Genetic characteristics of three new Y-STRs: DYS631, DYS634 and DYS635 in a Chinese population.
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China↗
Biomedical subjects
Y He
Publications and source records attributed to Y He.
Identification of a hTid-1 mutation which sensitizes gliomas to apoptosis.
Human Tid-1 (hTid-1) is a DnaJ chaperone protein with homology to the Drosophila tumor suppressor Tid56. We report the first case of a tumor-associated mutation at the human TID1 locus, which was identified in the SF767 glioma cell line giving rise to aberrantly high levels of a hTid-1(L) mutant variant. In this study, we set out to determine whether this change in hTid-1 status influences the response of glioma cells to adenoviral (Ad)-mediated delivery of the two major isoforms of TID1, hTid-1(L) and hTid-1(S). Ad-hTid-1(S) induced apoptosis in hTid-1 mutant SF767 cells, while causing growth arrest in wild-type hTid-1-expressing U373 and U87 cells. By contrast, Ad-hTid-1(L) infection had no apparent effect on glioma cell growth. The apoptosis induced by hTid-1(S) was accompanied by mitochondrial cytochrome C release and caspase activation and blocked by stable overexpression of Bcl-X(L). Our findings suggest that the status of hTid-1 in gliomas may contribute to their susceptibility to cell death triggers.
Adenoviridae↗
Impact of APOE in mild cognitive impairment.
OBJECTIVE: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. METHODS: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. RESULTS: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. CONCLUSION: MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.
Activities of Daily Living↗
Influence of spectral diffusion on single-molecule photon statistics.
We investigate the distribution of the number of photons emitted by a single molecule undergoing a spectral diffusion process and interacting with a continuous wave field. Using a generating function formalism an exact analytical formula for Mandel's Q parameter is obtained. The solution, which is valid for weak and strong excitation fields, exhibits transitions between (i) quantum sub-Poissonian and classical super-Poissonian behaviors, and (ii) fast to slow modulation limits.
Algorithms↗
Differential qualitative responses to rivastigmine in APOE epsilon 4 carriers and noncarriers.
This retrospective analysis of two double-blind, placebo-controlled studies in patients with mild to moderately severe AD investigated the efficacy of rivastigmine 6-12 mg/day on cognitive outcomes in patients with or without the apolipoprotein (APOE) epsilon4 allele. APOE data were collected from patients who consented to pharmacogenetic testing. Treatment differences within each subgroup were compared, using the Observed Case (OC) population. The APOE epsilon4 and non-APOE epsilon4 subgroups comprised 246 and 121 patients, respectively. Overall, APOE epsilon4 noncarriers showed greater decline than carriers (P<0.05). However, at 26 weeks, placebo-treated APOE epsilon4 patients declined 3.04 points below baseline on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), and rivastigmine-treated patients improved by 1.67 points. Non-APOE epsilon4 placebo-treated patients declined by 4.59 points and rivastigmine-treated patients declined by 0.48 points. Thus, non-APOE epsilon4 carriers showed a less favorable course under either placebo or rivastigmine, but both genotype-defined subgroups showed quantitatively similar responses to therapy (both P<0.05 vs placebo).
Aged↗
Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach.
Peptide deformylase (PDF), a metallohydrolase essential for bacterial growth, is an attractive target for use in the discovery of novel antibiotics. Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of Staphylococcus aureus growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [N-hydroxy-3-R-butyl-3-(2-S-(tert-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl)propionamide] was identified as having the most favorable properties through an integrated combinatorial and medicinal chemistry effort. This compound is a potent PDF inhibitor with a K(i) of 0.24 nM against the Escherichia coli Ni(2+) enzyme, possesses activity against gram-positive and gram-negative bacterial pathogens, and has a low cytotoxicity. Mechanistic experiments demonstrate that the compound inhibits bacterial growth through PDF inhibition. Pharmacokinetic studies of this drug in mice indicate that VRC3375 is orally bioavailable and rapidly distributed among various tissues. VRC3375 has in vivo activity against S. aureus in a murine septicemia model, with 50% effective doses of 32, 17, and 21 mg/kg of body weight after dosing by intravenous (i.v.), subcutaneous (s.c.), and oral (p.o.) administration, respectively. In murine single-dose toxicity studies, no adverse effects were observed after dosing with more than 400 mg of VRC3375 per kg by i.v., p.o., or s.c. administration. The in vivo efficacy and low toxicity of VRC3375 suggest the potential for developing this class of compounds to be used in future antibacterial drugs.
Algorithms↗
Early versus deferred treatment for early stage multiple myeloma.
BACKGROUND: Early stage multiple myeloma (MM) represents about 20% of MM. Most of the patients are asymptomatic. Thus, it is far less dramatic than advanced disease and may require different treatment strategies. For these patients, it is not clear whether it is better to start chemotherapy right after the diagnosis or to delay the treatment until symptoms become obvious as the disease progresses. OBJECTIVES: To identify and synthesize all available research evidence on whether early treatment intervention results in improved clinical outcomes when compared with observation alone. The main outcomes of interest that were examined included mortality, disease progression, response rate, and toxicity of early treatment. SEARCH STRATEGY: Searches of the following electronic databases were undertaken: MEDLINE, EMBASE, CANCERLIT, LILLIACS and Cochrane Database of RCTs. We have recently compiled a comprehensive database of RCTs in myeloma. This search was updated and supplemented by hand-search of abstracts from main society meetings such as the ASH (American Society of Hematology), ASCO (American Society of Clinical Oncology), and EHA (European Haematology Association). In addition, we compared our list with a list of RCTs maintained by the Oxford Clinical Trial Service Unit. SELECTION CRITERIA: Randomized controlled trials (RCT) with a parallel design that compared early versus deferred treatment of patients with early stage multiple myeloma based on Durie-Salmon (D-S) staging system. We also considered those trials that did not define early stage myeloma according to D-S staging system, but enrolled patients according to clinical uncertainty about the benefits of immediate intervention. DATA COLLECTION AND ANALYSIS: Data synthesis was performed for all studies and according to the defined quality criteria. The first reviewer and the contact reviewer of this proposal independently extracted data. Disagreement was resolved by consensus. Revman software (ver 4.1) was used to combine results from all studies and expressed as an overall odds ratio or Peto's Odds Ratio, with 95% confidence interval. MAIN RESULTS: Three trials were included with a total of 131 patients in each of the early treatment and deferred treatment groups. Early MM is asymptomatic stage I in these trials. All trials used standard Melphalan treatment but not stem cell transplantation. No statistically significant heterogeneity among the studies was detected. Beneficial effects of early treatment were seen in delay of myeloma progression (Peto's OR = 0.16, 95% CI: 0.09-0.29), and reduced vertebral compression (OR = 0.18, 95%CI: 0.02-1.59, NNT = 23, 95% CI: an NNT of 11, via infinity, to an NNH of 50). No significant effects on mortality and response rate were seen (Peto's OR = 1.11, 95% CI: 0.67-1.84, and OR = 0.63, 95% CI: 0.33-1.23, respectively). Early treatment may increase the risk of acute leukemia (Peto's OR = 3.20, 95% CI: 0.55-18.73, NNH = 44, 95% CI: an NNT of 63, via infinity, to an NNH of 15). REVIEWER'S CONCLUSIONS: Early treatment of early stage multiple myeloma inhibits disease progression, and may reduce vertebral compression. However, early treatment may increase the risk of acute leukemia. However, the data on vertebral compression and leukaemic transformation may not be interpretable due to very small numbers. Based on the current evidence, mortality and response rate are not significantly affected by introducing early treatment in the progression of myeloma. However, it is quite possible that the lack of beneficial effects of early intervention in myeloma is a false negative result due to the paucity of the existing evidence. In addition, data on quality of life and toxicity were sparsely reported adding to additional difficulties about management decisions in early stage myeloma.
Disease Progression↗
Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes.
