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51.
The subfraction distribution of HDL-associated peptides has implications for their functions and the impact of pathological modifications to lipoprotein metabolism on these functions. We have analyzed the subfraction distribution of paraoxonase-1 (PON1) and the consequences for enzyme activity and stability. HDL subfractions were defined by the presence (LpA-I,A-II) or absence (LpA-I) of apolipoprotein A-II (apoA-II). PON1 was present in both subfractions, although increased concentrations of HDL were associated with significantly increased PON1 in LpA-I. ApoA-II did not modify the capacity of native human HDL or reconstituted HDL to promote PON1 secretion from cells or to stabilize enzyme activity, nor did apoA-II decrease PON1 activity when added to rabbit serum normally devoid of the apolipoprotein. LpA-I,A-II particles isolated from human serum or reconstituted HDL (LpA-I,A-II) showed a significantly greater capacity than HDL(LpA-I) to stabilize secreted PON1 and purified recombinant PON1 added to such particles. PON1 associated with apoA-II-containing particles showed greater resistance to inactivation arising from oxidation. ApoA-I, apoA-II, and LpA-I,A-II, but not LpA-I, were independent determinants of serum PON1 concentration and activity in multivariate analyses. PON1 is at least equally distributed between LpA-I and LpA-II,A-II HDL particles. This dichotomous distribution has implications for PON1 activity and stability that may impact on the physiological role of the enzyme. 相似文献
52.
Zeynep N. Erdem Stefanie Schwarz Daniel Drev Christine Heinzle Andrea Reti Petra Heffeter Xenia Hudec Klaus Holzmann Bettina Grasl-Kraupp Walter Berger Michael Grusch Brigitte Marian 《Translational oncology》2017,10(3):332-339
BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed. RESULTS: IRI exposure induced expression of FGFR3 as well as its ligands FGF8 and FGF18 both in cell cultures and in xenograft tumors. As overexpression of FGFR3 mitigated IRI-induced apoptosis in CRC cell models, this suggests that the drug itself activated a survival response. On the cellular level, the antiapoptotic protein bcl-xl was upregulated and caspase 3 activation was inhibited. Targeting FGFR3 signaling using a dominant-negative receptor mutant sensitized cells for IRI. In addition, the FGFR inhibitor PD173074 acted synergistically with the chemotherapeutic drug and significantly enhanced IRI-induced caspase 3 activity in vitro. In vivo, PD173074 strongly inhibited growth of IRI-treated tumors. CONCLUSION: Together, our results indicate that targeting FGFR3 can be a promising strategy to enhance IRI response in CRC patients. 相似文献
53.
Hesseler M Bogdanović X Hidalgo A Berenguer J Palm GJ Hinrichs W Bornscheuer UT 《Applied microbiology and biotechnology》2011,91(4):1049-1060
A haloalkane dehalogenase (DppA) from Plesiocystis pacifica SIR-1 was identified by sequence comparison in the NCBI database, cloned, functionally expressed in Escherichia coli, purified, and biochemically characterized. The three-dimensional (3D) structure was determined by X-ray crystallography and has been refined at 1.95 Å resolution to an R-factor of 21.93%. The enzyme is composed of an α/β-hydrolase fold and a cap domain and the overall fold is similar to other known haloalkane dehalogenases. Active site residues were identified as Asp123, His278, and Asp249 and Trp124 and Trp163 as halide-stabilizing residues. DppA, like DhlA from Xanthobacter autotrophicus GJ10, is a member of the haloalkane dehalogenase subfamily HLD-I. As a consequence, these enzymes have in common the relative position of their catalytic residues within the structure and also show some similarities in the substrate specificity. The enzyme shows high preference for 1-bromobutane and does not accept chlorinated alkanes, halo acids, or halo alcohols. It is a monomeric protein with a molecular mass of 32.6 kDa and exhibits maximum activity between 33 and 37°C with a pH optimum between pH 8 and 9. The Km and kcat values for 1-bromobutane were 24.0 mM and 8.08 s?1. Furthermore, from the 3D-structure of DppA, it was found that the enzyme possesses a large and open active site pocket. Docking experiments were performed to explain the experimentally determined substrate preferences. 相似文献
54.
Jacobo Reyes‐Velasco Joseph D. Manthey Xenia Freilich Stéphane Boissinot 《Molecular ecology》2018,27(9):2256-2270
The frog genus Leptopelis is composed of ~50 species that occur across sub‐Saharan Africa. The majority of these frogs are typically arboreal; however, a few species have evolved a fossorial lifestyle. Most species inhabit lowland forests, but a few species have adapted to high elevations. Five species of Leptopelis occupy the Ethiopian highlands and provide a good opportunity to study the evolutionary transition from an arboreal to a fossorial lifestyle, as well as the diversification in this biodiversity hot spot. We sequenced 14 nuclear and three mitochondrial genes, and generated thousands of SNPs from ddRAD sequencing to study the evolutionary relationships of Ethiopian Leptopelis. The five species of highland Leptopelis form a monophyletic group, which diversified during the late Miocene and Pliocene. We found strong population structure in the fossorial species L. gramineus, with levels of genetic differentiation between populations similar to those found between arboreal species. This could indicate that L. gramineus is a complex of cryptic species. We propose that after the original colonization of the Ethiopian highlands by the ancestor of the L. gramineus group, episodes of vicariance fragmented the ancestral populations of this group. We also report the re‐evolution of arboreality in L. susanae, which evolved from a fossorial ancestor, a rare ecological switch in frogs that had previously been reported only once. 相似文献
55.
