The influence of fuels treatment and landscape arrangement on simulated fire behavior, southern Cascade Range, California

Treesearch

David A. Schmidt; Alan H. Taylor; Carl N. Skinner

2008-01-01

Wildfire behavior can be modified by altering the quantity, structure, and arrangement of fuel (flammable vegetation) by silvicultural treatments such as forest thinning and prescribed burning. The type and arrangement (including landscape location) of treated areas have been demonstrated to influence wildfire behavior. This study analyzes the response of several key...

Molecular Modeling of the Structural and Dynamical Changes in Calcium Channel TRPV5 Induced by the African-Specific A563T Variation.

PubMed

Wang, Lingyun; Holmes, Ross P; Peng, Ji-Bin

2016-03-01

Transient receptor potential cation channels, vanilloid subfamily, member 5 (TRPV5) plays a key role in active Ca(2+) reabsorption in the kidney. Variations in TRPV5 occur at high frequency in African populations and may contribute to their higher efficiency of Ca(2+) reabsorption. One of the African specific variations, A563T, exhibits increased Ca(2+) transport ability. However, it is unclear how this variation influences the channel pore. On the basis of the structure of TRPV1, a TRPV5 model was generated to simulate the structural and dynamical changes induced by the A563T variation. On the basis of this model, amino acid residue 563 interacts with V540, which is one residue away from the key residue, D542, involved in Ca(2+) selectivity and Mg(2+) blockade. The A563T variation increases secondary structure stability and reduces dynamical motion of D542. In addition, the A563T variation alters the electrostatic potential of the outer surface of the pore. Differences in contact between selective filter residues and residue 563 and in electrostatic potential between the two TRPV5 variants were also observed in another model derived from an alternative alignment in the selective filters between TRPV5 and TRPV1. These findings indicate that the A563T variation induces structural, dynamical, and electrostatic changes in the TRPV5 pore, providing structural insight into the functional alterations associated with the A563T variation.

Small mitochondria-targeting molecules as anti-cancer agents

PubMed Central

Wang, Feng; Ogasawara, Marcia A.; Huang, Peng

2009-01-01

Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anticancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed. PMID:19995573

Ocean acidification alters predator behaviour and reduces predation rate.

PubMed

Watson, Sue-Ann; Fields, Jennifer B; Munday, Philip L

2017-02-01

Ocean acidification poses a range of threats to marine invertebrates; however, the emerging and likely widespread effects of rising carbon dioxide (CO 2 ) levels on marine invertebrate behaviour are still little understood. Here, we show that ocean acidification alters and impairs key ecological behaviours of the predatory cone snail Conus marmoreus Projected near-future seawater CO 2 levels (975 µatm) increased activity in this coral reef molluscivore more than threefold (from less than 4 to more than 12 mm min -1 ) and decreased the time spent buried to less than one-third when compared with the present-day control conditions (390 µatm). Despite increasing activity, elevated CO 2 reduced predation rate during predator-prey interactions with control-treated humpbacked conch, Gibberulus gibberulus gibbosus; 60% of control predators successfully captured and consumed their prey, compared with only 10% of elevated CO 2 predators. The alteration of key ecological behaviours of predatory invertebrates by near-future ocean acidification could have potentially far-reaching implications for predator-prey interactions and trophic dynamics in marine ecosystems. Combined evidence that the behaviours of both species in this predator-prey relationship are altered by elevated CO 2 suggests food web interactions and ecosystem structure will become increasingly difficult to predict as ocean acidification advances over coming decades. © 2017 The Author(s).

Ocean acidification alters predator behaviour and reduces predation rate

PubMed Central

Fields, Jennifer B.; Munday, Philip L.

2017-01-01

Ocean acidification poses a range of threats to marine invertebrates; however, the emerging and likely widespread effects of rising carbon dioxide (CO2) levels on marine invertebrate behaviour are still little understood. Here, we show that ocean acidification alters and impairs key ecological behaviours of the predatory cone snail Conus marmoreus. Projected near-future seawater CO2 levels (975 µatm) increased activity in this coral reef molluscivore more than threefold (from less than 4 to more than 12 mm min−1) and decreased the time spent buried to less than one-third when compared with the present-day control conditions (390 µatm). Despite increasing activity, elevated CO2 reduced predation rate during predator–prey interactions with control-treated humpbacked conch, Gibberulus gibberulus gibbosus; 60% of control predators successfully captured and consumed their prey, compared with only 10% of elevated CO2 predators. The alteration of key ecological behaviours of predatory invertebrates by near-future ocean acidification could have potentially far-reaching implications for predator–prey interactions and trophic dynamics in marine ecosystems. Combined evidence that the behaviours of both species in this predator–prey relationship are altered by elevated CO2 suggests food web interactions and ecosystem structure will become increasingly difficult to predict as ocean acidification advances over coming decades. PMID:28148828

Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

PubMed Central

Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.

2012-01-01

Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363

Early development of structural networks and the impact of prematurity on brain connectivity.

PubMed

Batalle, Dafnis; Hughes, Emer J; Zhang, Hui; Tournier, J-Donald; Tusor, Nora; Aljabar, Paul; Wali, Luqman; Alexander, Daniel C; Hajnal, Joseph V; Nosarti, Chiara; Edwards, A David; Counsell, Serena J

2017-04-01

Preterm infants are at high risk of neurodevelopmental impairment, which may be due to altered development of brain connectivity. We aimed to (i) assess structural brain development from 25 to 45 weeks gestational age (GA) using graph theoretical approaches and (ii) test the hypothesis that preterm birth results in altered white matter network topology. Sixty-five infants underwent MRI between 25 +3 and 45 +6 weeks GA. Structural networks were constructed using constrained spherical deconvolution tractography and were weighted by measures of white matter microstructure (fractional anisotropy, neurite density and orientation dispersion index). We observed regional differences in brain maturation, with connections to and from deep grey matter showing most rapid developmental changes during this period. Intra-frontal, frontal to cingulate, frontal to caudate and inter-hemispheric connections matured more slowly. We demonstrated a core of key connections that was not affected by GA at birth. However, local connectivity involving thalamus, cerebellum, superior frontal lobe, cingulate gyrus and short range cortico-cortical connections was related to the degree of prematurity and contributed to altered global topology of the structural brain network. The relative preservation of core connections at the expense of local connections may support more effective use of impaired white matter reserve following preterm birth. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Aging and Circadian Rhythms

PubMed Central

Duffy, Jeanne F.; Zitting, Kirsi-Marja; Chinoy, Evan D.

2015-01-01

Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. Here, we review key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. PMID:26568120

Vegetation response to a short interval between high-severity wildfires in a mixed-evergreen forest

Treesearch

Daniel C. Donato; Joseph B. Fontaine; W. Douglas Robinson; J. Boone Kauffman; Beverly E. Law

2009-01-01

Variations in disturbance regime strongly influence ecosystem structure and function. A prominent form of such variation is when multiple high-severity wildfires occur in rapid succession (i.e. short-interval (SI) severe fires, or ‘re-burns’). These events have been proposed as key mechanisms altering successional rates and pathways....

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

PubMed Central

Krshnan, Logesvaran; Park, Soohyung; Im, Wonpil; Call, Melissa J.; Call, Matthew E.

2016-01-01

The T-cell antigen receptor (TCR) is an assembly of eight type I single-pass membrane proteins that occupies a central position in adaptive immunity. Many TCR-triggering models invoke an alteration in receptor complex structure as the initiating event, but both the precise subunit organization and the pathway by which ligand-induced alterations are transferred to the cytoplasmic signaling domains are unknown. Here, we show that the receptor complex transmembrane (TM) domains form an intimately associated eight-helix bundle organized by a specific interhelical TCR TM interface. The salient features of this core structure are absolutely conserved between αβ and γδ TCR sequences and throughout vertebrate evolution, and mutations at key interface residues caused defects in the formation of stable TCRαβ:CD3δε:CD3γε:ζζ complexes. These findings demonstrate that the eight TCR–CD3 subunits form a compact and precisely organized structure within the membrane and provide a structural basis for further investigation of conformationally regulated models of transbilayer TCR signaling. PMID:27791034

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane.

PubMed

Krshnan, Logesvaran; Park, Soohyung; Im, Wonpil; Call, Melissa J; Call, Matthew E

2016-10-25

The T-cell antigen receptor (TCR) is an assembly of eight type I single-pass membrane proteins that occupies a central position in adaptive immunity. Many TCR-triggering models invoke an alteration in receptor complex structure as the initiating event, but both the precise subunit organization and the pathway by which ligand-induced alterations are transferred to the cytoplasmic signaling domains are unknown. Here, we show that the receptor complex transmembrane (TM) domains form an intimately associated eight-helix bundle organized by a specific interhelical TCR TM interface. The salient features of this core structure are absolutely conserved between αβ and γδ TCR sequences and throughout vertebrate evolution, and mutations at key interface residues caused defects in the formation of stable TCRαβ:CD3δε:CD3γε:ζζ complexes. These findings demonstrate that the eight TCR-CD3 subunits form a compact and precisely organized structure within the membrane and provide a structural basis for further investigation of conformationally regulated models of transbilayer TCR signaling.

