Metabolic substrates,histone modifications,and heart failure

Histone epigenetic modifications are chemical modification changes to histone amino acid residues that modulate gene expression without altering the DNA sequence. As both the phenotypic and causal factors, cardiac metabolism disorder exacerbates mitochondrial ATP generation deficiency, thus promoting pathological cardiac hypertrophy. Moreover, several concomitant metabolic substrates also promote the expression of hypertrophy-responsive genes via regulating histone modifications as substrates or enzyme-modifiers, indicating their dual roles as metabolic and epigenetic regulators. This review focuses on the cardiac acetyl-CoA-dependent histone acetylation, NAD⁺-dependent SIRT-mediated deacetylation, FAD⁺-dependent LSD-mediated, and α-KG-dependent JMJD-mediated demethylation after briefly addressing the pathological and physiological cardiac energy metabolism. Besides using an “iceberg model” to explain the dual role of metabolic substrates as both metabolic and epigenetic regulators, we also put forward that the therapeutic supplementation of metabolic substrates is promising to blunt HF via re-establishing histone modifications.     

Ending a decade of deception: a valiant failure, a not-so-valiant failure, and a success story

Prior studies involving two methods, Brooks Parsimony Analysis (BPA) and TreeMap, have found BPA to be the more reliable method. Recent criticisms leveled at these studies argue that the tests were unfairly created and biased in favor of BPA. The authors of a recent critique offered new exemplars to demonstrate flaws in BPA, plus a simple fix to correct the flaws found in TreeMap. A re‐evaluation of their exemplars clearly shows that the authors' calculations are incorrect, their understanding of the methods is lacking, and that their simple fix does not work. Additional analyses using TreeMap 2.02 are run to show that TreeMap 2.02, like TreeMap 1.0, cannot adequately deal with widespread parasites, contrary to the claims of its supporters. Furthermore, the exemplars corroborate previous findings that BPA, when calculated correctly, is more reliable than TreeMap1.0 and TreeMap 2.02 and therefore the method of choice in coevolutionary and biogeographic studies.     

Electrode failure: tissue, electrical, and material responses

The development of invasive, rehabilitative neuroprosthetics for humans requires reliable neural probes that are capable of recording large ensembles of neurons for a long period of time. Recent advances in the development of neuroprosthetics in animals and humans have shown that communication and control can be directly derived from the central nervous system (CNS) for restoring lost motor ability. This proof of concept has opened the possibility of new therapies for the millions of individuals suffering from neurological disorders of the nervous system. The success of these therapies hinges on the ability to reliably access the relevant signals from the brain with high quality for the lifetime of the patient. As a result, research has focused on the cascade of events that follow chronic implantation of microelectrodes and temporal degradation in the signal and electrode quality: signal-to-noise ratio, noise floor, peak amplitude, and neuronal yield. Implanted microelectrodes have been reported to suffer from time-dependent degradation in signal quality due to unknown issues related to tissue interfaces.     

Writing failure: knowledge production,temporalities, ethics,and traces

This volume follows failures out into the world, exploring how they unfold ethnographically. Taking a longer view shows how objects, narratives, and diagnoses of failures may be crafted, acted on, suffered, resisted – unmade or recomposed. Thus while tropes and diagnoses of failure can temporarily (re)organize, narrate, and stabilize the world, the kinds of failures explored here also indicate a mode of uncontainable excess that refuses the boundedness of knowledge objects, temporalities, and spaces. This volume offers three main interventions. The first concerns knowledge production: how objects of failure are crafted through selective ways of knowing that occlude both other modes of apprehension at different scales and failure's many affective valences. The second thinks through the knotted temporalities – whether pasts, futures, suspended presents, or repetition and sedimentation – that make and are made by failure. Finally, writing about unfurling failures requires careful attention to non-linear reverberations and traces as well as to open-ended and mobile narratives that produce different social and material effects.     

CaMKII inhibition in heart failure, beneficial, harmful, or both

Calmodulin-dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca(2+) handling, excitation-contraction coupling, and in vivo β-adrenergic regulation in pressure-overload HF mice with CaMKIIδ knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to β-adrenergic stimulation. Compared with WT HF, L-type calcium channel current (I(Ca)) density in KO HF LV was decreased without changes in I(Ca) activation and inactivation kinetics, whereas I(Ca) recovery from inactivation was accelerated and Ca(2+)-dependent I(Ca) facilitation, a positive staircase blunted in WT HF, was recovered. However, I(Ca) response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca(2+) leak and slowed cytostolic Ca(2+) concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca(2+) and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKIIδ KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to β-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.     

