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81.
Pituitary prolactin, like growth hormone (GH) and several other protein hormones, shows an episodic pattern of molecular evolution in which sustained bursts of rapid change contrast with long periods of slow evolution. A period of rapid change occurred in the evolution of prolactin in primates, leading to marked sequence differences between human prolactin and that of nonprimate mammals. We have defined this burst more precisely by sequencing the coding regions of prolactin genes for a prosimian, the slow loris (Nycticebus pygmaeus), and a New World monkey, the marmoset (Callithrix jacchus). Slow loris prolactin is very similar in sequence to pig prolactin, so the episode of rapid change occurred during primate evolution, after the separation of lines leading to prosimians and higher primates. Marmoset prolactin is similar in sequence to human prolactin, so the accelerated evolution occurred before divergence of New World monkeys and Old World monkeys/apes. The burst of change was confined largely to coding sequence (nonsynonymous sites) for mature prolactin and is not marked in other components of the gene sequence. This and the observations that (1) there was no apparent loss of function during the episode of rapid evolution, (2) the rate of evolution slowed toward the basal rate after this burst, and (3) the distribution of substitutions in the prolactin molecule is very uneven support the idea that this episode of rapid change was due to positive adaptive selection. In the slow loris and marmoset there is no evidence for duplication of the prolactin gene, and evidence from another New World monkey (Cebus albifrons) and from the chimpanzee and human genome sequences, suggests that this is the general position in primates, contrasting with the situation for GH genes. The chimpanzee prolactin sequence differs from that of human at two residues and comparison of human and chimpanzee prolactin gene sequences suggests that noncoding regions associated with regulating expression may be evolving differently from other noncoding regions. 相似文献
82.
Tesco G Ginestroni A Hiltunen M Kim M Dolios G Hyman BT Wang R Berezovska O Tanzi RE 《Journal of neurochemistry》2005,95(2):446-456
The 37-43 amino acid Abeta peptide is the principal component of beta-amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by beta- and gamma-secretase. gamma-Secretase also cleaves APP at Val50 in the Abeta numbering (epsilon cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Abeta and AICD generation. We found that the APPV715F substitution, which has been previously shown to dramatically decrease Abeta40 and Abeta42 while increasing Abeta38 levels, does not affect in vitro generation of AICD. Furthermore, we found that the APPL720P substitution, which has been previously shown to prevent in vitro generation of AICD, completely prevents Abeta generation. Using a fluorescence resonance energy transfer (FRET) method, we next found that both the APPV715F and APPL720P substitutions significantly increase the distance between the N- and C-terminus of presenilin 1 (PS1), which has been proposed to contain the catalytic site of gamma-secretase. In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Abeta and AICD production. 相似文献
83.
In humans, leukocyte cell-derived chemotaxin 2 (LECT2) is a 16kDa chemotactic protein that consists of 133 amino acids and three intramolecular disulphide bonds. Although it was originally demonstrated to have a chemotactic function in vitro, recent data sustain a further multifunctional role of LECT2 that extends from cell growth, differentiation, damage/repair process and carcinogenesis to autoimmune diseases. The in vivo function of LECT2 protein still remains obscure. In order to study the phylogeny of LECT2, a full-length cDNA clone of LECT2 gene, 720 bp in size, was isolated in rainbow trout (Oncorhynchus mykiss). Its deduced amino acid sequence of 156 residues, presents 40, 45 and 61% overall identity to human, mouse and carp LECT2 proteins, respectively. In contrast to mammalian LECT2 protein, trout LECT2 protein reveals two potential N-glycosylation sites. Phylogenetic analysis shows that trout LECT2 is clustered with the known homologous proteins. Trout LECT2 mRNA is predominately expressed in liver and spleen, showing lower expression in kidney, intestine, heart and brain. 相似文献
84.
