Peak Tricuspid Regurgitation Jet Velocity and Kidney Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

Introduction: Although venous congestion secondary to elevated pulmonary artery pressure (PAP) has been hypothesized to worsen kidney function, the association of peak tricuspid regurgitation jet velocity (pTRV), a surrogate of PAP, with kidney outcomes remains uncertain in heart failure (HF) with preserved ejection fraction (HFpEF).

Methods: This analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial analyzed participants with a left ventricular ejection fraction (LVEF) of ≥45% who had pTRV measured by echocardiography at baseline. For the cross-sectional analysis, the association of baseline pTRV with baseline estimated glomerular filtration rate (eGFR) was assessed using linear regression.

Relmapirazin, a new exogenous filtration marker, and more widespread use of measured GFR.

Plasma or urinary clearance of exogenous filtration markers is required for assessment of measured glomerular filtration rate. Although multiple methods are available, none is widely used because of their complexity, each has measurement error, and standardization is limited. Recently, a study validated the plasma clearance of a new exogenous filtration marker, relmapirazin, which can be detected by its transdermal fluorescence, potentially simplifying the procedure and increasing access to measured glomerular filtration rate.

Epidemiology and Management of Patients With Kidney Disease and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) comprises approximately one-half of all diagnoses of heart failure. There is significant overlap of this clinical syndrome with chronic kidney disease (CKD), with many shared comorbid conditions. The presence of CKD in patients with HFpEF is one of the most powerful risk factors for adverse clinical outcomes, including death and heart failure hospitalization.

An enhanced CRISPR repressor for targeted mammalian gene regulation.

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.

Precise Cas9 targeting enables genomic mutation prevention.

Here, we present a generalized method of guide RNA "tuning" that enables Cas9 to discriminate between two target sites that differ by a single-nucleotide polymorphism. We employ our methodology to generate an in vivo mutation prevention system in which Cas9 actively restricts the occurrence of undesired gain-of-function mutations within a population of engineered organisms. We further demonstrate that the system is scalable to a multitude of targets and that the general tuning and prevention concepts are portable across engineered Cas9 variants and Cas9 orthologs.

Next stop for the CRISPR revolution: RNA-guided epigenetic regulators.

Clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins offer a breakthrough platform for cheap, programmable, and effective sequence-specific DNA targeting. The CRISPR-Cas system is naturally equipped for targeted DNA cutting through its native nuclease activity. As such, groups researching a broad spectrum of biological organisms have quickly adopted the technology with groundbreaking applications to genomic sequence editing in over 20 different species.

Cas9 gRNA engineering for genome editing, activation and repression.

We demonstrate that by altering the length of Cas9-associated guide RNA (gRNA) we were able to control Cas9 nuclease activity and simultaneously perform genome editing and transcriptional regulation with a single Cas9 protein. We exploited these principles to engineer mammalian synthetic circuits with combined transcriptional regulation and kill functions governed by a single multifunctional Cas9 protein.