Reconstructing Thermal Properties of Firn at Summit, Greenland, from a Temperature Profile Time Series

We have constrained the value for thermal diffusivity of near-surface snow and firn at Summit Station, Greenland, using a Fourier-type analysis applied to hourly temperature measurements collected from eight thermistors in a closed-off, air-filled borehole between May 2004 and July 2008. An implicit, finite-difference method suggests that a bulk diffusivity of ∼25 ± 3m2 a−1 is the most reasonable for representing macroscale heat transport in the top 30 m of firn and snow. This value represents an average diffusivity and, in a conduction-only model, generates temperature series whose phase shifts with depth most closely match those of the Summit borehole data (rms difference between measurements and model output is ∼6 days). This bulk value, derived numerically and corroborated analytically, is useful over large tracts of the Greenland ice sheet where density and microstructure are unknown

Detecting supraglacial debris thickness with GPR under suboptimal conditions

The thickness of a supraglacial layer is critical to the magnitude and time frame of glacier melt. Field-based, short pulse, ground-penetrating radar (GPR) has successfully measured debris thickness during a glacier\u27s melt season, when there is a strong return from the ice-debris interface, but profiling with GPR in the absence of a highly reflective ice interface has not been explored. We investigated the performance of 960 MHz signals over 2 km of transects on Changri Nup Glacier, Nepal, during the post-monsoon. We also performed laboratory experiments to interpret the field data and investigate electromagnetic wave propagation into dry rocky debris. Laboratory tests confirmed wave penetration into the glacier ice and suggest that the ice-debris interface return was missing in field data because of a weak dielectric contrast between solid ice and porous dry debris. We developed a new method to estimate debris thicknesses by applying a statistical approach to volumetric backscatter, and our backscatter-based calculated thickness retrievals gave reasonable agreement with debris depths measured manually in the field (10-40 cm). We conclude that, when melt season profiling is not an option, a remote system near 1 GHz could allow dry debris thickness to be estimated based on volumetric backscatter

Unmet needs of Australians in endometriosis research : a qualitative study of research priorities, drivers, and barriers to participation in people with endometriosis

Background and Objectives: Endometriosis causes significant personal and societal burden. Despite this, research funding lags behind other chronic conditions. Determining where to prioritise these limited funds is therefore vital. Research priorities may also differ between individuals with endometriosis and clinicians/researchers. The aim of this research project is to explore research priorities and factors shaping participation in endometriosis research from the perspective of people with endometriosis in Australia. Materials and Methods: Four focus groups involving 30 people with endometriosis were conducted and analysed using qualitative inductive content analysis. Results: Two categories were developed from the data: unmet research needs and motivators and barriers to participation in endometriosis research. Participants expressed interest in developing non-invasive diagnostic tools and a more multidisciplinary or holistic approach to treatment. Participants urgently desired research on treatment options for symptom management, with many prioritising non-hormonal treatments, including medicinal cannabis and complementary medicine. Others prioritised research on the causes of endometriosis over research on treatments to assist with prevention and eventual cure of the disease. The main drivers for participating in endometriosis research were hope for symptom improvement and a reduction in time to diagnosis. Research design features that were important in supporting participation included ease of access to testing centres (e.g., for blood tests) and sharing test results and automated data collection reminders, with simple strategies to record data measurements. Research incentives for younger people with endometriosis and a broad dissemination of information about research projects was considered likely to increase participant numbers. Barriers included time commitments, a lack of flexibility around research appointments for data collection, travel or work commitments, concerns about the safety of some products, and trying to conceive a child. Conclusions: People with endometriosis were open to participating in research they felt aligned with their needs, with a significant focus on diagnostic tools and symptom relief. However, researchers must co-design approaches to ensure convenience and flexibility for research participation

Quantifying Patterns of Supraglacial Debris Thickness and Their Glaciological Controls in High Mountain Asia