1. The relative roles of human hepatic cytochrome P450 (CYP) subfamilies participating in ethosuximide metabolism have been studied in vitro using humanized heterologous CYP microsomal systems expressing either CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1 or CYP3A4. 2. Ethosuximide was incubated with each expression system at 37 degrees C, and its hydroxylated metabolite was quantified by HPLC assay. 3. K(m) and V(max) values for metabolite formation were estimated for CYP3A4 and CYP2E1. The K(m) values for the metabolite formed were 1.40 and 0.24 mM for CYP3A4 and CYP2E1, respectively. The V(max) values were 0.65 and 0.14 nmol mg-1 protein min(-1) for CYP3A4 and CYP2E1, respectively. 4. These parameters could not be measured for other enzymes, since metabolite concentrations formed were below the HPLC detection limits. 5. Immuno-inhibition studies using specific antibodies against CYP3A4 or CYP2E1 revealed that ethosuximide metabolite levels decreased when the amount of added CYP3A4 or CYP2E1 antibody increased, with anti-CYP3A4 antibodies yielding a greater inhibitory effect. 6. Simulations of scaled-up in vivo ethosuximide CL(hepatic) mediated by CYP3A4 and CYP2E1 based on the in vitro CL'(int) values, which were calculated from the foregoing respective V(max) and K(m) values, project that well over 90% of in vivo CL(hepatic) is due to CYP3A4. These results support an important role for CYP3A in human ethosuximide metabolism, and a minor role for CYP2E1.
Algorithms↗
Total synthesis of the CP-molecules (CP-263,114 and CP-225,917, phomoidrides B and A). 1. Racemic and asymmetric synthesis of bicyclo[4.3.1] key building blocks.
A brief introduction into the chemistry of the CP-molecules is followed by first-generation synthetic sequences toward key building blocks for their total synthesis. Processes for both racemic and enantiomerically enriched bicyclo[4.3.1] ketone 6 or its equivalent are described, and the absolute stereochemistries of the optically enriched intermediates are determined. The efficient route developed to racemic 6 and the ready access to both enantiomers of key building blocks provided the opportunity for the total synthesis of the CP-molecules and determination of their absolute stereochemistry.
Enzyme Inhibitors↗
Effect of antibiotics on the properties of poly(methylmethacrylate)-based bone cement.
The goal of this study was to examine the relationship between gentamicin concentration in Palacos R bone cement (in the mass fraction range of 0-9.4%) and various properties of the cement. The results from the thermal, density, and static compression tests show that gentamicin favors the cement polymerization in its final steps, and forms a diphasic structure with the cement [poly(methylmethacrylate)] matrix. The static compression properties in the dry state are only slightly modified by the presence of the antibiotic. Concerning aging in water at 37 degrees C, two types of behavior can be distinguished: below a critical concentration, approximately 3-4%, the extraction of gentamicin by water is slow and there is only a slight change of static compression properties. In contrast, above this critical concentration, the gentamicin extraction is fast and almost complete after 48 weeks, and there is a considerable loss of static compression properties.
Anti-Bacterial Agents↗
Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function.
The antiepileptic drug riluzole is a use-dependent blocker of voltage-gated Na(+) channels and selectively depresses action potential-driven glutamate over gamma-aminobutyric acid (GABA) release. Here we report that in addition to its presynaptic effect, riluzole at higher concentrations also strongly potentiates postsynaptic GABA(A) responses both in cultured hippocampal neurons and in Xenopus oocytes expressing recombinant receptors. Although peak inhibitory postsynaptic currents (IPSCs) of autaptic hippocampal neurons were inhibited, 20-100 microM riluzole significantly prolonged the decay of IPSCs, resulting in little change in total charge transfer. The effect was dose-dependent and reversible. Riluzole selectively increased miniature IPSC fast and slow decay time constants, without affecting their relative proportions. Miniature IPSC peak amplitude, rise time and frequency were unaffected, indicating a postsynaptic mechanism. In the Xenopus oocyte expression system, riluzole potentiated GABA responses by lowering the EC(50) for GABA activation. Riluzole directly gated a GABA(A) current that was partially blocked by bicuculline and gabazine. Pharmacological experiments suggest that the action of riluzole did not involve a benzodiazepine, barbiturate, or neurosteroid site. Instead, riluzole-induced potentiation was inhibited by the lactone antagonist alpha-isopropyl-alpha-methyl-gamma-butyrolatone (alpha-IMGBL). While most anticonvulsants either block voltage-gated Na(+) channels or potentiate GABA(A) receptors, our results suggest that riluzole may define an advantageous class of anticonvulsants with both effects.
