Use of Antihypertensive Agents and Association With Risk of Adverse Outcomes in Chronic Kidney Disease: Focus on Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

Background Our objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD . Methods and Results We studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time-dependent angiotensin-converting enzyme inhibitor or angiotensin receptor blocker , β-blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2-3 CKD ] versus advanced disease [stage 4-5 CKD ]). During median follow-up of 7.5 years, renin-angiotensin-aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β-blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD . Renin-angiotensin-aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67-0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67-0.90), regardless of severity of CKD . Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD . β-Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29-2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43), especially during early CKD ( P<0.05 for interaction). Conclusions Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD . Use of agents besides angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD

Effect of Blood Pressure Control on Long-Term Risk of End-Stage Renal Disease and Death Among Subgroups of Patients With Chronic Kidney Disease.

Background Our objective was to explore the effect of intensive blood pressure (BP) control on kidney and death outcomes among subgroups of patients with chronic kidney disease divided by baseline proteinuria, glomerular filtration rate, age, and body mass index. Methods and Results We included 840 MDRD (Modification of Diet in Renal Disease) trial and 1067 AASK (African American Study of Kidney Disease and Hypertension) participants. We used Cox models to examine whether the association between intensive BP control and risk of end-stage renal disease (ESRD) or death is modified by baseline proteinuria (≥0.44 versus <0.44 g/g), glomerular filtration rate (≥30 versus <30 mL/min per 1.73 m2), age (≥40 versus <40 years), or body mass index (≥30 versus <30 kg/m2). The median follow-up was 14.9 years. Strict (versus usual) BP control was protective against ESRD (hazard ratio [HR]ESRD, 0.77; 95% CI, 0.64-0.92) among those with proteinuria ≥0.44 g/g but not proteinuria <0.44 g/g. Strict (versus usual) BP control was protective against death (HRdeath, 0.73; 95% CI, 0.59-0.92) among those with glomerular filtration rate <30 mL/min per 1.73 m2 but not glomerular filtration rate ≥30 mL/min per 1.73 m2 (HRdeath, 0.98; 95% CI, 0.84-1.15). Strict (versus usual) BP control was protective against ESRD among those ≥40 years (HRESRD, 0.82; 95% CI, 0.71-0.94) but not <40 years. Strict (versus usual) BP control was also protective against ESRD among those with body mass index ≥30 kg/m2 (HRESRD, 0.75; 95% CI, 0.61-0.92) but not body mass index <30 kg/m2. Conclusions The ESRD and all-cause mortality benefits of intensive BP lowering may not be uniform across all subgroups of patients with chronic kidney disease. But intensive BP lowering was not associated with increased risk of ESRD or death among any subgroups that we examined

The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins

Molding photonic boxes into fluorescent emitters by direct laser writing

We acknowledge financial support from the European Research Council Starting Grant ABLASE (ERC StG 640012), the Scottish Funding Council (via SUPA) and the European Union Marie Curie Career Integration Grant (PCIG12-GA-2012-334407). M.K. acknowledges funding from the EPSRC DTG (EP/M506631/1). S.H. gratefully acknowledges support from the Engineering and Physical Sciences Research Council through the ’Hybrid Polaritonics’ Program Grant (Project EP/M025330/1).Direct laser writing of photonic boxes into active layers of biologically produced recombinant fluorescent protein in optical microcavities is demonstrated. Irradiation with laser light above the photobleaching threshold induces photonic confinement potentials on the order of 40 meV. The technique provides high spatial selectivity and enables room-temperature lasing in protein rings, and circular and elliptical pillars with customized beam shapes.Publisher PDFPeer reviewe

Maxwell's two-demon engine under pure dephasing noise

The interplay between thermal machines and quantum correlations is of great interest in both quantum thermodynamics and quantum information science. Recently, a quantum Szil\'ard engine has been proposed, showing that the quantum steerability between a Maxwell's demon and a work medium can be beneficial to a work extraction task. Nevertheless, this type of quantum-fueled machine is usually fragile in the presence of decoherence effects. We provide an example of the pure dephasing process, showing that the engine's quantumness can be degraded. Therefore, in this work, we tackle this question by introducing a second demon who can access a control system and make the work medium pass through two dephasing channels in a manner of quantum superposition. Furthermore, we provide a quantum circuit to simulate our proposed concept and test it on IBMQ and IonQ quantum computers.Comment: 10 pages, 7 figures, 2 table

Functional phosphoproteomic profiling of phosphorylation sites in membrane fractions of salt-stressed Arabidopsis thaliana

<p>Abstract</p> <p>Background</p> <p>Under conditions of salt stress, plants respond by initiating phosphorylation cascades. Many key phosphorylation events occur at the membrane. However, to date only limited sites have been identified that are phosphorylated in response to salt stress in plants.</p> <p>Results</p> <p>Membrane fractions from three-day and 200 mM salt-treated Arabidopsis suspension plants were isolated, followed by protease shaving and enrichment using Zirconium ion-charged magnetic beads, and tandem mass spectrometry analyses. From this isolation, 18 phosphorylation sites from 15 <it>Arabidopsis </it>proteins were identified. A unique phosphorylation site in 14-3-3-interacting protein AHA1 was predominately identified in 200 mM salt-treated plants. We also identified some phosphorylation sites in aquaporins. A doubly phosphorylated peptide of PIP2;1 as well as a phosphopeptide containing a single phosphorylation site (Ser-283) and a phosphopeptide containing another site (Ser-286) of aquaporin PIP2;4 were identified respectively. These two sites appeared to be novel of which were not reported before. In addition, quantitative analyses of protein phosphorylation with either label-free or stable-isotope labeling were also employed in this study. The results indicated that level of phosphopeptides on five membrane proteins such as AHA1, STP1, Patellin-2, probable inactive receptor kinase (At3g02880), and probable purine permease 18 showed at least two-fold increase in comparison to control in response to 200 mM salt-stress.</p> <p>Conclusion</p> <p>In this study, we successfully identified novel salt stress-responsive protein phosphorylation sites from membrane isolates of abiotic-stressed plants by membrane shaving followed by Zr⁴⁺-IMAC enrichment. The identified phosphorylation sites can be important in the salt stress response in plants.</p

The client-binding domain of the cochaperone Sgt2 has a helical-hand structure that binds a short hydrophobic helix

The targeting and insertion of tail-anchored (TA) integral membrane proteins (IMP) into the correct membrane is critical for cellular homeostasis. The fungal protein Sgt2, and its human homolog SGTA, binds hydrophobic clients and is the entry point for targeting of ER-bound TA IMPs. Here we reveal molecular details that underlie the mechanism of Sgt2 binding to TA IMP clients. We establish that the Sgt2 C-terminal region is flexible but conserved and sufficient for client binding. A molecular model for this domain reveals a helical hand forming a hydrophobic groove, consistent with a higher affinity for TA IMP clients with hydrophobic faces and a minimal length of 11 residues. This work places Sgt2 into a broader family of TPR-containing co-chaperone proteins