Type II diabetes mellitus,congestive heart failure,and zinc metabolism

Zinc status was assessed in patients with type II diabetes mellitus and congestive heart failure (CHF). Three groups of patients were enrolled into the study: Group 1: 15 patients with type II diabetes mellitus and CHF; Group 2: 20 patients with isolated type II diabetes mellitus; and Group 3: nine patients with isolated CHF. Twenty-four-hour urine was measured for creatinine, protein, and zinc, and blood was drawn for creatinine, proteins, liver enzymes, hemoglobin A₁c, and zinc. Insulin treatment and hemoglobin A₁c were comparable in the diabetic patients of groups 1 and 2, but group 1 was also treated with captopril and diuretics like the CHF patients of group 3. Plasma zinc levels were statistically similar in all three groups, but urinary zinc excretion (μmol/24 h) and urinary zinc: creatinine (μmol/mmol) ratio were significantly higher in the type II diabetics and CHF group (27.2±1.5; 1.69±0.6, respectively) compared to the diabetic patients alone (19.4±0.76; 0.97±0.3, respectively) and the CHF patients (9.7±0.3; 0.62±0.3, respectively). Patients with type II diabetes mellitus and CHF were treated with higher doses of captopril than the CHF patients (56.25±24 mg vs 18.8±11 mgP<0.05). Thus, patients with type II diabetes mellitus and CHF excrete larger amounts of zinc, which may eventually lead to zinc deficiency.     

Contraceptive failure: levels, trends and determinants in Matlab, Bangladesh

This study investigated the levels, trends and determinants of contraceptive use-failure in Matlab, Bangladesh, using a set of prospective data on 25,960 women of reproductive age. The data were extracted from the Record Keeping System (RKS) of Matlab for the period 1978-94. If there was any live birth during the use or within 7 months after the discontinuation of use, it was considered as a failure. The life table technique and hazard model were used as analytical tools. The results suggest that use-failure for pills, IUDs (TCu 200) and injectables and other temporary methods increased from 1978 to 1988, but began to decline after 1988. The cumulative probability of first-method failure within 1 year of method acceptance of the cohort of 1990-94 acceptors was 12.9% for pills, 2.0% for IUDs, 0.5% for injectables, 22.0% for condoms and 13.4% for 'other' methods (sampoon, foam, jelly and traditional methods). For pills, condoms and 'other' methods, the likelihood of failure declined with the duration of use; by contrast, the probability of an IUD failure increased over time, peaking at 3 years of use. The injectables maintained a low likelihood of failure regardless of the duration of use. The quality of Community Health Workers' (CHWs) performance was associated with the risk of failure of all temporary methods except condoms; women's background characteristics associated with failure varied by method. The effect of the quality of the CHWs' performance and the background variables on failure did not change much over time. It is felt that contraceptive failure deserves the serious attention of programme managers and policy makers to make the Bangladesh national family planning programme more successful.     

Human myocardial Na,K-ATPase concentration in heart failure

The Na,K-ATPase is of major importance for active ion transport across the sarcolemma and thus for electrical as well as contractile function of the myocardium. Furthermore, it is receptor for digitalis glycosides. In human studies of the regulatory aspects of myocardial Na,K-ATPase concentration a major problem has been to obtain tissue samples. Methodological accomplishments in quantification of myocardial Na,K-ATPase using vanadate facilitated ³H-ouabain binding to intact samples have, however, made it possible to obtain reliable measurements on human myocardial necropsies obtained at autopsy as well as on biopsies of a wet weight of only 1–2 mg obtained during heart catheterisation. However, access to the ultimately, normal, vital myocardial tissue has come from the heart transplantation programs, through which myocardial samples from cardiovascular healthy organ donors have become available. In the present paper we evaluate the various values reported for normal human myocardial Na,K-ATPase concentration, its regulation in heart disease and the association with digitalization. Normal myocardial Na,K-ATPase concentration level is found to be 700 pmol/g wet weight. No major variations were found between or within the walls of the heart ventricles. During the first few years of life a marked decrease in myocardial Na,K-ATPase concentration is followed by a stable level obtained in early adulthood and normally maintained throughout life. In patients with enlarged cardiac x-ray silhouette a significant positive, linear correlation between left ventricular ejection fraction (EF) and Na,K-ATPase concentration was established. A maximum reduction in Na,K-ATPase concentration of 89% was obtained when EF was reduced to 20%. Generally, heart failure associated with heart dilatation, myocardial hypertrophy as well as ischaemic heart disease is associated with reductions in myocardial Na,K-ATPase concentration of around 25%. During digoxin treatment of heart failure patients a further reduction in functional myocardial Na,K-ATPase concentration of 15% has been found. Thus, the total reduction in functional myocardial Na,K-ATPase concentration in digitalised heart failure patients may well be of the magnitude 40%. In conclusion, it has become possible to quantify human myocardial Na,K-ATPase in health and disease. Revealed reductions are in heart failure of importance for contractile function, generation of arrhythmia and for digoxin treatment.     