Animals↗
AMPA GluR2 subunit is differentially distributed on GABAergic neurons and pyramidal cells in the macaque monkey visual cortex.
The cellular and synaptic distribution of the AMPA receptor subunit GluR2 was analyzed in the monkey primary visual cortex (area V1), by immunocytochemistry and postembedding immunogold methods. GluR2 immunoreactivity was widely distributed in all of the layers of area V1. A quantitative double labeling analysis in layers II and III revealed that the vast majority of GABAergic interneurons in this area also contained GluR2. Postembedding immunogold analysis revealed that GluR2 immunoreactivity was present at asymmetric synapses on both GABAergic interneurons and pyramidal cells. A quantitative study indicated that the number of GluR2 immunogold particles at asymmetric synapses on pyramidal cells was significantly higher than that on GABAergic interneurons. These results from the primate neocortex are in agreement with and extend our previous studies on the rat hippocampus and amygdala. In view of the dominant role of the GluR2 subunit in regulating calcium flux through AMPA receptors, the differential synaptic distribution of GluR2 on different neuronal types might provide a mechanism for cell-specific response properties to glutamate as well as clues to selective neuronal vulnerability and cell death mediated by calcium-dependent excitotoxic mechanisms.
Animals↗
Analysis of heterogeneous fluorescence decays. Distribution of pyrene derivatives in an octadecylsilane layer in capillary electrochromatography.
The distribution of solute molecules in the stationary phase in capillary electrochromatography (CEC) has been investigated with time-resolved fluorescence in the frequency domain. The analysis of fluorescence decay poses a challenging problem for the complex decay kinetics of heterogeneous systems such as the C18 stationary phase. The nonlinear least-squares (NLLS) method selects the decay model by minimizing the chi2 value. The chi2 criterion, in conjunction with the requirement that the residues should be randomly distributed around zero, frequently leads to a feasible set of multiple decay models that can all fit the data satisfactorily. The maximum entropy method (MEM) further chooses a unique model from the group of feasible ones by maximizing the Shannon-Jaynes entropy. The unique model, however, is not necessarily the most probable one. In this paper, the best model for the fluorescence decays of solute molecules is selected with NLLS using the chi2 statistics, the stability of the fit, and the consistency within replicate experiments. In addition, the recovered lifetime parameters of the true model should display the same trend as the fluorescence decay profiles when an experimental condition is varied. Using these criteria, a Gaussian distribution of fluorescence lifetimes satisfactorily fits the data under all experimental conditions. An additional minor component with a discrete lifetime is attributed to the systematic errors in the measurements. The distribution is a manifestation of an ensemble of heterogeneous microenvironments in the stationary phase of CEC. MEM is not suitable for the modeling of CEC data because of its inaccuracy in recovering broad fluorescence lifetime distributions and its lack of consistency in the replicate measurements in the studies of high-voltage effects.
Journal Article↗
Ab initio VCD calculation of a transition-metal containing molecule and a new intensity enhancement mechanism for VCD.
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Circular Dichroism↗
Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson's disease.
Microglial activation and oxidative stress are significant components of the pathology of Parkinson's disease (PD), but their exact contributions to disease pathogenesis are unclear. We have developed an in vitro model of nigral injury, in which lipopolysaccharide-induced microglial activation leads to injury of a dopaminergic cell line (MES 23.5 cells) and dopaminergic neurons in primary mesencephalic cell cultures. The microglia are also activated by PD IgGs in the presence of low-dose dopa-quinone- or H(2)O(2)-modified dopaminergic cell membranes but not cholinergic cell membranes. The activation requires the microglial FCgammaR receptor as demonstrated by the lack of activation with PD IgG Fab fragments or microglia from FCgammaR-/- mice. Although microglial activation results in the release of several cytokines and reactive oxygen species, only nitric oxide and H(2)O(2) appear to mediate the microglia-induced dopaminergic cell injury. These studies suggest a significant role for microglia in dopaminergic cell injury and provide a mechanism whereby immune/inflammatory reactions in PD could target oxidative injury relatively specifically to dopaminergic cells.
