Reduced Sympathetic Innervation Underlies Adjacent Noninfarcted Region Dysfunction During Left Ventricular Remodeling

AbstractObjectives. We examined the association of sympathetic denervation and reduced blood flow with mechanical dysfunction in adjacent noninfarcted regions late after myocardial infarction (MI).Background. Using a well characterized ovine model of left ventricular (LV) remodeling after transmural anteroapical MI, we previously showed that histologically normal adjacent noninfarcted regions demonstrate mechanical dysfunction.Methods. Ten sheep underwent coronary ligation. Magnetic resonance imaging was performed before and 8 weeks after infarction for measurement of LV mass, volumes, ejection fraction and regional intramyocardial circumferential shortening (%S). Iodine-123 metaiodobenzylguanidine (I-123 MIBG) and fluorescent microspheres before and after administration of adenosine were infused before death for measurement of sympathetic innervation, blood flow and blood flow reserve from matched postmortem regions.Results. From baseline to 8 weeks after infarction, LV end-diastolic volume increased from (mean ± SD) 1.5 ± 0.3 to 2.6 ± 0.5 ml/kg (p < 0.001), and LV mass increased from 2.0 ± 0.3 to 2.6 ± 0.5 g/kg (p = 0.001). Regionally, the decline in subendocardial %S was greater in adjacent (19 ± 5% to 8 ± 5%) than in remote noninfarcted regions (20 ± 6% to 19 ± 6%, p < 0.002). No difference in regional blood flow or blood flow reserve was found between adjacent and remote regions, whereas I-123 MIBG uptake was lower in adjacent than in remote myocardium (1.09 ± 0.30 vs. 1.31 ± 0.40 nmol/g, p < 0.003). Topographically, from apex to base at 8 weeks after infarction, %S correlated closely with I-123 MIBG uptake (r = 0.93, p = 0.003).Conclusions. In mechanically dysfunctional noninfarcted regions adjacent to chronic transmural myocardial infarction in the remodeled left ventricle, blood flow and blood flow reserve are preserved, yet sympathetic innervation is reduced. Chronic sympathetic denervation in adjacent noninfarcted regions, in association with regional mechanical dysfunction, may contribute to LV remodeling after infarction

Decoding Polo-like kinase 1 signaling along the kinetochore–centromere axis

Protein kinase signaling along the kinetochore-centromere axis is crucial to assure mitotic fidelity, yet its spatial coordination is obscure. Here, we examined how pools of human Polo-like kinase 1 (Plk1) within this axis control signaling events to elicit mitotic functions. To do this, we restricted active Plk1 to discrete subcompartments within the kinetochore-centromere axis using chemical genetics and decoded functional and phosphoproteomic signatures of each. We observe distinct phosphoproteomic and functional roles, suggesting that Plk1 exists and functions in discrete pools along this axis. Deep within the centromere, Plk1 operates to assure proper chromosome alignment and segregation. Thus, Plk1 at the kinetochore is a conglomerate of an observable bulk pool coupled with additional functional pools below the threshold of microscopic detection/resolution. Although complex, this multiplicity of locales provides an opportunity to decouple functional and phosphoproteomic signatures for a comprehensive understanding of Plk1’s kinetochore functions

Premature differentiation of nephron progenitor cell and dysregulation of gene pathways critical to kidney development in a model of preterm birth

Preterm birth is a leading cause of neonatal morbidity. Survivors have a greater risk for kidney dysfunction and hypertension. Little is known about the molecular changes that occur in the kidney of individuals born preterm. Here, we demonstrate that mice delivered two days prior to full term gestation undergo premature cessation of nephrogenesis, resulting in a lower glomerular density. Kidneys from preterm and term groups exhibited differences in gene expression profiles at 20- and 27-days post-conception, including significant differences in the expression of fat-soluble vitamin-related genes. Kidneys of the preterm mice exhibited decreased proportions of endothelial cells and a lower expression of genes promoting angiogenesis compared to the term group. Kidneys from the preterm mice also had altered nephron progenitor subpopulations, early Six2 depletion, and altered Jag1 expression in the nephrogenic zone, consistent with premature differentiation of nephron progenitor cells. In conclusion, preterm birth alone was sufficient to shorten the duration of nephrogenesis and cause premature differentiation of nephron progenitor cells. These candidate genes and pathways may provide targets to improve kidney health in preterm infants

Blending of nanoscale and microscale in uniform large-area sculptured thin-film architectures

The combination of large thickness ($>3$ $\mu$m), large--area uniformity (75 mm diameter), high growth rate (up to 0.4 $\mu$m/min) in assemblies of complex--shaped nanowires on lithographically defined patterns has been achieved for the first time. The nanoscale and the microscale have thus been blended together in sculptured thin films with transverse architectures. SiO$_x$ ($x\approx 2$) nanowires were grown by electron--beam evaporation onto silicon substrates both with and without photoresist lines (1--D arrays) and checkerboard (2--D arrays) patterns. Atomic self--shadowing due to oblique--angle deposition enables the nanowires to grow continuously, to change direction abruptly, and to maintain constant cross--sectional diameter. The selective growth of nanowire assemblies on the top surfaces of both 1--D and 2--D arrays can be understood and predicted using simple geometrical shadowing equations.Comment: 17 pages, 9 figure

Complex WKB Analysis of a PT Symmetric Eigenvalue Problem

The spectra of a particular class of PT symmetric eigenvalue problems has previously been studied, and found to have an extremely rich structure. In this paper we present an explanation for these spectral properties in terms of quantisation conditions obtained from the complex WKB method. In particular, we consider the relation of the quantisation conditions to the reality and positivity properties of the eigenvalues. The methods are also used to examine further the pattern of eigenvalue degeneracies observed by Dorey et al. in [1,2].Comment: 22 pages, 13 figures. Added references, minor revision

Photon Pair Generation in Silicon Micro-Ring Resonator with Reverse Bias Enhancement

Photon sources are fundamental components for any quantum photonic technology. The ability to generate high count-rate and low-noise correlated photon pairs via spontaneous parametric down-conversion using bulk crystals has been the cornerstone of modern quantum optics. However, future practical quantum technologies will require a scalable integration approach, and waveguide-based photon sources with high-count rate and low-noise characteristics will be an essential part of chip-based quantum technologies. Here, we demonstrate photon pair generation through spontaneous four-wave mixing in a silicon micro-ring resonator, reporting a maximum coincidence-to-accidental (CAR) ratio of 602 (+-) 37, and a maximum photon pair generation rate of 123 MHz (+-) 11 KHz. To overcome free-carrier related performance degradations we have investigated reverse biased p-i-n structures, demonstrating an improvement in the pair generation rate by a factor of up to 2, with negligible impact on CAR.Comment: 5 pages, 3 figure

Vibrotactile pedals : provision of haptic feedback to support economical driving

The use of haptic feedback is currently an underused modality in the driving environment, especially with respect to vehicle manufacturers. This exploratory study evaluates the effects of a vibrotactile (or haptic) accelerator pedal on car driving performance and perceived workload using a driving simulator. A stimulus was triggered when the driver exceeded a 50% throttle threshold, past which is deemed excessive for economical driving. Results showed significant decreases in mean acceleration values, and maximum and excess throttle use when the haptic pedal was active as compared to a baseline condition. As well as the positive changes to driver behaviour, subjective workload decreased when driving with the haptic pedal as compared to when drivers were simply asked to drive economically. The literature suggests that the haptic processing channel offers a largely untapped resource in the driving environment, and could provide information without overloading the other attentional resource pools used in driving

VLT/XSHOOTER and Subaru/MOIRCS spectroscopy of HUDF.YD3: no evidence for Lyman emission at z = 8.55

We present spectroscopic observations with VLT/XSHOOTER and Subaru/MOIRCS of a relatively bright Y-band drop-out galaxy in the Hubble Ultra Deep Field (HUDF), first selected by Bunker et al., McLure et al. and Bouwens et al. to be a likely z ≈ 8–9 galaxy on the basis of its colours in the Hubble Space Telescope (HST) Advanced Camera for Surveys and Wide Field Camera 3 images. This galaxy, HUDF.YD3 (also known as UDFy-38135539), has been targetted for VLT/SINFONI integral field spectroscopy by Lehnert et al., who published a candidate Lyman α emission line at z = 8.55 from this source. In our independent spectroscopy using two different infrared spectrographs (5 h with VLT/XSHOOTER and 11 h with Subaru/MOIRCS), we are unable to reproduce this line. We do not detect any emission line at the spectral and spatial location reported in Lehnert et al., despite the expected signal in our combined MOIRCS and XSHOOTER data being 5σ. The line emission also seems to be ruled out by the faintness of this object in recently extremely deep F105W (Y band) HST/WFC 3 imaging from HUDF12; the line would fall within this filter and such a galaxy should have been detected at YAB = 28.6 mag (∼20σ) rather than the marginal YAB ≈ 30 mag observed in the Y-band image, >3 times fainter than would be expected if the emission line was real. Hence, it appears highly unlikely that the reported Lyman α line emission at z > 8 is real, meaning that the highest redshift sources for which Lyman α emission has been seen are at z = 6.9-7.2. It is conceivable that Lyman α does not escape galaxies at higher redshifts, where the Gunn–Peterson absorption renders the Universe optically thick to this line. However, deeper spectroscopy on a larger sample of candidate z > 7 galaxies will be needed to test this

Deficiency and Also Transgenic Overexpression of Timp-3 Both Lead to Compromised Bone Mass and Architecture In Vivo

Tissue inhibitor of metalloproteinases-3 (TIMP-3) regulates extracellular matrix via its inhibition of matrix metalloproteinases and membrane-bound sheddases. Timp-3 is expressed at multiple sites of extensive tissue remodelling. This extends to bone where its role, however, remains largely unresolved. In this study, we have used Micro-CT to assess bone mass and architecture, histological and histochemical evaluation to characterise the skeletal phenotype of Timp-3 KO mice and have complemented this by also examining similar indices in mice harbouring a Timp-3 transgene driven via a Col-2a-driven promoter to specifically target overexpression to chondrocytes. Our data show that Timp-3 deficiency compromises tibial bone mass and structure in both cortical and trabecular compartments, with corresponding increases in osteoclasts. Transgenic overexpression also generates defects in tibial structure predominantly in the cortical bone along the entire shaft without significant increases in osteoclasts. These alterations in cortical mass significantly compromise predicted tibial load-bearing resistance to torsion in both genotypes. Neither Timp-3 KO nor transgenic mouse growth plates are significantly affected. The impact of Timp-3 deficiency and of transgenic overexpression extends to produce modification in craniofacial bones of both endochondral and intramembranous origins. These data indicate that the levels of Timp-3 are crucial in the attainment of functionally-appropriate bone mass and architecture and that this arises from chondrogenic and osteogenic lineages