Leukotoxin, 9, 10-epoxy-12-octadecenoate, causes cardiac failure in dogs

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.     

Caretakers, child care practices, and growth failure in highland Ecuador

Problems for child health have been attributed to child and sibling caretaking. Nevertheless, our data from highland Ecuador suggest an ambiguous relationship between growth failure and the practice of peer care. In a region where levels of chronic undernutrition as measured by stunting exceed 75 percent and fully one-quarter of children under five are underweight, analysis of structured observations of a sample of 28 children reveals no statistical association between growth indices and the practice of older children caring for younger children. Qualitative data, however, indicate that the practice can be a complication in specific cases where children already suffer compromised health. While the advantages or disadvantages associated with particular caretakers appear secondary to the risks attending inadequate diets or the broader environment of rural poverty, the potential for difficulties to emerge from peer care suggests that community day care provides a valuable alternative in this context.     

After Grenfell: accumulation,debris, and forming failure in London

The Grenfell Tower fire in London in 2017 is popularly associated with a litany of failures: political, structural, moral, material. But while the official inquiry has sought to frame the fire as a discrete event, for local residents it is inextricable from accumulated histories of injustice and inequality. Years on, the fire still reverberates, its afterlife constellating with new narratives and politics. Drawing on literature on ruination and remains, as well as methodological theory, this essay examines how the form of failure is never pre-known but must be made to appear. Through diverse encounters with the tower's debris – material and conceptual – failure is made to matter, acting both backwards and forwards in time. Reflecting on remainders and erasures at the tower site, as well as debates about the parameters of the inquiry, I explore how failure is continually recomposed, becoming both an object of knowledge and an instrument for its formation.     

Trimethoprim, failure to penetrate into Pseudomonas aeruginosa cells

Abstract Permeability mutants of Escherichia coli and Pseudomonas aeruginosa demonstrated a significantly higher susceptibility for trimethoprim (TMP). Although the target enzyme of this drug, dihydrofolic acid reductase, expressed about the same activity, it was comparably inhibited by TMP in permeability mutants and in wild-type strains. The weak activity in wild-type strains depends on the decreased uptake.     

Differential effects of strength training leading to failure versus not to failure on hormonal responses, strength, and muscle power gains.

The purpose of this study was to examine the efficacy of 11 wk of resistance training to failure vs. nonfailure, followed by an identical 5-wk peaking period of maximal strength and power training for both groups as well as to examine the underlying physiological changes in basal circulating anabolic and catabolic hormones. Forty-two physically active men were matched and then randomly assigned to either a training to failure (RF; n = 14), nonfailure (NRF; n = 15), or control groups (C; n = 13). Muscular and power testing and blood draws to determine basal hormonal concentrations were conducted before the initiation of training (T0), after 6 wk of training (T1), after 11 wk of training (T2), and after 16 wk of training (T3). Both RF and NRF resulted in similar gains in 1-repetition maximum bench press (23 and 23%) and parallel squat (22 and 23%), muscle power output of the arm (27 and 28%) and leg extensor muscles (26 and 29%), and maximal number of repetitions performed during parallel squat (66 and 69%). RF group experienced larger gains in the maximal number of repetitions performed during the bench press. The peaking phase (T2 to T3) after NRF resulted in larger gains in muscle power output of the lower extremities, whereas after RF it resulted in larger gains in the maximal number of repetitions performed during the bench press. Strength training leading to RF resulted in reductions in resting concentrations of IGF-1 and elevations in IGFBP-3, whereas NRF resulted in reduced resting cortisol concentrations and an elevation in resting serum total testosterone concentration. This investigation demonstrated a potential beneficial stimulus of NRF for improving strength and power, especially during the subsequent peaking training period, whereas performing sets to failure resulted in greater gains in local muscular endurance. Elevation in IGFBP-3 after resistance training may have been compensatory to accommodate the reduction in IGF-1 to preserve IGF availability.