At Physiological Temperatures the ATPase Rates of Shortening Soleus and Psoas Myofibrils Are Similar

AbstractWe obtained the temperature dependences of the adenosine triphosphatase (ATPase) activities (calcium-activated and relaxed) of myofibrils from a slow muscle, which we compared with those from a fast muscle. We chose rabbit soleus and psoas because their myosin heavy chains are almost pure: isoforms I and IIX, respectively. The Arrhenius plots of the ATPases are linear (4–35°C) with energies of activation for soleus myofibrils 155kJmol−1 (activated) and 78kJmol−1 (relaxed). With psoas myofibrils, the energies of activation were 71kJmol−1 (activated) and 60kJmol−1 (relaxed). When extrapolated to 42°C the ATPase rates of the two types of myofibril were identical: 50s−1 (activated) and 0.23s−1 (relaxed). Whereas with psoas myofibrils the Km for adenosine triphosphate (activated ATPase) is relatively insensitive to temperature, that for soleus myofibrils increased from 0.3μM at 4°C to 66.5μM at 35°C. Our results illustrate the importance of temperature when comparing the mechanochemical coupling in different types of muscle. We discuss the problem of how to reconcile the similarity of the myofibrillar ATPase rates at physiological temperatures with their different mechanical properties

Cyanomethylene-bis(phosphonate) as ditopical ligand: stepwise formation of a 2-D heterometallic Fe(III)-Ag(I) coordination network

A new heteroditopic ligand, cyanomethylene-bis(5,5-dimethyl-2-oxo-1,3,2 lambda(5)-dioxa-phosphorinane) 1 (bphosCN), has been reacted with Fe(ClO4)(3) to afford the mononuclear complex Fe(bphosCN)(3) 2 which crystallized in the cubic system, space group Pa (3) over bar. The iron center, chelated by the oxygen atoms of the ligand, shows an almost perfect octahedral geometry, with the CN groups disposed at 120 degrees each other. Further reaction with AgClO4 provided the heterometallic coordination polymer (infinity)(2) {[(Fe (bphosCN)(3))(3)Ag-3(H2O)(2)]center dot(ClO4)(3)} 3 as the unique crystalline polymorph, in the monoclinic space group P21/a. The targeted 2D honeycomb type structure has been achieved through an interplay between coordinative CN-Ag bonds and CN center dot center dot center dot H2O bonds. The magnetic measurements demonstrate the existence of isolated paramagnetic Fe(III) centers in both complexes

Statin utilization and lipid goal attainment in high or very-high cardiovascular risk patients: Insights from Italian general practice

Background and aims: Statin utilization and lipid goal achievement were estimated in a large sample of Italian patients at high/very-high cardiovascular (CV) risk. Methods: Patients aged â¥18 years with a valid low-density lipoprotein cholesterol (LDL-C) measurement in 2015 were selected from the IMS Health Real World Data database; non-high-density lipoprotein cholesterol (non-HDL-C) was assessed in those with available total cholesterol measurements. Index dates were defined as the last valid lipid measurement in 2015. Patients were hierarchically classified into mutually exclusive risk categories: heterozygous familial hypercholesterolemia (primary and secondary prevention), atherosclerotic CV disease (including recent acute coronary syndrome [ACS], chronic coronary heart disease, stroke, and peripheral arterial disease), and diabetes mellitus (DM) alone. Statin and non-statin lipid-modifying therapy (LMT) use, and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline-recommended goal attainment, were assessed. Results: Among 66,158 patients meeting selection criteria, the overall rate of LMT prescriptions was 53.3%, including 7.7% on high-intensity statin therapy. Statin use was highest for recent ACS and lowest for DM alone. LDL-C goal attainment was 16.0% for <1.8 mmol/l and 45.0% for <2.5 mmol/l; 24.3% reached non-HDL-C <2.6 mmol/l and 52.2% were at <3.3 mmol/l. Goal achievement was greatest with high-intensity statin use. Conclusions: Statin use in this cohort was consistent with previous reports in Italian patients at high/very-high CV risk, and low relative to statin use in other European countries. The low rate of ESC/EAS lipid goal attainment observed was consistent with outcomes of other European studies

Paraganglioma of the cauda equina: a tertiary centre experience and scoping review of the current literature.

