Alternative mechanisms of structuring biomembranes: Self-assembly vs. self-organization

We study two mechanisms for the formation of protein patterns near membranes of living cells by mathematical modelling. Self-assembly of protein domains by electrostatic lipid-protein interactions is contrasted with self-organization due to a nonequilibrium biochemical reaction cycle of proteins near the membrane. While both processes lead eventually to quite similar patterns, their evolution occurs on very different length and time scales. Self-assembly produces periodic protein patterns on a spatial scale below 0.1 micron in a few seconds followed by extremely slow coarsening, whereas self-organization results in a pattern wavelength comparable to the typical cell size of 100 micron within a few minutes suggesting different biological functions for the two processes.Comment: 4 pages, 5 figure

Gait and Cognition: A Complementary Approach to Understanding Brain Function and the Risk of Falling

Until recently, clinicians and researchers have performed gait assessments and cognitive assessments separately when evaluating older adults, but increasing evidence from clinical practice, epidemiological studies, and clinical trials shows that gait and cognition are interrelated in older adults. Quantifiable alterations in gait in older adults are associated with falls, dementia, and disability. At the same time, emerging evidence indicates that early disturbances in cognitive processes such as attention, executive function, and working memory are associated with slower gait and gait instability during single- and dual-task testing and that these cognitive disturbances assist in the prediction of future mobility loss, falls, and progression to dementia. This article reviews the importance of the interrelationship between gait and cognition in aging and presents evidence that gait assessments can provide a window into the understanding of cognitive function and dysfunction and fall risk in older people in clinical practice. To this end, the benefits of dual-task gait assessments (e.g., walking while performing an attention-demanding task) as a marker of fall risk are summarized. A potential complementary approach for reducing the risk of falls by improving certain aspects of cognition through nonpharmacological and pharmacological treatments is also presented. Untangling the relationship between early gait disturbances and early cognitive changes may be helpful in identifying older adults at risk of experiencing mobility decline, falls, and progression to dementia. J Am Geriatr Soc 60: 2127-2136, 2012

Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism

Table S1. Demographic and clinical features of human subjects used in this study. Figure S1. Aβ deposition in microvessels in AD patients and APPSw/0 mice. Figure S2. Biochemical analysis of Aβ42 aggregates. Figure S3. Cy3-Aβ42 cellular uptake in wild type mouse brain slices within 30 min. Figure S4. Pericyte coverages in Lrp1lox/lox and Lrp1lox/lox; Cspg4-Cre mice. Figure S5.. LRP1 and apoE suppression with siRNA. (DOCX 1454 kb

Computational reverse chemical ecology: Virtual screening and predicting behaviorally active semiochemicals for Bactrocera dorsalis

BACKGROUND: Semiochemical is a generic term used for a chemical substance that influences the behaviour of an organism. It is a common term used in the field of chemical ecology to encompass pheromones, allomones, kairomones, attractants and repellents. Insects have mastered the art of using semiochemicals as communication signals and rely on them to find mates, host or habitat. This dependency of insects on semiochemicals has allowed chemical ecologists to develop environment friendly pest management strategies. However, discovering semiochemicals is a laborious process that involves a plethora of behavioural and analytical techniques, making it expansively time consuming. Recently, reverse chemical ecology approach using odorant binding proteins (OBPs) as target for elucidating behaviourally active compounds is gaining eminence. In this scenario, we describe a “computational reverse chemical ecology” approach for rapid screening of potential semiochemicals. RESULTS: We illustrate the high prediction accuracy of our computational method. We screened 25 semiochemicals for their binding potential to a GOBP of B. dorsalis using molecular docking (in silico) and molecular dynamics. Parallely, compounds were subjected to fluorescent quenching assays (Experimental). The correlation between in silico and experimental data were significant (r(2) = 0.9408; P < 0.0001). Further, predicted compounds were subjected to behavioral bioassays and were found to be highly attractive to insects. CONCLUSIONS: The present study provides a unique methodology for rapid screening and predicting behaviorally active semiochemicals. This methodology may be developed as a viable approach for prospecting active semiochemicals for pest control, which otherwise is a laborious process

Continuous quantitative monitoring of cerebral oxygen metabolism in neonates by ventilator-gated analysis of NIRS recordings

Oxidative stress during fetal development, delivery, or early postnatal life is a major cause of neuropathology, as both hypoxic and hyperoxic insults can significantly damage the developing brain. Despite the obvious need for reliable cerebral oxygenation monitoring, no technology currently exists to monitor cerebral oxygen metabolism continuously and noninvasively in infants at high risk for developing brain injury. Consequently, a rational approach to titrating oxygen supply to cerebral oxygen demand – and thus avoiding hyperoxic or hypoxic insults – is currently lacking. We present a promising method to close this crucial technology gap in the important case of neonates on conventional ventilators. By using cerebral near-infrared spectroscopy and signals from conventional ventilators, along with arterial oxygen saturation, we derive continuous (breath-by-breath) estimates of cerebral venous oxygen saturation, cerebral oxygen extraction fraction, cerebral blood flow, and cerebral metabolic rate of oxygen. The resultant estimates compare very favorably to previously reported data obtained by non-continuous and invasive means from preterm infants in neonatal critical care.National Institutes of Health (U.S.) (Grant R01EB001659)National Institutes of Health (U.S.) (Grant K24NS057568)National Institutes of Health (U.S.) (Grant R21HD056009

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Effect of photoperiod and host distribution on the horizontal transmission of Isaria fumosorosea (Hypocreales: Cordycipitaceae) in greenhouse whitefly assessed using a novel model bioassay