Queued History based Mediator Identification for an Incentive Attached peer to peer Electronic Coupon System

NASA Astrophysics Data System (ADS)

Shojima, Taiki; Ikkai, Yoshitomo; Komoda, Norihisa

An incentive attached peer to peer (P2P) electronic coupon system is proposed in which users forward e-coupons to potential users by providing incentives to those mediators. A service provider needs to acquire distribution history for incentive payment by recording UserIDs (UIDs) in the e-coupons, since this system is intended for pure P2P environment. This causes problems of dishonestly altering distribution history. In order to solve such problems, distribution history is realized in a couple of queues structure. They are the UID queue, and the public key queue. Each element of the UID queue at the initial state consists of index, a secret key, and a digital signature. In recording one's UID, the encrypted UID is enqueued to the UID queue with a new digital signature created by a secret key of the dequeued element, so that each UID cannot be altered. The public key queue provides the functionality of validating digital signatures on mobile devices. This method makes it possible both each UID and sequence of them to be certificated. The availability of the method is evaluated by quantifying risk reduction using Fault Tree Analysis (FTA). And it's recognized that the method is better than common encryption methods.

Role of Altered Sialylation of the I-Like Domain of β1 Integrin in the Binding of Fibronectin to β1 Integrin: Thermodynamics and Conformational Analyses

PubMed Central

Pan, Di; Song, Yuhua

2010-01-01

Abstract N-glycosylation of the I-like domain of β1 integrin plays an essential role in integrin structure and function, and the altered sialylation of β1 integrin regulates β1 integrin binding to fibronectin. However, the structural basis underlying the effect of altered sialylation of the β1 I-like domain on β1 integrin binding to fibronectin remains largely unknown. In this study, we used a combination of molecular dynamics simulations and binding free energy analyses to investigate changes in binding thermodynamics and in conformation of the glycosylated β1 I-like domain-FN-III9-10 complex caused by altered sialylation of the β1 I-like domain. Binding free energy analyses showed that desialylation of β1 I-like domain increased β1 integrin binding to fibronectin, consistent with experimental results. Interaction analyses showed that altered sialylation of the β1 I-like domain resulted in significant changes in the interaction of the N-glycans of the I-like domain with both the I-like domain and fibronectin, and these changes could directly affect the allosteric regulation of the interaction between the I-like domain and fibronectin. Altered sialylation of the β1 I-like domain caused significant conformational changes in key functional sites of both the β1 I-like domain and fibronectin. In addition, altered sialylation of the β1 I-like domain resulted in changes in the degree of correlated motions between residues in the I-like domain and residues in fibronectin, and in the degree of motion changes in fibronectin, which could affect β1 integrin binding to fibronectin. We believe results from this study provide thermodynamic and structural evidence for a role of altered sialylation of β1 integrin in regulating β1 integrin binding to fibronectin and it's induced cellular activities. PMID:20655849

Structural and spectroscopic changes to natural nontronite induced by experimental impacts between 10 and 40 GPa

NASA Astrophysics Data System (ADS)

Friedlander, Lonia R.; Glotch, Timothy D.; Bish, David L.; Dyar, M. Darby; Sharp, Thomas G.; Sklute, Elizabeth C.; Michalski, Joseph R.

2015-05-01

Many phyllosilicate deposits remotely detected on Mars occur within bombarded terrains. Shock metamorphism from meteor impacts alters mineral structures, producing changed mineral spectra. Thus, impacts have likely affected the spectra of remotely sensed Martian phyllosilicates. We present spectral analysis results for a natural nontronite sample before and after laboratory-generated impacts over five peak pressures between 10 and 40 GPa. We conducted a suite of spectroscopic analyses to characterize the sample's impact-induced structural and spectral changes. Nontronite becomes increasingly disordered with increasing peak impact pressure. Every infrared spectroscopic technique used showed evidence of structural changes at shock pressures above ~25 GPa. Reflectance spectroscopy in the visible near-infrared region is primarily sensitive to the vibrations of metal-OH and interlayer H2O groups in the nontronite octahedral sheet. Midinfrared (MIR) spectroscopic techniques are sensitive to the vibrations of silicon and oxygen in the nontronite tetrahedral sheet. Because the tetrahedral and octahedral sheets of nontronite deform differently, impact-driven structural deformation may contribute to differences in phyllosilicate detection between remote sensing techniques sensitive to different parts of the nontronite structure. Observed spectroscopic changes also indicated that the sample's octahedral and tetrahedral sheets were structurally deformed but not completely dehydroxylated. This finding is an important distinction from previous studies of thermally altered phyllosilicates in which dehydroxylation follows dehydration in a stepwise progression preceding structural deformation. Impact alteration may thus complicate mineral-specific identifications based on the location of OH-group bands in remotely detected spectra. This is a key implication for Martian remote sensing arising from our results.

Long-term variability in the water budget and its controls in an oak-dominated temperate forest

Treesearch

Jing Xie; Ge Sun; Hou-Sen Chu; Junguo Liu; Steven G. McNulty; Asko Noormets; Ranjeet John; Zutao Ouyang; Tianshan Zha; Haitao Li; Wenbin Guan; Jiquan Chen

2014-01-01

Water availability is one of the key environmental factors that control ecosystem functions in temperate forests. Changing climate is likely to alter the ecohydrology and other ecosystem processes, which affect forest structures and functions. We constructed a multi-year water budget (2004–2010) and quantified environmental controls on an evapotranspiration (ET) in a...

Hyperspectral remote sensing applied to mineral exploration in southern Peru: A multiple data integration approach in the Chapi Chiara gold prospect

NASA Astrophysics Data System (ADS)

Carrino, Thais Andressa; Crósta, Alvaro Penteado; Toledo, Catarina Labouré Bemfica; Silva, Adalene Moreira

2018-02-01

Remote sensing is a strategic key tool for mineral exploration, due to its capacity of detecting hydrothermal alteration minerals or alteration mineral zones associated with different types of mineralization systems. A case study of an epithermal system located in southern Peru is presented, aimed at the characterization of mineral assemblies for discriminating potential high sulfidation epithermal targets, using hyperspectral imagery integrated with petrography, XRD and magnetic data. HyMap images were processed using the Mixture Tuned Matched Filtering (MTMF) technique for producing alteration map in the Chapi Chiara epithermal gold prospect. Extensive areas marked by advanced argillic alteration (alunite-kaolinite-dickite ± topaz) were mapped in detail, as well as limited argillic (illite-smectite) and propylitic (chlorite spectral domain) alteration. The magmatic-hydrothermal processes responsible for the formation of hypogene minerals were also related to the destruction of ferrimagnetic minerals (e.g., magnetite) of host rocks such as andesite, and the remobilization/formation of paramagnetic Fe-Ti oxides (e.g., rutile, anatase). The large alteration zones of advanced argillic alteration are controlled by structures related to a regional NW-SE trend, and also by local NE-SW and ENE-WSW ones.

Obesity resistance and deregulation of lipogenesis in Δ6-fatty acid desaturase (FADS2) deficiency.

PubMed

Stoffel, Wilhelm; Hammels, Ina; Jenke, Britta; Binczek, Erika; Schmidt-Soltau, Inga; Brodesser, Susanne; Odenthal, Margarete; Thevis, Mario

2014-01-01

Δ-6-fatty acid desaturase (FADS2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids (PUFAs), the essential structural determinants of mammalian membrane lipid-bilayers. We developed the auxotrophic fads2(-/-) mouse mutant to assess the enigmatic role of ω3- and ω6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2(-/-) mutant, the molecular basis of which is unknown. Phospholipidomic profiling of membrane systems of fads2(-/-)mice revealed diacylglycerol-structures, deprived of PUFAs but substituted with surrogate eicosa-5,11,14-trienoic acid. ω6-Arachidonic (AA) and ω3-docosahexaenoic acid (DHA) supplemented diets transformed fads2(-/-) into AA-fads2(-/-) and DHA-fads2(-/-) mutants. Severely altered phospholipid-bilayer structures of subcellular membranes of fads2(-/-) liver specifically interfered with maturation of transcription factor sterol-regulatory-element-binding protein, the key regulator of lipogenesis and lipid homeostasis. This study strengthens the concept that specific PUFA-substituted membrane phospholipid species are critical constituents of the structural platform operative in lipid homeostasis in normal and disease conditions.

