Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke.

Background and Objectives: To test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set. Methods: We used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately. Results: Increasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction. Discussion: In this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration

Benchmark of Selected Digital Image Processing Algorithms Implemented in Python

Tato bakalářská práce se zabývá digitálním zpracováním obrazu v Pythonu, popisem vybraných algoritmů, jejich implementací a použitou technologií. Porovnává rychlosti běhu vybraných algoritmů na zpracování obrazu v C++ a Pythonu, potom Pyhonu s využitím speciální knihovny Numpy a mezi překladači PyPy a Cython.This Bachelor thesis deals with the digital image processing in Python, description of selected algorithms their implementation and used technology. Specifically, it is focused on comparison of speed among selected algorithms, implemented in languages C++ and Python, Python with NumPy library and compilers PyPy and Cython.460 - Katedra informatikydobř

Circulating levels of vascular endothelial growth factor and post-stroke long-term functional outcome

OBJECTIVES: Vascular endothelial growth factor (VEGF) acts in angiogenesis and neuroprotection, although the beneficial effects on experimental ischemic stroke (IS) have not been replicated in clinical studies. We investigated serum VEGF (s-VEGF) in the acute stage (baseline) and 3 months post-stroke in relation to stroke severity and functional outcome. METHODS: The s-VEGF and serum high-sensitivity C-reactive protein (hs-CRP) concentrations were measured in patients enrolled in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) at the acute time-point (median 4 days, N=492, 36% female; mean age, 57 years) and at 3 months post-stroke (N=469). Baseline stroke severity was classified according to the National Institutes of Health Stroke Scale (NIHSS) and functional outcomes (3 months and 2 years) were evaluated using the modified Rankin Scale (mRS), dichotomized into good (mRS 0-2) and poor (mRS 3-6) outcomes. Multivariable logistic regression analyses were adjusted for covariates. RESULTS: The baseline s-VEGF did not correlate with stroke severity but correlated moderately with hs-CRP (r=0.17, p<0.001). The baseline s-VEGF was 39.8% higher in total anterior cerebral infarctions than in lacunar cerebral infarctions. In binary logistic regression analysis, associations with 3-month functional outcome were non-significant. However, an association between the 3-month s-VEGF and poor 2-year outcome withstood adjustments for age, sex, cardiovascular covariates, and stroke severity (per ten-fold increase in s-VEGF, odds ratio [OR], 2.56, 95% confidence interval [CI] 1.12-5.82) or hs-CRP (OR 2.53, CI 1.15-5.55). CONCLUSIONS: High 3-month s-VEGF is independently associated with poor 2-year functional outcome but not with 3-month outcome

Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase

Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi’s inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration

Experiences of severe childhood maltreatment, depression, anxiety and alcohol abuse among adults in Finland

Childhood maltreatment increases the risk of subsequent depression, anxiety and alcohol abuse, but the rate of resilient victims is unknown. Here, we investigated the rate of victims that do not suffer from clinical levels of these problems after severe maltreatment in a population-based sample of 10980 adult participants. Compared to men, women reported more severe emotional and sexual abuse, as well as more severe emotional neglect. For both genders, severe emotional abuse (OR = 3.80 [2.22, 6.52]); severe physical abuse (OR = 3.97 [1.72, 9.16]); severe emotional neglect (OR = 3.36 [1.73, 6.54]); and severe physical neglect (OR = 11.90 [2.66, 53.22]) were associated with depression and anxiety while only severe physical abuse (OR = 3.40 [1.28, 9.03]) was associated with alcohol abuse. Looking at men and women separately, severe emotional abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.74 [2.06, 6.81] in women) and severe physical abuse (OR = 6.05 [1.62, 22.60] in men; OR = 3.03 [0.99, 9.33] in women) were associated with clinical levels of depression and anxiety. In addition, in women, severe sexual abuse (OR = 2.40 [1.10, 5.21]), emotional neglect (OR = 4.78 [2.40, 9.56]), and severe physical neglect (OR = 9.86 [1.99, 48.93]) were associated with clinical levels of depression and anxiety. Severe emotional abuse in men (OR = 3.86 [0.96, 15.48]) and severe physical abuse in women (OR = 5.18 [1.48, 18.12]) were associated with alcohol abuse. Concerning resilience, the majority of severely maltreated participants did not report clinically significant levels of depression or anxiety (72%), or alcohol abuse (93%) in adulthood. Although the majority of severely abused or neglected individuals did not show clinical levels of depression, anxiety or alcohol use, severe childhood maltreatment increased the risk for showing clinical levels of psychopathology in adulthood

