mA in CAG repeat RNA binds to TDP-43 and induces neurodegeneration.

Microsatellite repeat expansions within genes contribute to a number of neurological diseases. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N-methyladenosine (mA) by TRMT61A, and that mA can be demethylated by ALKBH3.

Impact assessment of metabolite instability in the development and validation of LC-MS/MS bioanalytical assays for measurement of rosuvastatin in human plasma and urine samples.

During bioanalytical assay development and validation, maintaining the stability of the parent drug and metabolites of interest is critical. While stability of the parent drug has been thoroughly investigated, the stability of unanalyzed metabolites is often overlooked. When an unstable metabolite is known or suspected to interfere with measurement of the parent drug or other metabolites of interest through back-conversion or other routes, additional tests with these unstable metabolites should be conducted.

Breakage of cytoplasmic chromosomes by pathological DNA base excision repair.

Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease. Chromothripsis originates from aberrations of nuclei called micronuclei or chromosome bridges. These structures are associated with fragile nuclear envelopes that spontaneously rupture, leading to DNA damage when chromatin is exposed to the interphase cytoplasm.

An aged immune system drives senescence and ageing of solid organs.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice.

Normalized retention time for scheduled liquid chromatography-multistage mass spectrometry analysis of epitranscriptomic modifications.

Investigations into post-transcriptional modifications of RNA and their regulatory proteins have revealed pivotal roles of these modifications in cellular functions. A robust method for the quantitative analysis of modified nucleosides in RNA may facilitate the assessment about their functions in RNA biology and disease etiology. Here, we developed a sensitive nano-liquid chromatography-multistage mass spectrometry (nLC-MS) method for profiling simultaneously 27 modified ribonucleosides.

Collision-Induced Dissociation Studies of Protonated Ions of Alkylated Thymidine and 2'-Deoxyguanosine.

Mass spectrometry and tandem MS (MS/MS) have been widely employed for the identification and quantification of damaged nucleosides in DNA, including those induced by alkylating agents. Upon collisional activation, protonated ions of alkylated nucleosides frequently undergo facile neutral loss of a 2-deoxyribose in MS/MS, and further cleavage of the resulting protonated nucleobases in MS can sometimes be employed for differentiating regioisomeric alkylated DNA lesions. Herein, we investigated systematically the collision-induced dissociation (CID) of the protonated ions of -alkylthymidine (-alkyldT), -alkyldT, -alkyl-2'-deoxyguanosine (-alkyldG), and -alkyldG through MS analysis.

Normalized Retention Time for Targeted Analysis of the DNA Adductome.

A wide spectrum of DNA lesions can be generated from byproducts of endogenous metabolism and/or from environmental exposure. A DNA adductomic approach for the robust quantification of DNA adducts in cellular and tissue DNA may facilitate the use of DNA adducts for biomonitoring studies and enable comprehensive assessment about DNA repair. Normalized retention time (iRT) has been widely used in scheduled selected-reaction monitoring (SRM) methods for highly sensitive and high-throughput analyses of protein samples in complicated matrices.

Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging.

DNA damage is presumed to be one type of stochastic macromolecular damage that contributes to aging, yet little is known about the precise mechanism by which DNA damage drives aging. Here, we attempt to address this gap in knowledge using DNA repair-deficient C. elegans and mice.

Occurrence, Biological Consequences, and Human Health Relevance of Oxidative Stress-Induced DNA Damage.

A variety of endogenous and exogenous agents can induce DNA damage and lead to genomic instability. Reactive oxygen species (ROS), an important class of DNA damaging agents, are constantly generated in cells as a consequence of endogenous metabolism, infection/inflammation, and/or exposure to environmental toxicants. A wide array of DNA lesions can be induced by ROS directly, including single-nucleobase lesions, tandem lesions, and hypochlorous acid (HOCl)/hypobromous acid (HOBr)-derived DNA adducts.

Effect of KCl substitution on bacterial viability of Escherichia coli (ATCC 25922) and selected probiotics.

Excessive intake of NaCl has been associated with the increased risk of several diseases, particularly hypertension. Strategies to reduce sodium intake include substitution of NaCl with other salts, such as KCl. In this study, the effects of NaCl reduction and its substitution with KCl on cell membranes of a cheese starter bacterium (Lactococcus lactis ssp.