Climate change can cause complex responses in Baltic Sea macroalgae: A systematic review

NASA Astrophysics Data System (ADS)

Takolander, Antti; Cabeza, Mar; Leskinen, Elina

2017-05-01

Estuarine macroalgae are important primary producers in aquatic ecosystems, and often foundation species providing structurally complex habitat. Climate change alters many abiotic factors that affect their long-term persistence and distribution. Here, we review the existing scientific literature on the tolerance of key macroalgal species in the Baltic Sea, the world's largest brackish water body. Elevated temperature is expected to intensify coastal eutrophication, further promoting growth of opportunistic, filamentous species, especially green algae, which are often species associated with intensive filamentous algal blooms. Declining salinities will push the distributions of marine species towards south, which may alter the Baltic Sea community compositions towards a more limnic state. Together with increasing eutrophication trends this may cause losses in marine-originating foundation species such as Fucus, causing severe biodiversity impacts. Experimental results on ocean acidification effects on macroalgae are mixed, with only few studies conducted in the Baltic Sea. We conclude that climate change can alter the structure and functioning of macroalgal ecosystems especially in the northern Baltic coastal areas, and can potentially act synergistically with eutrophication. We briefly discuss potential adaptation measures.

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms.

PubMed

Lechuga, Susana; Ivanov, Andrei I

2017-07-01

The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

Coastal oceanography sets the pace of rocky intertidal community dynamics.

PubMed

Menge, B A; Lubchenco, J; Bracken, M E S; Chan, F; Foley, M M; Freidenburg, T L; Gaines, S D; Hudson, G; Krenz, C; Leslie, H; Menge, D N L; Russell, R; Webster, M S

2003-10-14

The structure of ecological communities reflects a tension among forces that alter populations. Marine ecologists previously emphasized control by locally operating forces (predation, competition, and disturbance), but newer studies suggest that inputs from large-scale oceanographically modulated subsidies (nutrients, particulates, and propagules) can strongly influence community structure and dynamics. On New Zealand rocky shores, the magnitude of such subsidies differs profoundly between contrasting oceanographic regimes. Community structure, and particularly the pace of community dynamics, differ dramatically between intermittent upwelling regimes compared with relatively persistent down-welling regimes. We suggest that subsidy rates are a key determinant of the intensity of species interactions, and thus of structure in marine systems, and perhaps also nonmarine communities.

Co-extinction in a host-parasite network: identifying key hosts for network stability.

PubMed

Dallas, Tad; Cornelius, Emily

2015-08-17

Parasites comprise a substantial portion of total biodiversity. Ultimately, this means that host extinction could result in many secondary extinctions of obligate parasites and potentially alter host-parasite network structure. Here, we examined a highly resolved fish-parasite network to determine key hosts responsible for maintaining parasite diversity and network structure (quantified here as nestedness and modularity). We evaluated four possible host extinction orders and compared the resulting co-extinction dynamics to random extinction simulations; including host removal based on estimated extinction risk, parasite species richness and host level contributions to nestedness and modularity. We found that all extinction orders, except the one based on realistic extinction risk, resulted in faster declines in parasite diversity and network structure relative to random biodiversity loss. Further, we determined species-level contributions to network structure were best predicted by parasite species richness and host family. Taken together, we demonstrate that a small proportion of hosts contribute substantially to network structure and that removal of these hosts results in rapid declines in parasite diversity and network structure. As network stability can potentially be inferred through measures of network structure, our findings may provide insight into species traits that confer stability.

Structured Illumination Microscopy for the Investigation of Synaptic Structure and Function.

PubMed

Hong, Soyon; Wilton, Daniel K; Stevens, Beth; Richardson, Douglas S

2017-01-01

The neuronal synapse is a primary building block of the nervous system to which alterations in structure or function can result in numerous pathologies. Studying its formation and elimination is the key to understanding how brains are wired during development, maintained throughout adulthood plasticity, and disrupted during disease. However, due to its diffraction-limited size, investigations of the synaptic junction at the structural level have primarily relied on labor-intensive electron microscopy or ultra-thin section array tomography. Recent advances in the field of super-resolution light microscopy now allow researchers to image synapses and associated molecules with high-spatial resolution, while taking advantage of the key characteristics of light microscopy, such as easy sample preparation and the ability to detect multiple targets with molecular specificity. One such super-resolution technique, Structured Illumination Microscopy (SIM), has emerged as an attractive method to examine synapse structure and function. SIM requires little change in standard light microscopy sample preparation steps, but results in a twofold improvement in both lateral and axial resolutions compared to widefield microscopy. The following protocol outlines a method for imaging synaptic structures at resolutions capable of resolving the intricacies of these neuronal connections.

Feedbacks Between Soil Structure and Microbial Activities in Soil

NASA Astrophysics Data System (ADS)

Bailey, V. L.; Smith, A. P.; Fansler, S.; Varga, T.; Kemner, K. M.; McCue, L. A.

2017-12-01

Soil structure provides the physical framework for soil microbial habitats. The connectivity and size distribution of soil pores controls the microbial access to nutrient resources for growth and metabolism. Thus, a crucial component of soil research is how a soil's three-dimensional structure and organization influences its biological potential on a multitude of spatial and temporal scales. In an effort to understand microbial processes at scale more consistent with a microbial community, we have used soil aggregates as discrete units of soil microbial habitats. Our research has shown that mean pore diameter (x-ray computed tomography) of soil aggregates varies with the aggregate diameter itself. Analyzing both the bacterial composition (16S) and enzyme activities of individual aggregates showed significant differences in the relative abundances of key members the microbial communities associated with high enzyme activities compared to those with low activities, even though we observed no differences in the size of the biomass, nor in the overall richness or diversity of these communities. We hypothesize that resources and substrates have stimulated key populations in the aggregates identified as highly active, and as such, we conducted further research that explored how such key populations (i.e. fungal or bacterial dominated populations) alter pathways of C accumulation in aggregate size domains and microbial C utilization. Fungi support and stabilize soil structure through both physical and chemical effects of their hyphal networks. In contrast, bacterial-dominated communities are purported to facilitate micro- and fine aggregate stabilization. Here we quantify the direct effects fungal versus bacterial dominated communities on aggregate formation (both the rate of aggregation and the quality, quantity and distribution of SOC contained within aggregates). A quantitative understanding of the different mechanisms through which fungi or bacteria shape aggregate formation could alter how we currently treat our predictions of soil biogeochemistry. Current predictions are largely site- or biome-specific; quantitative mechanisms could underpin "rules" that operate at the pore-scale leading to more robust, mechanistic models.

Physical Alteration of Martian Dust Grains, Its Influence on Detection of Clays and Identification of Aqueous Processes on Mars

NASA Technical Reports Server (NTRS)

Bishop, Janice L.; Drief, Ahmed; Dyar, Darby

2003-01-01

Clays, if present on Mars, have been illusive. Determining whether or not clay minerals and other aqueous alteration species are present on Mars provides key information about the extent and duration of aqueous processes on Mars. The purpose of this study is to characterize in detail changes in the mineral grains resulting from grinding and to assess the influence of physical processes on clay minerals on the surface of Mars. Physical alteration through grinding was shown to greatly affect the structure and a number of properties of antigorite and kaolinite. This project builds on an initial study and includes a combination of SEM, HRTEM, reflectance and M ssbauer spectroscopies. Grain size was found to decrease, as expected, with grinding. In addition, nanophase carbonate, Si-OH and iron oxide species were formed.

A Temporal Chromatin Signature in Human Embryonic Stem Cells Identifies Regulators of Cardiac Development

PubMed Central

Paige, Sharon L.; Thomas, Sean; Stoick-Cooper, Cristi L.; Wang, Hao; Maves, Lisa; Sandstrom, Richard; Pabon, Lil; Reinecke, Hans; Pratt, Gabriel; Keller, Gordon; Moon, Randall T.; Stamatoyannopoulos, John; Murry, Charles E.

2012-01-01

Summary Directed differentiation of human embryonic stem cells (ESCs) into cardiovascular cells provides a model for studying molecular mechanisms of human cardiovascular development. Though it is known that chromatin modification patterns in ESCs differ markedly from those in lineage-committed progenitors and differentiated cells, the temporal dynamics of chromatin alterations during differentiation along a defined lineage have not been studied. We show that differentiation of human ESCs into cardiovascular cells is accompanied by programmed temporal alterations in chromatin structure that distinguish key regulators of cardiovascular development from other genes. We used this temporal chromatin signature to identify regulators of cardiac development, including the homeobox gene MEIS2. We demonstrate using the zebrafish model that MEIS2 is critical for proper heart tube formation and subsequent cardiac looping. Temporal chromatin signatures should be broadly applicable to other models of stem cell differentiation to identify regulators and provide key insights into major developmental decisions. PMID:22981225

Cortical Structure Alterations and Social Behavior Impairment in p50-Deficient Mice.

