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Background Hypertension afflicts most patients with chronic kidney disease (CKD) and contributes to kidney disease progression, cardiovascular disease, and death in this patient population. The evidence and clinical guidelines support lowering blood pressure (BP) goals in patients with CKD. We evaluated if BP control improved among US adults with CKD. Methods and Results In the NHANES (National Health and Nutrition Examination Survey) for the periods 2011 to 2014, 2015 to 2016, and 2017 to 2020, we identified individuals with CKD defined as estimated glomerular filtration rate 20 to 59 mL/min per 1.73 m2 or urinary albumin/creatinine ratio≥30 mg/g. The following systolic BP categories were evaluated:

Abstract The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo‐responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B‐type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank‐sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo‐responsiveness to NPs.

Abstract Background Sedentary behaviors are associated with adverse health outcomes in older adults. The feasibility of behavioral interventions in this population is unclear. Methods In the Sit Less, Interact, Move More (SLIMM) trial of 106 participants who had obesity, those randomized to the SLIMM intervention (N = 54) were instructed to replace sedentary activities with stepping. An accelerometer was used to measure physical activity. In this secondary analysis, mixed effect models were used to examine the effects of the SLIMM intervention on sedentary and stepping durations and steps/day by age (

Background Intensive systolic blood pressure (SBP) lowering significantly reduced cardiovascular disease (CVD) events in SPRINT (Systolic Blood Pressure Intervention Trial) but not in ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure). Methods and Results SPRINT tested the effects of intensive (

Understanding protein-small-molecule interactions is a critical component of rational drug-design. Structure-activity relationship (SAR)-guided medicinal chemistry is informed by the biological outcome, as assessed by biochemical activity or cellular effect, of chemical modifications on small molecules. The effectiveness of SAR is reliant on the sturdiness and durability of assay design and the quality of information garnered from assays. Lack of quality data at this step can lead to obstruction of the drug discovery pipeline with profound implications for the timelines of introducing a drug into the market. Hence, it would not be an overstatement to consider biochemical/biological assays as the backbone of drug-discovery. Enzyme assays can fail for many different reasons, with the enzyme and the substrate being the principal players. Lack of clarity can hamper progress and can lead to mounting costs and potentially losing competitive advantage. Although each assay is unique and requires a specific approach to troubleshoot the problem at hand, there are general guidelines that can be followed to maximize the chances of success. This review is a step-by-step attempt at reintroducing fundamental biochemical concepts within the context of an enzyme assay, delineating probable causes for failure and potential approaches to get an assay back up and running., (© 2020 Wiley Periodicals, Inc.)

In vitro systems that mimic organ functionality have become increasingly important tools in drug development studies. Systems that measure the functional properties of skeletal muscle are beneficial to compound screening studies and also for integration into multiorgan devices. To date, no studies have investigated human skeletal muscle responses to drug treatments at the single myotube level in vitro. This report details a microscale cantilever chip-based assay system for culturing individual human myotubes. The cantilevers, along with a laser and photo-detector system, enable measurement of myotube contractions in response to broad-field electrical stimulation. This system was used to obtain baseline functional parameters for untreated human myotubes, including peak contractile force and time-to-fatigue data. The cultured myotubes were then treated with known myotoxic compounds and the resulting functional changes were compared to baseline measurements as well as known physiological responses in vivo. The collected data demonstrate the system's capacity for screening direct effects of compound action on individual human skeletal myotubes in a reliable, reproducible, and noninvasive manner. Furthermore, it has the potential to be utilized for high-content screening, disease modeling, and exercise studies of human skeletal muscle performance utilizing iPSCs derived from specific patient populations such as the muscular dystrophies., (© 2019 Wiley Periodicals, Inc.)

Escherichia coli Dihydrofolate reductase is an important enzyme that is essential for the survival of the Gram-negative microorganism. Inhibitors designed against this enzyme have demonstrated application as antibiotics. However, either because of poor bioavailability of the small-molecules resulting from their inability to cross the double membrane in Gram-negative bacteria or because the microorganism develops resistance to the antibiotics by mutating the DHFR target, discovery of new antibiotics against the enzyme is mandatory to overcome drug-resistance. This review summarizes the field of DHFR inhibition with special focus on recent efforts to effectively interface computational and experimental efforts to discover novel classes of inhibitors that target allosteric and active-sites in drug-resistant variants of EcDHFR., (© 2018 Wiley Periodicals, Inc.)

Conventional small molecule drug-discovery approaches target protein pockets. However, the limited number of geometrically distinct pockets leads to widespread promiscuity and deleterious side-effects. Here, the idea of COmposite protein LIGands (COLIG) that interact with each other as well as the protein within a single ligand binding pocket is examined. As a practical illustration, experimental evidence that E. coli Dihydrofolate reductase inhibitors are COLIGs is presented. Then, analysis of a non-redundant set of all holo PDB structures indicates that almost 47-76% of proteins (based on different sequence identity thresholds) can simultaneously bind multiple, interacting ligands in the same pocket. Moreover, most ligands that are either Singletons and COLIGs bind at the bottom of ligand binding pocket and occupy 30% and 43% of the volume of the bottom of the pocket. This suggests the use of COLIGs as a potential new class of small molecule drugs. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

A kinetic-metabolic model of Solanum tuberosum hairy roots is presented in the interest of understanding the effect on the plant cell metabolism of a 90% decrease in cytosolic triosephosphate isomerase (cTPI, EC 5.3.1.1) expression by antisense RNA. The model considers major metabolic pathways including glycolysis, pentose phosphate pathway, and TCA cycle, as well as anabolic reactions leading to lipids, nucleic acids, amino acids, and structural hexoses synthesis. Measurements were taken from shake flask cultures for six extracellular nutrients (sucrose, fructose, glucose, ammonia, nitrate, and inorganic phosphate) and 15 intracellular compounds including sugar phosphates (G6P, F6P, R5P, E4P) and organic acids (PYR, aKG, SUCC, FUM, MAL) and the six nutrients. From model simulations and experimental data it can be noted that plant cell metabolism redistributes metabolic fluxes to compensate for the cTPI decrease, leading to modifications in metabolites levels. Antisense roots showed increased exchanges between the pentose phosphate pathway and the glycolysis, an increased oxygen uptake and growth rate., (Copyright © 2012 Wiley Periodicals, Inc.)

A general method is introduced to immobilize organic molecules on magnetic nanoparticles through silanization reactions and determine the maximum loading level by UV-vis spectroscopy. Loading levels of 1.5 x 10(-3) mol per gram of nanoparticle were obtained with structurally diverse compounds such as rhodamine B and glucosamine. The length of the linker did not have a significant effect on loading as comparable maximum amounts of rhodamine B were immobilized on magnetic nanoparticles regardless of the linker length. Interestingly, rhodamine B derivatives lost conjugation during synthetic manipulations due to reversible spiroisobenzofuran formation. Full regeneration of conjugation was found to be slow with rhodamine B attached on magnetic nanoparticles. The results obtained from these studies will be useful for studying surface functionalization of MNPs in general., ((c) 2007 Wiley-Liss, Inc.)

Optimization of a fixed-bed bioreactor used in wastewater treatment is addressed. The objective of optimization is to maximize the treatment efficiency of the biofilter by manipulating the feed flow rate while satisfying operational constraints. Numerical results indicate that the optimal input is characterized as being on the boundary of the admissible region. Thus, the characterized optimal solution is implemented using a simple feedback control law, which provides the optimal input profile despite variations in substrate inlet concentration and biomass growth rate., (Copyright 2001 John Wiley & Sons, Inc.)