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41.
Erik D. Pendleton Challise J. Sullivan Henri H. Sasmor Kristy D. Bruse Tifanie B. Mayfield David L. Valente Rachel E. Abrams Richard H. Griffey John Dresios 《Biochemistry and Biophysics Reports》2016
BackgroundIdentification of wound-specific markers would represent an important step toward damaged tissue detection and targeted delivery of biologically important materials to injured sites. Such delivery could minimize the amount of therapeutic materials that must be administered and limit potential collateral damage on nearby normal tissues. Yet, biological markers that are specific for injured tissue sites remain elusive.MethodsIn this study, we have developed an immunohistological approach for identification of protein epitopes specifically exposed in wounded tissue sites.ResultsUsing ex-vivo tissue samples in combination with fluorescently-labeled antibodies we show that actin, an intracellular cytoskeletal protein, is specifically exposed upon injury. The targetability of actin in injured sites has been demonstrated in vivo through the specific delivery of anti-actin conjugated particles to the wounded tissue in a lethal rat model of grade IV liver injury.ConclusionsThese results illustrate that identification of injury-specific protein markers and their targetability for specific delivery is feasible.General significanceIdentification of wound-specific targets has important medical applications as it could enable specific delivery of various products, such as expression vectors, therapeutic drugs, hemostatic materials, tissue healing, or scar prevention agents, to internal sites of penetrating or surgical wounds regardless of origin, geometry or location. 相似文献
42.
The Escherichia coli chaperonin GroEL is a complex of identical subunit proteins (57 kDa each) arranged in a back-to-back stacking of two heptameric rings. Its hallmarks include nested positive intra-ring and negative inter-ring cooperativity in adenosine trisphosphate (ATP) binding and the ability to mediate the folding of newly transcribed and/or denatured substrate proteins. We performed unbiased molecular dynamics simulations of the GroEL subunit protein in explicit water both with and without the nucleotide KMgATP to understand better the details of the structural transitions that enable these behaviors. Placing KMgATP in the equatorial domain binding pocket of a t state subunit, which corresponds to a low ATP-affinity state, produced a short-lived (6 ns) state that spontaneously transitioned to the high ATP-affinity r state. The important feature of this transition is a large-scale rotation of the intermediate domain's helix M to close the ATP binding pocket. Pivoting of helix M is accompanied by counterclockwise rotation and slight deformation of the apical domain, important for lowering the affinity for substrate protein. Aligning simulation conformations into model heptamer rings demonstrates that the t-->r transition in one subunit is not sterically hindered by t state neighbors, but requires breakage of Arg(197)-Glu(386) intersubunit salt bridges, which are important for inter-ring positive cooperativity. Lowest-frequency quasi-harmonic modes of vibration computed pre- and post-transition clearly show that natural vibrations facilitate the transition. Finally, we propose a novel mechanism for inter-ring cooperativity in ATP binding inspired by the observation of spontaneous insertion of the side chain of Ala(480) into the empty nucleotide pocket. 相似文献
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Chronic L‐DOPA induces hyperactivity,normalization of gait and dyskinetic behavior in MitoPark mice 下载免费PDF全文
Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L‐DOPA‐induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin‐induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long‐term L‐DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long‐term treatment with a moderate, clinically relevant dose of L‐DOPA (8 mg/kg) gradually produced age‐dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long‐term L‐DOPA treatment. The cylinder test showed an age‐dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long‐term L‐DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID. 相似文献
46.
Peter Abrams 《Theoretical population biology》1983,24(1):22-38
The optimal life histories are examined for models in which the average life-history strategy adopted by the population affects the costs and benefits of any individual's strategy. The situation modeled is one in which organisms can gain energy to be used in reproduction by foraging, but in doing so, they expose themselves to increased mortality; thus the proportion of time spent foraging can be used to measure reproductive effort. Simple models of a demographically homogeneous population are used to reexamine questions which have been studied previously using other models. The effects upon optimal reproductive effort of the following factors are examined: increased births per unit effort, increased mortality, and variability in population parameters. In addition, the questions of whether optimal reproductive effort maximizes population size and whether there can be multiple alternative life histories are examined. Results in most cases differ significantly from those of previous studies. No generalizations emerge regarding the effects of the three factors listed above. Optimal life histories in this model generally do not maximize population size. It is possible to have globally stable alternative life histories. It is concluded that frequency dependence will often be important in determining optimal life histories. 相似文献
47.
