A new model for molecule exchange in the brain microvascular system: consequences of capillary occlusions in Alzheimer's disease

The brain microvascular system is a key actor in Alzheimer’s disease (AD) development. Indeed, a significant decrease of cerebral blood flow is the earliest biomarker of AD. In vivo TPLSM of cortical vasculature in APP/PS1 mice suggests the mechanism underlying the blood flow reduction is capillary occlusions. Leucocytes adhere to inflamed vessel walls and limit the flow. The impact of capillary occlusions on blood flow has been quantified numerically in large (>10000 vessels) anatomical networks in humans and mice. The regional blood flow has been found to depend linearly with no threshold effect on the fraction of capillary occlusions, so that a small fraction of stalls (2-4%) yields a significant decrease in blood flow (5-12%). Such flow decrease has a strong impact on nutrient delivery and waste clearance. That is why we devised a new model to study the effect of capillary stalling on molecule transport. The geometry of anatomical networks is too complex to use classic numerical approaches like finite elements. Instead, our model, inspired by pore-network approaches, reduces computational costs while capturing most of the underlying physics. To derive this model, we apply upscaling methods to the 3D transport equations within each vessel to obtain 1D average equations along the axis. Contrary to previous models, this new formulation describes accurately radial concentration gradients, capturing effects like longitudinal dispersion. We further use a Green’s function formulation to calculate the concentration fields inside the tissue where diffusion and reaction occur. The coupling between vessels and tissues is modelled using a membrane condition representing the blood brain barrier. This new molecule transport model is coupled with our previously validated blood flow model to examine the effects of capillary stalling on molecular exchange in transient and stationary regimes in anatomical networks. In particular, in stationnary regimes, we demonstrate an increase of the extraction coefficient with the proportion of stalled capillaries, which does not compensate for the associated blood flow reduction

Inequality, Fiscal Capacity and the Political Regime: Lessons from the Post-Communist Transition

Using panel data for twenty-seven post-communist economies between 1987-2003, we examine the nexus of relationships between inequality, fiscal capacity (defined as the ability to raise taxes efficiently) and the political regime. Investigating the impact of political reform we find that full political freedom is associated with lower levels of income inequality. Under more oligarchic (authoritarian) regimes, the level of inequality is conditioned by the state’s fiscal capacity. Specifically, oligarchic regimes with more developed fiscal systems are able to defend the prevailing vested interests at a lower cost in terms of social injustice. This empirical finding is consistent with the model developed by Acemoglu (2006). We also find that transition countries undertaking early macroeconomic stabilisation now enjoy lower levels of inequality; we confirm that education fosters equality and the suggestion of Commander et al (1999) that larger countries are prone to higher levels of inequality.http://deepblue.lib.umich.edu/bitstream/2027.42/57211/1/wp831 .pd

Comparison of brain vasculature network characteristics between wild type and Alzheimer’s disease mice using topological metrics

There is a strong clinical correlation between Alzheimer’s disease (AD) and microvascular disorders. In mouse models of AD, our lab has found blood flow dysfunction in brain capillaries, suggesting the need to study the function of vascular networks at the capillary level. However, the ability to deliver blood flow continuously to all neurons also depends on connections between vessels, requiring that we also characterize the topology of brain vascular networks. Here, we use graph theory and topological metrics to characterize the connectivity of brain capillary networks in AD and control mice

Psychology as a natural science in the eighteenth century

Psychology considered as a natural science began as Aristotelian "physics" or "natural philosophy" of the soul. C. Wolff placed psychology under metaphysics, coordinate with cosmology. Scottish thinkers placed it within moral philosophy, but distinguished its "physical" laws from properly moral laws (for guiding conduct). Several Germans sought to establish an autonomous empirical psychology as a branch of natural science. British and French visual theorists developed mathematically precise theories of size and distance perception; they created instruments to test these theories and to measure visual phenomena such as the duration of visual impressions. These investigators typically were dualists who included mental phenomena within nature

Environmental Predictors of Seasonal Influenza Epidemics across Temperate and Tropical Climates

Human influenza infections exhibit a strong seasonal cycle in temperate regions. Recent laboratory and epidemiological evidence suggests that low specific humidity conditions facilitate the airborne survival and transmission of the influenza virus in temperate regions, resulting in annual winter epidemics. However, this relationship is unlikely to account for the epidemiology of influenza in tropical and subtropical regions where epidemics often occur during the rainy season or transmit year-round without a well-defined season. We assessed the role of specific humidity and other local climatic variables on influenza virus seasonality by modeling epidemiological and climatic information from 78 study sites sampled globally. We substantiated that there are two types of environmental conditions associated with seasonal influenza epidemics: “cold-dry” and “humid-rainy”. For sites where monthly average specific humidity or temperature decreases below thresholds of approximately 11–12 g/kg and 18–21°C during the year, influenza activity peaks during the cold-dry season (i.e., winter) when specific humidity and temperature are at minimal levels. For sites where specific humidity and temperature do not decrease below these thresholds, seasonal influenza activity is more likely to peak in months when average precipitation totals are maximal and greater than 150 mm per month. These findings provide a simple climate-based model rooted in empirical data that accounts for the diversity of seasonal influenza patterns observed across temperate, subtropical and tropical climates

