Ventricular Arrhythmia Burden in Patients With Heart Failure and Cardiac Resynchronization Devices: The Importance of Renal Function

Background: Chronic kidney disease (CKD) is a risk factor for arrhythmias in patients with heart failure (HF). However, the effects of CKD on ventricular arrhythmia (VA) burden in patients with cardiac resynchronization therapy and defibrillator (CRT‐D) devices in a primary prevention setting are unknown. Objective: To determine whether baseline CKD is associated with increased risk of VA in patients implanted with primary prevention CRT‐D devices. Methods and Results: In this retrospective study, 199 consecutive primary prevention CRT‐D recipients (2005–2010) were stratified by estimated glomerular filtration rate (eGFR) levels prior to device implantation with 106 (53.2%) ≥CKD III (eGFR III as the only predictor of sustained VA in this group (adjusted hazard ratio [HR] 2.92, CI = 1.39–6.1, P = 0.004). Conclusion: Baseline CKD is a strong independent risk factor for VA in primary prevention CRT‐D recipients. Further understanding of the underlying arrhythmogenic mechanisms relating to CKD may be of interest to allow appropriate correction and prevention. Device programming in this cohort may need to reflect this increased risk

A new multicompartmental reaction-diffusion modeling method links transient membrane attachment of E. coli MinE to E-ring formation

Many important cellular processes are regulated by reaction-diffusion (RD) of molecules that takes place both in the cytoplasm and on the membrane. To model and analyze such multicompartmental processes, we developed a lattice-based Monte Carlo method, Spatiocyte that supports RD in volume and surface compartments at single molecule resolution. Stochasticity in RD and the excluded volume effect brought by intracellular molecular crowding, both of which can significantly affect RD and thus, cellular processes, are also supported. We verified the method by comparing simulation results of diffusion, irreversible and reversible reactions with the predicted analytical and best available numerical solutions. Moreover, to directly compare the localization patterns of molecules in fluorescence microscopy images with simulation, we devised a visualization method that mimics the microphotography process by showing the trajectory of simulated molecules averaged according to the camera exposure time. In the rod-shaped bacterium _Escherichia coli_, the division site is suppressed at the cell poles by periodic pole-to-pole oscillations of the Min proteins (MinC, MinD and MinE) arising from carefully orchestrated RD in both cytoplasm and membrane compartments. Using Spatiocyte we could model and reproduce the _in vivo_ MinDE localization dynamics by accounting for the established properties of MinE. Our results suggest that the MinE ring, which is essential in preventing polar septation, is largely composed of MinE that is transiently attached to the membrane independently after recruited by MinD. Overall, Spatiocyte allows simulation and visualization of complex spatial and reaction-diffusion mediated cellular processes in volumes and surfaces. As we showed, it can potentially provide mechanistic insights otherwise difficult to obtain experimentally

Fire triggers reestablishment of invasive grasses in a neotropical savanna under restoration

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordExcluding invasive grasses is a significant challenge for neotropical savanna restoration. Invasive grasses alter fire regimes with feedbacks on soil nutrient pools, favoring their own dominance over native species. Here we combine remote sensing with an opportunistic experiment to monitor a savanna under restoration before and after a large natural fire. We measured vegetation and soil fertility in a 4-year-old restoration area in Central Brazil, which was subsequently hit by a lightning fire. The restoration area was originally utilized as pasture, dominated by invasive grasses. Over the restoration period, native fast-growing grasses replaced the invasive species. Within the first year after the fire, we found that the fire had reduced aboveground biomass, species diversity, and abundance of native species with acquisitive resource-use strategies. Soil phosphorus and pH increased after the fire and favored the re-invasion of exotic grass species. Our findings suggest that fire occurrence early in the restoration process may trigger exotic grass re-invasion driven by soil nutrient enrichment. To diminish the re-invasion risk from exotic grasses in savannas undergoing restoration, managers should beware of the early fire or manage soil fertility after fire events. Successful restoration may also benefit by incorporating native species with high post-fire recovery capacity.Natural Environment Research Council (NERC)FAPESPFundação Grupo Boticário de Proteção à NaturezaCoordenação de Aperfeiçoamento Pessoal de Nível Superior - Brasil (CAPES)Instituto SerrapilheiraCNP

Hydrophilicity Matching – A Potential Prerequisite for the Formation of Protein-Protein Complexes in the Cell

