A unifying probabilistic framework for analyzing residual dipolar couplings

Residual dipolar couplings provide complementary information to the nuclear Overhauser effect measurements that are traditionally used in biomolecular structure determination by NMR. In a de novo structure determination, however, lack of knowledge about the degree and orientation of molecular alignment complicates the analysis of dipolar coupling data. We present a probabilistic framework for analyzing residual dipolar couplings and demonstrate that it is possible to estimate the atomic coordinates, the complete molecular alignment tensor, and the error of the couplings simultaneously. As a by-product, we also obtain estimates of the uncertainty in the coordinates and the alignment tensor. We show that our approach encompasses existing methods for determining the alignment tensor as special cases, including least squares estimation, histogram fitting, and elimination of an explicit alignment tensor in the restraint energy

Parallel Tempering: Theory, Applications, and New Perspectives

We review the history of the parallel tempering simulation method. From its origins in data analysis, the parallel tempering method has become a standard workhorse of physiochemical simulations. We discuss the theory behind the method and its various generalizations. We mention a selected set of the many applications that have become possible with the introduction of parallel tempering and we suggest several promising avenues for future research.Comment: 21 pages, 4 figure

The “Ets” Factor: Vessel Formation in Zebrafish—The Missing Link?

The zebrafish offers a powerful model for studying the development of new blood vessels

Baroreflex sensitivity differs among same strain Wistar rats from the same laboratory

Previous studies showed that a proportion of normotensive Sprague-Dawley rats spontaneously exhibit lower baroreflex sensitivity. However, investigations have not yet been carried out on Wistar rats. We aimed to compare baroreflex sensitivity among rats from the same strain and the same laboratory. Male Wistar normotensive rats (300–400g) were studied. Cannulas were inserted into the abdominal aortic artery through the right femoral artery to measure mean arterial pressure and heart rate. Baroreflex was calculated as the derivative of the variation of heart rate in function of the mean arterial pressure variation (ΔHR/ΔMAP) tested with a depressor dose of sodium nitroprusside (50 µg/kg) and with a pressor dose of phenylephrine (8µg/kg) in the right femoral venous approach through an inserted cannula. We divided the rats into four groups: i) high bradycardic baroreflex, baroreflex gain less than −2 tested with phenylephrine; ii) low bradycardic baroreflex, baroreflex gain between −1 and −2 tested with phenylephrine; iii) high tachycardic baroreflex, baroreflex gain less than −3 tested with sodium nitroprusside; and iv) low tachycardic baroreflex, baroreflex gain between −1 and −3 tested with sodium nitroprusside. Approximately 71% of the rats presented a decrease in bradycardic reflex while around half showed an increase in tachycardic reflex. No significant changes in basal mean arterial pressure and heart rate, tachycardic and bradycardic peak and heart rate range were observed. There was a significant change in baroreflex sensitivity among rats from the same strain and the same laboratory

Hedgehog signaling via a calcitonin receptor-like receptor can induce arterial differentiation independently of VEGF signaling in zebrafish

Multiple signaling pathways control the specification of endothelial cells (ECs) to become arteries or veins during vertebrate embryogenesis. Current models propose that a cascade of Hedgehog (Hh), vascular endothelial growth factor (VEGF), and Notch signaling acts instructively on ECs to control the choice between arterial or venous fate. Differences in the phenotypes induced by Hh, VEGF, or Notch inhibition suggest that not all of the effects of Hh on arteriovenous specification are mediated by VEGF. We establish that full derepression of the Hh pathway in ptc1;ptc2 mutants converts the posterior cardinal vein into a second arterial vessel that manifests intact arterial gene expression, intersegmental vessel sprouting, and HSC gene expression. Importantly, although VEGF was thought to be absolutely essential for arterial fates, we find that normal and ectopic arterial differentiation can occur without VEGF signaling in ptc1;ptc2 mutants. Furthermore, Hh is able to bypass VEGF to induce arterial differentiation in ECs via the calcitonin receptor-like receptor, thus revealing a surprising complexity in the interplay between Hh and VEGF signaling during arteriovenous specification. Finally, our experiments establish a dual function of Hh during induction of runx1+ HSCs

Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal aging, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state-fMRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: First, we included 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls. Second, we included 156 amyloid-PET positive subjects across the spectrum of sporadic Alzheimer's disease as well as 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal-lobe tau-PET (i.e. composite across Braak stage I & III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher fMRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (p = 0.007). Similarly, for sporadic Alzheimer's disease patients, higher fMRI-assessed system segregation was associated with less decrement in global cognition (p = 0.001) and episodic memory (p = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease

The bounds of education in the human brain connectome

Inter-individual heterogeneity is evident in aging; education level is known to contribute for this heterogeneity. Using a cross-sectional study design and network inference applied to resting-state fMRI data, we show that aging was associated with decreased functional connectivity in a large cortical network. On the other hand, education level, as measured by years of formal education, produced an opposite effect on the long-term. These results demonstrate the increased brain efficiency in individuals with higher education level that may mitigate the impact of age on brain functional connectivity.This work was funded by the European Commission (FP7): “SwitchBox” (Contract HEALTH-F2-2010-259772) and co-financed by the Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). José M. Soares, Paulo Marques, and Nadine C. Santos are supported by fellowships of the project “SwitchBox”; Ricardo Magalhães is supported by a fellowship from the project FCT ANR/NEU-OSD/0258/2012 funded by FCT/MEC (www.fct.pt) and by ON.2 – ONOVONORTE – North Portugal Regional Operational Programme 2007/2013, of the National Strategic Reference Framework (NSRF) 2007/2013, through FEDER

“Frozen-Ground Cartoons”: Permafrost comics as an innovative tool for polar outreach, education, and engagement

Permafrost occupies 20 million square kilometres of Earth’s high-latitude and high-altitude landscapes. These regions are sensitive to climate change and human activities; hence, permafrost research is of considerable scientific and societal importance. However, the results of this research are generally not known by the general public. Communicating scientific concepts is an increasingly important task in the research world. Different ways to engage learners and incorporate narratives in teaching materials exist, yet they are generally underused. Here we report on an international scientific outreach project called “Frozen-Ground Cartoons”, which aims at making permafrost science accessible and fun for students, teachers, and parents through the creation of comic strips.We present the context in which the project was initiated, as well as recent education and outreach activities. The future phases of the project primarily involve a series of augmented reality materials, such as maps, photos, videos, and 3D drawings. With this project we aim to foster understanding of permafrost research among broader audiences, inspire future permafrost researchers, and raise public and science community awareness of polar science, education, outreach, and engagement