bilateral ST-25 and ST-36 for 30 minutes twice a day after modeling for 3 days. Arterial blood, pancreas, lung, and intestinal tissues were collected for detecting the inflammatory factors and histopathology. Intestinal propulsion rate (IPR) was also measured at 72 h. Results. EA treatment improved IPR and increased CCK-8 level compared with model group (P < 0.05). It lowered the serum levels of TNF-α and IL-6 and increased the level of IL-4 with no effect on IL-10. EA treatment reduced serum vasoactive intestinal peptide (VIP) and myeloperoxidase (MPO) level in the lung and the pathologic scores of pancreas, lung and intestine were decreased (P < 0.05). Conclusion. EA treatment could promote gastrointestinal motility through inhibiting VIP, and promoting CCK expression and regulate pro- and anti-inflammatory mediators to ameliorate ALI in AP.
PMCID: PMC4020394  PMID: 24876883
9.  Optical properties of epitaxial BiFeO3 thin film grown on SrRuO3-buffered SrTiO3 substrate 
Nanoscale Research Letters  2014;9(1):188.
The BiFeO3 (BFO) thin film was deposited by pulsed-laser deposition on SrRuO3 (SRO)-buffered (111) SrTiO3 (STO) substrate. X-ray diffraction pattern reveals a well-grown epitaxial BFO thin film. Atomic force microscopy study indicates that the BFO film is rather dense with a smooth surface. The ellipsometric spectra of the STO substrate, the SRO buffer layer, and the BFO thin film were measured, respectively, in the photon energy range 1.55 to 5.40 eV. Following the dielectric functions of STO and SRO, the ones of BFO described by the Lorentz model are received by fitting the spectra data to a five-medium optical model consisting of a semi-infinite STO substrate/SRO layer/BFO film/surface roughness/air ambient structure. The thickness and the optical constants of the BFO film are obtained. Then a direct bandgap is calculated at 2.68 eV, which is believed to be influenced by near-bandgap transitions. Compared to BFO films on other substrates, the dependence of the bandgap for the BFO thin film on in-plane compressive strain from epitaxial structure is received. Moreover, the bandgap and the transition revealed by the Lorentz model also provide a ground for the assessment of the bandgap for BFO single crystals.
PMCID: PMC4002908  PMID: 24791162
BiFeO3 thin film; Optical properties; Spectroscopic ellipsometry; Lorentz model; Dielectric function; 78.67.-n; 78.20.-e; 07.60.Fs
10.  Effect of electroacupuncture stimulation at Zusanli acupoint (ST36) on gastric motility: possible through PKC and MAPK signal transduction pathways 
Electroacupuncture (EA) stimulation has been shown to have a great therapeutic potential for treating gastrointestinal motility disorders. However, no evidence has clarified the mechanisms contributing to the effects of EA stimulation at the Zusanli acupoint (ST.36). This study was designed to investigate the regulative effect of EA stimulation at the ST.36 on gastric motility and to explore its possible mechanisms.
Thirty Sprague-Dawley rats were randomly divided into three groups: the ST.36 group, the non-acupoint group, and the control group. EA stimulation was set at 2 Hz, continuous mode, and 1 V for 30 min. The frequency and average peak amplitude of gastric motility were measured by electrogastrography. The protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signaling pathways were assessed using real-time polymerase chain reactions. Caldesmon (CaD) and calponin (CaP) protein expression in the gastric antrum were detected on Western blots. A Computed Video Processing System was used to evaluate morphological changes in smooth muscle cells (SMCs) from the gastric antrum.
EA stimulation at ST.36 had a dual effect on the frequency and average peak amplitude. Additionally, EA stimulation at ST.36 regulated the expression of some genes in the PKC and MAPK signaling pathways, and it regulated the expression of the CaD and CaP proteins. EA serum induced SMC contractility. Promotion of gastric motility may correlate with up-regulation of MAPK6 (ERK3), MAPK13, and Prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression, and the down-regulation of the collagen, type I, alpha 1 (COL1A1) gene and CaD and CaP protein expression. Inhibition of gastric motility may correlate with down-regulation of the Interleukin-1 receptor type 2 (IL1R2) and Matrix metalloproteinase-9 (MMP9) genes, and up-regulation of CaD and CaP protein expression.
EA stimulation at ST.36 regulated gastric motility, and the effects were both promoting and inhibiting in rats. The possible mechanisms may correlate with the PKC and MAPK signal transduction pathways.