PubMed

Bonini, Sara Anna; Mastinu, Andrea; Maccarinelli, Giuseppina; Mitola, Stefania; Premoli, Marika; La Rosa, Luca Rosario; Ferrari-Toninelli, Giulia; Grilli, Mariagrazia; Memo, Maurizio

2016-06-01

Alterations in genes that regulate neurodevelopment can lead to cortical malformations, resulting in malfunction during postnatal life. The NF-κB pathway has a key role during neurodevelopment by regulating the maintenance of the neural progenitor cell pool and inhibiting neuronal differentiation. In this study, we evaluated whether mice lacking the NF-κB p50 subunit (KO) present alterations in cortical structure and associated behavioral impairment. We found that, compared with wild type (WT), KO mice at postnatal day 2 present an increase in radial glial cells, an increase in Reelin protein expression levels, in addition to an increase of specific layer thickness. Moreover, adult KO mice display abnormal columnar organization in the somatosensory cortex, a specific decrease in somatostatin- and parvalbumin-expressing interneurons, altered neurite orientation, and a decrease in Synapsin I protein levels. Concerning behavior, KO mice, in addition to an increase in locomotor and exploratory activity, display impairment in social behaviors, with a reduction in social interaction. Finally, we found that risperidone treatment decreased hyperactivity of KO mice, but had no effect on defective social interaction. Altogether, these data add complexity to a growing body of data, suggesting a link between dysregulation of the NF-κB pathway and neurodevelopmental disorders pathogenesis. © The Author 2016. Published by Oxford University Press.

Organic Crystal Engineering of Thermosetting Cyanate Ester Monomers: Influence of Structure on Melting Point

DTIC Science & Technology

2016-05-27

often discussed in the field of thermosetting materials, crystal engineering1-4 plays a key role in facilitating the successful utilization of these...not to alter the desirable properties of the polymerized networks. Fortunately, the field of crystal engineering provides examples where even very...Chickos and Acree.26 For molecular modeling, methods ranging from atomistic simulations with semi-empirical force fields to density functional

The original colours of fossil beetles

PubMed Central

McNamara, Maria E.; Briggs, Derek E. G.; Orr, Patrick J.; Noh, Heeso; Cao, Hui

2012-01-01

Structural colours, the most intense, reflective and pure colours in nature, are generated when light is scattered by complex nanostructures. Metallic structural colours are widespread among modern insects and can be preserved in their fossil counterparts, but it is unclear whether the colours have been altered during fossilization, and whether the absence of colours is always real. To resolve these issues, we investigated fossil beetles from five Cenozoic biotas. Metallic colours in these specimens are generated by an epicuticular multi-layer reflector; the fidelity of its preservation correlates with that of other key cuticular ultrastructures. Where these other ultrastructures are well preserved in non-metallic fossil specimens, we can infer that the original cuticle lacked a multi-layer reflector; its absence in the fossil is not a preservational artefact. Reconstructions of the original colours of the fossils based on the structure of the multi-layer reflector show that the preserved colours are offset systematically to longer wavelengths; this probably reflects alteration of the refractive index of the epicuticle during fossilization. These findings will allow the former presence, and original hue, of metallic structural colours to be identified in diverse fossil insects, thus providing critical evidence of the evolution of structural colour in this group. PMID:21957131

The original colours of fossil beetles.

PubMed

McNamara, Maria E; Briggs, Derek E G; Orr, Patrick J; Noh, Heeso; Cao, Hui

2012-03-22

Structural colours, the most intense, reflective and pure colours in nature, are generated when light is scattered by complex nanostructures. Metallic structural colours are widespread among modern insects and can be preserved in their fossil counterparts, but it is unclear whether the colours have been altered during fossilization, and whether the absence of colours is always real. To resolve these issues, we investigated fossil beetles from five Cenozoic biotas. Metallic colours in these specimens are generated by an epicuticular multi-layer reflector; the fidelity of its preservation correlates with that of other key cuticular ultrastructures. Where these other ultrastructures are well preserved in non-metallic fossil specimens, we can infer that the original cuticle lacked a multi-layer reflector; its absence in the fossil is not a preservational artefact. Reconstructions of the original colours of the fossils based on the structure of the multi-layer reflector show that the preserved colours are offset systematically to longer wavelengths; this probably reflects alteration of the refractive index of the epicuticle during fossilization. These findings will allow the former presence, and original hue, of metallic structural colours to be identified in diverse fossil insects, thus providing critical evidence of the evolution of structural colour in this group.

TSPO Expression and Brain Structure in the Psychosis Spectrum.

PubMed

Hafizi, Sina; Guma, Elisa; Koppel, Alex; Da Silva, Tania; Kiang, Michael; Houle, Sylvain; Wilson, Alan A; Rusjan, Pablo M; Chakravarty, M Mallar; Mizrahi, Romina

2018-06-12

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [ 18 F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [ 18 F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [ 18 F]FEPPA V T (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [ 18 F]FEPPA V T and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis. Copyright © 2018. Published by Elsevier Inc.

Cardiolipin effects on membrane structure and dynamics.

PubMed

Unsay, Joseph D; Cosentino, Katia; Subburaj, Yamunadevi; García-Sáez, Ana J

2013-12-23

Cardiolipin (CL) is a lipid with unique properties solely found in membranes generating electrochemical potential. It contains four acyl chains and tends to form nonlamellar structures, which are believed to play a key role in membrane structure and function. Indeed, CL alterations have been linked to disorders such as Barth syndrome and Parkinson's disease. However, the molecular effects of CL on membrane organization remain poorly understood. Here, we investigated the structure and physical properties of CL-containing membranes using confocal microscopy, fluorescence correlation spectroscopy, and atomic force microscopy. We found that the fluidity of the lipid bilayer increased and its mechanical stability decreased with CL concentration, indicating that CL decreases the packing of the membrane. Although the presence of up to 20% CL gave rise to flat, stable bilayers, the inclusion of 5% CL promoted the formation of flowerlike domains that grew with time. Surprisingly, we often observed two membrane-piercing events in atomic force spectroscopy experiments with CL-containing membranes. Similar behavior was observed with a lipid mixture mimicking the mitochondrial outer membrane composition. This suggests that CL promotes the formation of membrane areas with apposed double bilayers or nonlamellar structures, similar to those proposed for mitochondrial contact sites. All together, we show that CL induces membrane alterations that support the role of CL in facilitating bilayer structure remodeling, deformation, and permeabilization.

Nuclear transport, oxidative stress, and neurodegeneration

PubMed Central

Patel, Vivek P; Chu, Charleen T

2011-01-01

Trafficking of transcription factors between the cytoplasm and the nucleus is an essential aspect of signal transduction, which is particularly challenging in neurons due to their highly polarized structure. Disruption in the subcellular localization of many proteins, including transcription factors, is observed in affected neurons of human neurodegenerative diseases. In these diseases, there is also growing evidence supporting alterations in nuclear transport as potential mechanisms underlying the observed mislocalization of proteins. Oxidative stress, which plays a key pathogenic role in these diseases, has also been associated with significant alterations in nuclear transport. After providing an overview of the major nuclear import and export pathways and discussing the impact of oxidative injury on nuclear trafficking of proteins, this review synthesizes emerging evidence for altered nuclear transport as a possible mechanism in the pathogenesis of neurodegenerative diseases. Potential strategies to overcome such deficits are also discussed. PMID:21487518

Epigenomics and breast cancer

PubMed Central

Lo, Pang-Kuo

2009-01-01

Breast carcinogenesis involves genetic and epigenetic alterations that cause aberrant gene function. Recent progress in the knowledge of epigenomics has had a profound impact on the understanding of mechanisms leading to breast cancer, and consequently the development of new strategies for diagnosis and treatment of breast cancer. Epigenetic regulation has been known to involve three mutually interacting events – DNA methylation, histone modifications and nucleosomal remodeling. These processes modulate chromatin structure to form euchromatin or heterochromatin, and in turn activate or silence gene expression. Alteration in expression of key genes through aberrant epigenetic regulation in breast cells can lead to initiation, promotion and maintenance of carcinogenesis, and is even implicated in the generation of drug resistance. We currently review known roles of the epigenetic machinery in the development and recurrence of breast cancer. Furthermore, we highlight the significance of epigenetic alterations as predictive biomarkers and as new targets of anticancer therapy. PMID:19072646

Random motor generation in a finger tapping task: influence of spatial contingency and of cortical and subcortical hemispheric brain lesions

PubMed Central

Annoni, J.; Pegna, A.

1997-01-01

OBJECTIVE—To test the hypothesis that, during random motor generation, the spatial contingencies inherent to the task would induce additional preferences in normal subjects, shifting their performances farther from randomness. By contrast, perceptual or executive dysfunction could alter these task related biases in patients with brain damage.
METHODS—Two groups of patients, with right and left focal brain lesions, as well as 25 right handed subjects matched for age and handedness were asked to execute a random choice motor task—namely, to generate a random series of 180 button presses from a set of 10 keys placed vertically in front of them.
RESULTS—In the control group, as in the left brain lesion group, motor generation was subject to deviations from theoretical expected randomness, similar to those when numbers are generated mentally, as immediate repetitions (successive presses on the same key) are avoided. However, the distribution of button presses was also contingent on the topographic disposition of the keys: the central keys were chosen more often than those placed at extreme positions. Small distances were favoured, particularly with the left hand. These patterns were influenced by implicit strategies and task related contingencies.
 By contrast, right brain lesion patients with frontal involvement tended to show a more square distribution of key presses—that is, the number of key presses tended to be more equally distributed. The strategies were also altered by brain lesions: the number of immediate repetitions was more frequent when the lesion involved the right frontal areas yielding a random generation nearer to expected theoretical randomness. The frequency of adjacent key presses was increased by right anterior and left posterior cortical as well as by right subcortical lesions, but decreased by left subcortical lesions.
CONCLUSIONS—Depending on the side of the lesion and the degree of cortical-subcortical involvement, the deficits take on a different aspect and direct repetions and adjacent key presses have different patterns of alterations. Motor random generation is therefore a complex task which seems to necessitate the participation of numerous cerebral structures, among which those situated in the right frontal, left posterior, and subcortical regions have a predominant role.

