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Articles by L Zhao
Total Records ( 10 ) for L Zhao
  L Zhao , T. E Hanson and B. P. Carlin
 

Mixtures of Polya trees offer a very flexible nonparametric approach for modelling time-to-event data. Many such settings also feature spatial association that requires further sophistication, either at the point level or at the lattice level. In this paper, we combine these two aspects within three competing survival models, obtaining a data analytic approach that remains computationally feasible in a fully hierarchical Bayesian framework using Markov chain Monte Carlo methods. We illustrate our proposed methods with an analysis of spatially oriented breast cancer survival data from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. Our results indicate appreciable advantages for our approach over competing methods that impose unrealistic parametric assumptions, ignore spatial association or both.

  X Pan , N Gong , J Zhao , Z Yu , F Gu , J Chen , X Sun , L Zhao , M Yu , Z Xu , W Dong , Y Qin , G Fei , C Zhong and T. L. Xu
 

Reduction of glucose metabolism in brain is one of the main features of Alzheimer’s disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer’s disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer’s disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3 and -3β, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer’s disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer’s disease treatment.

  M Fuchita , A Ardiani , L Zhao , K Serve , B. L Stoddard and M. E. Black
 

Cytosine deaminase is used in combination with 5-fluorocytosine as an enzyme-prodrug combination for targeted genetic cancer treatment. This approach is limited by inefficient gene delivery and poor prodrug conversion activities. Previously, we reported individual point mutations within the substrate binding pocket of bacterial cytosine deaminase (bCD) that result in marginal improvements in the ability to sensitize cells to 5-fluorocytosine (5FC). Here, we describe an expanded random mutagenesis and selection experiment that yielded enzyme variants, which provide significant improvement in prodrug sensitization. Three of these mutants were evaluated using enzyme kinetic analyses and then assayed in three cancer cell lines for 5FC sensitization, bystander effects, and formation of 5-fluorouracil metabolites. All variants displayed 18- to 19-fold shifts in substrate preference toward 5FC, a significant reduction in IC50 values and improved bystander effect compared with wild-type bCD. In a xenograft tumor model, the best enzyme mutant was shown to prevent tumor growth at much lower doses of 5FC than is observed when tumor cells express wild-type bCD. Crystallographic analyses of this construct show the basis for improved activity toward 5FC, and also how two different mutagenesis strategies yield closely related but mutually exclusive mutations that each result in a significant alteration of enzyme specificity. [Cancer Res 2009;69(11):4791–9]

  J Stamler , I. J Brown , M. L Daviglus , Q Chan , H Kesteloot , H Ueshima , L Zhao , P Elliott and for the INTERMAP Research Group
 

Background— Data are available that indicate an independent inverse relationship of dietary vegetable protein to the blood pressure (BP) of individuals. Here, we assess whether BP is associated with glutamic acid intake (the predominant dietary amino acid, especially in vegetable protein) and with each of 4 other amino acids that are relatively higher in vegetable than animal protein (proline, phenylalanine, serine, and cystine).

Methods and Results— This was a cross-sectional epidemiological study with 4680 persons 40 to 59 years of age from 17 random population samples in China, Japan, the United Kingdom, and the United States. BP was measured 8 times at 4 visits; dietary data (83 nutrients, 18 amino acids) were obtained from 4 standardized, multipass, 24-hour dietary recalls and 2 timed 24-hour urine collections. Dietary glutamic acid (percentage of total protein intake) was inversely related to BP. Across multivariate regression models (model 1, which controlled for age, gender, and sample, through model 5, which controlled for 16 possible nonnutrient and nutrient confounders), estimated average BP differences associated with a glutamic acid intake that was higher by 4.72% of total dietary protein (2 SD) were –1.5 to –3.0 mm Hg systolic and –1.0 to –1.6 mm Hg diastolic (z scores –2.15 to –5.11). Results were similar for the glutamic acid–BP relationship with each of the other amino acids also in the model; eg, with control for 15 variables plus proline, systolic/diastolic pressure differences were –2.7/–2.0 mm Hg (z scores –2.51, –2.82). In these 2–amino acid models, higher intake (by 2 SD) of each of the other amino acids was associated with small BP differences and z scores.

Conclusions— Dietary glutamic acid may have independent BP-lowering effects, which may contribute to the inverse relation of vegetable protein to BP.

  Y Yuan , W Zhang , R Yan , Y Liao , L Zhao , C Ruan , X Du and K. Dai
 

Rationale: The interaction between platelet glycoprotein (GP) Ib-IX and von Willebrand factor (VWF) is initiated by conformational changes in immobilized VWF and is also regulated by the intraplatelet proteins 14-3-3 and filamin A. Both 14-3-3 and filamin A associate with the cytoplasmic domain of GPIb, whereas little is known about their relationship in regulating the VWF binding function of GPIb-IX.

Objective: To explore the mechanism underlying the roles of 14-3-3 and filamin A in regulating the VWF binding function of GPIb-IX.

Methods and Results: A truncation mutant of GPIb (565) deleting the C-terminal 14-3-3 binding sites retained 14-3-3 binding function, in contrast, deletion of the C-terminal residues 551 to 610 of GPIb totally abolished 14-3-3 binding, indicating that the residues 551 to 564 of GPIb are important in the interaction between 14-3-3 and GPIb-IX. An antibody recognizing phosphorylated R557GpSLP561 sequence reacted with GPIb suggesting phosphorylation of a population of GPIb molecules at Ser559, and a membrane permeable phosphopeptide (MP-P), R557GpSLP561 corresponding to residues 557 to 561 of GPIb eliminated the association of 14-3-3 with 565. MP-P also promoted GPIb-IX association with the membrane skeleton, and inhibited ristocetin-induced platelet agglutination, VWF binding to platelets and platelet adhesion to immobilized VWF. Furthermore, a GPIb-IX mutant replacing Ser559 of GPIb with alanine showed an enhanced association with the membrane skeleton, reduced ristocetin-induced VWF binding, and diminished ability to mediate cell adhesion to VWF under flow conditions.

Conclusions: These data suggest a phosphorylation-dependent binding of 14-3-3 to central filamin A binding site of GPIb, and the dimeric 14-3-3 binding to both the C-terminal site and central RGpSLP site inhibits GPIb-IX association with the membrane skeleton and promotes the VWF binding function of GPIb-IX.

  A Goyal , C. R Norton , T. N Thomas , R. L Davis , J Butler , V Ashok , L Zhao , V Vaccarino and P. W. F. Wilson
  Background—

Studies on the incidence and predictors of heart failure (HF) are often restricted to elderly persons or identify only inpatient cases.

Methods and Results—

We determined the incidence and predictors of new HF diagnosed in either outpatient or inpatient settings, among 359 947 women and men (age ≥18 years) insured by Kaiser Permanente Georgia at any time during calendar years 2000 to 2005. Subjects were free of HF at baseline, and incident HF was identified with ICD-9 codes (1 inpatient or 2 outpatient HF visits). We developed multivariable Cox models to assess the association of antecedent factors (coronary heart disease, hypertension, diabetes mellitus, atrial fibrillation, and valvular heart disease) with incident HF. Separate models were created for each sex and for newly diagnosed HF in outpatient or inpatient settings. There were 4001 incident HF cases (50% women and 48% in subjects <65 years old), during 1 015 794 person-years of follow-up. The incidence rate of HF was greater in men than in women (4.24 versus 3.68 per 1000 person-years) but was stable across the study interval in both sexes. Two thirds of incident HF cases from this population occurred in outpatients. These 5 antecedent factors and age yielded excellent discrimination for incident HF in both outpatients and inpatients and in both sexes (C >0.85 in all models).

Conclusions—

Common modifiable risk factors accurately discriminate women and men at risk for HF diagnosed in either outpatient or inpatient settings. Approximately two thirds of new HF cases in our insured population were diagnosed in outpatients; more research is needed to characterize these subjects and their prognosis.

  L Liu , J Wang , L Zhao , J Nilsen , K McClure , K Wong and R. D. Brinton
 

Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G0/G1 phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK1/2 inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.

  A. L Bi , Y Wang , B. Q Li , Q. Q Wang , L Ma , H Yu , L Zhao and Z. Y. Chen
 

Actin rearrangement plays an essential role in learning and memory; however, the spatial and temporal regulation of actin dynamics in different phases of associative memory has not been fully understood. Here, using the conditioned taste aversion (CTA) paradigm, we investigated the region-specific involvement of actin rearrangement-related synaptic structure alterations in different memory processes. We found that CTA training could induce increased postsynaptic density (PSD) length in insular cortex (IC), but not in basolateral amygdala (BLA) and prelimbic cortex (PrL) during short-term memory (STM) formation, whereas it led to increased PSD length and synapse density in both IC and PrL during long-term memory (LTM) formation. Inhibition of actin rearrangement in the IC, but not in the BLA and PrL, impaired memory acquisition. Furthermore, actin dynamics in the IC or PrL is necessary for memory consolidation. On the contrary, inhibition of actin dynamics in the IC, BLA, or PrL had no effect on CTA memory retrieval. Our results suggest temporal and regional-specific regulation of actin rearrangement-related synaptic structure in different phases of CTA memory.

  S Zhu , W Pan , P Shi , H Gao , F Zhao , X Song , Y Liu , L Zhao , X Li , Y Shi and Y. Qian
 

Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17–induced NF-B and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R–Act1–TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17–induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.

 
 
 
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