PMCID: PMC4021071  PMID: 24739144
Electroacupuncture; Zusanli; Gastric motility; PKC; MAPK
11.  Treatment of lipoid proteinosis due to the p.C220G mutation in ECM1, a major allele in Chinese patients 
Lipoid proteinosis (LP) is known to be resulted from mutations of the extracellular matrix protein 1 gene (ECM1). However, no effective or sustained therapeutic methods to alleviate LP symptoms have been reported.
Here, we report a 12-year-old boy with LP and recurrent anaphylaxis. The laboratory and histopathological investigations were adopted to confirm the diagnosis, and gene sequencing was performed. We treated this patient with glucocorticoid for three years to relieve the patient’s lipid metabolism disorder and symptoms related to LP and anaphylaxis.
The Laboratory and histopathological investigations showed a lipid metabolism disorder and anaphylaxis in the patient. A homozygous missense mutation p.C220G of ECM1 was identified by Sanger sequencing, which is a major allele in Chinese patients with LP. Notably, after three years’ treatment, the symptoms such as skin lesions, stiff oral mucosa and hoarse voice in the patient were significantly relieved or recovered.
Our report may provide a potentially effective therapeutic approach for the first time to other LP patients who are experiencing recurrent anaphylaxis and/or chronic inflammation.
PMCID: PMC4021827  PMID: 24708644
Extracellular matrix protein 1; Lipoid proteinosis; Anaphylaxis; Glucocorticoid; Anaphylaxis; Treatment
12.  Draft Genome Sequence of Sphingobium sp. Strain BHC-A, Revealing Genes for the Degradation of Hexachlorocyclohexane 
Genome Announcements  2014;2(2):e00254-14.
Here, we report the draft genome sequence of Sphingobium sp. strain BHC-A, a lin gene-based hexachlorocyclohexane (HCH)-degrading strain, isolated from soil that suffered long-term HCH contamination in an insecticide factory.
PMCID: PMC3974940  PMID: 24699958
13.  Molecular Typing of CTX-M-Producing Escherichia coli Isolates from Environmental Water, Swine Feces, Specimens from Healthy Humans, and Human Patients 
Applied and Environmental Microbiology  2013;79(19):5988-5996.
CTX-M-producing Escherichia coli is the predominant type of extended-spectrum β-lactamase (ESBL)-producing E. coli worldwide. In this study, molecular typing was conducted for 139 CTX-M-producing E. coli isolates, phenotypically positive for ESBLs, isolated from environmental water, swine, healthy humans, and hospitalized patients in Hangzhou, China. The antibiotic resistance profiles of the isolates for the cephalosporins and fluoroquinolones were determined. The isolates showed 100% resistance to cefotaxime and ceftriaxone while maintaining relatively high susceptibility to cefoxitin, cefepime, and ceftazidime. A total of 61.9% (86/139) of the isolates, regardless of origin, showed high resistance to fluoroquinolones. PCRs and DNA sequencing indicated that blaCTX-M-14 was the most prevalent CTX-M-9 group gene and that blaCTX-M-15 and blaCTX-M-55 were the dominant CTX-M-1 group genes. Isolates from all sources with CTX-M types belonging to the CTX-M-1 or CTX-M-9 group were most frequently associated with epidemics. Molecular homology analysis of the isolates, conducted by phylogenetic grouping, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST), demonstrated that the dominant clones belonged to B2-ST131, D-ST648, D-ST38, or A-CC10. These four sequence types (STs) were discovered in E. coli isolates both from humans and from environmental water, suggesting frequent and continuous intercompartment transmission between humans and the aquatic environment. Seven novel sequence types were identified in the current study. In conclusion, this study is the first to report the molecular homology analysis of CTX-M-producing E. coli isolates collected from water, swine, and healthy and hospitalized humans, suggesting that pathogens in the environment might originate both from humans and from animals.
PMCID: PMC3811354  PMID: 23892737
14.  Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth 
Biological Research  2014;47(1):4.
Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.
The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.
These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.
PMCID: PMC4060374
Apolipoprotein; ATP-binding cassette transporter 1 gene; Gene polymorphism; High-carbohydrate/low-fat diet; Lipid ratios
15.  The Regulation of Autophagy by Influenza A Virus 
BioMed Research International  2014;2014:498083.