Mapping patterns of supraglacial debris thickness and understanding their controls are important for quantifying the energy balance and melt of debris-covered glaciers and building process understanding into predictive models. Here, we find empirical relationships between measured debris thickness and satellite-derived surface temperature in the form of a rational curve and a linear relationship consistently outperform two different exponential relationships, for five glaciers in High Mountain Asia (HMA). Across these five glaciers, we demonstrate the covariance of velocity and elevation, and of slope and aspect using principal component analysis, and we show that the former two variables provide stronger predictors of debris thickness distribution than the latter two. Although the relationship between debris thickness and slope/aspect varies between glaciers, thicker debris occurs at lower elevations, where ice flow is slower, in the majority of cases. We also find the first empirical evidence for a statistical correlation between curvature and debris thickness, with thicker debris on concave slopes in some settings and convex slopes in others. Finally, debris thickness and surface temperature data are collated for the five glaciers, and supplemented with data from one more, to produce an empirical relationship, which we apply to all glaciers across the entire HMA region. This rational curve: 1) for the six glaciers studied has a similar accuracy to but greater precision than that of an exponential relationship widely quoted in the literature; and 2) produces qualitatively similar debris thickness distributions to those that exist in the literature for three other glaciers. Despite the encouraging results, they should be treated with caution given our relationship is extrapolated using data from only six glaciers and validated only qualitatively. More (freely available) data on debris thickness distribution of HMA glaciers are required

Wasp controls oriented migration of endothelial cells to achieve functional vascular patterning

Endothelial cell migration and proliferation are essential for the establishment of a hierarchical organization of blood vessels and optimal distribution of blood. However, how these cellular processes are coordinated remains unknown. Here, using the zebrafish trunk vasculature we show that in future veins endothelial cells proliferate more than in future arteries and migrate preferentially towards neighboring arteries. In future arteries endothelial cells show a biphasic migration profile. During sprouting cells move away from the dorsal aorta, during remodelling cells stop or move towards the feeding aorta. The final morphology of blood vessels is thus established by local proliferation and oriented cell migration to and from neighboring vessels. Additionally, we identify WASp to be essential for this differential migration. Loss of WASp leads to irregular distribution of endothelial cells, substantially enlarged veins and persistent arteriovenous shunting. Mechanistically, we report that WASp drives the assembly of junctional associated actin filaments and is required for junctional expression of PECAM-1. Together, our data identify that functional vascular patterning in the zebrafish trunk utilizes differential cell movement regulated by junctional actin, and that interruption of differential migration may represent a pathomechanism in vascular malformations

Targeting Extracellular Domains D4 and D7 of Vascular Endothelial Growth Factor Receptor 2 Reveals Allosteric Receptor Regulatory Sites

Vascular endothelial growth factors (VEGFs) activate three receptor tyrosine kinases, VEGFR-1, -2, and -3, which regulate angiogenic and lymphangiogenic signaling. VEGFR-2 is the most prominent receptor in angiogenic signaling by VEGF ligands. The extracellular part of VEGF receptors consists of seven immunoglobulin homology domains (Ig domains). Earlier studies showed that domains 2 and 3 (D23) mediate ligand binding, while structural analysis of dimeric ligand/receptor complexes by electron microscopy and small-angle solution scattering revealed additional homotypic contacts in membrane-proximal Ig domains D4 and D7. Here we show that D4 and D7 are indispensable for receptor signaling. To confirm the essential role of these domains in signaling, we isolated VEGFR-2-inhibitory “designed ankyrin repeat proteins” (DARPins) that interact with D23, D4, or D7. DARPins that interact with D23 inhibited ligand binding, receptor dimerization, and receptor kinase activation, while DARPins specific for D4 or D7 did not prevent ligand binding or receptor dimerization but effectively blocked receptor signaling and functional output. These data show that D4 and D7 allosterically regulate VEGFR-2 activity. We propose that these extracellular-domain-specific DARPins represent a novel generation of receptor-inhibitory drugs for in vivo applications such as targeting of VEGFRs in medical diagnostics and for treating vascular pathologies

Determinants of female sexual function in inflammatory bowel disease: a survey based cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Sexual function is impaired in women with inflammatory bowel disease (IBD) as compared to normal controls. We examined disease specific determinants of different aspects of low sexual function.</p> <p>Methods</p> <p>Women with IBD aged 18 to 65 presenting to the university departments of internal medicine and surgery were included. In addition, a random sample from the national patients organization was used (separate analyses). Sexual function was assessed by the Brief Index of Sexual Function in Women, comprising seven different domains of sexuality. Function was considered impaired if subscores were < -1 on a z-normalized scale. Results are presented as age adjusted odds ratios with 95% CI based on multiple logistic regression.</p> <p>Results</p> <p>336 questionnaires were included (219 Crohn's disease, 117 ulcerative colitis). Most women reported low sexual activity (63%; 17% none at all, 20% moderate or high activity). Partnership satisfaction was high in spite of low sexual interest in this group. Depressed mood was the strongest predictor of low sexual function scores in all domains. Urban residency and higher socioecomic status had a protective effect. Disease activity was moderately associated with low desire (OR 1.8, 95% CI 1.0 to 3.2). Severity of the disease course impacted most on intercourse frequency (OR 2.3, 95% CI 1.4 to 4.7). Lubrication problems were more common in smokers (OR 2.5, 95% CI 1.3 to 5.1).</p> <p>Conclusion</p> <p>Mood disturbances and social environment impacted more on sexual function in women with IBD than disease specific factors. Smoking is associated with lubrication problems.</p

