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51.
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Bloodstream‐form Trypanosoma brucei acquire iron by receptor‐mediated endocytosis of host transferrin. However, the mechanism(s) by which iron is then transferred from the lysosome to the cytosol are unresolved. Here, we provide evidence for the involvement of a protein (TbMLP) orthologous to the mammalian endolysosomal cation channel Mucolipin 1. In T. brucei, we show that this protein is localized to the single parasite lysosome. TbMLP null mutants could only be generated in the presence of an expressed ectopic copy, suggesting that the protein is essential. RNAi‐mediated ablation resulted in a growth defect in vitro and led to a sevenfold increase in susceptibility to the iron‐chelators deferoxamine and salicylhydroxamic acid. Conditional null mutants remained viable when the ectopic copy was repressed, but were hypersensitive to deferoxamine and displayed a growth defect similar to that observed following RNAi. The conditional nulls also retained virulence in vivo in the absence of the doxycycline inducer. These data provide strong evidence that TbMLP has a role in import of iron into the cytosol of African trypanosomes. They also indicate that even when expression is greatly reduced, there is sufficient protein, or an alternative mechanism, to provide the parasite with an adequate supply of cytosolic iron. 相似文献
53.
Thomas Heiberg Birgit Kriener Tom Tetzlaff Alex Casti Gaute T. Einevoll Hans E. Plesser 《Journal of computational neuroscience》2013,35(3):359-375
Firing-rate models provide a practical tool for studying signal processing in the early visual system, permitting more thorough mathematical analysis than spike-based models. We show here that essential response properties of relay cells in the lateral geniculate nucleus (LGN) can be captured by surprisingly simple firing-rate models consisting of a low-pass filter and a nonlinear activation function. The starting point for our analysis are two spiking neuron models based on experimental data: a spike-response model fitted to data from macaque (Carandini et al. J. Vis., 20(14), 1–2011, 2007), and a model with conductance-based synapses and afterhyperpolarizing currents fitted to data from cat (Casti et al. J. Comput. Neurosci., 24(2), 235–252, 2008). We obtained the nonlinear activation function by stimulating the model neurons with stationary stochastic spike trains, while we characterized the linear filter by fitting a low-pass filter to responses to sinusoidally modulated stochastic spike trains. To account for the non-Poisson nature of retinal spike trains, we performed all analyses with spike trains with higher-order gamma statistics in addition to Poissonian spike trains. Interestingly, the properties of the low-pass filter depend only on the average input rate, but not on the modulation depth of sinusoidally modulated input. Thus, the response properties of our model are fully specified by just three parameters (low-frequency gain, cutoff frequency, and delay) for a given mean input rate and input regularity. This simple firing-rate model reproduces the response of spiking neurons to a step in input rate very well for Poissonian as well as for non-Poissonian input. We also found that the cutoff frequencies, and thus the filter time constants, of the rate-based model are unrelated to the membrane time constants of the underlying spiking models, in agreement with similar observations for simpler models. 相似文献
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Davy Vancampfort Martien Wampers Alex J. Mitchell Christoph U. Correll Amber De Herdt Michel Probst Marc De Hert 《World psychiatry》2013,12(3):240-250
A meta‐analysis was conducted to explore the risk for cardio‐metabolic abnormalities in drug naïve, first‐episode and multi‐episode patients with schizophrenia and age‐ and gender‐ or cohort‐matched general population controls. Our literature search generated 203 relevant studies, of which 136 were included. The final dataset comprised 185,606 unique patients with schizophrenia, and 28 studies provided data for age‐ and gender‐matched or cohort‐matched general population controls (n=3,898,739). We found that multi‐episode patients with schizophrenia were at increased risk for abdominal obesity (OR=4.43; CI=2.52‐7.82; p<0.001), hypertension (OR=1.36; CI=1.21‐1.53; p<0.001), low high‐density lipoprotein cholesterol (OR=2.35; CI=1.78‐3.10; p<0.001), hypertriglyceridemia (OR=2.73; CI=1.95‐3.83; p<0.001), metabolic syndrome (OR=2.35; CI=1.68‐3.29; p<0.001), and diabetes (OR=1.99; CI=1.55‐2.54; p<0.001), compared to controls. Multi‐episode patients with schizophrenia were also at increased risk, compared to first‐episode (p<0.001) and drug‐naïve (p<0.001) patients, for the above abnormalities, with the exception of hypertension and diabetes. Our data provide further evidence supporting WPA recommendations on screening, follow‐up, health education and lifestyle changes in people with schizophrenia. 相似文献
