Identification of DNA motifs implicated in maintenance of bacterial core genomes by predictive modeling

Bacterial biodiversity at the species level, in terms of gene acquisition or loss, is so immense that it raises the question of how essential chromosomal regions are spared from uncontrolled rearrangements. Protection of the genome likely depends on specific DNA motifs that impose limits on the regions that undergo recombination. Although most such motifs remain unidentified, they are theoretically predictable based on their genomic distribution properties. We examined the distribution of the “crossover hotspot instigator,” or Chi, in Escherichia coli, and found that its exceptional distribution is restricted to the core genome common to three strains. We then formulated a set of criteria that were incorporated in a statistical model to search core genomes for motifs potentially involved in genome stability in other species. Our strategy led us to identify and biologically validate two distinct heptamers that possess Chi properties, one in Staphylococcus aureus, and the other in several streptococci. This strategy paves the way for wide-scale discovery of other important functional noncoding motifs that distinguish core genomes from the strain-variable regions.     

Binge alcohol exposure in the second trimester attenuates fetal cerebral blood flow response to hypoxia.

Alcohol is detrimental to the developing brain and remains the leading cause of mental retardation in developed countries. The mechanism of alcohol brain damage remains elusive. Studies of neurological problems in adults have focused on alcohol's cerebrovascular effects, because alcoholism is a major risk factor for stroke and cerebrovascular injuries. However, few studies have examined similar cerebrovascular effects of fetal alcohol exposure. We examined the effect of chronic binge alcohol exposure during the second trimester on fetal cerebrovascular and metabolic responses to hypoxia in near-term sheep and tested the hypothesis that fetal alcohol exposure would attenuate cerebrovascular dilation to hypoxia. Pregnant ewes were infused with alcohol (1.5 g/kg) or saline intravenously at 60-90 days of gestation (full term = 150 days). At 125 days of gestation, we measured fetal cerebral blood flow (CBF) and oxygen metabolism at baseline and during hypoxia. Maternal blood alcohol averaged 214 +/- 5.9 mg/dl immediately after the 1.5-h infusion, with similar values throughout the month of infusion. Hypoxia resulted in a robust increase in CBF in saline-infused fetuses. However, the CBF response to hypoxia in fetuses chronically exposed to alcohol was significantly attenuated. Cerebral oxygen delivery decreased in both groups of fetuses during hypoxia but to a greater degree in the alcohol-exposed fetuses. Prenatal alcohol exposure during the second trimester attenuates cerebrovascular responses to hypoxia in the third trimester. Altered cerebrovascular reactivity might be one mechanism for alcohol-related brain damage and might set the stage for further brain injury if a hypoxic insult occurs.     

Matching habitat choice promotes species persistence under climate change

Species may survive under contemporary climate change by either shifting their range or adapting locally to the warmer conditions. Theoretical and empirical studies recently underlined that dispersal, the central mechanism behind these responses, may depend on the match between an individuals’ phenotype and local environment. Such matching habitat choice is expected to induce an adaptive gene flow, but it now remains to be studied whether this local process could promote species’ responses to climate change. Here, we investigate this by developing an individual‐based model including either random dispersal or temperature‐dependent matching habitat choice. We monitored population composition and distribution through space and time under climate change. Relative to random dispersal, matching habitat choice induced an adaptive gene flow that lessened spatial range loss during climate warming by improving populations’ viability within the range (i.e. limiting range fragmentation) and by facilitating colonization of new habitats at the cold margin. The model even predicted range contraction under random dispersal but range expansion under optimal matching habitat choice. These benefits of matching habitat choice for population persistence mostly resulted from adaptive immigration decision and were greater for populations with larger dispersal distance and higher emigration probability. We also found that environmental stochasticity resulted in suboptimal matching habitat choice, decreasing the benefits of this dispersal mode under climate change. However population persistence was still better under suboptimal matching habitat choice than under random dispersal. Our results highlight the urgent need to implement more realistic mechanisms of dispersal such as matching habitat choice into models predicting the impacts of ongoing climate change on biodiversity.     

Application of green analytical chemistry to a green chemistry process: Magnetic resonance and Raman spectroscopic process monitoring of continuous ethanolic fermentation

Compact ¹H NMR and Raman spectrometers were used for real-time process monitoring of alcoholic fermentation in a continuous flow reactor. Yeast cells catalyzing the sucrose conversion were immobilized in alginate beads floating in the reactor. The spectrometers proved to be robust and could be easily attached to the reaction apparatus. As environmentally friendly analysis methods, ¹H NMR and Raman spectroscopy were selected to match the resource- and energy-saving process. Analyses took only a few seconds to minutes compared to chromatographic procedures and were, therefore, suitable for real-time control realized as a feedback loop. Both compact spectrometers were successfully implemented online. Raman spectroscopy allowed for faster spectral acquisition and higher quantitative precision, NMR yielded more resolved signals thus higher specificity. By using the software Matlab for automated data loading and processing, relevant parameters such as the ethanol, glycerol, and sugar content could be easily obtained. The subsequent multivariate data analysis using partial linear least-squares regression type 2 enabled the quantitative monitoring of all reactants within a single model in real time.     

Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

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Vitamin E alleviates non-alcoholic fatty liver disease in phosphatidylethanolamine N-methyltransferase deficient mice

Phosphatidylethanolamine N-methyltransferase (PEMT) converts phosphatidylethanolamine (PE) to phosphatidylcholine (PC), mainly in the liver. Pemt^?/? mice are protected from high-fat diet (HFD)-induced obesity and insulin resistance, but develop severe non-alcoholic fatty liver disease (NAFLD) when fed a HFD, mostly due to impaired VLDL secretion. Oxidative stress is thought to be an essential factor in the progression from simple steatosis to steatohepatitis. Vitamin E is an antioxidant that has been clinically used to improve NAFLD pathology. Our aim was to determine whether supplementation of the diet with vitamin E could attenuate HFD-induced hepatic steatosis and its progression to NASH in Pemt^?/? mice. Treatment with vitamin E (0.5?g/kg) for 3?weeks improved VLDL-TG secretion and normalized cholesterol metabolism, but failed to reduce hepatic TG content. Moreover, vitamin E treatment was able to reduce hepatic oxidative stress, inflammation and fibrosis. We also observed abnormal ceramide metabolism in Pemt^?/? mice fed a HFD, with elevation of ceramides and other sphingolipids and higher expression of mRNAs for acid ceramidase (Asah1) and ceramide kinase (Cerk). Interestingly, vitamin E supplementation restored Asah1 and Cerk mRNA and sphingolipid levels. Together this study shows that vitamin E treatment efficiently prevented the progression from simple steatosis to steatohepatitis in mice lacking PEMT.     

Genetic associations of adult height with risk of cardioembolic and other subtypes of ischemic stroke: A mendelian randomization study in multiple ancestries

BackgroundTaller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke.Methods and findingsHeight-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations.ConclusionsThe findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

In a Mendelian randomization study, Andrew B. Linden and colleagues study the relationship between height and risk of stroke subtypes among individuals from the MEGASTROKE consortium, China Kadoorie Biobank, and UK Biobank.