 PMID:9408109

Cell proliferation and plant development under novel altered gravity environments.

PubMed

Herranz, R; Medina, F J

2014-01-01

Gravity is a key factor for life on Earth. It is the only environmental factor that has remained constant throughout evolution, and plants use it to modulate important physiological activities; gravity removal or alteration produces substantial changes in essential functions. For root gravitropism, gravity is sensed in specialised cells, which are capable of detecting magnitudes of the g vector lower than 10(-3) . Then, the mechanosignal is transduced to upper zones of the root, resulting in changes in the lateral distribution of auxin and in the rate of auxin polar transport. Gravity alteration has consequences for cell growth and proliferation rates in root meristems, which are the basis of the developmental programme of a plant, in which regulation via auxin is involved. The effect is disruption of meristematic competence, i.e. the strict coordination between cell proliferation and growth, which characterises meristematic cells. This effect can be related to changes in the transport and distribution of auxin throughout the root. However, similar effects of gravity alteration have been found in plant cell cultures in vitro, in which neither specialised structures for gravity sensing and signal transduction, nor apparent gravitropism have been described. We postulate that gravity resistance, a general mechanism of cellular origin for developing rigid structures in plants capable of resisting the gravity force, could also be responsible for the changes in cell growth and proliferation parameters detected in non-specialised cells. The mechanisms of gravitropism and graviresistance are complementary, the first being mostly sensitive to the direction of the gravity vector, and the second to its magnitude. At a global molecular level, the consequence of gravity alteration is that the genome should be finely tuned to counteract a type of stress that plants have never encountered before throughout evolution. Multigene families and redundant genes present an advantage in that they can experience changes without the risk of being deleterious and, for this reason, they should play a key role in the response to gravitational stress. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

Effects of the beta2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia.

PubMed

Salazar-Degracia, Anna; Busquets, Sílvia; Argilés, Josep M; Bargalló-Gispert, Núria; López-Soriano, Francisco J; Barreiro, Esther

2018-06-01

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta 2 agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 10 8 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta 2 agonist formoterol in the cachectic muscles through several key biological pathways. Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Flap Conformations in HIV-1 Protease are Altered by Mutations

NASA Astrophysics Data System (ADS)

Fanucci, Gail; Blackburn, Mandy; Veloro, Angelo; Galiano, Luis; Fangu, Ding; Simmerling, Carlos

2009-03-01

HIV-1 protease (PR) is an enzyme that is a major drug target in the treatment of AIDS. Although the structure and function of HIV-1 PR have been studied for over 20 years, questions remain regarding the conformations and dynamics of the β-hairpin turns (flaps) that cover the active site cavity. Distance measurements with pulsed EPR spectroscopy of spin labeled constructs of HIV-1 PR have been used to characterize the flap conformations in the apo and inhibitor bound states. From the most probably distances and the breadth of the distance distribution profiles from analysis of the EPR data, insights regarding the flap conformations and flexibility are gained. The EPR results clearly show how drug pressure selected mutations alter the average conformation of the flaps and the degree of opening of the flaps. Molecular dynamics simulations successfully regenerate the experimentally determined distance distribution profiles, and more importantly, provide structural models for full interpretation of the EPR results. By combining experiment and theory to understand the role that altered flap flexibility/conformations play in the mechanism of drug resistance, key insights are gained toward the rational development of new inhibitors of this important enzyme.

Stromal matrix metalloprotease-13 knockout alters Collagen I structure at the tumor-host interface and increases lung metastasis of C57BL/6 syngeneic E0771 mammary tumor cells.

PubMed

Perry, Seth W; Schueckler, Jill M; Burke, Kathleen; Arcuri, Giuseppe L; Brown, Edward B

2013-09-05

Matrix metalloproteases and collagen are key participants in breast cancer, but their precise roles in cancer etiology and progression remain unclear. MMP13 helps regulate collagen structure and has been ascribed largely harmful roles in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology. Other studies indicate that collagen's organizational patterns at the breast tumor-host interface influence metastatic potential. Therefore we investigated how MMP13 modulates collagen I, a principal collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer. Tumors were implanted into murine mammary tissues, and their growth analyzed in Wildtype and MMP13 KO mice. Following extraction, tumors were analyzed for collagen I levels and collagen I macro- and micro-structural properties at the tumor-host boundary using immunocytochemistry and two-photon and second harmonic generation microscopy. Lungs were analyzed for metastases counts, to correlate collagen I changes with a clinically significant functional parameter. Statistical analyses were performed by t-test, analysis of variance, or Wilcoxon-Mann-Whitney tests as appropriate. We found that genetic ablation of host stromal MMP13 led to: 1. Increased mammary tumor collagen I content, 2. Marked changes in collagen I spatial organization, and 3. Altered collagen I microstructure at the tumor-host boundary, as well as 4. Increased metastasis from the primary mammary tumor to lungs. These results implicate host MMP13 as a key regulator of collagen I structure and metastasis in mammary tumors, thus making it an attractive potential therapeutic target by which we might alter metastatic potential, one of the chief determinants of clinical outcome in breast cancer. In addition to identifying stromal MMP13 is an important regulator of the tumor microenvironment and metastasis, these results also suggest that stromal MMP13 may protect against breast cancer pathology under some conditions, a finding with important implications for development of chemotherapies directed against matrix metalloproteases.

Forest legacies, climate change, altered disturbance regimes, invasive species and water

USGS Publications Warehouse

Stohlgren, T.; Jarnevich, C.; Kumar, S.

2007-01-01

The factors that must be considered in seeking to predict changes in water availability has been examined. These factors are the following: forest legacies including logging, mining, agriculture, grazing, elimination of large carnivores, human-caused wildfire, and pollution; climate change and stream flow; altered disturbances such as frequency intensity and pattern of wildfires and insect outbreaks as well as flood control; lastly, invasive species like forest pests and pathogens. An integrated approach quantifying the current and past condition trends can be combined with spatial and temporal modeling to develop future change in forest structures and water supply. The key is a combination of geographic information system technologies with climate and land use scenarios, while preventing and minimizing the effects of harmful invasive species.

Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments

PubMed Central

Siedler, Declan G.; Chuah, Meng Inn; Kirkcaldie, Matthew T. K.; Vickers, James C.; King, Anna E.

2014-01-01

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury. PMID:25565963

The Crystal Structure of a Cardiovirus RNA-Dependent RNA Polymerase Reveals an Unusual Conformation of the Polymerase Active Site

PubMed Central

Vives-Adrian, Laia; Lujan, Celia; Oliva, Baldo; van der Linden, Lonneke; Selisko, Barbara; Coutard, Bruno; Canard, Bruno; van Kuppeveld, Frank J. M.

2014-01-01

ABSTRACT Encephalomyocarditis virus (EMCV) is a member of the Cardiovirus genus within the large Picornaviridae family, which includes a number of important human and animal pathogens. The RNA-dependent RNA polymerase (RdRp) 3Dpol is a key enzyme for viral genome replication. In this study, we report the X-ray structures of two different crystal forms of the EMCV RdRp determined at 2.8- and 2.15-Å resolution. The in vitro elongation and VPg uridylylation activities of the purified enzyme have also been demonstrated. Although the overall structure of EMCV 3Dpol is shown to be similar to that of the known RdRps of other members of the Picornaviridae family, structural comparisons show a large reorganization of the active-site cavity in one of the crystal forms. The rearrangement affects mainly motif A, where the conserved residue Asp240, involved in ribonucleoside triphosphate (rNTP) selection, and its neighbor residue, Phe239, move about 10 Å from their expected positions within the ribose binding pocket toward the entrance of the rNTP tunnel. This altered conformation of motif A is stabilized by a cation-π interaction established between the aromatic ring of Phe239 and the side chain of Lys56 within the finger domain. Other contacts, involving Phe239 and different residues of motif F, are also observed. The movement of motif A is connected with important conformational changes in the finger region flanked by residues 54 to 63, harboring Lys56, and in the polymerase N terminus. The structures determined in this work provide essential information for studies on the cardiovirus RNA replication process and may have important implications for the development of new antivirals targeting the altered conformation of motif A. IMPORTANCE The Picornaviridae family is one of the largest virus families known, including many important human and animal pathogens. The RNA-dependent RNA polymerase (RdRp) 3Dpol is a key enzyme for picornavirus genome replication and a validated target for the development of antiviral therapies. Solving the X-ray structure of the first cardiovirus RdRp, EMCV 3Dpol, we captured an altered conformation of a conserved motif in the polymerase active site (motif A) containing the aspartic acid residue involved in rNTP selection and binding. This altered conformation of motif A, which interferes with the correct positioning of the rNTP substrate in the active site, is stabilized by a number of residues strictly conserved among picornaviruses. The rearrangements observed suggest that this motif A segment is a dynamic element that can be modulated by external effectors, either activating or inhibiting enzyme activity, and this type of modulation appears to be general to all picornaviruses. PMID:24600002

The crystal structure of a cardiovirus RNA-dependent RNA polymerase reveals an unusual conformation of the polymerase active site.