Mild Sensory Stimulation Completely Protects the Adult Rodent Cortex from Ischemic Stroke

Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex, but only if administered within a critical time window. Animals that receive early treatment are histologically and behaviorally equivalent to healthy controls and have normal neuronal function. Protection of the cortex clearly requires reperfusion to the ischemic area despite permanent occlusion. Using blood flow imaging and other techniques we found evidence of reversed blood flow into MCA branches from an alternate arterial source via collateral vessels (inter-arterial connections), a potential mechanism for reperfusion. These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential

Deconvoluting Post-Transplant Immunity: Cell Subset-Specific Mapping Reveals Pathways for Activation and Expansion of Memory T, Monocytes and B Cells

A major challenge for the field of transplantation is the lack of understanding of genomic and molecular drivers of early post-transplant immunity. The early immune response creates a complex milieu that determines the course of ensuing immune events and the ultimate outcome of the transplant. The objective of the current study was to mechanistically deconvolute the early immune response by purifying and profiling the constituent cell subsets of the peripheral blood. We employed genome-wide profiling of whole blood and purified CD4, CD8, B cells and monocytes in tandem with high-throughput laser-scanning cytometry in 10 kidney transplants sampled serially pre-transplant, 1, 2, 4, 8 and 12 weeks. Cytometry confirmed early cell subset depletion by antibody induction and immunosuppression. Multiple markers revealed the activation and proliferative expansion of CD45RO+CD62L− effector memory CD4/CD8 T cells as well as progressive activation of monocytes and B cells. Next, we mechanistically deconvoluted early post-transplant immunity by serial monitoring of whole blood using DNA microarrays. Parallel analysis of cell subset-specific gene expression revealed a unique spectrum of time-dependent changes and functional pathways. Gene expression profiling results were validated with 157 different probesets matching all 65 antigens detected by cytometry. Thus, serial blood cell monitoring reflects the profound changes in blood cell composition and immune activation early post-transplant. Each cell subset reveals distinct pathways and functional programs. These changes illuminate a complex, early phase of immunity and inflammation that includes activation and proliferative expansion of the memory effector and regulatory cells that may determine the phenotype and outcome of the kidney transplant

Galaxy Clusters Discovered via the Sunyaev-Zel'dovich Effect in the First 720 Square Degrees of the South Pole Telescope Survey

We present a catalog of galaxy cluster candidates, selected through their Sunyaev-Zel'dovich (SZ) effect signature in the first 720 deg^2 of the South Pole Telescope (SPT) survey. This area was mapped with the SPT in the 2008 and 2009 austral winters to a depth of ~18 μK_(CMB)-arcmin at 150 GHz; 550 deg2 of it was also mapped to ~44 μK_(CMB)-arcmin at 95 GHz. Based on optical imaging of all 224 candidates and near-infrared imaging of the majority of candidates, we have found optical and/or infrared counterparts for 158, which we then classify as confirmed galaxy clusters. Of these 158 clusters, 135 were first identified as clusters in SPT data, including 117 new discoveries reported in this work. This catalog triples the number of confirmed galaxy clusters discovered through the SZ effect. We report photometrically derived (and in some cases spectroscopic) redshifts for confirmed clusters and redshift lower limits for the remaining candidates. The catalog extends to high redshift with a median redshift of z = 0.55 and maximum confirmed redshift of z = 1.37. Forty-five of the clusters have counterparts in the ROSAT bright or faint source catalogs from which we estimate X-ray fluxes. Based on simulations, we expect the catalog to be nearly 100% complete above M_(500) ≈ 5 × 10^(14) M_☉ h^(–1) 70 at z ≳0.6. There are 121 candidates detected at signal-to-noise ratio greater than five, at which the catalog purity is measured to be 95%. From this high-purity subsample, we exclude the z < 0.3 clusters and use the remaining 100 candidates to improve cosmological constraints following the method presented by Benson et al. Adding the cluster data to CMB + BAO + H_0 data leads to a preference for non-zero neutrino masses while only slightly reducing the upper limit on the sum of neutrino masses to ∑m_ν < 0.38 eV (95% CL). For a spatially flat wCDM cosmological model, the addition of this catalog to the CMB + BAO + H_0 + SNe results yields σ_8 = 0.807 ± 0.027 and w = –1.010 ± 0.058, improving the constraints on these parameters by a factor of 1.4 and 1.3, respectively. The larger cluster catalog presented in this work leads to slight improvements in cosmological constraints from those presented by Benson et al. These cosmological constraints are currently limited by uncertainty in the cluster mass calibration, not the size or quality of the cluster catalog. A multi-wavelength observation program to improve the cluster mass calibration will make it possible to realize the full potential of the final 2500 deg^2 SPT cluster catalog to constrain cosmology