Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We ...searched for specific characteristics of HWE-departure due to genotyping error.
Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at
< 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure.
The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (
< 0.001) and in variants with higher MAF-SD (
= 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at
< 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project.
We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.
Risk factors for pancreatic ductal adenocarcinoma (PDAC) progression after surgery are unclear, and additional prognostic factors are needed to inform treatment regimens and therapeutic targets. PDAC ...is characterized by advanced sclerosis of the extracellular matrix, and interactions between cancer cells, fibrillar collagen, and other stromal components play an integral role in progression. Changes in stromal collagen alignment have been shown to modulate cancer cell behavior and have important clinical value in other cancer types, but little is known about its role in PDAC and prognostic value. We hypothesized that the alignment of collagen is associated with PDAC patient survival. To address this, pathology-confirmed tissues from 114 PDAC patients that underwent curative-intent surgery were retrospectively imaged with Second Harmonic Generation (SHG) microscopy, quantified with fiber segmentation algorithms, and correlated to patient survival. The same tissue regions were analyzed for epithelial-to-mesenchymal (EMT), α-SMA, and syndecan-1 using complimentary immunohistostaining and visualization techniques. Significant inter-tumoral variation in collagen alignment was found, and notably high collagen alignment was observed in 12% of the patient cohort. Stratification of patients according to collagen alignment revealed that high alignment is an independent negative factor following PDAC resection (p = 0.0153, multivariate). We also found that epithelial expression of EMT and the stromal expression of α-SMA and syndecan-1 were positively correlated with collagen alignment. In summary, stromal collagen alignment may provide additional, clinically-relevant information about PDAC tumors and underscores the importance of stroma-cancer interactions.
Our primary goal is to therapeutically target the oncogenic transcription factor MYC to stop tumor growth and cancer progression. Here, we report aspects of the biophysical states of the MYC protein ...and its interaction with one of the best-characterized MYC cofactors, TRansactivation/tRansformation-domain Associated Protein (TRRAP). The MYC:TRRAP interaction is critical for MYC function in promoting cancer. The interaction between MYC and TRRAP occurs at a precise region in the MYC protein, called MYC Homology Box 2 (MB2), which is central to the MYC transactivation domain (TAD). Although the MYC TAD is inherently disordered, this report suggests that MB2 may acquire a defined structure when complexed with TRRAP which could be exploited for the investigation of inhibitors of MYC function by preventing this protein-protein interaction (PPI). The MYC TAD, and in particular the MB2 motif, is unique and invariant in evolution, suggesting that MB2 is an ideal site for inhibiting MYC function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long paleoecological records are critical for understanding evolutionary responses to environmental forcing and unparalleled tools for elucidating the mechanisms that lead to the development of ...regions of high biodiversity. We use a 1.2-My record from Lake Malawi, a textbook example of biological diversification, to document how climate and tectonics have driven ecosystem and evolutionary dynamics. Before ∼800 ka, Lake Malawi was much shallower than today, with higher frequency but much lower amplitude waterlevel and oxygenation changes. Since ∼800 ka, the lake has experienced much larger environmental fluctuations, best explained by a punctuated, tectonically driven rise in its outlet location and level. Following the reorganization of the basin, a change in the pacing of hydroclimate variability associated with the Mid-Pleistocene Transition resulted in hydrologic change dominated by precession rather than the high-latitude teleconnections recorded elsewhere. During this time, extended, deep lake phases have abruptly alternated with times of extreme aridity and ecosystem variability. Repeated crossings of hydroclimatic thresholds within the lake system were critical for establishing the rhythm of diversification, hybridization, and extinction that dominate the modern system. The chronology of these changes closely matches both the timing and pattern of phylogenetic history inferred independently for the lake’s extraordinary array of cichlid fish species, suggesting a direct link between environmental and evolutionary dynamics.