PubMed

Vives-Adrian, Laia; Lujan, Celia; Oliva, Baldo; van der Linden, Lonneke; Selisko, Barbara; Coutard, Bruno; Canard, Bruno; van Kuppeveld, Frank J M; Ferrer-Orta, Cristina; Verdaguer, Núria

2014-05-01

Encephalomyocarditis virus (EMCV) is a member of the Cardiovirus genus within the large Picornaviridae family, which includes a number of important human and animal pathogens. The RNA-dependent RNA polymerase (RdRp) 3Dpol is a key enzyme for viral genome replication. In this study, we report the X-ray structures of two different crystal forms of the EMCV RdRp determined at 2.8- and 2.15-Å resolution. The in vitro elongation and VPg uridylylation activities of the purified enzyme have also been demonstrated. Although the overall structure of EMCV 3Dpol is shown to be similar to that of the known RdRps of other members of the Picornaviridae family, structural comparisons show a large reorganization of the active-site cavity in one of the crystal forms. The rearrangement affects mainly motif A, where the conserved residue Asp240, involved in ribonucleoside triphosphate (rNTP) selection, and its neighbor residue, Phe239, move about 10 Å from their expected positions within the ribose binding pocket toward the entrance of the rNTP tunnel. This altered conformation of motif A is stabilized by a cation-π interaction established between the aromatic ring of Phe239 and the side chain of Lys56 within the finger domain. Other contacts, involving Phe239 and different residues of motif F, are also observed. The movement of motif A is connected with important conformational changes in the finger region flanked by residues 54 to 63, harboring Lys56, and in the polymerase N terminus. The structures determined in this work provide essential information for studies on the cardiovirus RNA replication process and may have important implications for the development of new antivirals targeting the altered conformation of motif A. The Picornaviridae family is one of the largest virus families known, including many important human and animal pathogens. The RNA-dependent RNA polymerase (RdRp) 3Dpol is a key enzyme for picornavirus genome replication and a validated target for the development of antiviral therapies. Solving the X-ray structure of the first cardiovirus RdRp, EMCV 3Dpol, we captured an altered conformation of a conserved motif in the polymerase active site (motif A) containing the aspartic acid residue involved in rNTP selection and binding. This altered conformation of motif A, which interferes with the correct positioning of the rNTP substrate in the active site, is stabilized by a number of residues strictly conserved among picornaviruses. The rearrangements observed suggest that this motif A segment is a dynamic element that can be modulated by external effectors, either activating or inhibiting enzyme activity, and this type of modulation appears to be general to all picornaviruses.

Structural differences in interictal migraine attack after epilepsy: A diffusion tensor imaging analysis.

PubMed

Huang, Qi; Lv, Xin; He, Yushuang; Wei, Xing; Ma, Meigang; Liao, Yuhan; Qin, Chao; Wu, Yuan

2017-12-01

Patients with epilepsy (PWE) are more likely to suffer from migraine attack, and aberrant white matter (WM) organization may be the mechanism underlying this phenomenon. This study aimed to use diffusion tensor imaging (DTI) technique to quantify WM structural differences in PWE with interictal migraine. Diffusion tensor imaging data were acquired in 13 PWE with migraine and 12 PWE without migraine. Diffusion metrics were analyzed using tract-atlas-based spatial statistics analysis. Atlas-based and tract-based spatial statistical analyses were conducted for robustness analysis. Correlation was explored between altered DTI metrics and clinical parameters. The main results are as follows: (i) Axonal damage plays a key role in PWE with interictal migraine. (ii) Significant diffusing alterations included higher fractional anisotropy (FA) in the fornix, higher mean diffusivity (MD) in the middle cerebellar peduncle (CP), left superior CP, and right uncinate fasciculus, and higher axial diffusivity (AD) in the middle CP and right medial lemniscus. (iii) Diffusion tensor imaging metrics has the tendency of correlation with seizure/migraine type and duration. Results indicate that characteristic structural impairments exist in PWE with interictal migraine. Epilepsy may contribute to migraine by altering WMs in the brain stem. White matter tracts in the fornix and right uncinate fasciculus also mediate migraine after epilepsy. This finding may improve our understanding of the pathological mechanisms underlying migraine attack after epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Gold grade distribution within an epithermal quartz vein system, Kestanelik, NW Turkey: implications for gold exploration

NASA Astrophysics Data System (ADS)

Gulyuz, Nilay; Shipton, Zoe; Gulyuz, Erhan; Lord, Richard; Kaymakci, Nuretdin; Kuscu, İlkay

2017-04-01

Vein-hosted gold deposits contribute a large part to the global gold production. Discovery of these deposits mainly include drilling of hundreds of holes, collecting thousands of soil and rock samples and some geophysical surveys which are expensive and time consuming. Understanding the structures hosting the veins and the variations in gold concentrations within the veins is crucial to constrain a more economic exploration program. The main aim of this study is to investigate the gold grade distribution in the mineralized quartz veins of a well exposed epithermal gold deposit hosted by Paleozoic schist and Eocene quartz-feldspar-hornblende porphyry in Lapseki, NW Turkey. We have constructed 3D architecture of the vein surfaces by mapping their outcrop geometries using a highly sensitive Trimble GPS, collecting detailed field data, well-logs and geochemistry data from 396 drill holes (255 diamond cut and 141 reverse circulation holes). Modelling was performed in MOVE Structural Modelling and Analysis software granted by Midland Valley's Academic Software Initiative, and GIS application softwares Global Mapper and Esri-ArcGIS. We envisaged that while fluid entering the conduit ascents, a sudden thickness increase in the conduit would lead to a drop in the fluid pressure causing boiling (the most dominant gold precipitation mechanism) and associated gold precipitation. Regression analysis was performed between the orthogonal thickness values and gold grades of each vein, and statistical analyses were performed to see if the gold is concentrated at specific structural positions along dip. Gold grades in the alteration zones were compared to those in the adjacent veins to understand the degree of mineralization in alteration zones. A possible correlation was also examined between the host rock type and the gold grades in the veins. These studies indicated that gold grades are elevated in the adjacent alteration zones where high gold grades exist in the veins. Schist-hosted veins host the majority of gold mineralization (94.39%). While there is almost no correlation between the true vein thickness and the gold grade, 77.65% of high gold grades are located where the veins bend along dip. These results suggest that multiple gold precipitation mechanisms may have been active and boiling mechanism responsible for gold precipitation along the structural pathways was more effective than possible fluid-rock interaction or throttling mechanisms which will precipitate gold at adjacent alteration zones around the pathways at Kestanelik. In addition, specific structural locations such as vein bends are favorable for gold precipitation. This study emphasizes that structural architecture of the veins is one of the key controls on the location of high gold grades. In addition, adding structural data collection and mapping specific structural locations such as bends to the exploration program could permit the key locations of high gold grade to be identified faster, and to focus further drilling and assays.

Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex

PubMed Central

Schaefer, Anne; Sampath, Srihari C.; Intrator, Adam; Min, Alice; Gertler, Tracy S.; Surmeier, D. James; Tarakhovsky, Alexander; Greengard, Paul

2009-01-01

SUMMARY The genetic basis of cognition and behavioral adaptation to the environment remains poorly understood. Here we demonstrate that the histone methyltransferase complex GLP/G9a controls cognition and adaptive responses in a region-specific fashion in the adult brain. Using conditional mutagenesis in mice, we show that postnatal, neuron-specific deficiency of GLP/G9a leads to de-repression of numerous non-neuronal and neuron progenitor genes in adult neurons. This transcriptional alteration is associated with complex behavioral abnormalities, including defects in learning, motivation and environmental adaptation. The behavioral changes triggered by GLP/G9a deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with structural alterations of the GLP gene. The likely causal role of GLP/G9a in mental retardation in mice and humans suggests a key role for the GLP/G9a controlled histone H3K9 di-methylation in regulation of brain function through maintenance of the transcriptional homeostasis in adult neurons. PMID:20005824

Confronting structural violence in sex work: lessons from a community-led HIV prevention project in Mysore, India.

