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91.
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
92.
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
93.
ATP-binding cassette (ABC) transporters serve as importers and exporters for a wide variety of solutes in both prokaryotes
and eukaryotes, and are implicated in microbial drug resistance and a number of significant human genetic disorders. Initial
crystal structures of the soluble nucleotide binding domains (NBDs) of ABC transporters, while a significant step towards
understanding the coupling of ATP binding and hydrolysis to transport, presented researchers with important questions surrounding
the role of the signature sequence residues, the composition of the nucleotide binding sites, and the mode of NBD dimerization
during the transport reaction cycle. Recent studies have begun to address these concerns. This mini-review summarizes the
biochemical and structural characterizations of two archaebacterial NBDs from Methanocaldococcus jannaschii, MJ0796 and MJ1267, and offers current perspectives on the functional mechanism of ABC transporters. 相似文献
94.
Discerning an effective balance between equine infectious anemia virus attenuation and vaccine efficacy 总被引:2,自引:0,他引:2 下载免费PDF全文
Craigo JK Li F Steckbeck JD Durkin S Howe L Cook SJ Issel C Montelaro RC 《Journal of virology》2005,79(5):2666-2677
Among the diverse experimental vaccines evaluated in various animal lentivirus models, live attenuated vaccines have proven to be the most effective, thus providing an important model for examining critical immune correlates of protective vaccine immunity. We previously reported that an experimental live attenuated vaccine for equine infectious anemia virus (EIAV), based on mutation of the viral S2 accessory gene, elicited protection from detectable infection by virulent virus challenge (F. Li et al., J. Virol. 77:7244-7253, 2003). To better understand the critical components of EIAV vaccine efficacy, we examine here the relationship between the extent of virus attenuation, the maturation of host immune responses, and vaccine efficacy in a comparative study of three related attenuated EIAV proviral vaccine strains: the previously described EIAV(UK)DeltaS2 derived from a virulent proviral clone, EIAV(UK)DeltaS2/DU containing a second gene mutation in the virulent proviral clone, and EIAV(PR)DeltaS2 derived from a reference avirulent proviral clone. Inoculations of parallel groups of eight horses resulted in relatively low levels of viral replication (average of 10(2) to 10(3) RNA copies/ml) and a similar maturation of EIAV envelope-specific antibody responses as determined in quantitative and qualitative serological assays. However, experimental challenge of the experimentally immunized horses by our standard virulent EIAV(PV) strain by using a low-dose multiple exposure protocol (three inoculations with 10 median horse infective doses, administered intravenously) revealed a marked difference in the protective efficacy of the various attenuated proviral vaccine strains that was evidently associated with the extent of vaccine virus attenuation, time of viral challenge, and the apparent maturation of virus-specific immunity. 相似文献
95.
Trivedi CM Luo Y Yin Z Zhang M Zhu W Wang T Floss T Goettlicher M Noppinger PR Wurst W Ferrari VA Abrams CS Gruber PJ Epstein JA 《Nature medicine》2007,13(3):324-331
In the adult heart, a variety of stresses induce re-expression of a fetal gene program in association with myocyte hypertrophy and heart failure. Here we show that histone deacetylase-2 (Hdac2) regulates expression of many fetal cardiac isoforms. Hdac2 deficiency or chemical histone deacetylase (HDAC) inhibition prevented the re-expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli. Resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate-5-phosphatase f (Inpp5f) resulting in constitutive activation of glycogen synthase kinase 3beta (Gsk3beta) via inactivation of thymoma viral proto-oncogene (Akt) and 3-phosphoinositide-dependent protein kinase-1 (Pdk1). In contrast, Hdac2 transgenic mice had augmented hypertrophy associated with inactivated Gsk3beta. Chemical inhibition of activated Gsk3beta allowed Hdac2-deficient adults to become sensitive to hypertrophic stimulation. These results suggest that Hdac2 is an important molecular target of HDAC inhibitors in the heart and that Hdac2 and Gsk3beta are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure. 相似文献
96.
Jonathan Kaplan 《Biology & philosophy》2008,23(5):625-638
The concepts of adaptive/fitness landscapes and adaptive peaks are a central part of much of contemporary evolutionary biology;
the concepts are introduced in introductory texts, developed in more detail in graduate-level treatments, and are used extensively
in papers published in the major journals in the field. The appeal of visualizing the process of evolution in terms of the
movement of populations on such landscapes is very strong; as one becomes familiar with the metaphor, one often develops the
feeling that it is possible to gain deep insights into evolution by thinking about the movement of populations on landscapes
consisting of adaptive valleys and peaks. But, since Wright first introduced the metaphor in 1932, the metaphor has been the
subject of persistent confusion, from equivocation over just what the features of the landscape are meant to represent to
how we ought to expect the landscapes to look. Recent advances—conceptual, empirical, and computational—have pointed towards
the inadequacy and indeed incoherence of the landscapes as usually pictured. I argue that attempts to reform the metaphor
are misguided; it is time to give up the pictorial metaphor of the landscape entirely and rely instead on the results of formal
modeling, however difficult such results are to understand in ‘intuitive’ terms.
相似文献
Jonathan KaplanEmail: |
97.