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Generation and functional characterization of specific receptor inhibitors based on an analysis of the VEGFR-2 activation mechanism

Angiogenesis, the formation of new blood vessels from preexisting vasculature, mainly occurs during embryonic development. In the adult it takes place in the female reproductive system and during wound healing. Unregulated angiogenesis is associated with various diseases such as atherosclerosis, retinopathies, lymphoproliferative or rheumatoid disease, and cancer. Tumor neovascularization enables cancer cells to enter the blood circulation and to metastasize to other organs and is a hallmark of many types of cancer. Vascular Endothelial Growth Factors (VEGFs) constitute a family of proteins that play an important role in blood and lymphatic vessel development. VEGFs interact with three type V receptor tyrosine kinases, VEGFR�1, �2, and �3 promoting endothelial cell survival, migration, proliferation, and differentiation. VEGFR-2 is the major mediator of angiogenic signaling in endothelial cells and its activity is regulated at multiple levels. Ligand binding to the extracellular domain (ECD) of VEGFR-2 leads to receptor dimerization followed by activation of the intracellular kinase domain and downstream signaling. However, at present the specific structural changes in the ECD and the exact molecular mechanisms underlying kinase activation are only partially understood. In this study, we investigated the role of ECD Immunoglobulin (Ig)�homology domains D4 and D7 in receptor dimerization and activation. We expressed a series of receptor ECD mutants in tissue culture cells and determined receptor activation. Mutation or deletion of D4 or D7 drastically reduced receptor activation. We interpret these data as the demonstration that Ig�homology domains 4 and 7 are required for correctly aligning receptor monomers in active dimers and are thus indispensable for kinase activation. Based on our insights into the activation mechanism of VEGFR�2, we generated two types of ECD binders, single chain Fvs (scFvs) and Designed Ankyrin Repeat Proteins (DARPins), specifically interacting with single Ig-homology domains. We tested these reagents for inhibition of ligand-stimulated receptor activation. We identified several DARPins interacting with D2-3 and thereby blocking ligand binding and receptor activation. Most interestingly, DARPins binding to D4 inhibited receptor activation without interfering with receptor dimerization and therefore behave as allosteric regulators of VEGFR-2. Furthermore, scFvs specifically binding to D7 were identified. These new reagents will be useful for in vivo studies aiming at vessel imaging or for inhibiting VEGFR�2. We furthermore characterized variations in the VEGFR-2 gene which might contribute to the phenotypic variability in tumor endothelial function and, consequently, may affect cancer progression and the susceptibility of tumors to VEGFR-2 inhibitors. VEGFR-2 genomic sequencing in three different ethnic groups led to the discovery of 120 genetic variants, single nucleotide polymorphisms (SNPs), of which 25 had not been previously reported. The functionality of the genetic variants was assessed by phosphorylation assays, mRNA and protein expression arrays, as well as by the measurement of microvessel density in non-small cell lung cancer (NSCLC) tumor samples. The correlations found may have important implications for understanding the molecular basis of genetic associations between VEGFR-2 variation and clinical phenotypes related to VEGFR-2 function. Finally, we were interested in the influence of extracellular matrix components on VEGF�induced angiogenesis. In vivo, endothelial cells are exposed to concentration gradients of soluble growth factors and matrix immobilized guidance cues. To better mimic the complexity of angiogenic tissues in vitro, we generated micropatterned coverslips derivatized with VEGF for the cultivation of endothelial cells and the monitoring of their migration. Immobilized VEGF was shown to be biologically active and endothelial cells migrated and adhered to the patterned surfaces. The micropatterned coverslips present a robust and reproducible platform for the characterization of complex cellular behaviors generated by multiple VEGF isoforms