During early postnatal development, apoptosis of retinal ganglion cells (RGCs) is regulated by target contact with the optic tectum. The neurotrophins BDNF and NT-4, but not NGF, prevent the ...apoptosis of retinal ganglion cells that is otherwise observed after target ablation or axotomy. Thus receptors activated by BDNF and NT-4 are candidates to mediate the early postnatal survival of RGCs. BDNF and NT-4, but not NGF, bind to all isoforms of the receptor TrkB, whether or not they contain a tyrosine kinase domain. To examine the roles of TrkB receptor isoforms in early postnatal survival, we compared RGC numbers in wild-type mice to those in a mutant lacking all isoforms of TrkB. Surprisingly, no reduction in RGCs was observed in the mutant at postnatal day 16, the latest age at which these animals are consistently viable, so TrkB signaling is not essential for target-dependent survival of these cells. In wild-type mice, RGCs also are lost gradually during adulthood, possibly due to oxidative stress. To determine whether TrkB signaling regulates this phase of RGC degeneration, RGC numbers were examined in a viable mutant of TrkB that expresses only about 25% the normal level of TrkB receptor kinase. Compared to controls, approximately 20% of the RGC were lost in mutant 3-month-old-animals. Thus, TrkB signaling is not required for survival of RGCs during the period of target-dependent survival, but does appear to reduce degeneration of RGCs in adult animals.
Background: Reproductive efficiency has a great impact on the economic success of pork production. Gilts comprise a significant portion of breeding females and gilts that reach puberty earlier tend ...to stay in the herd longer and be more productive. About 10 to 30 % of gilts never farrow a litter and the most common reasons for removal are anestrus and failure to conceive. Puberty in pigs is usually defined as the female’s first estrus in the presence of boar stimulation. Genetic markers associated with age at puberty will allow for selection on age at puberty and traits correlated with sow lifetime productivity. Results: Gilts (n = 759) with estrus detection measurements ranging from 140–240 days were genotyped using the Illumina PorcineSNP60 BeadChip and SNP were tested for significant effects with a Bayesian approach using GENSEL software. Of the available 8111 five-marker windows, 27 were found to be statistically significant with a comparison-wise error of P < 0.01. Ten QTL were highly significant at P < 0.005 level. Two QTL, one on SSC12 at 15 Mb and the other on SSC7 at 75 Mb, explained 16.87 % of the total genetic variance. The most compelling candidate genes in these two regions included the growth hormone gene (GH1) on SSC12 and PRKD1 on SSC7. Several loci confirmed associations previously identified for age at puberty in the pig and loci for age at menarche in humans. Conclusions: Several of the loci identified in this study have a physiological role for the onset of puberty and a genetic basis for sexual maturation in humans. Understanding the genes involved in regulation of the onset of puberty would allow for the improvement of reproductive efficiency in swine. Because age at puberty is a predictive factor for sow longevity and lifetime productivity, but not routinely measured or selected for in commercial herds, it would be beneficial to be able to use genomic or marker-assisted selection to improve these traits.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Androstenediol analogs as ER-β-selective SERMs Blizzard, Timothy A.; Gude, Candido; Morgan, Jerry D. ...
Bioorganic & medicinal chemistry letters,
02/2006, Letnik:
16, Številka:
4
Journal Article
Recenzirano
A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-β.
A series of 19-substituted androstenediol ...derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-β.
OBJECTIVE To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar ...degeneration (FTLD). PARTICIPANTS AND DESIGN A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN− FTLD-TDP cases. RESULTS Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations. CONCLUSION GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.Arch Neurol. 2011;68(4):488-497-->
Heparin, a polyanionic glycosaminoglycan, is used routinely before the induction of cardiopulmonary bypass. Earlier observations in our laboratory suggested that the postoperative bleeding that ...occurs, despite neutralization of heparin with protamine, is secondary to hypothermia and dilutional anemia during bypass. An additional, potential mechanism for excessive bleeding following cardiopulmonary bypass is that heparin activates the fibrinolytic system, which may, in turn, adversely affect hemostasis. To understand better the effects of heparin administration on the fibrinolytic system in vivo, we simulated the anticoagulant regimen of cardiopulmonary bypass by administering increasing doses of intravenous heparin to five adult baboons over 60 min. We measured fibrinolytic parameters serially following heparinization and demonstrated that heparin induces activation of the fibrinolytic system. We showed that the fibrinolytic system was activated in vivo as evidenced by an increase in plasmin activity and immunoreactive plasmin light chain, as well as an increase in immunoreactive fibrinogen fragment E in vitro. These results demonstrate that the fibrinolytic system is activated in vivo by the administration of heparin during cardiopulmonary bypass. These data suggest that, despite administration of a neutralizing agent such as protamine, heparin may contribute to postoperative bleeding complications following cardiopulmonary bypass surgery owing principally to its longer lived effects on the fibrinolytic system.
The anisotropic transverse relaxation times T 2 of the primary and secondary acceptor quinone radical anions QA -• and QB -• in Zn-substituted photosynthetic bacterial reaction centers of Rhodobacter ...sphaeroides R26 have been studied by means of 2D high-field/high-frequency (3.4 T/95 GHz, W-band) electron spin−echo spectroscopy. The swept magnetic field is the first, and the pulse-separation time is the second variable. Because of the high magnetic field in W-band EPR, the anisotropic Zeeman interactions of quinone radical anions are resolved; therefore, the orientation dependence of the T 2 relaxation time can be investigated. For QA -• and QB -•, the monoexponential echo decays at 120 K have different orientation-dependent time constants. The anisotropy of the relaxation times is related to anisotropic stochastic fluctuations of the quinones in their protein-binding pockets, which are temperature-dependent. A model is proposed in which the orientation-dependent relaxation originates in reorientational fluctuations around the quinones' specific hydrogen bonds to surrounding amino acids in the binding sites.
The neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic ...underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.
We used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.
We found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses,
,
,
,
, and
, appear to be novel bvFTD risk loci.
Our findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.
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