Long-term impacts of disturbance on nitrogen-cycling bacteria in a New England salt marsh

Recent studies on the impacts of disturbance on microbial communities indicate communities show differential responses to disturbance, yet our understanding of how different microbial communities may respond to and recover from disturbance is still rudimentary. We investigated impacts of tidal restriction followed by tidal restoration on abundance and diversity of denitrifying bacteria, ammonia-oxidizing bacteria (AOB), and ammonia-oxidizing archaea (AOA) in New England salt marshes by analyzing nirS and bacterial and archaeal amoA genes, respectively. TRFLP analysis of nirS and betaproteobacterial amoA genes revealed significant differences between restored and undisturbed marshes, with the greatest differences detected in deeper sediments. Additionally, community patterns indicated a potential recovery trajectory for denitrifiers. Analysis of archaeal amoA genes, however, revealed no differences in community composition between restored and undisturbed marshes, but we detected significantly higher gene abundance in deeper sediment at restored sites. Abundances of nirS and betaproteobacterial amoA genes were also significantly greater in deeper sediments at restored sites. Porewater ammonium was significantly higher at depth in restored sediments compared to undisturbed sediments, suggesting a possible mechanism driving some of the community differences. Our results suggest that impacts of disturbance on denitrifying and ammonia-oxidizing communities remain nearly 30 years after restoration, potentially impacting nitrogen-cycling processes in the marsh. We also present data suggesting that sampling deeper in sediments may be critical for detecting disturbance effects in coastal sediments

A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML

Translocations of the KMT2A (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype

Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation.

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach

Drugs with a negative impact on cognitive functions (Part 2): drug classes to consider while prescribing in CKD patients

International audienceThere is growing evidence that chronic kidney disease (CKD) is an independent risk factor for cognitive impairment, especially due to vascular damage, blood–brain barrier disruption and uremic toxins. Given the presence of multiple comorbidities, the medication regimen of CKD patients often becomes very complex. Several medications such as psychotropic agents, drugs with anticholinergic properties, GABAergic drugs, opioids, corticosteroids, antibiotics and others have been linked to negative effects on cognition. These drugs are frequently included in the treatment regimen of CKD patients. The first review of this series described how CKD could represent a risk factor for adverse drug reactions affecting the central nervous system. This second review will describe some of the most common medications associated with cognitive impairment (in the general population and in CKD) and describe their effects

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor

International audiencePeople living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood–brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics