Alterations in Spontaneous Brain Oscillations during Stroke Recovery

Amplitude or frequency alterations of spontaneous brain oscillations may reveal pathological phenomena in the brain or predict recovery from brain lesions, but the temporal evolution and the functional significance of these changes is not well known. We performed follow-up recordings of spontaneous brain oscillations with whole-head MEG in 16 patients with first-ever stroke in the middle cerebral artery territory, affecting upper limb motor function, 1–7 days (T₀), 1 month (T₁), and 3 months (T₂) after stroke, with concomitant clinical examination. Clinical test results improved significantly from T₀ to T₁ or T₂. During recovery (at T₁ and T₂), the strength of temporo–parietal ∼10-Hz oscillations in the affected hemisphere (AH) was increased as compared with the unaffected hemisphere. Abnormal low-frequency magnetic activity (ALFMA) at ∼1 Hz in the AH was detected in the perilesional cortex in seven patients at T₀. In four of these, ALFMA persisted at T₂. In patients with ALFMA, the lesion size was significantly larger than in the rest of the patients, and worse clinical outcome was observed in patients with persisting ALFMA. Our results indicate that temporo–parietal ∼10-Hz oscillations are enhanced in the AH during recovery from stroke. Moreover, stroke causes ALFMA, which seems to persist in patients with worse clinical outcome.     

Assessing the Effect of Treatment Duration on the Association between Anti-Diabetic Medication and Cancer Risk

Most studies that have evaluated the association between anti-diabetic medication and cancer risk have suffered from methodological drawbacks. To avoid time-related biases, we evaluated the effect of treatment duration on the cancer risk among naive users of anti-diabetic medication as compared to non-users. In addition, we addressed the influence of common risk factors such as smoking and BMI. The study population comprised 23,394 participants of FINRISK surveys. Data on cancer and anti-diabetic medication were linked with the study cohorts. We applied Lexis tabulation to the data and analyzed split records by using Poisson regression. Changes in cancer incidence in relation to treatment duration were examined by modeling the rate ratio (RR). After a median follow-up of 9 years, 53 cancer cases among users of anti-diabetic medication and 1,028 among non-users were diagnosed. No significant difference in cancer risk between users and non-users was observed after adjustment. The RR for all medication regardless of its duration was 1.01 [95% CI 0.75–1.33], and 1.37 [0.94–1.94] for period of 1–4 years. The results were similar for metformin, sulfonylurea, and insulin. This study demonstrates that evaluation of the variation in cancer risk in relation to treatment duration is of particular importance for enhancing the accuracy of conclusions on the link between exposure to anti-diabetic medication and cancer risk.     

1-Stearoylglycerol is associated with risk of prostate cancer: results from a serum metabolomic profiling analysis

Although prostate cancer is the most commonly diagnosed cancer among men in developed populations, recent recommendations against routine prostate-specific antigen screening have cast doubt on its utility for early detection. We compared the metabolomic profiles of prospectively collected fasting serum from 74 prostate cancer cases and 74 controls selected from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of male smokers. Circulating 1-stearoylglycerol (1-SG, or 1-monostearin) was statistically significantly inversely associated with risk of prostate cancer after Bonferroni correction for multiple comparisons (i.e., 420 identified metabolites) (OR 0.34, 95 % CI 0.20–0.58, p 6.3 × 10^?5). The magnitude of this association did not differ by disease aggressiveness and was observed for cases diagnosed up to 23 years after blood collection. Similar but somewhat weaker prostate cancer risk signals were also evident for glycerol and alpha-ketoglutarate. In this population, men with higher serum 1-SG were less likely to develop prostate cancer, supporting a role for dysregulation of lipid metabolism in this malignancy. Additional studies are needed to retest the association and to examine 1-SG for its potential as a prostate cancer early detection marker.     

Zn2+ Promoted Hydrolysis of RNA

Abstract

The Zn²⁺ promoted hydrolysis of phosphodiester bonds of RNA has been studied by using a series of model compounds from dinucleoside monophosphates to oligo- and polynucleotides. The results will be discussed with respect to complex formation between the metal ion catalysts and substrates.     