Tabar V Panagiotakos G Greenberg ED Chan BK Sadelain M Gutin PH Studer L 《Nature biotechnology》2005,23(5):601-606
Human embryonic stem (hES) cells provide a potentially unlimited cell source for regenerative medicine. Recently, differentiation strategies were developed to direct hES cells towards neural fates in vitro. However, the interaction of hES cell progeny with the adult brain environment remains unexplored. Here we report that hES cell-derived neural precursors differentiate into neurons, astrocytes and oligodendrocytes in the normal and lesioned brain of young adult rats and migrate extensively along white matter tracts. The differentiation and migration behavior of hES cell progeny was region specific. The hES cell-derived neural precursors integrated into the endogenous precursor pool in the subventricular zone, a site of persistent neurogenesis. Like adult neural stem cells, hES cell-derived precursors traveled along the rostral migratory stream to the olfactory bulb, where they contributed to neurogenesis. We found no evidence of cell fusion, suggesting that hES cell progeny are capable of responding appropriately to host cues in the subventricular zone. 相似文献
85.
Mandolesi G Menna E Harauzov A von Bartheld CS Caleo M Maffei L 《Current biology : CB》2005,15(23):2119-2124
Visual deprivation is a classical tool to study the plasticity of visual cortical connections. After eyelid closure in young animals (monocular deprivation, MD), visual cortical neurons become dominated by the open eye, a phenomenon known as ocular dominance (OD) plasticity . It is commonly held that the molecular mediators of OD plasticity are cortically derived and that the retina is immune to the effects of MD . Recently, it has been reported that visual deprivation induces neurochemical, structural, and functional changes in the retina , but whether these retinal changes contribute to the effects of MD in the cortex is unknown. Here, we provide evidence that brain-derived neurotrophic factor (BDNF) produced in the retina influences OD plasticity. We found a reduction of BDNF expression in the deprived retina of young rats. We compensated this BDNF imbalance between the two eyes by either injecting exogenous BDNF in the deprived eye or reducing endogenous BDNF expression in the nondeprived eye. Both treatments were effective in counteracting the OD shift induced by MD. Retinal BDNF could also influence OD distribution in normal animals. These results show for the first time that OD plasticity is modulated by BDNF produced in the retina. 相似文献
86.
McGowan E Pickford F Kim J Onstead L Eriksen J Yu C Skipper L Murphy MP Beard J Das P Jansen K Delucia M Lin WL Dolios G Wang R Eckman CB Dickson DW Hutton M Hardy J Golde T 《Neuron》2005,47(2):191-199
Considerable circumstantial evidence suggests that Abeta42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for Abeta42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express Abeta1-40 or Abeta1-42 in the absence of human amyloid beta protein precursor (APP) overexpression. Mice expressing high levels of Abeta1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of Abeta1-42 accumulate insoluble Abeta1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse Abeta deposits. When mice expressing Abeta1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels. 相似文献
87.
Martini G Zulian F Calabrese F Bortoli M Facco M Cabrelle A Valente M Zacchello F Agostini C 《Arthritis research & therapy》2005,7(2):R241-R249
The accumulation of T cells in the synovial membrane is the crucial step in the pathophysiology of the inflammatory processes
characterizing juvenile idiopathic arthritis (JIA). In this study, we evaluated the expression and the pathogenetic role in
oligoarticular JIA of a CXC chemokine involved in the directional migration of activated T cells, i.e. IFNγ-inducible protein
10 (CXCL10) and its receptor, CXCR3. Immunochemistry with an antihuman CXCL10 showed that synovial macrophages, epithelial
cells, and endothelial cells bear the chemokine. By flow cytometry and immunochemistry, it has been shown that CXCR3 is expressed
at high density by virtually all T lymphocytes isolated from synovial fluid (SF) and infiltrating the synovial membrane. Particularly
strongly stained CXCR3+ T cells can be observed close to the luminal space and in the perivascular area. Furthermore, densitometric analysis has
revealed that the mRNA levels for CXCR3 are significantly higher in JIA patients than in controls. T cells purified from SF
exhibit a definite migratory capability in response to CXCL10. Furthermore, SF exerts significant chemotactic activity on
the CXCR3+ T-cell line, and this activity is inhibited by the addition of an anti-CXCL10 neutralizing antibody. Taken together, these
data suggest that CXCR3/CXCL10 interactions are involved in the pathophysiology of JIA-associated inflammatory processes,
regulating both the activation of T cells and their recruitment into the inflamed synovium. 相似文献
88.