Cigarette smoking is a well-established risk factor for all forms of stroke. While both the general public and the global healthcare system are aware of the vascular risks associated with smoking, ...the prevalence of tobacco use has remained largely unchanged over the last quarter of a century. Approximately one in five US adults are classified as regular smokers, with the initiation of smoking typically occurring during the teenage years. Although the increased risk of stroke associated with smoking is generally acknowledged, it is less well recognized that considerable scientific evidence implicates a strong dose-response relationship between smoking and stroke risk. In this article, we summarize the literature regarding smoking-related stroke risk, the dose-response relationship, and the costs of this detrimental habit to both the individual and society as a whole.
Drought is the most important environmental stress limiting crop yields. The C4 cereal sorghum Sorghum bicolor (L.) Moench is a critical food, forage, and emerging bioenergy crop that is notably ...drought-tolerant. We conducted a large-scale field experiment, imposing preflowering and postflowering drought stress on 2 genotypes of sorghum across a tightly resolved time series, from plant emergence to postanthesis, resulting in a dataset of nearly 400 transcriptomes. We observed a fast and global transcriptomic response in leaf and root tissues with clear temporal patterns, including modulation of well-known drought pathways. We also identified genotypic differences in core photosynthesis and reactive oxygen species scavenging pathways, highlighting possible mechanisms of drought tolerance and of the delayed senescence, characteristic of the stay-green phenotype. Finally, we discovered a large-scale depletion in the expression of genes critical to arbuscular mycorrhizal (AM) symbiosis, with a corresponding drop in AM fungal mass in the plants’ roots.
BACKGROUND AND PURPOSE—There is a strong dose–response relationship between smoking and risk of ischemic stroke in young women, but there are few data examining this association in young men. We ...examined the dose–response relationship between the quantity of cigarettes smoked and the odds of developing an ischemic stroke in men under age 50 years.
METHODS—The Stroke Prevention in Young Men Study is a population-based case–control study of risk factors for ischemic stroke in men ages 15 to 49 years. The χ test was used to test categorical comparisons. Logistic regression models were used to calculate the odds ratio for ischemic stroke occurrence comparing current and former smokers to never smokers. In the first model, we adjusted solely for age. In the second model, we adjusted for potential confounding factors, including age, race, education, hypertension, myocardial infarction, angina, diabetes mellitus, and body mass index.
RESULTS—The study population consisted of 615 cases and 530 controls. The odds ratio for the current smoking group compared with never smokers was 1.88. Furthermore, when the current smoking group was stratified by number of cigarettes smoked, there was a dose–response relationship for the odds ratio, ranging from 1.46 for those smoking <11 cigarettes per day to 5.66 for those smoking 40+ cigarettes per day.
CONCLUSIONS—We found a strong dose–response relationship between the number of cigarettes smoked daily and ischemic stroke among young men. Although complete smoking cessation is the goal, even smoking fewer cigarettes may reduce the risk of ischemic stroke in young men.
BACKGROUND AND PURPOSE—Body mass index has been associated with ischemic stroke in older populations, but its association with stroke in younger populations is not known. In light of the current ...obesity epidemic in the United States, the potential impact of obesity on stroke risk in young adults deserves attention.
METHODS—A population-based case–control study design with 1201 cases and 1154 controls was used to investigate the relationship of obesity and young onset ischemic stroke. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between body mass index and ischemic stroke with and without adjustment for comorbid conditions associated with stroke.
RESULTS—In analyses adjusted for age, sex, and ethnicity, obesity (body mass index >30 kg/m) was associated with an increased stroke risk (odds ratio, 1.57; 95% confidence interval, 1.28–1.94) although this increased risk was highly attenuated and not statistically significant after adjustment for smoking, hypertension, and diabetes mellitus.
CONCLUSIONS—These results indicate that obesity is a risk factor for young onset ischemic stroke and suggest that this association may be partially mediated through hypertension, diabetes mellitus, or other variables associated with these conditions.
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