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101.
Fiona E. Matthews Carol Brayne James Lowe Ian McKeith Stephen B. Wharton Paul Ince 《PLoS medicine》2009,6(11)
Background
Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS).Methods and Findings
A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).Conclusions
Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively “pure,” but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia. Please see later in the article for the Editors'' Summary 相似文献102.
The role of mutation rate in optimizing key features of evolutionary dynamics has recently been investigated in various computational models. Here, we address the related question of how maximum mutation size affects the formation of species in a simple computational evolutionary model. We find that the number of species is maximized for intermediate values of a mutation size parameter μ; the result is observed for evolving organisms on a randomly changing landscape as well as in a version of the model where negative feedback exists between the local population size and the fitness provided by the landscape. The same result is observed for various distributions of mutation values within the limits set by μ. When organisms with various values of μ compete against each other, those with intermediate μ values are found to survive. The surviving values of μ from these competition simulations, however, do not necessarily coincide with the values that maximize the number of species. These results suggest that various complex factors are involved in determining optimal mutation parameters for any population, and may also suggest approaches for building a computational bridge between the (micro) dynamics of mutations at the level of individual organisms and (macro) evolutionary dynamics at the species level. 相似文献
103.
104.
105.
Tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) genetic variants which resulting in TNF-α and IL-1 overproduction
may increase susceptibility to autoimmune diseases such as atherosclerosis. We have studied the association of TNF-α G308A
and IL-1β (+3953) C/T polymorphism with myocardial infarction in Turkish population. 143 patients with myocardial infarction
and 213 age-matched healthy controls were included in the study. In univariant analysis, the frequencies of IL-1β, TNF-α genotype
or allele, and haplotype of C:A and T:A were significantly elevated in patients when compared with those of controls. GA genotype
of TNF-α, T allele of IL-1β and A of TNF-α allele seem to be risk factors for myocardial infarction. In contrast, CC genotype
of IL-1β and GG genotype of TNF-α have protective effect against myocardial infarction. In multivariate logistic regression
analysis, TNF-α A allele, gender and smoking were associated with myocardial infarction. In conclusion, we can state that
TNF-α A allele might be associated with myocardial infarction. 相似文献
106.
Ignacio J. General Ying Liu Mandy E. Blackburn Wenzhi Mao Lila M. Gierasch Ivet Bahar 《PLoS computational biology》2014,10(5)
The versatile functions of the heat shock protein 70 (Hsp70) family of molecular chaperones rely on allosteric interactions between their nucleotide-binding and substrate-binding domains, NBD and SBD. Understanding the mechanism of interdomain allostery is essential to rational design of Hsp70 modulators. Yet, despite significant progress in recent years, how the two Hsp70 domains regulate each other''s activity remains elusive. Covariance data from experiments and computations emerged in recent years as valuable sources of information towards gaining insights into the molecular events that mediate allostery. In the present study, conservation and covariance properties derived from both sequence and structural dynamics data are integrated with results from Perturbation Response Scanning and in vivo functional assays, so as to establish the dynamical basis of interdomain signal transduction in Hsp70s. Our study highlights the critical roles of SBD residues D481 and T417 in mediating the coupled motions of the two domains, as well as that of G506 in enabling the movements of the α-helical lid with respect to the β-sandwich. It also draws attention to the distinctive role of the NBD subdomains: Subdomain IA acts as a key mediator of signal transduction between the ATP- and substrate-binding sites, this function being achieved by a cascade of interactions predominantly involving conserved residues such as V139, D148, R167 and K155. Subdomain IIA, on the other hand, is distinguished by strong coevolutionary signals (with the SBD) exhibited by a series of residues (D211, E217, L219, T383) implicated in DnaJ recognition. The occurrence of coevolving residues at the DnaJ recognition region parallels the behavior recently observed at the nucleotide-exchange-factor recognition region of subdomain IIB. These findings suggest that Hsp70 tends to adapt to co-chaperone recognition and activity via coevolving residues, whereas interdomain allostery, critical to chaperoning, is robustly enabled by conserved interactions. 相似文献
107.
Thermal sensitivity is a crucial determinant of insect abundance and distribution. The way it is measured can have a critical influence on the conclusions made. Diamondback moth (DBM), Plutella xylostella (L.) (Lepidoptera: Plutellidae) is an important insect pest of cruciferous crops around the world and the thermal responses of polyphagous species are critical to understand the influences of a rapidly changing climate on their distribution and abundance. Experiments were carried out to the lethal temperature limits (ULT0 and LLT0: temperatures where there is no survival) as well as Upper and Lower Lethal Temperature (ULT25 and LLT25) (temperature where 25% DBM survived) of lab-reared adult DBM population to extreme temperatures attained by either two-way ramping (ramping temperatures from baseline to LT25 and ramping back again) or sudden plunging method. In this study the ULT0 for DBM was recorded as 42.6°C and LLT0 was recorded as −16.5°C. DBM had an ULT25 of 41.8°C and LLT25 of −15.2°C. The duration of exposure to extreme temperatures had significant impacts on survival of DBM, with extreme temperatures and/or longer durations contributing to higher lethality. Comparing the two-way ramping temperature treatment to that of direct plunging temperature treatment, our study clearly demonstrated that DBM was more tolerant to temperature in the two-way ramping assay than that of the plunging assay for cold temperatures, but at warmer temperatures survival exhibited no differences between ramping and plunging. These results suggest that DBM will not be put under physiological stress from a rapidly changing climate, rather access to host plants in marginal habitats has enabled them to expand their distribution. Two-way temperature ramping enhances survival of DBM at cold temperatures, and this needs to be examined across a range of taxa and life stages to determine if enhanced survival is widespread incorporating a ramping recovery method. 相似文献
108.