Polycystin-2 (PC2), a member of the transient receptor potential family of ion channels (TRPP2), forms a calcium-permeable cation channel. Mutations in PC2 lead to polycystic kidney disease. From the primary sequence and by analogy with other channels in this family, PC2 is modeled to have six transmembrane domains. However, most of the structural features of PC2, such as how large the channel is and how many subunits make up the pore of the channel, are unknown. In this study, we estimated the pore size of PC2 from the permeation properties of the channel. Organic cations of increasing size were used as current carriers through the PC2 channel after PC2 was incorporated into lipid bilayers. We found that dimethylamine, triethylamine, tetraethylammonium, tetrabutylammonium, tetrapropylammonium, and tetrapentylammonium were permeable through the PC2 channel. The slope conductance of the PC2 channel decreased as the ionic diameter of the organic cation increased. For each organic cation tested, the currents were inhibited by gadolinium and anti-PC2 antibody. Using the dimensions of the largest permeant cation, the minimum pore diameter of the PC2 channel was estimated to be at least 11 A. The large pore size suggests that the primary state of this channel found in vivo is closed to avoid rundown of cation gradients across the plasma membrane and excessive calcium leak from endoplasmic reticulum stores. 相似文献
89.
Relini A Torrassa S Rolandi R Gliozzi A Rosano C Canale C Bolognesi M Plakoutsi G Bucciantini M Chiti F Stefani M 《Journal of molecular biology》2004,338(5):943-957
Much information has appeared in the last few years on the low resolution structure of amyloid fibrils and on their non-fibrillar precursors formed by a number of proteins and peptides associated with amyloid diseases. The fine structure and the dynamics of the process leading misfolded molecules to aggregate into amyloid assemblies are far from being fully understood. Evidence has been provided in the last five years that protein aggregation and aggregate toxicity are rather generic processes, possibly affecting all polypeptide chains under suitable experimental conditions. This evidence extends the number of model proteins one can investigate to assess the molecular bases and general features of protein aggregation and aggregate toxicity. We have used tapping mode atomic force microscopy to investigate the morphological features of the pre-fibrillar aggregates and of the mature fibrils produced by the aggregation of the hydrogenase maturation factor HypF N-terminal domain (HypF-N), a protein not associated to any amyloid disease. We have also studied the aggregate-induced permeabilization of liposomes by fluorescence techniques. Our results show that HypF-N aggregation follows a hierarchical path whereby initial globules assemble into crescents; these generate large rings, which evolve into ribbons, further organizing into differently supercoiled fibrils. The early pre-fibrillar aggregates were shown to be able to permeabilize synthetic phospholipid membranes, thus showing that this disease-unrelated protein displays the same amyloidogenic behaviour found for the aggregates of most pathological proteins and peptides. These data complement previously reported findings, and support the idea that protein aggregation, aggregate structure and toxicity are generic properties of polypeptide chains. 相似文献
90.
The most simple and commonly used approach for genetic associations is the case-control study design of unrelated people. This design is susceptible to population stratification. This problem is obviated in family-based studies, but it is usually difficult to accumulate large enough samples of well-characterized families. We addressed empirically whether the two designs give similar estimates of association in 93 investigations where both unrelated case-control and family-based designs had been employed. Estimated odds ratios differed beyond chance between the two designs in only four instances (4%). The summary relative odds ratio (ROR) (the ratio of odds ratios obtained from unrelated case-control and family-based studies) was close to unity (0.96 [95% confidence interval, 0.91-1.01]). There was no heterogeneity in the ROR across studies (amount of heterogeneity beyond chance I(2) = 0%). Differences on whether results were nominally statistically significant (p < 0.05) or not with the two designs were common (opposite classification rates 14% and 17%); this reflected largely differences in power. Conclusions were largely similar in diverse subgroup analyses. Unrelated case-control and family-based designs give overall similar estimates of association. We cannot rule out rare large biases or common small biases. 相似文献