Those standard historiographic themes of evolution and revolution need replacing. They perpetuate mid-Victorian scientists history of science. Historians history of science does well to take in the long run from the Greek and Hebrew heritages on, and to work at avoiding misleading anachronism and teleology. As an alternative to the usual evo-revo themes, a historiography of origins and species, of cosmologies (including microcosmogonies and macrocosmogonies) and ontologies, is developed here. The advantages of such a historiography are illustrated by looking briefly at a number of transitions the transition from Greek and Hebrew doctrines to their integrations by medieval authors; the transition from the Platonist, Aristotelian, Christian Aquinas to the Newtonian Buffon and to the no less Newtonian Lamarck; the departures the early Darwin made away from Lamarcks and from Lyells views. Issues concerning historical thinking about nature, concerning essentialism and concerning classification are addressed in an attempt to challenge customary stereotypes. Questions about originality and influence are raised, especially concerning Darwins tree of life scheme. The broader historiography of Darwinian science as a social ideology, and as a worldview, is examined and the scope for revisions emphasised. Throughout, graduate students are encouraged to see this topic area not as worked out, but as full of opportunities for fresh contributions. 相似文献
98.
Norton PA Comunale MA Krakover J Rodemich L Pirog N D'Amelio A Philip R Mehta AS Block TM 《Journal of cellular biochemistry》2008,104(1):136-149
The association between elevated circulating levels of GP73 (and fucosylated GP73 in particular) and hepatocellular carcinoma suggests that a thorough analysis of the extent of GP73 glycosylation is warranted. Detailed analysis of the glycosylation patterns of such low abundance proteins are hampered by technical difficulties. Using conventional lectin affinity chromatography, we have established that three quarters of the GP73 secreted from a cell line derived from HCC is fucosylated. Using mass spectrometry, we have established that at least two of three potential sites of N-linked glycosylation are occupied on most molecules of GP73 secreted from cultured hepatoma cells. Furthermore, the oligosaccharides added to recombinant GP73 resemble those present in the bulk of secreted protein, mostly bi-antennary with core fucose, with a smaller fraction of tri- and tetra-antennary structures. The frequency of fucosylation observed on the recombinant protein agrees well with the pattern of lectin binding of the endogenous secreted protein. Finally, we have developed a method to interrogate the glycans added to either the near full length protein or at a particular sequon, providing proof of concept that a small peptide embedded in a heterologous context can preserve both fucosylation and a high level of branching of oligosaccharides added. 相似文献
99.
Lei JT Mazumdar T Martinez-Moczygemba M 《The Journal of biological chemistry》2011,286(46):40091-40103
Eosinophils are multifunctional leukocytes implicated in the pathogenesis of numerous inflammatory diseases including allergic asthma and hypereosinophilic syndrome. Eosinophil physiology is critically dependent on IL-5 and the IL-5 receptor (IL-5R), composed of a ligand binding α chain (IL-5Rα), and a common β chain, βc. Previously, we demonstrated that the βc cytoplasmic tail is ubiquitinated and degraded by proteasomes following IL-5 stimulation. However, a complete understanding of the role of βc ubiquitination in IL-5R biology is currently lacking. By using a well established, stably transduced HEK293 cell model system, we show here that in the absence of ubiquitination, βc subcellular localization, IL-5-induced endocytosis, turnover, and IL-5R signaling were significantly impaired. Whereas ubiquitinated IL-5Rs internalized into trafficking endosomes for their degradation, ubiquitination-deficient IL-5Rs accumulated on the cell surface and displayed blunted signaling even after IL-5 stimulation. Importantly, we identified a cluster of three membrane-proximal βc lysine residues (Lys(457), Lys(461), and Lys(467)) whose presence was required for both JAK1/2 binding to βc and receptor ubiquitination. These findings establish that JAK kinase binding to βc requires the presence of three critical βc lysine residues, and this binding event is essential for receptor ubiquitination, endocytosis, and signaling. 相似文献
100.
James Skelton Michelle A. Jusino Paige S. Carlson Katherine Smith Mark T. Banik Daniel L. Lindner Jonathan M. Palmer Jiri Hulcr 《Molecular ecology》2019,28(22):4971-4986
A prevailing paradigm in forest ecology is that wood‐boring beetles facilitate wood decay and carbon cycling, but empirical tests have yielded mixed results. We experimentally determined the effects of wood borers on fungal community assembly and wood decay within pine trunks in the southeastern United States. Pine trunks were made either beetle‐accessible or inaccessible. Fungal communities were compared using culturing and high‐throughput amplicon sequencing (HTAS) of DNA and RNA. Prior to beetle infestation, living pines had diverse fungal endophyte communities. Endophytes were displaced by beetle‐associated fungi in beetle‐accessible trees, whereas some endophytes persisted as saprotrophs in beetle‐excluded trees. Beetles increased fungal diversity several fold. Over forty taxa of Ascomycota were significantly associated with beetles, but beetles were not consistently associated with any known wood‐decaying fungi. Instead, increasing ambrosia beetle infestations caused reduced decay, consistent with previous in vitro experiments that showed beetle‐associated fungi reduce decay rates by competing with decay fungi. No effect of bark‐inhabiting beetles on decay was detected. Platypodines carried significantly more fungal taxa than scolytines. Molecular results were validated by synthetic and biological mock communities and were consistent across methodologies. RNA sequencing confirmed that beetle‐associated fungi were biologically active in the wood. Metabarcode sequencing of the LSU/28S marker recovered important fungal symbionts that were missed by ITS2, though community‐level effects were similar between markers. In contrast to the current paradigm, our results indicate ambrosia beetles introduce diverse fungal communities that do not extensively decay wood, but instead reduce decay rates by competing with wood decay fungi. 相似文献