Influenza A virus is a dreadful pathogen of animals and humans, causing widespread infection and severe morbidity and mortality. It is essential to characterize the influenza A virus-host interaction and develop efficient counter measures against the viral infection. Autophagy is known as a catabolic process for the recycling of the cytoplasmic macromolecules. Recently, it has been shown that autophagy is a critical mechanism underlying the interaction between influenza A virus and its host. Autophagy can be induced by the infection with influenza A virus, which is considered as a necessary process for the viral proliferation, including the accumulation of viral elements during the replication of influenza A virus. On the other hand, influenza A virus can inhibit the autophagic formation via interaction with the autophagy-related genes (Atg) and signaling pathways. In addition, autophagy is involved in the influenza virus-regulated cell deaths, leading to significant changes in host apoptosis. Interestingly, the high pathogenic strains of influenza A virus, such as H5N1, stimulate autophagic cell death and appear to interplay with the autophagy in distinct ways as compared with low pathogenic strains. This review discusses the regulation of autophagy, an influenza A virus driven process.
PMCID: PMC3980786  PMID: 24779013
16.  Lack of Association between TLR4 Genetic Polymorphisms and Diabetic Nephropathy in a Chinese Population 
BioMed Research International  2014;2014:704167.
Objective. Toll-like receptor 4 (TLR4) plays a central role in innate immunity. Activation of innate immune response and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of diabetic nephropathy. In this study, we aimed to investigate whether TLR4 variants are associated with diabetic nephropathy in the Chinese population. Methods. Seven tagging single nucleotide polymorphisms (SNPs) of TLR4 based on HapMap Chinese data were genotyped in 1,455 Chinese type 2 diabetic patients. Of these patients, 622 were diagnosed with diabetic nephropathy and 833 were patients with diabetes for over 5 years but without diabetic nephropathy. Results. None of the SNPs and haplotypes showed significant association to diabetic nephropathy in our study. No association between the SNPs and quantitative traits was observed either. Conclusion. We concluded that common variants within TLR4 genes were not associated with diabetic nephropathy in the Chinese type 2 diabetes patients.
PMCID: PMC3980983  PMID: 24779014
17.  SERPINA3 promotes endometrial cancer cells growth by regulating G2/M cell cycle checkpoint and apoptosis 
Endometrial carcinoma (EC) is the most common gynecologic cancer worldwide and is one of the leading causes of death in women. Therefore, it is urgent to elucidate the pathological mechanisms of EC. SERPINA3 is a member of the serpin super-family of protease inhibitors. Its aberrant expression has been observed in various tumor cells. However, its clinical significance and biological function in endometrial cancer remains unknown. In the present study, we demonstrated that SERPINA3 expression was significantly up-regulated in EC samples and was closely correlated with lower differentiation, higher stage, positive lymph node or vascular thrombosis and negative estrogen receptor (ER), indicating a poor prognosis. We then demonstrated that SERPINA3 promoted EC cells proliferation by regulating G2/M checkpoint in cell cycle and inhibited cells apoptosis, and we further uncovered that the pro-proliferative effect of SERPINA3 on EC was likely ascribed to the activation of MAPK/ERK1/2 and PI3K/AKT signaling. The results of our study may provide insight into the application of SERPINA3 as a novel predictor of clinical outcomes and a potential therapeutic target of EC.
PMCID: PMC4014215  PMID: 24817931
SERPINA3; endometrial cancer; proliferation; G2/M checkpoint; apoptosis
18.  Structure of cyclin G-associated kinase (GAK) trapped in different conformations using nanobodies 
Biochemical Journal  2014;459(Pt 1):59-69.
GAK (cyclin G-associated kinase) is a key regulator of clathrin-coated vesicle trafficking and plays a central role during development. Additionally, due to the unusually high plasticity of its catalytic domain, it is a frequent ‘off-target’ of clinical kinase inhibitors associated with respiratory side effects of these drugs. In the present paper, we determined the crystal structure of the GAK catalytic domain alone and in complex with specific single-chain antibodies (nanobodies). GAK is constitutively active and weakly associates in solution. The GAK apo structure revealed a dimeric inactive state of the catalytic domain mediated by an unusual activation segment interaction. Co-crystallization with the nanobody NbGAK_4 trapped GAK in a dimeric arrangement similar to the one observed in the apo structure, whereas NbGAK_1 captured the activation segment of monomeric GAK in a well-ordered conformation, representing features of the active kinase. The presented structural and biochemical data provide insight into the domain plasticity of GAK and demonstrate the utility of nanobodies to gain insight into conformational changes of dynamic molecules. In addition, we present structural data on the binding mode of ATP mimetic inhibitors and enzyme kinetic data, which will support rational inhibitor design of inhibitors to reduce the off-target effect on GAK.