Adult↗
A novel growth suppressor gene on chromosome 17p13.3 with a high frequency of mutation in human hepatocellular carcinoma.
Previous studies have shown that there is a high frequency of loss of heterozygosity (LOH) on chromosome 17p13.3 in hepatocellular carcinoma [HCC (M. Fujimori et al., Cancer Res., 51: 89-93, 1991; H. Nagai et al., Oncogene, 14: 2927-2933, 1997; V. Boige et al., Cancer Res., 57: 1986-1990, 1997; Z. Piao et al., Int. J. Cancer, 75: 29-33, 1998; and B. Charroux et al., J. Cell Biol., 148: 1177-1186, 2000)]. The minimum region of LOH on chromosome 17p13.3 in HCC has been defined within the region between D17S643 and D17S1574. Moreover, D17S926 in the minimum region of LOH has the highest frequency of LOH, and its sequencing analysis has been accomplished. In this region, 6 of 13 novel genes have been characterized (X. Zhao, D. Wan, M. He, Yu. Ye, Yi. He, L. Han, M. Guo, Y. Huang, W. Qin, M-W. Wang, W. Chong, J. Chen, L. Zhang, N. Yang, B. Xu, M. Wu, L. Zuo, and J. Gu. A high frequency LOH region on chromosome 17p13.3 in human HCC with densely clustered genes identified, submitted for publication). Here we describe the cloning and characterization of one of these novel genes, designated HCC suppressor 1 (HCCS1), located at this region. HCCS1 had 18 exons, and its full-length cDNA was 2.0 kb. The protein expression product of HCCS1 was located in mitochondria. HCCS1 had a high frequency of mutations in HCC samples, whereas no alteration has been found in matched noncancerous liver tissues. Immunohistochemistry revealed a significantly higher expression of HCCS1 in the noncancerous liver tissues (33 of 35 samples) than in the HCC samples (2 of 35 samples). Transfection of HCCS1 cDNA into the HCC cell line remarkably reduced the efficiency of its colony formation and inhibited tumor growth in nude mice. Taken together, these findings strongly suggest a potential role of HCCS1 as a HCC putative suppressor gene.
3T3 Cells↗
Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study.
The authors report a case of congenital muscular dystrophy with mild nonprogressive muscle weakness, white matter hypodensity, and absence of the laminin alpha2 chain in muscle fibers with two antibodies, but not with four others. They identified mutations in LAMA2, which explain the partial laminin alpha2 deficiency. Analysis of this case and two others allows us to refine the epitopes of two of the commercial antibodies, and illustrate the importance of using antibodies directed against different domains of the protein.
Antibodies, Monoclonal↗
Differential synaptic localization of GluR2 and EAAC1 in the macaque monkey entorhinal cortex: a postembedding immunogold study.
The synaptic distribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit GluR2 and neuronal glutamate transporter subunit EAAC1 were studied using immunogold in layer II of the macaque monkey entorhinal cortex. Immunoreactivity for EAAC1 and GluR2 was frequent at asymmetric synapses and their associated membrane. The synaptic localization of EAAC1 differed considerably from that of GluR2, in that GluR2 immunolabelling was most commonly located within the postsynaptic density, but EAAC1 localization was more heterogeneous and was predominant at the edge of postsynaptic densities and perisynaptic zones. Since EAAC1 may play an important role in clearing glutamate from the synaptic cleft and intercellular spaces, the high perisynaptic expression of EAAC1 in these neurons could presumably offer a powerful mechanism through which high concentrations of glutamate could be efficiently removed from the synapses following release and interaction with glutamate receptors. The distribution of EAAC1 may also offer protection for these neurons against excessive glutamatergic stimuli that may occur under certain pathological conditions.
Amino Acid Transport System X-AG↗