Population responses to observed climate variability across multiple organismal groups

A major challenge in ecology is to understand how populations are affected by increased climate variability. Here, we assessed the effects of observed climate variability on different organismal groups (amphibians, insects, mammals, herbaceous plants and reptiles) by estimating the extent to which interannual variation in the annual population growth rates (CV_λ) and the absolute value of the long-term population growth rate (|log λ|) were associated with short-term climate variability. We used empirical data (≥ 20 consecutive years of annual abundances) from 59 wild populations in the Northern Hemisphere, and quantified variabilities in population growth rates and climatic conditions (temperature and precipitation in active and inactive seasons) calculated over four- and eight-year sliding time windows. We observed a positive relationship between the variability of growth rate (CV_λ) and the variability of temperature in the active season at the shorter timescale only. Moreover, |log λ| was positively associated with the variability of precipitation in the inactive season at both timescales. Otherwise, the direction of the relationships between population dynamics and climate variability (if any) depended largely on the season and organismal group in question. Both CV_λ and |log λ| correlated negatively with species' lifespan, indicating general differences in population dynamics between short-lived and long-lived species that were not related to climate variability. Our results suggest that although temporal variation in population growth rates and the magnitude of long-term population growth rates are partially associated with short-term interannual climate variability, demographic responses to climate fluctuations might still be population-specific rather than specific to given organismal groups, and driven by other factors than the observed climate variability.     

The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study

Background

One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.

Methods and Findings

We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10⁻⁸≤p≤5.21×10⁻⁷). A significant interaction (p = 4.0×10⁻⁴) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10⁻⁷), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10⁻³) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10⁻⁴, and HR = 1.35, p = 4.1×10⁻³, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10⁻⁹) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).

Conclusions

The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors'' Summary     

Increased Level of Myeloid-Derived Suppressor Cells,Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia

Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0,05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0,0079). Myeloid cells upregulated PD-L1 (p<0,05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0,0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression.     

αV-Integrins Are Required for Mechanotransduction in MDCK Epithelial Cells

The properties of epithelial cells within tissues are regulated by their immediate microenvironment, which consists of neighboring cells and the extracellular matrix (ECM). Integrin heterodimers orchestrate dynamic assembly and disassembly of cell-ECM connections and thereby convey biochemical and mechanical information from the ECM into cells. However, the specific contributions and functional hierarchy between different integrin heterodimers in the regulation of focal adhesion dynamics in epithelial cells are incompletely understood. Here, we have studied the functions of RGD-binding αV-integrins in a Madin Darby Canine Kidney (MDCK) cell model and found that αV-integrins regulate the maturation of focal adhesions (FAs) and cell spreading. αV-integrin-deficient MDCK cells bound collagen I (Col I) substrate via α2β1-integrins but failed to efficiently recruit FA components such as talin, focal adhesion kinase (FAK), vinculin and integrin-linked kinase (ILK). The apparent inability to mature α2β1-integrin-mediated FAs and link them to cellular actin cytoskeleton led to disrupted mechanotransduction in αV-integrin deficient cells seeded onto Col I substrate.     

Resonance assignments of the 56 kDa chimeric avidin in the biotin-bound and free forms

Avidin is a homotetrameric ~56 kDa protein found in chicken egg white. Avidin’s ability to bind biotin with a very high affinity has widely been exploited in biotechnological applications. Protein engineering has further diversified avidin’s feasibility. ChiAVD(I117Y) is a product of rational protein engineering. It is a hyperthermostable synthetic hybrid of avidin and avidin-related protein 4 (AVR4). In this chimeric protein a 23-residue segment in avidin has been replaced with the corresponding sequence found in AVR4, and a point mutation at subunit interface 1–3 (and 2–4) has been introduced. Here we report the backbone and sidechain resonance assignments of the biotin-bound form of ChiAVD(I117Y) as well as the backbone resonance assignments of the free form.