Cyclin G-associated kinase (GAK) is a regulator of clathrin-coated vesicle trafficking. The determined crystal structures of GAK in complex with specific single chain antibodies (nanobodies) revealed the domain plasticity of this kinase and unusual activation segment architecture.
PMCID: PMC3957475  PMID: 24438162
activation loop; cyclin G-associated kinase; drug side effect; kinase inhibitor; nanobody; protein structure; ASCH, activation segment C-terminal helix; AUC, analytical ultracentrifugation; CDR, complementarity-determining region; DARPin, designed ankyrin-repeat protein; EGFR, epidermal growth factor receptor; GAK, cyclin G-associated kinase; HA, haemagglutinin; MPSK1, myristoylated and palmitoylated serine/threonine kinase 1; NAK, numb-associated kinase; Nb, nanobody; RU, resonance unit; SeMet, selenomethionine; SPR, surface plasmon resonance; TCEP, tris-(2-carboxyethyl)phosphine; TEV, Tobacco etch virus
19.  Physiological Role of Kv1.3 Channel in T Lymphocyte Cell Investigated Quantitatively by Kinetic Modeling 
PLoS ONE  2014;9(3):e89975.
Kv1.3 channel is a delayed rectifier channel abundant in human T lymphocytes. Chronic inflammatory and autoimmune disorders lead to the over-expression of Kv1.3 in T cells. To quantitatively study the regulatory mechanism and physiological function of Kv1.3 in T cells, it is necessary to have a precise kinetic model of Kv1.3. In this study, we firstly established a kinetic model capable to precisely replicate all the kinetic features for Kv1.3 channels, and then constructed a T-cell model composed of ion channels including Ca2+-release activated calcium (CRAC) channel, intermediate K+ (IK) channel, TASK channel and Kv1.3 channel for quantitatively simulating the changes in membrane potentials and local Ca2+ signaling messengers during activation of T cells. Based on the experimental data from current-clamp recordings, we successfully demonstrated that Kv1.3 dominated the membrane potential of T cells to manipulate the Ca2+ influx via CRAC channel. Our results revealed that the deficient expression of Kv1.3 channel would cause the less Ca2+ signal, leading to the less efficiency in secretion. This was the first successful attempt to simulate membrane potential in non-excitable cells, which laid a solid basis for quantitatively studying the regulatory mechanism and physiological role of channels in non-excitable cells.
PMCID: PMC3940720  PMID: 24594979
20.  Mechanism for KRIT1 release of ICAP1-mediated integrin activation suppression 
Molecular cell  2013;49(4):719-729.
KRIT1 (Krev/Rap1 Interaction Trapped-1) mutations are observed in ~40% of autosomal dominant cerebral cavernous malformations (CCM), a disease occurring in up to 0.5% of the population. We show that KRIT1 functions as a switch for β1 integrin activation by antagonizing ICAP1 (Integrin Cytoplasmic Associated Protein-1)-mediated modulation of “inside-out” activation. We present co-crystal structures of KRIT1 with ICAP1 and ICAP1 with integrin β1 cytoplasmic tail to 2.54 Å and 3.0 Å resolution (the resolutions at which I/σI = 2 are 2.75 Å and 3.0 Å, respectively). We find that KRIT1 binds ICAP1 by a bidentate surface, KRIT1 directly competes with integrin β1 to bind ICAP1, and that KRIT1 antagonizes ICAP1-modulated integrin activation using this site. We also find that KRIT1 contains an N-terminal Nudix domain, in a region previously designated as unstructured. We therefore provide new insights to integrin regulation and CCM-associated KRIT1 function.
PMCID: PMC3684052  PMID: 23317506
Integrin activation; crystal structure; cerebral cavernous malformation; protein-protein interaction
21.  Endoscopic ultrasonography for staging of T1a and T1b esophageal squamous cell carcinoma 
AIM: To investigate the accuracy of Endoscopic ultrasound (EUS) in staging and sub-staging T1a and T1b esophageal squamous cell carcinoma (ESCC).
METHODS: A retrospective analysis involving 72 patients with pathologically confirmed T1a or T1b ESCC, was undertaken between January 2005 and December 2011 in Sun Yat-sen University Cancer Center. The accuracy and efficiency of EUS for detecting stages T1a and T1b ESCC were examined.
RESULTS: The overall accuracy of EUS for detecting stage T1a or T1b ESCC was 70.8% (51/72), and the sensitivity was 74.3%. 77.8% (7/9) of lesions originated in the upper thoracic region, 73.1% (38/52) in the mid-thoracic region and 72.7% (8/11) in the lower thoracic region. Multivariate analysis revealed that the diagnostic accuracy of EUS was closely related to lesion length (F = 4.984, P = 0.029).