Gustavo Glusman Anita Bahar Dror Sharon Yitzhak Pilpel Julia White Doron Lancet 《Mammalian genome》2000,11(11):1016-1023
The vertebrate olfactory receptor (OR) subgenome harbors the largest known gene family, which has been expanded by the need
to provide recognition capacity for millions of potential odorants. We implemented an automated procedure to identify all
OR coding regions from published sequences. This led us to the identification of 831 OR coding regions (including pseudogenes)
from 24 vertebrate species. The resulting dataset was subjected to neighbor-joining phylogenetic analysis and classified into
32 distinct families, 14 of which include only genes from tetrapodan species (Class II ORs). We also report here the first
identification of OR sequences from a marsupial (koala) and a monotreme (platypus). Analysis of these OR sequences suggests
that the ancestral mammal had a small OR repertoire, which expanded independently in all three mammalian subclasses. Classification
of ``fish-like' (Class I) ORs indicates that some of these ancient ORs were maintained and even expanded in mammals.
A nomenclature system for the OR gene superfamily is proposed, based on a divergence evolutionary model. The nomenclature
consists of the root symbol `OR', followed by a family numeral, subfamily letter(s), and a numeral representing the individual
gene within the subfamily. For example, OR3A1 is an OR gene of family 3, subfamily A, and OR7E12P is an OR pseudogene of family
7, subfamily E. The symbol is to be preceded by a species indicator. We have assigned the proposed nomenclature symbols for
all 330 human OR genes in the database. A WWW tool for automated name assignment is provided.
Received: / Accepted: 相似文献
109.
Anne-Sophie Fiorucci Olivier Michaud Emanuel Schmid-Siegert Martine Trevisan Laure Allenbach Petrolati Yetkin aka Ince Christian Fankhauser 《PLoS genetics》2022,18(5)
Shaded plants challenged with herbivores or pathogens prioritize growth over defense. However, most experiments have focused on the effect of shading light cues on defense responses. To investigate the potential interaction between shade-avoidance and wounding-induced Jasmonate (JA)-mediated signaling on leaf growth and movement, we used repetitive mechanical wounding of leaf blades to mimic herbivore attacks. Phenotyping experiments with combined treatments on Arabidopsis thaliana rosettes revealed that shade strongly inhibits the wound effect on leaf elevation. By contrast, petiole length is reduced by wounding both in the sun and in the shade. Thus, the relationship between the shade and wounding/JA pathways varies depending on the physiological response, implying that leaf growth and movement can be uncoupled. Using RNA-sequencing, we identified genes with expression patterns matching the hyponastic response (opposite regulation by both stimuli, interaction between treatments with shade dominating the wound signal). Among them were genes from the PKS (Phytochrome Kinase Substrate) family, which was previously studied for its role in phototropism and leaf positioning. Interestingly, we observed reduced shade suppression of the wounding effect in pks2pks4 double mutants while a PKS4 overexpressing line showed constitutively elevated leaves and was less sensitive to wounding. Our results indicate a trait-specific interrelationship between shade and wounding cues on Arabidopsis leaf growth and positioning. Moreover, we identify PKS genes as integrators of external cues in the control of leaf hyponasty further emphasizing the role of these genes in aerial organ positioning. 相似文献
110.
Bahar Moezzi Nicolangelo Iannella Mark D. McDonnell 《Journal of computational neuroscience》2016,40(2):193-206
Sensory neurons code information about stimuli in their sequence of action potentials (spikes). Intuitively, the spikes should represent stimuli with high fidelity. However, generating and propagating spikes is a metabolically expensive process. It is therefore likely that neural codes have been selected to balance energy expenditure against encoding error. Our recently proposed optimal, energy-constrained neural coder (Jones et al. Frontiers in Computational Neuroscience, 9, 61 2015) postulates that neurons time spikes to minimize the trade-off between stimulus reconstruction error and expended energy by adjusting the spike threshold using a simple dynamic threshold. Here, we show that this proposed coding scheme is related to existing coding schemes, such as rate and temporal codes. We derive an instantaneous rate coder and show that the spike-rate depends on the signal and its derivative. In the limit of high spike rates the spike train maximizes fidelity given an energy constraint (average spike-rate), and the predicted interspike intervals are identical to those generated by our existing optimal coding neuron. The instantaneous rate coder is shown to closely match the spike-rates recorded from P-type primary afferents in weakly electric fish. In particular, the coder is a predictor of the peristimulus time histogram (PSTH). When tested against in vitro cortical pyramidal neuron recordings, the instantaneous spike-rate approximates DC step inputs, matching both the average spike-rate and the time-to-first-spike (a simple temporal code). Overall, the instantaneous rate coder relates optimal, energy-constrained encoding to the concepts of rate-coding and temporal-coding, suggesting a possible unifying principle of neural encoding of sensory signals. 相似文献