A combination of traditional and emerging methodologies was used to assess the trade-offs between several life-history traits (linked to reproduction and condition) and parasitism in a commercially-exploited cold-water species, blue whiting Micromesistius poutassou, in the Mediterranean Sea. The use of histological and gravimetric methods revealed conflicting evidence as to the fecundity type (indeterminate or determinate) of this species. Moreover, there seem to be condition-mediated compensations between egg quality and egg quantity. The effects of parasitism on reproduction and condition are species-specific and occur mainly at high intensities of infection; they include a lower batch fecundity (affecting reproductive potential), a higher hepatosomatic index and a higher spleen-somatic index. Considering the fact that larger fish spawn more eggs and that the minimum landing size is lower than the size at maturity, these results may have implications for the future management of M. poutassou stocks in the Mediterranean Sea. Local environmental conditions may account for geographical differences regarding infection in M. poutassou. Altogether, the results support the idea that the complex trade-offs between parasitism, reproduction and condition need to be considered in order to understand the status of cold-water species such as M. poutassou. 相似文献
56.
Mechanisms of Accommodation in Different Types of Frog Neurons 总被引:1,自引:0,他引:1
Responses of individual spinal ganglion neurons, sympathetic ganglion neurons, and motoneurons of frogs to linearly rising currents were investigated utilizing microelectrodes for intracellular stimulation and recording. Spinal ganglion neurons exhibited rapid accommodation to linearly rising currents. Minimal current gradients (MCG's) required to excite these neurons (average value, 106 rheobases/sec) were of the same order of magnitude as for some nerve fibers. Although sympathetic ganglion neurons exhibited responses to lower current gradients than spinal ganglion neurons, distinct MCG's (average value, 26 rheobases/sec) could always be established. MCG's could not be detected in most motoneurons, even with current gradients as low as 0.6 rheobase/sec. A few motoneurons exhibited distinct MCG's (average value, 11 rheobases/sec). The failure of spinal ganglion neurons to respond to anything other than rapidly rising currents appears to be due primarily to the development of severe delayed rectification. The inability of sympathetic ganglion neurons to respond to low current gradients appears to depend not only on delayed rectification but also on increases in depolarization threshold. When present in motoneurons, accommodation appears to result from the same mechanisms responsible for its appearance in sympathetic ganglion neurons. 相似文献
57.
María Almuedo-Castillo Xenia Crespo Florian Seebeck Kerstin Bartscherer Emili Salò Teresa Adell 《PLoS genetics》2014,10(6)
Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun–NH2–kinase (JNK) links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal. 相似文献
58.
Loredana Castrì Sergio Tofanelli Paolo Garagnani Carla Bini Xenia Fosella Susi Pelotti Giorgio Paoli Davide Pettener Donata Luiselli 《American journal of physical anthropology》2009,140(2):302-311
In this study, we report novel data on mitochondrial DNA in two of the largest eastern Bantu‐speaking populations, the Shona from Zimbabwe and the Hutu from Rwanda. The goal is to evaluate the genetic relationships of these two ethnic groups with other Bantu‐speaking populations. Moreover, by comparing our data with those from other Niger‐Congo speaking populations, we aim to clarify some aspects of evolutionary and demographic processes accompanying the spread of Bantu languages in sub‐Saharan Africa and to test if patterns of genetic variation fit with models of population expansion based on linguistic and archeological data. The results indicate that the Shona and Hutu are closely related to the other Bantu‐speaking populations. However, there are some differences in haplogroup composition between the two populations, mainly due to different genetic contributions from neighboring populations. This result is confirmed by estimates of migration rates which show high levels of gene flow not only between pairs of Bantu‐speaking populations, but also between Bantu and non‐Bantu speakers. The observed pattern of genetic variability (high genetic homogeneity and high levels of gene flow) supports a linguistic model suggesting a gradual spread of Bantu‐speakers, with strong interactions between the different lines of Bantu‐speaker descent, and is also in agreement with recent archeological findings. In conclusion, our data emphasize the role that population admixture has played at different times and to varying degrees in the dispersal of Bantu languages. Am J Phys Anthropol, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
59.
60.
Xenia Latypova Marie Vincent Alice Mollé Oluwadamilare A. Adebambo Cynthia Fourgeux Tahir N. Khan Alfonso Caro Monica Rosello Carmen Orellana Dmitriy Niyazov Damien Lederer Marie Deprez Yline Capri Peter Kannu Anne Claude Tabet Jonathan Levy Emmelien Aten Nicolette den Hollander Bertrand Isidor 《American journal of human genetics》2021,108(5):929-941