Premature myocardial infarction novel susceptibility locus on chromosome 1P34-36 identified by genomewide linkage analysis

The most frequent causes of death and disability in the Western world are atherosclerotic coronary artery disease (CAD) and acute myocardial infarction (MI). This common disease is thought to have a polygenic basis with a complex interaction with environmental factors. Here, we report results of a genomewide search for susceptibility genes for MI in a well-characterized U.S. cohort consisting of 1,613 individuals in 428 multiplex families with familial premature CAD and MI: 712 with MI, 974 with CAD, and average age of onset of 44.4+/-9.7 years. Genotyping was performed at the National Heart, Lung, and Blood Institute Mammalian Genotyping Facility through use of 408 markers that span the entire human genome every 10 cM. Linkage analysis was performed with the modified Haseman-Elston regression model through use of the SIBPAL program. Three genomewide scans were conducted: single-point, multipoint, and multipoint performed on of white pedigrees only (92% of the cohort). One novel significant susceptibility locus was detected for MI on chromosomal region 1p34-36, with a multipoint allele-sharing P value of <10(-12) (LOD=11.68). Validation by use of a permutation test yielded a pointwise empirical P value of.00011 at this locus, which corresponds to a genomewide significance of P<.05. For the less restrictive phenotype of CAD, no genetic locus was detected, suggesting that CAD and MI may not share all susceptibility genes. The present study thus identifies a novel genetic-susceptibility locus for MI and provides a framework for the ultimate cloning of a gene for the complex disease MI.     

Within‐year variation in the vegetative spread of five temperate grasses

Questions: Do species planted outdoors in native soil differ in the timing of their period of vegetative spread during the growing season? Location: Cleish Hills, Fife, Scotland, UK. Methods: Patches (20 cm × 20 cm) of Agrostis capillaris, Festuca rubra, Holcus lanatus, Lolium perenne and Poa trivialis were arranged in plots so that every species patch had all the remaining species as neighbours. The plots were cut every 14 days at 3 cm and photographed monthly from above. The photographs of species boundaries were traced and digitised. Measurements were made on the digitised images of the distances each species spread and of the area occupied by each species. Results: Fitting some simple models to the data indicated firstly that species varied in their vegetative competitive ability, with A. capillaris and P. trivialis being the most and least competitive respectively, and secondly that the ability of a species to colonize can differ from its ability to resist colonization, the most discrepant species being H. lanatus. Our analysis also indicated statistically significant variation in the data over and above the simple models, providing evidence of additional, genuine, complexity in the seasonal patterns of spread. Conclusion: This study provides evidence to support the hypothesis that clonal grass species do not spread vegetatively at the same times within a growing season. Since sward height is known to affect species spread, there is some opportunity for the manipulation of species composition simply through temporal control of sward height.     

Genome Scan of M. tuberculosis Infection and Disease in Ugandans

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10⁻³) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system.     

Mechanical and biochemical modeling of cortical oscillations in spreading cells

Actomyosin-based cortical contractility is a common feature of eukaryotic cells and is involved in cell motility, cell division, and apoptosis. In nonmuscle cells, oscillations in contractility are induced by microtubule depolymerization during cell spreading. We developed an ordinary differential equation model to describe this behavior. The computational model includes 36 parameters. The values for all but two of the model parameters were taken from experimental measurements found in the literature. Using these values, we demonstrate that the model generates oscillatory behavior consistent with current experimental observations. The rhythmic behavior occurs because of the antagonistic effects of calcium-induced contractility and stretch-activated calcium channels. The model makes several experimentally testable predictions: 1), buffering intracellular calcium increases the period and decreases the amplitude of cortical oscillations; 2), increasing the number or activity of stretch activated channels leads to an increase in period and amplitude of cortical oscillations; 3), inhibiting Ca²⁺ pump activity increases the period and amplitude of oscillations; and 4), a threshold exists for the calcium concentration below which oscillations cease.     

