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Martinez Bell posted an update 6 months, 2 weeks ago
Acute kidney injury (AKI), once viewed predominantly as a self-limited and reversible condition, is now recognized as a growing problem associated with significant risks of adverse long-term health outcomes. Many cohort studies have established important relationships between AKI and subsequent risks of recurrent AKI, hospital re-admission, morbidity and mortality from cardiovascular disease and cancer, as well as the development of chronic kidney disease and end-stage kidney disease. In both high-income countries (HICs) and low-income or middle-income countries (LMICs), several challenges exist in providing high-quality, patient-centered care following AKI. Despite advances in our understanding about the long-term risks following AKI, large gaps in knowledge remain about effective interventions that can improve the outcomes of patients. Therapies for high blood pressure, glycaemic control (for patients with diabetes), renin-angiotensin inhibition and statins might be important in improving long-term cardiovascular and kidney outcomes after AKI. Novel strategies that incorporate risk stratification approaches, educational interventions and new models of ambulatory care following AKI have been described, and some of these are now being implemented and evaluated in clinical studies in HICs. Care for AKI in LMICs must overcome additional barriers due to limited resources for diagnosis and management.We investigated blood pressure (BP) and heart rate variability and baroreflex sensitivity (BRS) in white-coat, masked and sustained hypertension in untreated patients (n = 645). Normotension and white-coat, masked, and sustained hypertension were defined according to the clinic (cutoff 140/90 mmHg) and 24-h ambulatory (130/80 mmHg) BPs. The Finometer device recorded beat-to-beat finger BP and electrocardiograms in the supine and standing positions for the computation of frequency-domain power-spectral BP and heart rate variability indexes and BRS. In multivariate analysis, BP variability indexes in the supine position differed significantly (P less then 0.0001) for both low-frequency (LF) and high-frequency (HF) components and the LF/HF ratio, with the lowest LF and HF power and highest LF/HF ratio in white-coat hypertension (n = 28), the highest LF and HF power and lowest LF/HF ratio in sustained hypertension (n = 198), and intermediate values in normotension (n = 189) and masked hypertension (n = 230). These differences diminished in the standing position, being significant (P less then 0.0001) only for the LF component variability. The LF/HF ratio in BP in the supine position decreased with advancing age in normotension and sustained hypertension (P ≤ 0.03) but not white-coat or masked hypertension (P ≥ 0.12). For heart rate variability, a significant difference was observed only for the LF component in the supine position (P = 0.0005), which was lowest in white-coat hypertension. BRS in masked and sustained hypertension was significantly (P ≤ 0.0001) lower than that in normotension in both supine and standing positions and decreased with advancing age (P ≤ 0.0001). In conclusion, masked, but not white-coat, hypertension showed similar patterns of, but slightly less severe, changes in BP and heart rate variability and BRS to sustained hypertension.RNA interference (RNAi), a cellular process through which small RNAs target and regulate complementary RNA transcripts, has well-characterized roles in post-transcriptional gene regulation and transposon repression. Recent studies have revealed additional conserved roles for RNAi proteins, such as Argonaute and Dicer, in chromosome function. By guiding chromatin modification, RNAi components promote chromosome segregation during both mitosis and meiosis and regulate chromosomal and genomic dosage response. Small RNAs and the RNAi machinery also participate in the resolution of DNA damage. Interestingly, many of these lesser-studied functions seem to be more strongly conserved across eukaryotes than are well-characterized functions such as the processing of microRNAs. These findings have implications for the evolution of RNAi since the last eukaryotic common ancestor, and they provide a more complete view of the functions of RNAi.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Induced pluripotent stem cells (iPSCs) from patients with genetic disorders are a valuable source for in vitro disease models, which enable drug testing and validation of gene and cell therapies. We generated iPSCs from a severe congenital neutropenia (SCN) patient, who presented with a nonsense mutation in the glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene causing profound defects in granulopoiesis, associated with increased susceptibility of neutrophils to apoptosis. Generated SCN iPSC clones exhibited the capacity to differentiate into hematopoietic cells of the myeloid lineage and we identified two cytokine conditions, i.e., using granulocyte-colony stimulating factor or granulocyte-macrophage colony stimulating factor in combination with interleukin-3, to model the SCN phenotype in vitro. Reduced numbers of granulocytes were produced by SCN iPSCs compared with control iPSCs in both settings, which reflected the phenotype in patients. Interestingly, our model showed increased monocyte/macrophage production from the SCN iPSCs. Most importantly, lentiviral genetic correction of SCN iPSCs with a codon-optimized G6PC3 transgene restored granulopoiesis and reduced apoptosis of in vitro differentiated myeloid cells. Moreover, addition of vitamin B3 clearly induced granulocytic differentiation of SCN iPSCs and increased the number of neutrophils to levels comparable with those obtained from healthy control iPSCs. In summary, we established an iPSC-derived in vitro disease model, which will serve as a tool to test the potency of alternative treatment options for SCN patients, such as small molecules and gene therapeutic vectors.N6-methyladenine (N6-mA) of DNA is an emerging epigenetic mark in mammalian genome. Monastrol Levels of N6-mA undergo drastic fluctuation during early embryogenesis, indicative of active regulation. Here we show that the 2-oxoglutarate-dependent oxygenase ALKBH1 functions as a nuclear eraser of N6-mA in unpairing regions (e.g., SIDD, Stress-Induced DNA Double Helix Destabilization regions) of mammalian genomes. Enzymatic profiling studies revealed that ALKBH1 prefers bubbled or bulged DNAs as substrate, instead of single-stranded (ss-) or double-stranded (ds-) DNAs. Structural studies of ALKBH1 revealed an unexpected “stretch-out” conformation of its “Flip1” motif, a conserved element that usually bends over catalytic center to facilitate substrate base flipping in other DNA demethylases. Thus, lack of a bending “Flip1” explains the observed preference of ALKBH1 for unpairing substrates, in which the flipped N6-mA is primed for catalysis. Co-crystal structural studies of ALKBH1 bound to a 21-mer bulged DNA explained the need of both flanking duplexes and a flipped base for recognition and catalysis.