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21.
Dominic Holland Oleksandr Frei Rahul Desikan Chun-Chieh Fan Alexey A Shadrin Olav B Smeland Ole A Andreassen Anders M Dale 《Genetics》2021,217(3)
We propose an extended Gaussian mixture model for the distribution of causal effects of common single nucleotide polymorphisms (SNPs) for human complex phenotypes that depends on linkage disequilibrium (LD) and heterozygosity (H), while also allowing for independent components for small and large effects. Using a precise methodology showing how genome-wide association studies (GWASs) summary statistics (z-scores) arise through LD with underlying causal SNPs, we applied the model to GWAS of multiple human phenotypes. Our findings indicated that causal effects are distributed with dependence on total LD and H, whereby SNPs with lower total LD and H are more likely to be causal with larger effects; this dependence is consistent with models of the influence of negative pressure from natural selection. Compared with the basic Gaussian mixture model it is built on, the extended model—primarily through quantification of selection pressure—reproduces with greater accuracy the empirical distributions of z-scores, thus providing better estimates of genetic quantities, such as polygenicity and heritability, that arise from the distribution of causal effects. 相似文献
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Nitric oxide signalling in plants 总被引:13,自引:0,他引:13
24.
Monique C. Saleh Barry J. Connell Desikan Rajagopal Bobby V. Khan Alaa S. Abd-El-Aziz Inan Kucukkaya Tarek M. Saleh 《PloS one》2014,9(1)
The present study demonstrates the benefits of combinatorial antioxidant therapy in the treatment of ischemic stroke. Male Sprague-Dawley rats were anaesthetised and the middle cerebral artery (MCA) was occluded for 30 minutes followed by 5.5 hours of reperfusion. Pretreatment with resveratrol 30 minutes prior to MCA occlusion resulted in a significant, dose-dependent decrease in infarct volume (p<0.05) compared to vehicle-treated animals. Neuroprotection was also observed when resveratrol (2×10−3 mg/kg; iv) was administered within 60 minutes following the return of blood flow (reperfusion). Pretreatment with non-neuroprotective doses of resveratrol (2×10−6 mg/kg) and lipoic acid (LA; 0.005 mg/kg) in combination produced significant neuroprotection as well. This neuroprotection was also observed when resveratrol and LA were administered 15 minutes following the onset of MCA occlusion. Subsequently, we synthetically combined resveratrol and LA in both a 1∶3 (UPEI-200) and 1∶1 (UPEI-201) ratio, and screened these new chemical entities in both permanent and transient ischemia models. UPEI-200 was ineffective, while UPEI-201 demonstrated significant, dose-dependent neuroprotection. These results demonstrate that combining subthreshold doses of resveratrol and LA prior to ischemia-reperfusion can provide significant neuroprotection likely resulting from concurrent effects on multiple pathways. The additional protection observed in the novel compound UPEI 201 may present opportunities for addressing ischemia-induced damage in patients presenting with transient ischemic episodes. 相似文献
25.
Desikan RS Sabuncu MR Schmansky NJ Reuter M Cabral HJ Hess CP Weiner MW Biffi A Anderson CD Rosand J Salat DH Kemper TL Dale AM Sperling RA Fischl B;Alzheimer's Disease Neuroimaging Initiative 《PloS one》2010,5(9):e12853
Background
Alzheimer''s disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.Methodology/Principal Findings
In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) Aß levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer''s pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.Conclusions/Significance
Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer''s pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia. 相似文献26.