A unified association analysis approach for family and unrelated samples correcting for stratification

There are two common designs for association mapping of complex diseases: case-control and family-based designs. A case-control sample is more powerful to detect genetic effects than a family-based sample that contains the same numbers of affected and unaffected persons, although additional markers may be required to control for spurious association. When family and unrelated samples are available, statistical analyses are often performed in the family and unrelated samples separately, conditioning on parental information for the former, thus resulting in reduced power. In this report, we propose a unified approach that can incorporate both family and case-control samples and, provided the additional markers are available, at the same time corrects for population stratification. We apply the principal components of a marker matrix to adjust for the effect of population stratification. This unified approach makes it unnecessary to perform a conditional analysis of the family data and is more powerful than the separate analyses of unrelated and family samples, or a meta-analysis performed by combining the results of the usual separate analyses. This property is demonstrated in both a variety of simulation models and empirical data. The proposed approach can be equally applied to the analysis of both qualitative and quantitative traits.     

Cortical heterogeneity: Implications for visual processing and polysensory integration

Recent studies have revealed substantial variation in pyramidal cell structure in different cortical areas. Moreover, cell morphology has been shown to vary in a systematic fashion such that cells in visual association areas are larger and more spinous than those in the primary visual area. Various aspects of these structural differences appear to be important in influencing neuronal function. At the cellular level, differences in the branching patterns in the dendritic arbour may allow for varying degrees of non-linear compartmentalisation. Differences in total dendritic length and spine number may determine the number of inputs integrated by individual cells. Variations in spine density and geometry may affect cooperativity of inputs and shunting inhibition, and the tangential dimension of the dendritic arbours may determine sampling strategies within cortex. At the systems level, regional variation in pyramidal cell structure may determine thedegree of recurrent excitation through reentrant circuits influencing the discharge properties of individual neurones and the functional signature of the circuits they compose. The ability of pyramidal neurones in visual areas of the parietal and temporal lobes to integrate large numbers of excitatory inputs may also facilitate cortical binding. Here I summarise what I consider to be among the most salient, and testable, aspects of an inter-relationship between morphological and functional heterogeneity in visual cortex.     

末次盛冰期环境恶化对中国北方旧石器文化的影响

末次冰期间冰段时,中国北方地区水热条件普遍较好,旧石器文化也比较发达。然而,进入末次盛冰期后,随着气温的普遍降低和降水量的明显减少,草原和沙漠带急速向南扩张,动物群也大举南迁。对于这种严酷的生存环境,中国北方的旧石器文化是如何响应的呢?本文以宁夏彭阳PY01-02,PY03和PY05等地点的地层剖面和石制品的研究为基础,首先提出彭阳地点群地层沉积相由河湖相沉积迅速转变为黄土堆积说明由末次冰期间冰段到末次盛冰期自然环境发生了剧烈变化。其次,通过对上述两种不同沉积相中出土石制品的大小、重量、原料以及技术上的比较说明随着环境的变化石制品本身也发生了相应的变化。下层河湖相堆积中出土的石制品粗大笨重,主要以各种石英岩为原料,与同期泾水上游旧石器文化的特征相近,应是当地文化特征的一种具体体现。上层马兰黄土中的石制品的普遍较小,主要以石英和燧石为原料,其中用燧石制成的细石器具有宁夏灵武水洞沟下文化层同类制品的特征,而用石英制成的小石器则同海原一带的史前文化有着较为密切的联系,据此作者推测这可能与史前人类在环境日益恶劣的情况下向南迁移有关。山西南部地区的下川和柿子滩遗址的地层和石制品证据亦表明,末次盛冰期前后该地区旧石器文化的明显差异可能也与末次盛冰期环境恶化时人类的迁徙有关。最后,中国北方地区考古遗址的空间分布变化为上述史前人类南迁的推测提供了有力证据。因此,作者认为末次冰期的环境恶化对中国北方旧石器文化的影响具有普遍性。