Sympatho-renal axis in chronic disease

Essential hypertension, insulin resistance, heart failure, congestion, diuretic resistance, and functional renal disease are all characterized by excessive central sympathetic drive. The contribution of the kidney’s somatic afferent nerves, as an underlying cause of elevated central sympathetic drive, and the consequences of excessive efferent sympathetic signals to the kidney itself, as well as other organs, identify the renal sympathetic nerves as a uniquely logical therapeutic target for diseases linked by excessive central sympathetic drive. Clinical studies of renal denervation in patients with resistant hypertension using an endovascular radiofrequency ablation methodology have exposed the sympathetic link between these conditions. Renal denervation could be expected to simultaneously affect blood pressure, insulin resistance, sleep disorders, congestion in heart failure, cardiorenal syndrome and diuretic resistance. The striking epidemiologic evidence for coexistence of these disorders suggests common causal pathways. Chronic activation of the sympathetic nervous system has been associated with components of the metabolic syndrome, such as blood pressure elevation, obesity, dyslipidemia, and impaired fasting glucose with hyperinsulinemia. Over 50% of patients with essential hypertension are hyperinsulinemic, regardless of whether they are untreated or in a stable program of treatment. Insulin resistance is related to sympathetic drive via a bidirectional mechanism. In this manuscript, we review the data that suggests that selective impairment of renal somatic afferent and sympathetic efferent nerves in patients with resistant hypertension both reduces markers of central sympathetic drive and favorably impacts diseases linked through central sympathetics—insulin resistance, heart failure, congestion, diuretic resistance, and cardiorenal disorders

Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu

Surface-induced lamellar orientation of multilayer membrane arrays. Theoretical analysis and a new method with application to purple membrane fragments.

The orientation of membrane fragments into a lamellar array by a flat surface is analyzed. This analysis includes processes such as centrifugation and drying and physical effects due to membrane fragment steric interactions, finite size, elasticity, and thermal fluctuations. Several model calculations of optimal orientational order in multilayer membrane arrays are presented. The predictions of a smectic A model agree quantitatively with the measured spatial dependence of the fluctuations in layer orientation in a multilamellar arrays. A new technique, based in part on this analysis, for the preparation of well-oriented multilamellar arrays of natural and artificial membranes, isopotential spin-dry centrifugation, is described. The method involves the use of specially designed inserts for the buckets of a standard vacuum ultracentrifuge. The membrane fragments to be oriented are sedimented from solution or suspension onto a substrate of a convenient material which forms a gravitational isopotential surface at high g. Sedimentation is accompanied by removal of the suspending medium at high g to produce oriented films with a selected degree of solvation. In addition, a method is described whereby small solute molecules can be maintained in constant concentration with the membrane fragments during this process. Initial application of the method to the orientation of purple membrane fragments is described. The degree of orientation obtained in this system is evaluated using freeze-fracture and scanning electron microscopy, optical birefringence, linear dichroism, and microscopy