A study of bacterial surface oligosaccharides were investigated among
different strains of Neisseria gonorrhoeae to correlate structural features
essential for binding to the MAb 2C7. This epitope is widely expressed and
conserved in gonococcal isolates, characteristics essential to an effective
candidate vaccine antigen. Sample lipooligosaccharides (LOS), was prepared
by a modification of the hot phenol-water method from which de-O-acetylated
LOS and oligosaccharide (OS) components were analyzed by ES-MS-CID-MS and
ES-MSnin a triple quadrupole and an ion trap mass spectrometer,
respectively. Previously documented natural heterogeneity was apparent from
both LOS and OS preparations which was admixed with fragments induced by
hydrazine and mild acid treatment. Natural heterogeneity was limited to
phosphorylation and antenni extensions to the alpha-chain. Mild acid
hydrolysis to release OS also hydrolyzed the beta(1-->6) glycosidic
linkage of lipid A. OS structures were determined by collisional and
resonance excitation combined with MS and multistep MSn which provided
sequence information from both neutral loss, and nonreducing terminal
fragments. A comparison of OS structures, with earlier knowledge of MAb
binding, enzyme treatment, and partial acid hydrolysis indicates a generic
overlapping domain for 2C7 binding. Reoccurring structural features include
a Hepalpha(1-->3)Hepbeta(1-->5)KDO trisaccharide core branched on the
nonreducing terminus (Hep-2) with an alpha(1-->2) linked GlcNAc
(gamma-chain), and an alpha-linked lactose (beta-chain) residue. From the
central heptose (Hep-1), a beta(1-->4) linked lactose (alpha-chain),
moiety is required although extensions to this residue appear unnecessary.
相似文献
48.
Juan Manuel López-García Hugues-Alexandre Blain Jean-Marie Cordy Stéphane Pirson Grégory Abrams Kévin Di Modica 《Historical Biology》2017,29(8):1125-1142
The habitat weighting, the bioclimatic model methods and the Simpson diversity index are applied to the small-mammals assemblage of Scladina Cave (border between High and Middle Belgium) in order to reconstruct the environmental and climatic fluctuations that are reflected on the Middle to Late Pleistocene sequence of the cave. The small-mammal data analyzed come from two surveys carried out at the entrance of the cave and allow us to identify within the section one cold episode: a dry, cool phase in the upper part of the sequence (probably associated with the MIS 3). The environmental and climatic data show an alternation of open meadows and woodland formations through both sequences, punctuated by peaks in local watery environments together with lower temperatures and higher precipitations rates than at present. Finally, a comparison of the small-mammal fossil assemblage from the studied surveys with the small-mammals assemblage from the Holocene deposits of Scladina Cave shows that layers related with MIS 5 temperate sub-stages (MIS 5c and MIS 5a) present environmental characteristics similar to those prevailing nowadays (a landscape dominated by woodland formations and water streams) in the area surrounding the cave. This is coherent with the available chronostratigraphic datasets on this part of the sequence, suggesting the record of the humid and temperate phases at the beginning of the Late Pleistocene. 相似文献
49.
Tucker TJ Abrams MT Buser CA Davide JP Ellis-Hutchings M Fernandes C Gibbs JB Graham SL Hartman GD Huber HE Liu D Lobell RB Lumma WC Robinson RG Sisko JT Smith AM 《Bioorganic & medicinal chemistry letters》2002,12(15):2027-2030
We have prepared a series of potent, dual inhibitors of the prenyl transferases farnesyl protein transferase (FPTase) and geranyl-geranyl protein transferase I (GGPTase). The compounds were shown to possess potent activity against both enzymes in cell culture. Mechanistic analysis has shown that the compounds are CAAX competitive for FPTase inhibition but geranyl-geranyl pyrophosphate (GGPP) competitive for GGPTase inhibiton. 相似文献
50.
Folding changes in membrane-inserted diphtheria toxin that may play important roles in its translocation. 总被引:2,自引:0,他引:2
Diphtheria toxin membrane penetration is triggered by the low pH within the endosome lumen. Subsequent exposure to the neutral pH of the cytoplasm is believed to aid in translocation of the catalytic A domain of the toxin into the cytoplasm. To understand the effects of low pH and subsequent exposure to neutral pH on translocation, we studied toxin conformation in solution and in toxin inserted in model membranes. Two conformations were found at low pH. One form, L', predominates below 25-30 degrees C, and the other, L", predominates above 25-30 degrees C and is formed from the L' state by an unfolding event. Both forms are hydrophobic and penetrate deeply into membranes. After pH neutralization, the L' and L' conformations give rise to two new conformations, R' and R', respectively. The R' and R" conformations differ from each other in that in the R' state the A domain remains folded, whereas in the R" state the A domain is unfolded. This is confirmed by the finding that only the R' state possesses the capacity to bind and hydrolyze NAD+. It is also supported by the finding that the R' state can also be formed by thermal unfolding of the R' state. The R conformations differ from the low-pH L conformations in that although they remain largely membrane-inserted, it appears that a large portion of the toxin is no longer in contact with the hydrophobic core of the bilayer.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献