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Alex Gutteridge J. Michael Rukstalis Daniel Ziemek Mark Tié Lin Ji Rebeca Ramos-Zayas Nancy A. Nardone Lisa D. Norquay Martin B. Brenner Kim Tang John D. McNeish Rebecca K. Rowntree 《PloS one》2013,8(2)
We have used a previously unavailable model of pancreatic development, derived in vitro from human embryonic stem cells, to capture a time-course of gene, miRNA and histone modification levels in pancreatic endocrine cells. We investigated whether it is possible to better understand, and hence control, the biological pathways leading to pancreatic endocrine formation by analysing this information and combining it with the available scientific literature to generate models using a casual reasoning approach. We show that the embryonic stem cell differentiation protocol is highly reproducible in producing endocrine precursor cells and generates cells that recapitulate many aspects of human embryonic pancreas development, including maturation into functional endocrine cells when transplanted into recipient animals. The availability of whole genome gene and miRNA expression data from the early stages of human pancreatic development will be of great benefit to those in the fields of developmental biology and diabetes research. Our causal reasoning algorithm suggested the involvement of novel gene networks, such as NEUROG3/E2F1/KDM5B and SOCS3/STAT3/IL-6, in endocrine cell development We experimentally investigated the role of the top-ranked prediction by showing that addition of exogenous IL-6 could affect the expression of the endocrine progenitor genes NEUROG3 and NKX2.2. 相似文献
58.
Purpose
A recent large genome-wide association study (GWAS) identified multiple variants associated with primary angle-closure glaucoma (PACG). The present study investigated the role of these variants in two cohorts with PACG recruited from Australia and Nepal.Method
Patients with PACG and appropriate controls were recruited from eye clinics in Australia (n = 232 cases and n = 288 controls) and Nepal (n = 106 cases and 204 controls). Single nucleotide polymorphisms (SNPs) rs3753841 (COL11A1), rs1015213 (located between PCMTD1 and ST18), rs11024102 (PLEKHA7), and rs3788317 (TXNRD2) were selected and genotyped on the Sequenom. Analyses were conducted using PLINK and METAL.Results
After adjustment for age and sex, SNP rs3753841 was found to be significantly associated with PACG in the Australian cohort (p = 0.017; OR = 1.34). SNPs rs1015213 (p = 0.014; OR 2.35) and rs11024102 (p = 0.039; OR 1.43) were significantly associated with the disease development in the Nepalese cohort. None of these SNPs survived Bonferroni correction (p = 0.05/4 = 0.013). However, in the combined analysis, of both cohorts, rs3753841 and rs1015213 showed significant association with p-values of 0.009 and 0.004, respectively both surviving Bonferroni correction. SNP rs11024102 showed suggestive association with PACG (p-value 0.035) and no association was found with rs3788317.Conclusion
The present results support the initial GWAS findings, and confirm the SNP’s contribution to PACG. This is the first study to investigate these loci in both Australian Caucasian and Nepalese populations. 相似文献59.
Plants that can adapt their phenotype may be more likely to survive changing environmental conditions. Heritable epigenetic variation could provide a way to rapidly adapt to such changes. Here we tested whether environmental stress induces heritable, potentially adaptive phenotypic changes independent of genetic variation over few generations in Arabidopsis thaliana. We grew two accessions (Col-0, Sha-0) of A. thaliana for three generations under salt, heat and control conditions and tested for induced heritable phenotypic changes in the fourth generation (G4) and in reciprocal F1 hybrids generated in generation three. Using these crosses we further tested whether phenotypic changes were maternally or paternally transmitted. In generation five (G5), we assessed whether phenotypic effects persisted over two generations in the absence of stress. We found that exposure to heat stress in previous generations accelerated flowering under G4 control conditions in Sha-0, but heritable effects disappeared in G5 after two generations without stress exposure. Previous exposure to salt stress increased salt tolerance in one of two reciprocal F1 hybrids. Transgenerational effects were maternally and paternally inherited. Lacking genetic variability, maternal and paternal inheritance and reversibility of transgenerational effects together indicate that stress can induce heritable, potentially adaptive phenotypic changes, probably through epigenetic mechanisms. These effects were strongly dependent on plant genotype and may not be a general response to stress in A. thaliana. 相似文献
60.
Teresa Fiebig Giovanna Figueiredo Hanne Boll Hans Ulrich Kerl Ingo S. Noelte Alex Forster Christoph Groden Martin Kramer Marc A. Brockmann 《PloS one》2013,8(6)