UV RAMAN INVESTIGATION OF PEPTIDEHYDRATION AND HYDROPHOBIC COLLAPSE

Hydration of an alpha-helical, 21 residue, mainly Ala peptide was investigated by UV resonance Raman (UVR) spectroscopy. UVR spectra in the dehydrated solid state were compared to those in aqueous solution at different temperatures. The amide band frequencies of a dehydrated solid alpha-helix peptide show frequency shifts compared to those in aqueous solution due to the loss of amide backbone hydrogen bonding to water; the amide II and amide III bands of the solid alpha-helix downshift, while the amide I band upshifts. The shifts are identical in direction but smaller than those that occur for alpha-helices in aqueous solution as the temperature increases; water hydrogen bonding strengths decrease as the temperature increases. The UV Raman amide band frequency shifts can be used to monitor alpha-helix hydrogen bonding.In addition, the phenomenon of hydrophobic collapse was investigated in poly(N-isopropylacrylamide) hydrogel nanoparticles. ~100 nm hydrogel particles were synthesized and analyzed with variety of methods including UVR spectroscopy. The changes in UVR amide spectra are similar to those observed for peptide dehydration. The Raman bands associated with C-H stretching vibrations change in a manner expected to dehydration as well. Comparison of spectral changes of isopropyl group vibrations to that of amide group suggests different dehydration pattern of the two groups. Kinetics of the dehydration of the amide groups indicates a complex process, which can not be described by a two state model

On the relation of Voevodsky's algebraic cobordism to Quillen's K-theory

Quillen's algebraic K-theory is reconstructed via Voevodsky's algebraic cobordism. More precisely, for a ground field k the algebraic cobordism P^1-spectrum MGL of Voevodsky is considered as a commutative P^1-ring spectrum. There is a unique ring morphism MGL^{2*,*}(k)--> Z which sends the class [X]_{MGL} of a smooth projective k-variety X to the Euler characteristic of the structure sheaf of X. Our main result states that there is a canonical grade preserving isomorphism of ring cohomology theories MGL^{*,*}(X,U) \tensor_{MGL^{2*,*}(k)} Z --> K^{TT}_{- *}(X,U) = K'_{- *}(X-U)} on the category of smooth k-varieties, where K^{TT}_* is Thomason-Trobaugh K-theory and K'_* is Quillen's K'-theory. In particular, the left hand side is a ring cohomology theory. Moreover both theories are oriented and the isomorphism above respects the orientations. The result is an algebraic version of a theorem due to Conner and Floyd. That theorem reconstructs complex K-theory via complex cobordism.Comment: LaTeX, 18 pages, uses XY-pi

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Photocontrol of Voltage-Gated Ion Channel Activity by Azobenzene Trimethylammonium Bromide in Neonatal Rat Cardiomyocytes

<div><p>The ability of azobenzene trimethylammonium bromide (azoTAB) to sensitize cardiac tissue excitability to light was recently reported. The dark, thermally relaxed <i>trans</i>- isomer of azoTAB suppressed spontaneous activity and excitation propagation speed, whereas the <i>cis</i>- isomer had no detectable effect on the electrical properties of cardiomyocyte monolayers. As the membrane potential of cardiac cells is mainly controlled by activity of voltage-gated ion channels, this study examined whether the sensitization effect of azoTAB was exerted primarily via the modulation of voltage-gated ion channel activity. The effects of <i>trans</i>- and <i>cis</i>- isomers of azoTAB on voltage-dependent sodium (INav), calcium (ICav), and potassium (IKv) currents in isolated neonatal rat cardiomyocytes were investigated using the whole-cell patch-clamp technique. The experiments showed that azoTAB modulated ion currents, causing suppression of sodium (Na⁺) and calcium (Ca²⁺) currents and potentiation of net potassium (K⁺) currents. This finding confirms that azoTAB-effect on cardiac tissue excitability do indeed result from modulation of voltage-gated ion channels responsible for action potential.</p></div