Circulating granulocyte colony-stimulating factor and functional outcome after ischemic stroke: an observational study

Objectives: While granulocyte colony-stimulating factor (G-CSF) has shown beneficial effects in experimental ischemic stroke (IS), these effects have not been reproduced clinically. Small-to-medium-sized observational studies have reported varying associations for G-CSF with stroke severity and post-stroke functional outcome, prompting their investigation in a larger study. Methods: Endogenous serum G-CSF (S-GCSF) was measured in the acute phase and after 3 months in patients with IS (N = 435; 36% females; mean age, 57 years) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Stroke severity was scored according to the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) assessed functional outcomes at 3-month and 2-year post-stroke. Correlation and logistic regression analyses with confounder adjustments assessed the relationships. Results: The acute S-GCSF level was 23% higher than at 3-month post-stroke (p < 0.001). Acute G-CSF correlated weakly with stroke severity quintiles (r = 0.12, p = 0.013) and with high-sensitivity C-reactive protein (r = 0.29, p < 0.001). The association between S-GCSF (as quintiles, q) and poor functional outcome at 3 months (mRS 3–6; S-GCSF-q5 vs. S-GCSF-q1, age- and sex-adjusted odds ratio: 4.27, 95% confidence interval: 1.82–9.99; p = 0.001) withstood adjustment for cardiovascular risk factors and stroke subtype, but not additional correction for stroke severity. Post-stroke changes in S-GSCF and absolute 3-month S-GCSF were not associated with 3-month or 2-year functional outcomes. Discussion: Early post-stroke S-GCSF is increased in severe IS and associated with 3-month poor functional outcomes. The change in S-GCSF and the 3-month S-GCSF appear to be less-important, and S-GCSF likely reflects inflammation in large infarctions

Likely Role of APOBEC3G-Mediated G-to-A Mutations in HIV-1 Evolution and Drug Resistance

The role of APOBEC3 (A3) protein family members in inhibiting retrovirus infection and mobile element retrotransposition is well established. However, the evolutionary effects these restriction factors may have had on active retroviruses such as HIV-1 are less well understood. An HIV-1 variant that has been highly G-to-A mutated is unlikely to be transmitted due to accumulation of deleterious mutations. However, G-to-A mutated hA3G target sequences within which the mutations are the least deleterious are more likely to survive selection pressure. Thus, among hA3G targets in HIV-1, the ratio of nonsynonymous to synonymous changes will increase with virus generations, leaving a footprint of past activity. To study such footprints in HIV-1 evolution, we developed an in silico model based on calculated hA3G target probabilities derived from G-to-A mutation sequence contexts in the literature. We simulated G-to-A changes iteratively in independent sequential HIV-1 infections until a stop codon was introduced into any gene. In addition to our simulation results, we observed higher ratios of nonsynonymous to synonymous mutation at hA3G targets in extant HIV-1 genomes than in their putative ancestral genomes, compared to random controls, implying that moderate levels of A3G-mediated G-to-A mutation have been a factor in HIV-1 evolution. Results from in vitro passaging experiments of HIV-1 modified to be highly susceptible to hA3G mutagenesis verified our simulation accuracy. We also used our simulation to examine the possible role of A3G-induced mutations in the origin of drug resistance. We found that hA3G activity could have been responsible for only a small increase in mutations at known drug resistance sites and propose that concerns for increased resistance to other antiviral drugs should not prevent Vif from being considered a suitable target for development of new drugs