Skeletal myofiber VEGF deficiency leads to mitochondrial, structural and contractile alterations in mouse diaphragm

Diaphragm dysfunction accompanies cardiopulmonary disease and impaired oxygen delivery. Vascular endothelial growth factor (VEGF) regulates oxygen delivery through angiogenesis, capillary maintenance, and contraction-induced perfusion. We hypothesized that myofiber-specific VEGF deficiency contributes to diaphragm weakness and fatigability. Diaphragm protein expression, capillarity and fiber morphology, mitochondrial respiration and hydrogen peroxide (H2O2) generation, and contractile function were compared between adult mice with conditional gene ablation of skeletal myofiber VEGF (SkmVEGF-/-; n=12) and littermate controls (n=13). Diaphragm VEGF protein was ~50 % lower in SkmVEGF-/- than littermate controls (1.45±0.65 vs. 3.04±1.41 pg/total protein; P=0.001). This was accompanied by an ~15% impairment in maximal isometric specific force (F[1,23] = 15.01, P=0.001) and a trend for improved fatigue resistance (P=0.053). Mean fiber cross-sectional area and type I fiber cross-sectional area were lower in SkmVEGF-/- by ~40 % and ~25% (P0.05). However mitochondrial-derived reactive oxygen species (ROS) flux was lower in SkmVEGF-/- (P=0.0003). In conclusion, myofiber-specific VEGF gene deletion resulted in a lower capillary-to-fiber ratio, type I fiber atrophy, actin loss, and contractile dysfunction in the diaphragm. In contrast, mitochondrial respiratory function was preserved alongside lower ROS generation, which may play a compensatory role to preserve fatigue resistance in the diaphragm

Scratching Beneath the Surface : Intentionality in Great Ape Signal production

Despite important similarities having been found between human and animal communication systems, surprisingly little research effort has focussed on whether the cognitive mechanisms underpinning these behaviours are also similar. In particular, it is highly debated whether signal production is the result of reflexive processes, or can be characterised as intentional. Here, we critically evaluate the criteria that are used to identify signals produced with different degrees of intentionality, and discuss recent attempts to apply these criteria to the vocal, gestural, and multimodal communicative signals of great apes and more distantly related species. Finally, we outline the necessary research tools, such as physiologically validated measures of arousal, and empirical evidence that we believe would propel this debate forward and help unravel the evolutionary origins of human intentional communication

Cardiovascular magnetic resonance of pulmonary artery growth and ventricular function after Norwood procedure with Sano modification

For hypoplastic left heart syndrome (HLHS), there have been concerns regarding pulmonary artery growth and ventricular dysfunction after first stage surgery consisting of the Norwood procedure modified with a right ventricle-to-pulmonary artery conduit. We report our experience using cardiovascular magnetic resonance (CMR) to determine and follow pulmonary arterial growth and ventricular function in this cohort

Transcriptional activation of endothelial cells by TGFβ coincides with acute microvascular plasticity following focal spinal cord ischaemia/reperfusion injury

Microvascular dysfunction, loss of vascular support, ischaemia and sub-acute vascular instability in surviving blood vessels contribute to secondary injury following SCI (spinal cord injury). Neither the precise temporal profile of the cellular dynamics of spinal microvasculature nor the potential molecular effectors regulating this plasticity are well understood. TGFβ (transforming growth factor β) isoforms have been shown to be rapidly increased in response to SCI and CNS (central nervous system) ischaemia, but no data exist regarding their contribution to microvascular dysfunction following SCI. To examine these issues, in the present study we used a model of focal spinal cord ischaemia/reperfusion SCI to examine the cellular response(s) of affected microvessels from 30 min to 14 days post-ischaemia. Spinal endothelial cells were isolated from affected tissue and subjected to focused microarray analysis of TGFβ-responsive/related mRNAs 6 and 24 h post-SCI. Immunohistochemical analyses of histopathology show neuronal disruption/loss and astroglial regression from spinal microvessels by 3 h post-ischaemia, with complete dissolution of functional endfeet (loss of aquaporin-4) by 12 h post-ischaemia. Coincident with this microvascular plasticity, results from microarray analyses show 9 out of 22 TGFβ-responsive mRNAs significantly up-regulated by 6 h post-ischaemia. Of these, serpine 1/PAI-1 (plasminogen-activator inhibitor 1) demonstrated the greatest increase (>40-fold). Furthermore, uPA (urokinase-type plasminogen activator), another member of the PAS (plasminogen activator system), was also significantly increased (>7.5-fold). These results, along with other select up-regulated mRNAs, were confirmed biochemically or immunohistochemically. Taken together, these results implicate TGFβ as a potential molecular effector of the anatomical and functional plasticity of microvessels following SCI

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

A Profile Likelihood Analysis of the Constrained MSSM with Genetic Algorithms

The Constrained Minimal Supersymmetric Standard Model (CMSSM) is one of the simplest and most widely-studied supersymmetric extensions to the standard model of particle physics. Nevertheless, current data do not sufficiently constrain the model parameters in a way completely independent of priors, statistical measures and scanning techniques. We present a new technique for scanning supersymmetric parameter spaces, optimised for frequentist profile likelihood analyses and based on Genetic Algorithms. We apply this technique to the CMSSM, taking into account existing collider and cosmological data in our global fit. We compare our method to the MultiNest algorithm, an efficient Bayesian technique, paying particular attention to the best-fit points and implications for particle masses at the LHC and dark matter searches. Our global best-fit point lies in the focus point region. We find many high-likelihood points in both the stau co-annihilation and focus point regions, including a previously neglected section of the co-annihilation region at large m_0. We show that there are many high-likelihood points in the CMSSM parameter space commonly missed by existing scanning techniques, especially at high masses. This has a significant influence on the derived confidence regions for parameters and observables, and can dramatically change the entire statistical inference of such scans.Comment: 47 pages, 8 figures; Fig. 8, Table 7 and more discussions added to Sec. 3.4.2 in response to referee's comments; accepted for publication in JHE