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

ELECTRIC FIELD EFFECTS ON SINGLET-SINGLET TRANSITIONS IN LINEAR POLYENES

Author Institution: Department of Chemistry, Harvard UniversityWe give recent evidence concerning the excited singlet state orderings in linear polyenes. Progress in obtaining Stark-induced absorptions with an electronic data acquisition system will be presented along with theoretical considerations. Singlet state orderings in these molecules have implications for the photochemical behavior of analogous compounds

THE EXPERIMENTAL AND THEORETICAL DESCRIPTION OF 1, 3, 5-HEXATRIENE: SYMMETRY ORDERING OF EXCITED STATES

Author Institution: Department of Chemistry, Harvard UniversityThe recent discovery of a low-lying transition in $\alpha, \omega$-diphenyl-octatetraene and 2, 10-dimethylundecapentaene and its subsequent explanation on the basis of a semi-empirical calculation employing both singly- and doubly-excited configurations has led to disagreement as to the ordering of excited states in these molecules. Experiments by Kohler, Hudson and Christensen have suggested the state ordering of linear polyenes to be $^{1}A_{g}, ^{1}A_{g}, ^{1}B_{u}$, countering the H$\ddot{u}$ckel alternating $^{1}A_{g}, ^{1}B_{u}, ^{1}A_{g}$ state ordering expected for the idealized $C_{2h}$ point group (planar geometry). This ordering was also calculated semi-empirically for butadiene, hexatriene, and octatetraene via PPP methods by Schulten and Karplus, who included all single and double excitations in configuration interaction (CI), but their findings for butadiene have been challenged by more recent, non-empirical calculations. Besides high resolution absorption and emission spectral evidence for the state ordering in this unsubstituted polyene, our present paper presents qualitatively correct ab initio theoretical description. The lowest two $^{1}A_{g}$ and $^{1}B_{u}$ state energies of 1, 3, 5-hexatriene were calculated on the POLYCAL program using a minimum basis set of Slater-type orbitals (STO ‘s). Utilizing all singly- and doubly-excited configurations arising from the six carbon $p_{z}$ atomic orbitals. CI gave a state ordering: $^{1}A_{g}$ (ground state) $< ^{1}A_{g} (6.98 eV) < ^{1}B_{u} (8.24 ev).$ These ab initio results agree qualitatively with preliminary absorption and emission experiments as well as with one previous semi-empirical calculation and experiments on larger polyenes. Therefore it is suggested that, even for a relatively inflexible basis set, the inclusion of all singly- plus doubly-excited configurations of the $\pi$-system in the CI treatment yields a qualitatively correct picture of state ordering in these molecules

STARK FIELD-INDUCED INTENSITY IN ORBITALLY FORBIDDEN SINGLET-SINGLET TRANSITIONS IN LINEAR POLYENES

Author Institution: Department of Chemistry, Harvard UniversityThe recent finding that the lowest singlet-singlet electric dipole transition involving the ground state of linear polyenes is orbitally forbidden opens up many questions concerning the properties of lowest excited singlet states of these compounds. In low-temperature glasses and crystals, the forbiddenness of the lowest singlet-singlet transition $1^{1}A_{g}- 2^{1}A_{g}$ in polyenes of an idealized 2/m$(C_{2h})$ point group can be removed in several ways, including: (1) environmental effects; (2) asymmetric out-of-plane vibrations of methyl substituents altering g-u forbiddenness; (3) Stark effect mixing of vibronic levels of the $1^{1}B_{u}$ and $2^{1}A_{g}$ excited states by an externally applied electric field. We have examined all three techniques, with special emphasis on the last one for certain model polyenes. The intensity induced in the orbitally forbidden lowest singlet-singlet transition by an electric field is easily calculated. Since these compounds have no electric dipole moment, the induced intensity goes quadratically with field strength. General applicability of this technique requires electronic signal enhancement, whose instrumentation is also presented. The significance of this technique as well as the results obtained to date will be discussed

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

Evaluation of the Exposure–Response Relationship of Lung Cancer Mortality and Occupational Exposure to Hexavalent Chromium Based on Published Epidemiological Data

Some have suggested a threshold mechanism for the carcinogenicity of exposure to hexavalent chromium, Cr(VI). We evaluated the nature of the exposure–response relationship between occupational exposure to Cr(VI) and respiratory cancer based on results of two recently published epidemiological cohort studies. The combined cohort comprised a total of 2,849 workers employed at two U.S. chromate production plants between 1940 and 1974. Standardized mortality ratios (SMRs) for lung cancer in relation to cumulative Cr(VI) exposure categories were reported using regional mortality rates. Linear additive and multiplicative relative risk regression models were fit to the SMRs of the individual and combined studies. Both models fit the data from the individual studies reasonably well; however, the fit was somewhat less adequate for the pooled data. Meta-analysis of the slope estimates obtained from the multiplicative relative risk model showed substantial heterogeneity between the two epidemiological studies. In conclusion, these data indicate that a linear dose response describes the relationship between Cr(VI) and lung cancer reasonably well, and therefore these analyses do not necessarily support the threshold hypothesis for the lung carcinogenicity of Cr(VI). However, these results must be interpreted with recognition of the limitations of the use of epidemiological data in the evaluation of nonlinear exposure–response patterns