PubMed

Argento, Elena; Reza-Paul, Sushena; Lorway, Robert; Jain, Jinendra; Bhagya, M; Fathima, Mary; Sreeram, S V; Hafeezur, Rahman Syed; O'Neil, John

2011-01-01

Evidence from community-led HIV prevention projects suggests that structural interventions may result in reduced rates of HIV and STIs. The complex relationship between empowerment and confronting stigma, discrimination and physical abuse necessitates further investigation into the impact that such interventions have on the personal risks for sex workers. This article aims to describe lived experiences of members from a sex worker's collective in Mysore, India and how they have confronted structural violence. The narratives highlight experiences of violence and the development and implementation of strategies that have altered the social, physical, and emotional environment for sex workers. Building an enabling environment was key to reducing personal risks inherent to sex work, emphasizing the importance of community-led structural interventions for sex workers in India.

Thermally Altered Silurian Cyanobacterial Mats: A Key to Earth's Oldest Fossils

NASA Astrophysics Data System (ADS)

Kazmierczak, Józef; Kremer, Barbara

2009-10-01

Diagenetic changes in thermally altered cyanobacterial mats from early Silurian black radiolarian cherts of southwestern Poland (Bardzkie Montains, Sudetes) have been studied. These early diagenetically silicified mats are composed of variously degraded remains of benthic microbes that resemble some modern chroococcalean and pleurocapsalean cyanobacteria. Two modes of degradational processes have been recognized in the studied mats: (i) early postmortem biodegradation and (ii) late diagenetic thermal or thermobaric degradation. The latter led to partial transformation of the fossilized organic remnants of cyanobacterial sheaths and capsules, which resulted in the formation of objects morphologically distant from the original microbiota but preserved features that allow for their identification as bona fide biogenic structures. Some of these thermally generated Silurian fossils are highly similar to the controversial microfossil-like carbonaceous structures described from the Early Archean Apex Chert of Australia. This similarity opens a promising way for credible recognition of remnants of cyanobacteria and similar microbiota in other thermally metamorphosed Archean sedimentary rocks

Exploring the limits of sequence and structure in a variant βγ-crystallin domain of the protein absent in melanoma-1 (AIM1)

PubMed Central

Aravind, Penmatsa; Wistow, Graeme; Sharma, Yogendra; Sankaranarayanan, Rajan

2008-01-01

βγ-Crystallins belong to a superfamily of proteins in prokaryotes and eukaryotes that are based on duplications of a characteristic, highly conserved Greek Key motif. Most members of the superfamily in vertebrates are structural proteins of the eye lens that contain four motifs arranged as two structural domains. Absent in melanoma-1 (AIM1), an unusual member of the superfamily whose expression is associated with suppression of malignancy in melanoma, contains 12 βγ-crystallin motifs in six domains. Some of these motifs diverge considerably from the canonical motif sequence. AIM1g1, the first βγ-crystallin domain of AIM1, is the most variant of βγ-crystallin domains currently known. In order to understand the limits of sequence variation on the structure, we report the crystal structure of AIM1g1 at 1.9Å resolution. In spite of having changes in key residues, the domain retains the overall βγ-crystallin fold. The domain also contains an unusual extended surface loop that significantly alters the shape of the domain and its charge profile. This structure illustrates the resilience of the βγ fold to considerable sequence changes and its remarkable ability to adapt for novel functions. PMID:18582473

Oxidation of a critical methionine modulates DNA binding of the Drosophila melanogaster high mobility group protein, HMG-D.

PubMed

Dow, L K; Changela, A; Hefner, H E; Churchill, M E

1997-09-15

HMG-D is a major high mobility group chromosomal protein present during early embryogenesis in Drosophila melanogaster. During overexpression and purification of HMG-D from E. coli, a key DNA binding residue, methionine 13, undergoes oxidation to methionine sulfoxide. Oxidation of this critical residue decreases the affinity of HMG-D for DNA by three-fold, altering the structure of the HMG-D-DNA complex without affecting the structure of the free protein. This work shows that minor modification of DNA intercalating residues may be used to fine tune the DNA binding affinity of HMG domain proteins.

Consumer trait variation influences tritrophic interactions in salt marsh communities.

PubMed

Hughes, Anne Randall; Hanley, Torrance C; Orozco, Nohelia P; Zerebecki, Robyn A

2015-07-01

The importance of intraspecific variation has emerged as a key question in community ecology, helping to bridge the gap between ecology and evolution. Although much of this work has focused on plant species, recent syntheses have highlighted the prevalence and potential importance of morphological, behavioral, and life history variation within animals for ecological and evolutionary processes. Many small-bodied consumers live on the plant that they consume, often resulting in host plant-associated trait variation within and across consumer species. Given the central position of consumer species within tritrophic food webs, such consumer trait variation may play a particularly important role in mediating trophic dynamics, including trophic cascades. In this study, we used a series of field surveys and laboratory experiments to document intraspecific trait variation in a key consumer species, the marsh periwinkle Littoraria irrorata, based on its host plant species (Spartina alterniflora or Juncus roemerianus) in a mixed species assemblage. We then conducted a 12-week mesocosm experiment to examine the effects of Littoraria trait variation on plant community structure and dynamics in a tritrophic salt marsh food web. Littoraria from different host plant species varied across a suite of morphological and behavioral traits. These consumer trait differences interacted with plant community composition and predator presence to affect overall plant stem height, as well as differentially alter the density and biomass of the two key plant species in this system. Whether due to genetic differences or phenotypic plasticity, trait differences between consumer types had significant ecological consequences for the tritrophic marsh food web over seasonal time scales. By altering the cascading effects of the top predator on plant community structure and dynamics, consumer differences may generate a feedback over longer time scales, which in turn influences the degree of trait divergence in subsequent consumer populations.

Mysticism and schizophrenia: A phenomenological exploration of the structure of consciousness in the schizophrenia spectrum disorders.

PubMed

Parnas, Josef; Henriksen, Mads Gram

2016-07-01

Mysticism and schizophrenia are different categories of human existence and experience. Nonetheless, they exhibit important phenomenological affinities, which, however, remain largely unaddressed. In this study, we explore structural analogies between key features of mysticism and major clinical-phenomenological aspects of the schizophrenia spectrum disorders-i.e. attitudes, the nature of experience, and the 'other', mystical or psychotic reality. Not only do these features gravitate around the issue of the basic dimensions of consciousness, they crucially seem to implicate and presuppose a specific alteration of the very structure of consciousness. This finding has bearings for the understanding of consciousness and its psychopathological distortions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The Effect of Aqueous Alteration in Antarctic Carbonaceous Chondrites from Comparative ICP-MS Bulk Chemistry

NASA Technical Reports Server (NTRS)

Alonso-Azcarate, J.; Trigo-Rodriguez, J. M.; Moyano-Cambero, C. E.; Zolensky, M.

2014-01-01

Terrestrial ages of Antarctic carbonaceous chondrites (CC) indicate that these meteorites have been preserved in or on ice for, at least, tens of thousands of years. Due to the porous structure of these chondrites formed by the aggregation of silicate-rich chondrules, refractory inclusions, metal grains, and fine-grained matrix materials, the effect of pervasive terrestrial water is relevant. Our community defends that pristine CC matrices are representing samples of scarcely processed protoplanetary disk materials as they contain stellar grains, but they might also trace parent body processes. It is important to study the effects of terrestrial aqueous alteration in promoting bulk chemistry changes, and creating distinctive alteration minerals. Particularly because it is thought that aqueous alteration has particularly played a key role in some CC groups in modifying primordial bulk chemistry, and homogenizing the isotopic content of fine-grained matrix materials. Fortunately, the mineralogy produced by parent-body and terrestrial aqueous alteration processes is distinctive. With the goal to learn more about terrestrial alteration in Antarctica we are obtaining reflectance spectra of CCs, but also performing ICP-MS bulk chemistry of the different CC groups. A direct comparison with the mean bulk elemental composition of recovered falls might inform us on the effects of terrestrial alteration in finds. With such a goal, in the current work we have analyzed some members representative of CO and CM chondrite groups.

Total synthesis and structure-activity investigation of the marine natural product neopeltolide.

PubMed

Custar, Daniel W; Zabawa, Thomas P; Hines, John; Crews, Craig M; Scheidt, Karl A

2009-09-02

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity.

The mechanisms of humic substances self-assembly with biological molecules: The case study of the prion protein

PubMed Central

Nepravishta, Ridvan; Mandaliti, Walter; Melino, Sonia; Margon, Alja; Scaini, Denis; Mazzei, Pierluigi; Piccolo, Alessandro; Legname, Giuseppe; Paci, Maurizio; Leita, Liviana

2017-01-01

Humic substances (HS) are the largest constituent of soil organic matter and are considered as a key component of the terrestrial ecosystem. HS may facilitate the transport of organic and inorganic molecules, as well as the sorption interactions with environmentally relevant proteins such as prions. Prions enter the environment through shedding from live hosts, facilitating a sustained incidence of animal prion diseases such as Chronic Wasting Disease and scrapie in cervid and ovine populations, respectively. Changes in prion structure upon environmental exposure may be significant as they can affect prion infectivity and disease pathology. Despite its relevance, the mechanisms of prion interaction with HS are still not completely understood. The goal of this work is to advance a structural-level picture of the encapsulation of recombinant, non-infectious, prion protein (PrP) into different natural HS. We observed that PrP precipitation upon addition of HS is mainly driven by a mechanism of “salting-out” whereby PrP molecules are rapidly removed from the solution and aggregate in insoluble adducts with humic molecules. Importantly, this process does not alter the protein folding since insoluble PrP retains its α-helical content when in complex with HS. The observed ability of HS to promote PrP insolubilization without altering its secondary structure may have potential relevance in the context of “prion ecology”. These results suggest that soil organic matter interacts with prions possibly without altering the protein structures. This may facilitate prions preservation from biotic and abiotic degradation leading to their accumulation in the environment. PMID:29161325

Loss of Mitochondrial Function Impairs Lysosomes.