Nitric oxide evolution and perception 总被引:8,自引:0,他引:8
Neill S Bright J Desikan R Hancock J Harrison J Wilson I 《Journal of experimental botany》2008,59(1):25-35
Various experimental data indicate signalling roles for nitric oxide (NO) in processes such as xylogenesis, programmed cell death, pathogen defence, flowering, stomatal closure, and gravitropism. However, it still remains unclear how NO is synthesized. Nitric oxide synthase-like activity has been measured in various plant extracts, NO can be generated from nitrite via nitrate reductase and other mechanisms of NO generation are also likely to exist. NO removal mechanisms, for example, by reaction with haemoglobins, have also been identified. NO is a gas emitted by plants, with the rate of evolution increasing under conditions such as pathogen challenge or hypoxia. However, exactly how NO evolution relates to its bioactivity in planta remains to be established. NO has both aqueous and lipid solubility, but is relatively reactive and easily oxidized to other nitrogen oxides. It reacts with superoxide to form peroxynitrite, with other cellular components such as transition metals and haem-containing proteins and with thiol groups to form S-nitrosothiols. Thus, diffusion of NO within the plant may be relatively restricted and there might exist 'NO hot-spots' depending on the sites of NO generation and the local biochemical micro-environment. Alternatively, it is possible that NO is transported as chemical precursors such as nitrite or as nitrosothiols that might function as NO reservoirs. Cellular perception of NO may occur through its reaction with biologically active molecules that could function as 'NO-sensors'. These might include either haem-containing proteins such as guanylyl cyclase which generates the second messenger cGMP or other proteins containing exposed reactive thiol groups. Protein S-nitrosylation alters protein conformation, is reversible and thus, is likely to be of biological significance. 相似文献
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Ole A. Andreassen Wesley K. Thompson Andrew J. Schork Stephan Ripke Morten Mattingsdal John R. Kelsoe Kenneth S. Kendler Michael C. O'Donovan Dan Rujescu Thomas Werge Pamela Sklar The Psychiatric Genomics Consortium Bipolar Disorder Schizophrenia Working Groups J. Cooper Roddey Chi-Hua Chen Linda McEvoy Rahul S. Desikan Srdjan Djurovic Anders M. Dale 《PLoS genetics》2015,11(11)
29.
Short communication. H2O2 activates a MAP kinase-like enzyme in Arabidopsis thaliana suspension cultures 总被引:1,自引:0,他引:1
Treatment of Arabidopsis thaliana suspension cultures
with H2O2 results in the activation of a 44 kDa protein kinase with the
characteristics of a mitogen activated protein (MAP) kinase. It
preferentially phosphorylates myelin basic protein as an artificial
substrate, it requires tyrosine phosphorylation for its activity, is
tyrosine and threonine phosphorylated upon activation, and its activation
is rapid, transient, and occurs in a dose-dependent manner. This is the
first demonstration of the activation of a MAP kinase-like enzyme by H2O2
in plants. 相似文献
30.
D Holland RS Desikan AM Dale LK McEvoy;for the Alzheimer’s Disease Neuroimaging Initiative 《PloS one》2012,7(8):e42325
Age is the strongest risk factor for sporadic Alzheimer disease (AD), yet the effects of age on rates of clinical decline and brain atrophy in AD have been largely unexplored. Here, we examined longitudinal rates of change as a function of baseline age for measures of clinical decline and structural MRI-based regional brain atrophy, in cohorts of AD, mild cognitive impairment (MCI), and cognitively healthy (HC) individuals aged 65 to 90 years (total n = 723). The effect of age was modeled using mixed effects linear regression. There was pronounced reduction in rates of clinical decline and atrophy with age for AD and MCI individuals, whereas HCs showed increased rates of clinical decline and atrophy with age. This resulted in convergence in rates of change for HCs and patients with advancing age for several measures. Baseline cerebrospinal fluid densities of AD-relevant proteins, Aβ1–42, tau, and phospho-tau181p (ptau), showed a similar pattern of convergence with advanced age across cohorts, particularly for ptau. In contrast, baseline clinical measures did not differ by age, indicating uniformity of clinical severity at baseline. These results imply that the phenotypic expression of AD is relatively mild in individuals older than approximately 85 years, and this may affect the ability to distinguish AD from normal aging in the very old. Our findings show that inclusion of older individuals in clinical trials will substantially reduce the power to detect disease-modifying therapeutic effects, leading to dramatic increases in required clinical trial sample sizes with age of study sample. 相似文献