CONCLUSION: EUS demonstrated median degree of accuracy for distinguishing between stages T1a and T1b ESCC. Therefore, it is necessary to improve EUS for staging early ESCC.
PMCID: PMC3921517  PMID: 24574809
Endoscopic ultrasound; Esophageal cancer; Squamous carcinoma; Early cancer; Stage
22.  Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a folded helical domain at its C-terminus 
FEBS letters  2012;587(3):272-277.
Cerebral cavernous malformations (CCM) are neurovascular dysplasias affecting up to 0.5% of the population. Mutations in the CCM2 gene are associated with acquisition of CCM. We identify a previously uncharacterized domain at the C-terminus of CCM2 and determine its 1.9 Å resolution crystal structure. Because this domain is structurally homologous to the N-terminal domain of harmonin, we name it the CCM2 harmonin-homology domain or HHD. CCM2 HHD is observed in two conformations, and we employ analytical ultracentrifugation to test its oligomerization. Additionally, CCM2 HHD contains an unusually long 13-residue 310 helix. This study provides the first structural characterization of CCM2.
PMCID: PMC3558538  PMID: 23266514
Protein-protein interaction; Signal transduction; Cerebral cavernous malformation; X-ray crystallography; harmonin-homology domain
23.  Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise 
Alzheimer disease (AD) and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function.
PMCID: PMC3896879  PMID: 24478719
cerebral hemodynamics; aging; Alzheimer's disease; vascular dementia; regular aerobic exercise
24.  Dysregulated cell mechanical properties of endometrial stromal cells from endometriosis patients 
Endometriosis, diagnosed with ectopically implanted endometrial stromal cells (ESC) and epithelial cells to a location outside the uterine cavity, seriously threaten the quality of life and reproductive ability of women, yet the mechanisms and the pathophysiology of the disease remain unclear. Specially, the functional changes of ESC during endometriosis progression need in-depth investigation. In this study, we characterized mechanical properties of normal ESC (NESC) from healthy women and eutopic ESC (EuESC) and ectopic ESC (EcESC) from endometriosis patients. We found the collagen lattice contractile ability of EuESC was significantly stronger than that of NESC, and the cell mobility of EuESC and EcESC was significantly greater than that of NESC. Furthermore, the expression of F-actin and vinculin in NESC, EuESC and EcESC cells progressively increased, and the Rho GTPase activity, of which RhoA exhibited the highest activity, in the three cells gradually increased. Collectively, these results suggest that the mechanical characteristics of NESC, EuESC and EcESC cells exhibited progressive abnormalities. Therefore, the biomechanics of endometrial stromal cells may be a potent target for intervention in patients with endometriosis.
PMCID: PMC3925909  PMID: 24551285
Endometriosis; cell mechanics; contraction; motility; RhoA
25.  Genome-Wide Analysis of the MADS-Box Gene Family in Brachypodium distachyon 
PLoS ONE  2014;9(1):e84781.
MADS-box genes are important transcription factors for plant development, especially floral organogenesis. Brachypodium distachyon is a model for biofuel plants and temperate grasses such as wheat and barley, but a comprehensive analysis of MADS-box family proteins in Brachypodium is still missing. We report here a genome-wide analysis of the MADS-box gene family in Brachypodium distachyon. We identified 57 MADS-box genes and classified them into 32 MIKCc-type, 7 MIKC*-type, 9 Mα, 7 Mβ and 2 Mγ MADS-box genes according to their phylogenetic relationships to the Arabidopsis and rice MADS-box genes. Detailed gene structure and motif distribution were then studied. Investigation of their chromosomal localizations revealed that Brachypodium MADS-box genes distributed evenly across five chromosomes. In addition, five pairs of type II MADS-box genes were found on synteny blocks derived from whole genome duplication blocks. We then performed a systematic expression analysis of Brachypodium MADS-box genes in various tissues, particular floral organs. Further detection under salt, drought, and low-temperature conditions showed that some MADS-box genes may also be involved in abiotic stress responses, including type I genes. Comparative studies of MADS-box genes among Brachypodium, rice and Arabidopsis showed that Brachypodium had fewer gene duplication events. Taken together, this work provides useful data for further functional studies of MADS-box genes in Brachypodium distachyon.
PMCID: PMC3890268  PMID: 24454749

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