Cauda equina paragangliomas are rare benign extra-adrenal neuroendocrine tumours arising from the neural crest cells associated with autonomic ganglia. These tumours are often mistaken preoperatively for ependymomas or schwannomas. Patients present with axial or radicular pain with or without neurological deficits. Recurrence, secretory features and length of follow-up are controversial. We conducted a retrospective cohort study of paraganglioma through searching a prospectively maintained histopathology database. Patient demographics, presentation, surgery, complications, recurrence, follow-up and outcome between 2004 and 2016 were studied. The primary aim was to collate and describe the current evidence base for recurrence and secretory features of the tumour. The secondary objective was to report outcome and follow-up strategy. A scoping review was performed in accordance with the PRISMA-ScR Checklist. Ten patients were diagnosed (M:F 7:3) with a mean age of 53.6 ± 5.1 (range 34-71 years). MRI scans revealed intradural lumbar enhancing lesions. All patients had complete microsurgical excisions without adjuvant therapy with no recurrence with a mean follow-up of 5.1 ± 1.4 years. Tumours were attached to the filum terminale. Electron microscopic images demonstrated abundant neurosecretory granules with no evidence of catecholamine production. A total of 620 articles were screened and 65 papers (including ours) combining 121 patients (mean age 48.8 and M:F 71:50) were included. The mean follow-up was 3.48 ± 0.46 (range 0.15-23 years). Back pain was the most common symptom (94%). Cure following surgery was achieved in 93% of the patients whilst 7% had recurrence. Total resection likely results in cure without the need for adjuvant therapy or prolonged follow-up. However, in certain situations, the length of follow-up should be determined by the treating surgeon

The curious role of sarcomeric proteins in control of diverse processes in cardiac myocytes

Introduction Relatively recent developments in our understanding of sarcomeric proteins have expanded their role from the home of molecular motors generating force and shortening to a cellular organelle fully integrated in the control of structural, electrical, mechanical, chemical, and metabolic homeostasis. Even so, in some cases these diverse functions of sarcomeric proteins appear to remain a curiosity, not fully appreciated in the analysis of major controllers of cardiac function. This attitude toward the function of sarcomeric proteins in cardiac myocytes is summarized in the following definition of “curiosity,” which seems particularly apropos: “meddlesome; thrusting oneself into and taking an active part in others’ affairs.” We focus in this Perspective on how sarcomeric proteins function in integration with membrane channels and transporters in control of cardiac dynamics, especially in adrenergic control of cardiac function. Understanding these mechanisms at the level of cardiac sarcomeres took on special significance with the identification of mutations in sarcomeric proteins as the most common cause of familial hypertrophic and dilated cardiomyopathies. These mutations commonly lead to structural, electrical, and metabolic remodeling and to sudden death. These disorders indicate a critical role of processes at the level of the sarcomeres in homeostatic control of cardiac energetics, dynamics, and structure. Yet, control of Ca2+ delivery to and removal from the myofilaments has dominated discussions of mechanisms regulating cardiac contractility. We first provide an alternative perspective in which rate processes at the level of the sarcomeres appear to be dominant during the rise and maintenance of systolic elastance and of isovolumic relaxation. A discussion of established adrenergic mechanisms and newly understood anti-adrenergic mechanisms controlling sarcomere response to Ca2+ follows and expands on this perspective

Disease-Related Cardiac Troponins Alter Thin Filament Ca2+ Association and Dissociation Rates

The contractile response of the heart can be altered by disease-related protein modifications to numerous contractile proteins. By utilizing an IAANS labeled fluorescent troponin C, , we examined the effects of ten disease-related troponin modifications on the Ca2+ binding properties of the troponin complex and the reconstituted thin filament. The selected modifications are associated with a broad range of cardiac diseases: three subtypes of familial cardiomyopathies (dilated, hypertrophic and restrictive) and ischemia-reperfusion injury. Consistent with previous studies, the majority of the protein modifications had no effect on the Ca2+ binding properties of the isolated troponin complex. However, when incorporated into the thin filament, dilated cardiomyopathy mutations desensitized (up to 3.3-fold), while hypertrophic and restrictive cardiomyopathy mutations, and ischemia-induced truncation of troponin I, sensitized the thin filament to Ca2+ (up to 6.3-fold). Kinetically, the dilated cardiomyopathy mutations increased the rate of Ca2+ dissociation from the thin filament (up to 2.5-fold), while the hypertrophic and restrictive cardiomyopathy mutations, and the ischemia-induced truncation of troponin I decreased the rate (up to 2-fold). The protein modifications also increased (up to 5.4-fold) or decreased (up to 2.5-fold) the apparent rate of Ca2+ association to the thin filament. Thus, the disease-related protein modifications alter Ca2+ binding by influencing both the association and dissociation rates of thin filament Ca2+ exchange. These alterations in Ca2+ exchange kinetics influenced the response of the thin filament to artificial Ca2+ transients generated in a stopped-flow apparatus. Troponin C may act as a hub, sensing physiological and pathological stimuli to modulate the Ca2+-binding properties of the thin filament and influence the contractile performance of the heart

Identification of a Negative Allosteric Site on Human α4β2 and α3β4 Neuronal Nicotinic Acetylcholine Receptors

Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 µM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders