Alpha1 -adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries.

We have systematically investigated how vascular smooth muscle α1 -adrenoceptor activation impacts endothelium-mediated vasodilation in isolated, myogenically active, rat cremaster muscle 1A arteries. Cannulated cremaster arteries were pressurized intraluminally to 70 mmHg to induce myogenic tone, and exposed to vasoactive agents via bath superfusion at 34°C. Smooth muscle membrane potential was measured via sharp microelectrode recordings in pressurized, myogenic arteries. The α1 -adrenergic agonist phenylephrine (25-100 nmol/L) produced further constriction of myogenic arteries, but did not alter the vasorelaxant responses to acetylcholine (0.3 μmol/L), SKA-31 (an activator of endothelial Ca2+ -dependent K+ channels) (3 μmol/L) or sodium nitroprusside (10 μmol/L). Exposure to 0.25-1 μmol/L phenylephrine or 1 μmol/L norepinephrine generated more robust constrictions, and also enhanced the vasodilations evoked by acetylcholine and SKA-31, but not by sodium nitroprusside. In contrast, the thromboxane receptor agonist U46619 (250 nmol/L) dampened responses to all three vasodilators. Phenylephrine exposure depolarized myogenic arteries, and mimicking this effect with 4-aminopyridine (1 mmol/L) was sufficient to augment the SKA-31-evoked vasodilation. Inhibition of L-type Ca2+ channels by 1 μmol/L nifedipine decreased myogenic tone, phenylephrine-induced constriction and prevented α1 -adrenergic enhancement of endothelium-evoked vasodilation; these latter deficits were overcome by exposure to 3 and 10 μmol/L phenylephrine. Mechanistically, augmentation of ACh-evoked dilation by phenylephrine was dampened by eNOS inhibition and abolished by blockade of endothelial KCa channels. Collectively, these data suggest that increasing α1 -adrenoceptor activation beyond a threshold level augments endothelium-evoked vasodilation, likely by triggering transcellular signaling between smooth muscle and the endothelium. Physiologically, this negative feedback process may serve as a "brake" to limit the extent of vasoconstriction in the skeletal microcirculation evoked by the elevated sympathetic tone

Highly Ionized High-Velocity Clouds toward PKS 2155-304 and Markarian 509

To gain insight into four highly ionized high-velocity clouds (HVCs) discovered by Sembach et al. (1999), we have analyzed data from the Hubble Space Telescope (HST) and Far Ultraviolet Spectroscopic Explorer (FUSE) for the PKS 2155-304 and Mrk 509 sight lines. We measure strong absorption in OVI and column densities of multiple ionization stages of silicon (SiII/III/IV) and carbon (CII/III/IV). We interpret this ionization pattern as a multiphase medium that contains both collisionally ionized and photoionized gas. Toward PKS 2155-304, for HVCs at -140 and -270 km/s, respectively, we measure logN(OVI)=13.80+/-0.03 and log N(OVI)=13.56+/-0.06; from Lyman series absorption, we find log N(HI)=16.37^(+0.22)_(-0.14) and 15.23^(+0.38)_(-0.22). The presence of high-velocity OVI spread over a broad (100 km/s) profile, together with large amounts of low-ionization species, is difficult to reconcile with the low densities, n=5x10^(-6) cm^(-3), in the collisional/photoionization models of Nicastro et al. (2002), although the HVCs show a similar relation in N(SiIV)/N(CIV) versus N(CII)/N(CIV) as high-z intergalactic clouds. Our results suggest that the high-velocity OVI in these absorbers do not necessarily trace the WHIM, but instead may trace HVCs with low total hydrogen column density. We propose that the broad high-velocity OVI absorption arises from shock ionization, at bowshock interfaces produced from infalling clumps of gas with velocity shear. The similar ratios of high ions for HVC Complex C and these highly ionized HVCs suggest a common production mechanism in the Galactic halo.Comment: 38 pages, including 10 figures. ApJ, 10 April, 2004. Replaced with accepted versio

The B-L/Electroweak Hierarchy in Heterotic String and M-Theory

E8 x E8 heterotic string and M-theory, when compactified on a Calabi-Yau threefold admitting an SU(4) vector bundle with Wilson lines, can give rise to the exact MSSM spectrum with three right-handed neutrino chiral superields, one per family. Rank preserving Wilson lines require that the standard model group be augmented by a gauged U(1)_B-L. Since there are no fields in this theory for which 3(B-L) is an even, non-zero integer, the gauged B-L symmetry must be spontaneously broken at a low scale, not too far above the electroweak scale. It is shown that in these heterotic standard models, the B-L symmetry can be broken, with a phenomenologically viable B-L/electroweak hierarchy, by at least one right-handed sneutrino acquiring a vacuum expectation value. This is explicitly demonstrated, in a specific region of parameter space, using a renormalization group analysis and soft supersymmetry breaking operators. The vacuum state is shown to be a stable, local minimum of the potential and the resultant hierarchy is explicitly presented in terms of tan[beta].Comment: 16 pages; typos fixed, analysis generalize

Reproductive Success Across the Black-capped Chickadee (Poecile atricapillus) and Carolina Chickadee (P. carolinensis) Hybrid Zone in Ohio

Black-capped Chickadees (Poecile atricapillus) and Carolina Chickadees (P. carolinensis) hybridize in an east-west band from New Jersey to Kansas. Within the past century, the Ohio portion of this hybrid /one and the Carolina Chickadee range to the south have been moving northward, whereas the Black-capped Chickadee range has retracted. In Ohio, we characterized the genetic composition of the hybrid zone using five diagnostic molecular loci. Although there was no evidence of assortative mating in the center of the hybrid zone, we found a relative paucity of genetically intermediate breeding females as compared with breeding males. That suggests viability selection against female hybrids, in line with Haldane\u27s rule. On the basis of reproductive variables (number of nestlings, reproductive success), we found a decrease in productivity of breeding pairs in the hybrid zone that is significantly and positively related to their probability of producing homozygous offspring at each autosomal or sex-linked locus. We also found that the decrease in productivity was significantly and positively related to the genetic composition of the male of the pair {i.e. pure male chickadees more productive). These data strongly suggest that hybrids are at a selective disadvantage. Because the zone of reduced reproductive success was considerably narrower than the zone of introgression, our results demonstrate that genetic introgression is occurring in the face of substantial selection against hybrids

Weighted group algebras on groups of polynomial growth

Let G be a compactly generated group of polynomial growth and ! a weight function on G. For a large class of weights we characterize symmetry of the weighted group algebra (G; !). In particular, if the weight ! is sub-exponential, then the algebra L symmetric. For these weights we develop a functional calculus on a total part of L and use it to prove the Wiener property

Analysis of C4 and the C4 binding protein in the MRL/lpr mouse

Systemic lupus erythematosus is a complement-mediated autoimmune disease. While genetic deficiencies of classical pathway components lead to an increased risk of developing systemic lupus erythematosus, end organ damage is associated with complement activation and immune complex deposition. The role of classical pathway regulators in systemic lupus erythematosus is unknown. C4 binding protein (C4bp) is a major negative regulator of the classical pathway. In order to study the role of C4bp deficiency in an established murine model of lupus nephritis, mice with a targeted deletion in the gene encoding C4bp were backcrossed into the MRL/lpr genetic background. Compared with control MRL/lpr mice, C4bp knockout MLR/lpr mice had similar mortality and similar degrees of lymphoproliferation. There were no differences in the extent of proteinuria or renal inflammation. Staining for complement proteins and immunoglobulins in the kidneys of diseased mice revealed no significant strain differences. Moreover, there was no difference in autoantibody production or in levels of circulating immune complexes. In comparison with C57BL/6 mice, MRL/lpr mice had depressed C4 levels as early as 3 weeks of age. The absence of C4bp did not impact serum C4 levels or alter classical pathway hemolytic activity. Given that immune complex renal injury in the MRL/lpr mouse is independent of Fc receptors as well as the major negative regulator of the classical pathway, new mechanisms for immune-complex-mediated renal injury need to be considered

PAndAS in the mist: The stellar and gaseous mass within the halos of M31 and M33

Large scale surveys of the prominent members of the Local Group have provided compelling evidence for the hierarchical formation of massive galaxies, revealing a wealth of substructure that is thought to be the debris from ancient and on-going accretion events. In this paper, we compare two extant surveys of the M31-M33 subgroup of galaxies; the Pan-Andromeda Archaeological Survey (PAndAS) of the stellar structure, and a combination of observations of the HI gaseous content, detected at 21cm. Our key finding is a marked lack of spatial correlation between these two components on all scales, with only a few potential overlaps between stars and gas.The paucity of spatial correlation significantly restricts the analysis of kinematic correlations, although there does appear to the HI kinematically associated with the Giant Stellar Stream where it passes the disk of M31. These results demonstrate that that different processes must significantly influence the dynamical evolution of the stellar and HI components of substructures, such as ram pressure driving gas away from a purely gravitational path. Detailed modelling of the offset between the stellar and gaseous substructure will provide a determination of the properties of the gaseous halo of M31 and M33.Comment: 11 pages, 6 figures. Accepted for publication in the Astrophysical Journal. Figure quality reduced. High quality version available at http://www.physics.usyd.edu.au/~gfl/Arxiv_Papers/PAndAS_Mist

Opening the door to greater phylogeographic inference in Southeast Asia: Comparative genomic study of five codistributed rainforest bird species using target capture and historical DNA

Indochina and Sundaland are biologically diverse, interconnected regions of Southeast Asia with complex geographic histories. Few studies have examined phylogeography of bird species that span the two regions because of inadequate population sampling. To determine how geographic barriers/events and disparate dispersal potential have influenced the population structure, gene flow, and demographics of species that occupy the entire area, we studied five largely codistributed rainforest bird species: Arachnothera longirostra, Irena puella, Brachypodius atriceps, Niltava grandis, and Stachyris nigriceps. We accomplished relatively thorough sampling and data collection by sequencing ultraconserved elements (UCEs) using DNA extracted from modern and older (historical) specimens. We obtained a genome-wide set of 753–4,501 variable loci and 3,919–18,472 single nucleotide polymorphisms. The formation of major within-species lineages occurred within a similar span of time (0.5–1.5 mya). Major patterns in population genetic structure are largely consistent with the dispersal potential and habitat requirements of the study species. A population break across the Isthmus of Kra was shared only by the two hill/submontane insectivores (N. grandis and S. nigriceps). Across Sundaland, there is little structure in B. atriceps, which is a eurytopic and partially frugivorous species that often utilizes forest edges. Two other eurytopic species, A. longirostra and I. puella, possess highly divergent populations in peripheral Sunda Islands (Java and/or Palawan) and India. These species probably possess intermediate dispersal abilities that allowed them to colonize new areas, and then remained largely isolated subsequently. We also observed an east–west break in Indochina that was shared by B. atriceps and S. nigriceps, species with very different habitat requirements and dispersal potential. By analyzing high-throughput DNA data, our study provides an unprecedented comparative perspective on the process of avian population divergence across Southeast Asia, a process that is determined by geography, species characteristics, and the stochastic nature of dispersal and vicariance events

Comparative analysis reveals a role for TGF-β in shaping the residency-related transcriptional signature in tissue-resident memory CD8+ T cells.

Tissue-resident CD8+ memory T (TRM) cells are immune cells that permanently reside at tissue sites where they play an important role in providing rapid protection against reinfection. They are not only phenotypically and functionally distinct from their circulating memory counterparts, but also exhibit a unique transcriptional profile. To date, the local tissue signals required for their development and long-term residency are not well understood. So far, the best-characterised tissue-derived signal is transforming growth factor-β (TGF-β), which has been shown to promote the development of these cells within tissues. In this study, we aimed to determine to what extent the transcriptional signatures of TRM cells from multiple tissues reflects TGF-β imprinting. We activated murine CD8+ T cells, stimulated them in vitro by TGF-β, and profiled their transcriptomes using RNA-seq. Upon comparison, we identified a TGF-β-induced signature of differentially expressed genes between TGF-β-stimulated and -unstimulated cells. Next, we linked this in vitro TGF-β-induced signature to a previously identified in vivo TRM-specific gene set and found considerable (>50%) overlap between the two gene sets, thus showing that a substantial part of the TRM signature can be attributed to TGF-β signalling. Finally, gene set enrichment analysis further revealed that the altered gene signature following TGF-β exposure reflected transcriptional signatures found in TRM cells from both epithelial and non-epithelial tissues. In summary, these findings show that TGF-β has a broad footprint in establishing the residency-specific transcriptional profile of TRM cells, which is detectable in TRM cells from diverse tissues. They further suggest that constitutive TGF-β signaling might be involved for their long-term persistence at tissue sites