A binding event between two proteins typically consists of a diffusional search of binding partners for one another, followed by a specific recognition of the compatible binding sites resulting in the formation of the complex. However, it is unclear how binding partners find each other in the context of the crowded, constantly fluctuating, and interaction-rich cellular environment. Here we examine the non-specific component of protein-protein interactions, which refers to those physicochemical properties of the binding partners that are independent of the exact details of their binding sites, but which can affect their localization or diffusional search for one another. We show that, for a large set of high-resolution experimental 3D structures of binary, transient protein complexes taken from the DOCKGROUND database, the binding partners display a surprising, statistically significant similarity in terms of their total hydration free energies normalized by a size-dependent variable. We hypothesize that colocalization of binding partners, even within individual cellular compartments such as the cytoplasm, may be influenced by their relative hydrophilicity, potentially in response to local hydrophilic gradients

Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women

BACKGROUND: Isoflavones from soybeans may provide some beneficial impacts on postmenopausal health. The purpose of this study was to compare the pharmacokinetics and bioavailability of plasma isoflavones (daidzein and genistein) after a single dose of orally administered soy beverage and soy extract capsules in postmenopausal Thai women. METHODS: We conducted a randomized two-phase crossover pharmacokinetic study in 12 postmenopausal Thai women. In the first phase, each subject randomly received either 2 soy extract capsules (containing daidzin : genistin = 7.79 : 22.57 mg), or soy beverage prepared from 15 g of soy flour (containing daidzin : genistin = 9.27 : 10.51 mg). In the second phase, the subjects received an alternative preparation in the same manner after a washout period of at least 1 week. Blood samples were collected immediately before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 32 h after administration of the soy preparation in each phase. Plasma daidzein and genistein concentrations were determined by using high performance liquid chromatography (HPLC). The pharmacokinetic parameters of daidzein and genistein, i.e. maximal plasma concentration (C(max)), time to maximal plasma concentration (T(max)), area under the plasma concentration-time curve (AUC) and half-life (t(1/2)), were estimated using the TopFit version 2.0 software with noncompartmental model analysis. RESULTS: There were no significant differences in the mean values of C(max)/dose, AUC(0–32)/dose, AUC(0-∝)/dose, T(max), and t(1/2 )of genistein between both preparations. For pharmacokinetic parameters of daidzein, the mean values of C(max)/dose, T(max), and t(1/2 )did not significantly differ between both preparations. Nonetheless, the mean AUC(0–32)/dose and AUC(0-∝)/dose after administration of soy extract capsules were slightly (but significantly, p < 0.05) higher than those of soy beverage. CONCLUSION: The bioavailability of daidzein, which was adjusted for the administered dose (AUC/dose), following a single oral administration of soy beverage was slightly (but significantly) less than that of soy extract capsules, whereas, the bioavailability adjusted for administered dose of genistein from both soy preparations were comparable. The other pharmacokinetic parameters of daidzein and genistein, including C(max )adjusted for the dose, T(max )and t(1/2), were not different between both soy preparations

Mapping native and non-native vegetation in the Brazilian Cerrado using freely available satellite products

This is the final version. Available on open access from Nature Research via the DOI in this recordNative vegetation across the Brazilian Cerrado is highly heterogeneous and biodiverse and provides important ecosystem services, including carbon and water balance regulation, however, land-use changes have been extensive. Conservation and restoration of native vegetation is essential and could be facilitated by detailed landcover maps. Here, across a large case study region in Goiás State, Brazil (1.1 Mha), we produced physiognomy level maps of native vegetation (n = 8) and other landcover types (n = 5). Seven different classification schemes using different combinations of input satellite imagery were used, with a Random Forest classifier and 2-stage approach implemented within Google Earth Engine. Overall classification accuracies ranged from 88.6-92.6% for native and non-native vegetation at the formation level (stage-1), and 70.7-77.9% for native vegetation at the physiognomy level (stage-2), across the seven different classifications schemes. The differences in classification accuracy resulting from varying the input imagery combination and quality control procedures used were small. However, a combination of seasonal Sentinel-1 (C-band synthetic aperture radar) and Sentinel-2 (surface reflectance) imagery resulted in the most accurate classification at a spatial resolution of 20 m. Classification accuracies when using Landsat-8 imagery were marginally lower, but still reasonable. Quality control procedures that account for vegetation burning when selecting vegetation reference data may also improve classification accuracy for some native vegetation types. Detailed landcover maps, produced using freely available satellite imagery and upscalable techniques, will be important tools for understanding vegetation functioning at the landscape scale and for implementing restoration projects.ShellFAPESPNatural Environment Research Council (NERC

Selective and Irreversible Inhibitors of Mosquito Acetylcholinesterases for Controlling Malaria and Other Mosquito-Borne Diseases