A model bioassay was used to evaluate the epizootic potential and determine the horizontal transmission efficiency of Isaria fumosorosea Trinidadian strains against Trialeurodes vaporariorum pharate adults under optimum conditions (25±0.5°C, ~100% RH) at two different photoperiods. Untreated pharate adults were arranged on laminated graph paper at different distributions to simulate varying infestation levels on a leaf surface. Four potential hosts were located 7, 14 and 21 mm away from a central sporulating cadaver simulating high, medium and low infestation levels, respectively. Percent hosts colonized were recorded 7, 12, 14 and 21 days post-treatment during a 16- and 24-h photophase. After 21 days, mean percent hosts colonized at the highest, middle and lowest infestation levels were 93 and 100%, 22 and 58%, 25 and 39% under a 16- and 24-h photophase, respectively. From the results, it was concluded that the longer the photophase, the greater the percentage of hosts colonized, and as host distance increased from the central sporulating cadaver, colonization decreased. The use of this novel model bioassay technique is the first attempt to evaluate the epizootic potential and determine the horizontal transmission efficiency of I. fumosorosea Trinidadian strains under optimal environmental conditions at different photoperiods. This bioassay can be used to assess horizontal transmission efficiency for the selection of fungi being considered for commercial biopesticide development

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

Syntheses, structure, reactivity and species recognition studies of oxo-vanadium(V) and -molybdenum(VI) complexes

Alkoxo-rich Schiff-bases of potentially tri-, tetra- and penta-dentate binding capacity, and their sodium tetrahydroborate-reduced derivatives, have been synthesized. Their oxo-vanadium(V) and -molybdenum(VI) complexes were synthesized and characterized using several analytical and spectral techniques including multinuclear NMR spectroscopy and single-crystal X-ray diffraction studies. Eight structurally different types of complexes possessing distorted square-pyramidal, trigonal-bipyramidal and octahedral geometries have been obtained. While (VO)-O-V exhibits dimeric Structures with 2-HOC6H4CH=NC(CH2OH)(3) and 2-HOC6H4CH2-NHC(CH2OH)(3) and related ligands through the formation of a symmetric V2O2 core as a result of bridging of one of the CH2O- groups, Mo O-VI gives only mononuclear complexes even when some unbound CH2OH groups are available and the metal center is co-ordinatively unsaturated. In all the complexes the nitrogen atom from a HC=N or H2CNH group of the ligand occupies a near trans position to the M=O bond. While the Schiff-base ligands act in a tri- and tetra-dentate manner in the vanadium(V) complexes, they are only tridentate in the molybdenum(VI) complexes. Proton NMR spectra in the region of bound CH, provides a signature that helps to differentiate dinuclear from mononuclear complexes. Carbon-13 NMR co-ordination induced shifts of the bound CH, group fit well with the charge on the oxometal species and the terminal or bridging nature of the ligand. The reactivity of the vanadium(V) complexes towards bromination of the dye xylene cyanole was studied. Transmetallation reactions of several preformed metal complexes of 2-HOC6H4CH=NC(CH2OH)(3) with VO3+ were demonstrated as was selective extraction of VO3+ from a mixture of VO(acac)(2)] and MoO2(acac)(2)] using this Schiff base. The unusual selectivity and that of related derivatives for VO3+ is supported by binding constants and the solubility of the final products, and was established through a.c. conductivity measurements. The cis-MoO22+ complexes with alkoxo binding showed an average Mo-O-alk distance of 1.926 Angstrom, a value that is close to that observed in the molybdenum(VI) enzyme dmso reductase (1.92 Angstrom). Several correlations have been drawn based on the data

In vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis

BACKGROUND: The APOE4 allele variant is the strongest known genetic risk factor for developing late-onset Alzheimer’s disease. The link between apolipoprotein E (apoE) and Alzheimer’s disease is likely due in large part to the impact of apoE on the metabolism of amyloid β (Aβ) within the brain. Manipulation of apoE levels and lipidation within the brain has been proposed as a therapeutic target for the treatment of Alzheimer’s disease. However, we know little about the dynamic regulation of apoE levels and lipidation within the central nervous system. We have developed an assay to measure apoE levels in the brain interstitial fluid of awake and freely moving mice using large molecular weight cut-off microdialysis probes. RESULTS: We were able to recover apoE using microdialysis from human cerebrospinal fluid (CSF) in vitro and mouse brain parenchyma in vivo. Microdialysis probes were inserted into the hippocampus of wild-type mice and interstitial fluid was collected for 36 hours. Levels of apoE within the microdialysis samples were determined by ELISA. The levels of apoE were found to be relatively stable over 36 hours. No apoE was detected in microdialysis samples from apoE KO mice. Administration of the RXR agonist bexarotene increased ISF apoE levels while ISF Aβ levels were decreased. Extrapolation to zero-flow analysis allowed us to determine the absolute recoverable concentration of apoE3 in the brain ISF of apoE3 KI mice. Furthermore, analysis of microdialysis samples by non-denaturing gel electrophoresis determined lipidated apoE particles in microdialysis samples were consistent in size with apoE particles from CSF. Finally, we found that the concentration of apoE in the brain ISF was dependent upon apoE isoform in human apoE KI mice, following the pattern apoE2>apoE3>apoE4. CONCLUSIONS: We are able to collect lipidated apoE from the brain of awake and freely moving mice and monitor apoE levels over the course of several hours from a single mouse. Our technique enables assessment of brain apoE dynamics under physiological and pathophysiological conditions and in response to therapeutic interventions designed to affect apoE levels and lipidation within the brain