The rockefeller university

Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII)-initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.

The mechanisms by which early chronic low-level lead (Pb) exposure disrupts the developing brain are not yet understood. Rodent models have provided promising results however behavioral tests sensitive to effects at lowest levels of exposure during development are needed. Preadolescent animals (N = 52) exposed to low and higher levels of Pb via lactation from birth to PND 28 completed the Object-in-Place Task of visual spatial and visual object memory retrieval (at PND 28). Generalized linear mixed models were used, controlling for sex and litter as a random effect. As compared with controls, global vertical exploratory behavior (rearing) markedly increased during memory retrieval. The findings suggested that early chronic Pb exposure altered the development of critical exploratory functions needed for learning and survival. Behaviors exhibited in novel spatial and novel object zone perimeters suggested that the Object-in-Place task is a valid measure of visual spatial and visual object memory in pre-adolescent C57BL/6J mice. Additional studies are needed to understand how early chronic low-level lead exposure disrupts the trajectory and possible linkages of critical exploratory and perceptual systems during development. (C) 2017 Elsevier Inc. All rights reserved.

The bulk of studies of coupled oscillators use, as is appropriate in Physics, a global coupling constant controlling all individual interactions. However, because as the coupling is increased, the number of relevant degrees of freedom also increases, this setting conflates the strength of the coupling with the effective dimensionality of the resulting dynamics. We propose a coupling more appropriate to neural circuitry, where synaptic strengths are under biological, activity-dependent control and where the coupling strength and the dimensionality can be controlled separately. Here we study a set of N -> infinity strongly- and nonsymmetrically-coupled, dissipative, powered, rotational dynamical systems, and derive the equations of motion of the reduced system for dimensions 2 and 4. Our setting highlights the statistical structure of the eigenvectors of the connectivity matrix as the fundamental determinant of collective behavior, inheriting from this structure symmetries and singularities absent from the original microscopic dynamics.

Meso-scale turbulence is an innate phenomenon, distinct from inertial turbulence, that spontaneously occurs at low Reynolds number in fluidized biological systems. This spatiotemporal disordered flow radically changes nutrient and molecular transport in living fluids and can strongly affect the collective behaviour in prominent biological processes, including biofilm formation, morphogenesis and cancer invasion. Despite its crucial role in such physiological processes, understanding meso-scale turbulence and any relation to classical inertial turbulence remains obscure. Here we show how the motion of active matter along a micro-channel transitions to meso-scale turbulence through the evolution of locally disordered patches (active puffs) from an ordered vortex-lattice flow state. We demonstrate that the stationary critical exponents of this transition to meso-scale turbulence in a channel coincide with the directed percolation universality class. This finding bridges our understanding of the onset of low-Reynolds-number meso-scale turbulence and traditional scale-invariant turbulence in confinement.

The cell wall of Gram-positive bacteria contains abundant surface-exposed carbohydrate molecules that are highly conserved within and often across species. The potential therapeutic usefulness of high-affinity antibodies to cell wall carbohydrates is unquestioned, however obtaining such antibodies is challenging due to the poor overall immunogenicity of these bacterial targets. Autolysins and phage lysins are peptidoglycan hydrolases, enzymes that have evolved over a billion years to degrade bacterial cell wall. Such wall hydrolases are modular enzymes, composed of discrete domains for high-affinity binding to cell wall carbohydrates and cleavage activity. In this study, we demonstrate that binding domains from autolysins and lysins can be fused to the Fc region of human IgG, creating a fully functional homodimer (or "lysibody") with high-affinity binding and specificity for carbohydrate determinants on the bacterial surface. Furthermore, we demonstrate that this process is reproducible with three different binding domains specific to methicillin-resistant Staphylococcus aureus (MRSA). Cell-bound lysibodies induced the fixation of complement on the bacterial surface, promoted phagocytosis by macrophages and neutrophils, and protected mice from MRSA infection in two model systems. The lysibody approach could be used to target a range of difficult-to-treat pathogenic bacteria, given that cell wall hydrolases are ubiquitous in nature.

Perfluorooctane sulfonate (PFOS) is a persistent organic contaminant that may cause cardiotoxicity in animals and humans. However, little is known about the underlying mechanism by which it affects the organelle toxicity in cardiomyocytes during the cardiogenesis. Our previous proteomic study showed that differences of protein expression mainly existed in mitochondria of cardiomyocytes differentiated from embryonic stem (ES) cells after exposure to PFOS. Here, we focused on mitochondria] toxicity of PFOS in ES cell-derived cardiomyocytes. The cardiomyogenesis from ES cells in vitro was inhibited, and the expression of L-type Ca2+ channel (LTCC) was decreased to interrupt [Ca2+](c) transient amplitude in cardiomyocytes after PFOS treatment. Transmission electron microscope revealed that swollen mitochondrion with vacuole in PFOS-treated cells. Meanwhile, mitochondrial transmembrane potential (Delta Psi m) was declined and ATP production was lowered. These changes were related to the increased EGFR phosphorylation, activated Rictor signaling, then mediated HK2 binding to mitochondria] membrane. Furtherthore, PFOS reduced the interaction of IP3R-Grp75-VDAC and accumulated intracellular fatty acids by activating Rictor, thereby attenuating PGC-1 alpha. and Mfn2 expressions, then destroying mitochondria-associated endoplasmic reticulum membrane (MAM), which resulted in the decrease of [Ca2+](mito) transient amplitude triggered by ATP. In conclusion, mitochondria] structure damages and abnormal Ca2+ shuttle were the important aspects in PFOS-induced cardiomyocytes toxicity from ES cells by activating Rictor signaling pathway. (C) 2017 Elsevier B.V. All rights reserved.

Targeted inhibition of Rho-associated kinase (ROCK) 2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-alpha, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

Tissue adaptation is an intrinsic component of immune cell development, influencing both resistance to pathogens and tolerance. Chronically stimulated surfaces of the body, in particular the gut mucosa, are the major sites where immune cells traffic and reside. Their adaptation to these environments requires constant discrimination between natural stimulation coming from harmless microbiota and food, and pathogens that need to be cleared. This review will focus on the adaptation of lymphocytes to the gut mucosa, a highly specialized environment that can help us understand the plasticity of leukocytes arriving at various tissue sites and how tissue-related factors operate to shape immune cell fate and function.

Primate cognition requires interaction processing. Interactions can reveal otherwise hidden properties of intentional agents, such as thoughts and feelings, and of inanimate objects, such as mass and material. Where and how interaction analyses are implemented in the brain is unknown. Using whole-brain functional magnetic resonance imaging in macaque monkeys, we discovered a network centered in the medial and ventrolateral prefrontal cortex that is exclusively engaged in social interaction analysis. Exclusivity of specialization was found for no other function anywhere in the brain. Two additional networks, a parieto-premotor and a temporal one, exhibited both social and physical interaction preference, which, in the temporal lobe, mapped onto a fine-grain pattern of object, body, and face selectivity. Extent and location of a dedicated system for social interaction analysis suggest that this function is an evolutionary forerunner of human mind-reading capabilities.