New insecticides are urgently needed because resistance to current insecticides allows resurgence of disease-transmitting mosquitoes while concerns for human toxicity from current compounds are growing. We previously reported the finding of a free cysteine (Cys) residue at the entrance of the active site of acetylcholinesterase (AChE) in some insects but not in mammals, birds, and fish. These insects have two AChE genes (AP and AO), and only AP-AChE carries the Cys residue. Most of these insects are disease vectors such as the African malaria mosquito (Anopheles gambiae sensu stricto) or crop pests such as aphids. Recently we reported a Cys-targeting small molecule that irreversibly inhibited all AChE activity extracted from aphids while an identical exposure caused no effect on the human AChE. Full inhibition of AChE in aphids indicates that AP-AChE contributes most of the enzymatic activity and suggests that the Cys residue might serve as a target for developing better aphicides. It is therefore worth investigating whether the Cys-targeting strategy is applicable to mosquitocides. Herein, we report that, under conditions that spare the human AChE, a methanethiosulfonate-containing molecule at 6 µM irreversibly inhibited 95% of the AChE activity extracted from An. gambiae s. str. and >80% of the activity from the yellow fever mosquito (Aedes aegypti L.) or the northern house mosquito (Culex pipiens L.) that is a vector of St. Louis encephalitis. This type of inhibition is fast (∼30 min) and due to conjugation of the inhibitor to the active-site Cys of mosquito AP-AChE, according to our observed reactivation of the methanethiosulfonate-inhibited AChE by 2-mercaptoethanol. We also note that our sulfhydryl agents partially and irreversibly inhibited the human AChE after prolonged exposure (>4 hr). This slow inhibition is due to partial enzyme denaturation by the inhibitor and/or micelles of the inhibitor, according to our studies using atomic force microscopy, circular dichroism spectroscopy, X-ray crystallography, time-resolved fluorescence spectroscopy, and liquid chromatography triple quadrupole mass spectrometry. These results support our view that the mosquito-specific Cys is a viable target for developing new mosquitocides to control disease vectors and to alleviate resistance problems with reduced toxicity toward non-target species

Consumption of a soy drink has no effect on cognitive function but may alleviate vasomotor symptoms in post-menopausal women; a randomised trial

Purpose: Cognitive decline is commonly reported during the menopausal transition, with memory and attention being particularly affected. The aim of this study was to investigate the effects of a commercially available soy drink on cognitive function and menopausal symptoms in post-menopausal women. Methods: 101 post-menopausal women, aged 44–63 years, were randomly assigned to consume a volume of soy drink providing a low (10 mg/day; control group), medium (35 mg/day), or high (60 mg/day) dose of isoflavones for 12 weeks. Cognitive function (spatial working memory, spatial span, pattern recognition memory, 5-choice reaction time, and match to sample visual search) was assessed using CANTAB pre- and post-the 12 week intervention. Menopausal symptoms were assessed using Greene’s Climacteric Scale. Results: No significant differences were observed between the groups for any of the cognitive function outcomes measured. Soy drink consumption had no effect on menopausal symptoms overall; however, when women were stratified according to the severity of vasomotor symptoms (VMS) at baseline, women with more severe symptoms at baseline in the medium group had a significant reduction (P = 0.001) in VMS post-intervention (mean change from baseline score: − 2.15 ± 1.73) in comparison to those with less severe VMS (mean change from baseline score: 0.06 ± 1.21). Conclusions: Soy drink consumption had no effect on cognitive function in post-menopausal women. Consumption of ~ 350 ml/day (35 mg IFs) for 12 weeks significantly reduced VMS in those with more severe symptoms at baseline. This finding is clinically relevant as soy drinks may provide an alternative, natural, treatment for alleviating VMS, highly prevalent among western women

Nutrition and cancer: A review of the evidence for an anti-cancer diet

It has been estimated that 30–40 percent of all cancers can be prevented by lifestyle and dietary measures alone. Obesity, nutrient sparse foods such as concentrated sugars and refined flour products that contribute to impaired glucose metabolism (which leads to diabetes), low fiber intake, consumption of red meat, and imbalance of omega 3 and omega 6 fats all contribute to excess cancer risk. Intake of flax seed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk. Allium and cruciferous vegetables are especially beneficial, with broccoli sprouts being the densest source of sulforophane. Protective elements in a cancer prevention diet include selenium, folic acid, vitamin B-12, vitamin D, chlorophyll, and antioxidants such as the carotenoids (α-carotene, β-carotene, lycopene, lutein, cryptoxanthin). Ascorbic acid has limited benefits orally, but could be very beneficial intravenously. Supplementary use of oral digestive enzymes and probiotics also has merit as anticancer dietary measures. When a diet is compiled according to the guidelines here it is likely that there would be at least a 60–70 percent decrease in breast, colorectal, and prostate cancers, and even a 40–50 percent decrease in lung cancer, along with similar reductions in cancers at other sites. Such a diet would be conducive to preventing cancer and would favor recovery from cancer as well