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41.
ED Dean LM Mexas NL Cápiro JE McKeon MR DeLong KD Pennell JA Doorn V Tangpricha GW Miller ML Evatt 《PloS one》2012,7(7):e39227
Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson's disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism. 相似文献
42.
Eftimie R Dushoff J Bridle BW Bramson JL Earn DJ 《Bulletin of mathematical biology》2011,73(12):2932-2961
Recent advances in virology, gene therapy, and molecular and cell biology have provided insight into the mechanisms through
which viruses can boost the anti-tumor immune response, or can infect and directly kill tumor cells. A recent experimental
report (Bridle et al. in Molec. Ther. 18(8):1430–1439, 2010) showed that a sequential treatment approach that involves two viruses that carry the same tumor antigen leads to an improved
anti-tumor response compared to the effect of each virus alone. In this article, we derive a mathematical model to investigate
the anti-tumor effect of two viruses, and their interactions with the immune cells. We discuss the conditions necessary for
permanent tumor elimination and, in this context, we stress the importance of investigating the long-term effect of non-linear
interactions. In particular, we discuss multi-stability and multi-instability, two complex phenomena that can cause abrupt
transitions between different states in biological and physical systems. In the context of cancer immunotherapies, the transitions
between a tumor-free and a tumor-present state have so far been associated with the multi-stability phenomenon. Here, we show
that multi-instability can also cause the system to switch from one state to the other. In addition, we show that the multi-stability
is driven by the immune response, while the multi-instability is driven by the presence of the virus. 相似文献
43.
Jonathan W. Yewdell 《Molecular & cellular proteomics : MCP》2022,21(7):100230
In the 35 years since the revelation that short peptides bound to major histocompatibility complex class I and II molecules are the secret of the major histocompatibility complex–restricted nature of T-cell recognition, there has been enormous progress in characterizing the immunopeptidome, the repertoire of peptide presented for immunosurveillance. Here, the major milestones in the journey are marked, the contribution of proteasome-mediated splicing to the immunopeptidome is discussed, and exciting recent findings relating the immunopeptidome to the translatome revealed by ribosome profiling (RiboSeq) is detailed. Finally, what is needed for continued progress is opined about, which includes the infusion of talented young scientists into the antigen-processing field, currently undergoing a renaissance; thanks in part to the astounding success of T-cell–based cancer immunotherapy. 相似文献
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Risks and benefit evaluation for controlled human infection studies, where healthy volunteers are deliberately exposed to infectious agents to evaluate vaccine efficacy, should be explicit, systematic, thorough, and non-arbitrary. Decision analysis promotes these qualities using four steps: (1) determining explicit criteria and measures for evaluation, (2) identifying alternatives to the study, (3) defining the models used to estimate the measures for each alternative, and (4) running the models to produce the estimates and compare the alternatives. In this paper, we describe how decision analysis might be applied by funders and regulators, as well as by others contemplating the use of novel controlled human infection studies for vaccine development and evaluation. 相似文献
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48.
Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future. 相似文献
49.
Spain AM Peacock AD Istok JD Elshahed MS Najar FZ Roe BA White DC Krumholz LR 《Applied and environmental microbiology》2007,73(15):4892-4904
Immobilization of uranium in groundwater can be achieved through microbial reduction of U(VI) to U(IV) upon electron donor addition. Microbial community structure was analyzed in ethanol-biostimulated and control sediments from a high-nitrate (>130 mM), low-pH, uranium-contaminated site in Oak Ridge, TN. Analysis of small subunit (SSU) rRNA gene clone libraries and polar lipid fatty acids from sediments revealed that biostimulation resulted in a general decrease in bacterial diversity. Specifically, biostimulation resulted in an increase in the proportion of Betaproteobacteria (10% of total clones in the control sediment versus 50 and 79% in biostimulated sediments) and a decrease in the proportion of Gammaproteobacteria and Acidobacteria. Clone libraries derived from dissimilatory nitrite reductase genes (nirK and nirS) were also dominated by clones related to Betaproteobacteria (98% and 85% of total nirK and nirS clones, respectively). Within the nirK libraries, one clone sequence made up 59 and 76% of sequences from biostimulated sediments but only made up 10% of the control nirK library. Phylogenetic analysis of SSU rRNA and nirK gene sequences from denitrifying pure cultures isolated from the site indicate that all belong to a Castellaniella species; nearly identical sequences also constituted the majority of biostimulated SSU rRNA and nirK clone libraries. Thus, by combining culture-independent with culture-dependent techniques, we were able to link SSU rRNA clone library information with nirK sequence data and conclude that a potentially novel Castellaniella species is important for in situ nitrate removal at this site. 相似文献
50.
Analysis of trends in the suburbanization of whites, blacks, Asians, and Hispanics reveal that all groups are becoming more suburbanized, though the gap between whites and minorities remains large. Although central cities have made the transition to a majority-minority configuration, suburbs are still overwhelmingly white. Levels of minority-white segregation are nonetheless lower in suburbs than in cities. Blacks remain the most segregated group at both locations. Black segregation and isolation levels are declining in cities and suburbs; however, while Hispanic and Asian segregation levels have remained stable, spatial isolation levels have risen. Multivariate analyses suggest that Hispanics achieve desegregation indirectly by using socio-economic achievements to gain access to less-segregated suburban communities and directly by translating their status attainments into residence in white neighbourhoods. Blacks do not achieve desegregation indirectly through suburbanization and they are much less able than Hispanics to use their socio-economic attainments directly to enter white neighbourhoods. 相似文献