PubMed

Demers-Lamarche, Julie; Guillebaud, Gérald; Tlili, Mouna; Todkar, Kiran; Bélanger, Noémie; Grondin, Martine; Nguyen, Angela P; Michel, Jennifer; Germain, Marc

2016-05-06

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Cortactin Branches Out: Roles in Regulating Protrusive Actin Dynamics

PubMed Central

Ammer, Amanda Gatesman; Weed, Scott A.

2008-01-01

Since its discovery in the early 1990’s, cortactin has emerged as a key signaling protein in many cellular processes, including cell adhesion, migration, endocytosis, and tumor invasion. While the list of cellular functions influenced by cortactin grows, the ability of cortactin to interact with and alter the cortical actin network is central to its role in regulating these processes. Recently, several advances have been made in our understanding of the interaction between actin and cortactin, providing insight into how these two proteins work together to provide a framework for normal and altered cellular function. This review examines how regulation of cortactin through post-translational modifications and interactions with multiple binding partners elicits changes in cortical actin cytoskeletal organization, impacting the regulation and formation of actin-rich motility structures. PMID:18615630

Contribution of Circulatory Disturbances in Subchondral Bone to the Pathophysiology of Osteoarthritis.

PubMed

Aaron, Roy K; Racine, Jennifer; Dyke, Jonathan P

2017-08-01

This review describes the contributions of abnormal bone circulation to the pathophysiology of osteoarthritis. Combining dynamic imaging with MRI and PET with previous observations reveals that venous stasis and a venous outlet syndrome is most likely the key circulatory pathology associated with the initiation or progression of osteoarthritis. MRI and PET have revealed that venous outflow obstruction results in physicochemical changes in subchondral bone to which osteoblasts are responsive. The osteoblasts express an altered pattern of cytokines, many of which can serve as structural or signaling molecules contributing to both bone remodeling and cartilage degeneration. The patterns of circulatory changes are associated with alterations in the physicochemical environment of subchondral bone, including hypoxia. Osteoblast cytokines can transit the subchondral bone plate and calcified cartilage and communicate with chondrocytes.

[Algorithm of toxigenic genetically altered Vibrio cholerae El Tor biovar strain identification].

PubMed

Smirnova, N I; Agafonov, D A; Zadnova, S P; Cherkasov, A V; Kutyrev, V V

2014-01-01

Development of an algorithm of genetically altered Vibrio cholerae biovar El Tor strai identification that ensures determination of serogroup, serovar and biovar of the studied isolate based on pheno- and genotypic properties, detection of genetically altered cholera El Tor causative agents, their differentiation by epidemic potential as well as evaluation of variability of key pathogenicity genes. Complex analysis of 28 natural V. cholerae strains was carried out by using traditional microbiological methods, PCR and fragmentary sequencing. An algorithm of toxigenic genetically altered V. cholerae biovar El Tor strain identification was developed that includes 4 stages: determination of serogroup, serovar and biovar based on phenotypic properties, confirmation of serogroup and biovar based on molecular-genetic properties determination of strains as genetically altered, differentiation of genetically altered strains by their epidemic potential and detection of ctxB and tcpA key pathogenicity gene polymorphism. The algorithm is based on the use of traditional microbiological methods, PCR and sequencing of gene fragments. The use of the developed algorithm will increase the effectiveness of detection of genetically altered variants of the cholera El Tor causative agent, their differentiation by epidemic potential and will ensure establishment of polymorphism of genes that code key pathogenicity factors for determination of origins of the strains and possible routes of introduction of the infection.

Toward Repurposing Metformin as a Precision Anti-Cancer Therapy Using Structural Systems Pharmacology

PubMed Central

Hart, Thomas; Dider, Shihab; Han, Weiwei; Xu, Hua; Zhao, Zhongming; Xie, Lei

2016-01-01

Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin’s molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies. PMID:26841718

Redox Signaling in Diabetic Wound Healing Regulates Extracellular Matrix Deposition.

PubMed

Kunkemoeller, Britta; Kyriakides, Themis R

2017-10-20

Impaired wound healing is a major complication of diabetes, and can lead to development of chronic foot ulcers in a significant number of patients. Despite the danger posed by poor healing, very few specific therapies exist, leaving patients at risk of hospitalization, amputation, and further decline in overall health. Recent Advances: Redox signaling is a key regulator of wound healing, especially through its influence on the extracellular matrix (ECM). Normal redox signaling is disrupted in diabetes leading to several pathological mechanisms that alter the balance between reactive oxygen species (ROS) generation and scavenging. Importantly, pathological oxidative stress can alter ECM structure and function. There is limited understanding of the specific role of altered redox signaling in the diabetic wound, although there is evidence that ROS are involved in the underlying pathology. Preclinical studies of antioxidant-based therapies for diabetic wound healing have yielded promising results. Redox-based therapeutics constitute a novel approach for the treatment of wounds in diabetes patients that deserve further investigation. Antioxid. Redox Signal. 27, 823-838.

Topological Alterations and Symptom-Relevant Modules in the Whole-Brain Structural Network in Semantic Dementia.

PubMed

Ding, Junhua; Chen, Keliang; Zhang, Weibin; Li, Ming; Chen, Yan; Yang, Qing; Lv, Yingru; Guo, Qihao; Han, Zaizhu

2017-01-01

Semantic dementia (SD) is characterized by a selective decline in semantic processing. Although the neuropsychological pattern of this disease has been identified, its topological global alterations and symptom-relevant modules in the whole-brain anatomical network have not been fully elucidated. This study aims to explore the topological alteration of anatomical network in SD and reveal the modules associated with semantic deficits in this disease. We first constructed the whole-brain white-matter networks of 20 healthy controls and 19 patients with SD. Then, the network metrics of graph theory were compared between these two groups. Finally, we separated the network of SD patients into different modules and correlated the structural integrity of each module with the severity of the semantic deficits across patients. The network of the SD patients presented a significantly reduced global efficiency, indicating that the long-distance connections were damaged. The network was divided into the following four distinctive modules: the left temporal/occipital/parietal, frontal, right temporal/occipital, and frontal/parietal modules. The first two modules were associated with the semantic deficits of SD. These findings illustrate the skeleton of the neuroanatomical network of SD patients and highlight the key role of the left temporal/occipital/parietal module and the left frontal module in semantic processing.

Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain

NASA Astrophysics Data System (ADS)

Godin, Antoine G.; Varela, Juan A.; Gao, Zhenghong; Danné, Noémie; Dupuis, Julien P.; Lounis, Brahim; Groc, Laurent; Cognet, Laurent

2017-03-01

The brain is a dynamic structure with the extracellular space (ECS) taking up almost a quarter of its volume. Signalling molecules, neurotransmitters and nutrients transit via the ECS, which constitutes a key microenvironment for cellular communication and the clearance of toxic metabolites. The spatial organization of the ECS varies during sleep, development and aging and is probably altered in neuropsychiatric and degenerative diseases, as inferred from electron microscopy and macroscopic biophysical investigations. Here we show an approach to directly observe the local ECS structures and rheology in brain tissue using super-resolution imaging. We inject single-walled carbon nanotubes into rat cerebroventricles and follow the near-infrared emission of individual nanotubes as they diffuse inside the ECS for tens of minutes in acute slices. Because of the interplay between the nanotube geometry and the ECS local environment, we can extract information about the dimensions and local viscosity of the ECS. We find a striking diversity of ECS dimensions down to 40 nm, and as well as of local viscosity values. Moreover, by chemically altering the extracellular matrix of the brains of live animals before nanotube injection, we reveal that the rheological properties of the ECS are affected, but these alterations are local and inhomogeneous at the nanoscale.

F1174V mutation alters the ALK active conformation in response to Crizotinib in NSCLC: Insight from molecular simulations.

PubMed

Dehghanian, Fariba; Kay, Maryam; Vallian, Sadeq

2017-08-01

Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain. The results suggested that F1174V mutation could cause two important secondary structure alterations, which led to the local conformational change in ALK kinase domain. This causes more positive free energy in the mutant complex in comparison with the wild-type one. In addition, our structural analyses illustrated that F1174V mutation could result in some important interactions, which represent the key characteristics of the ALK active conformation. This study provided a molecular mechanism for ALK Crizotinib resistance caused by F1174V mutation,which could facilitate designing more efficient drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults

PubMed Central

DiBattista, Amanda Marie; Stevens, Benson W.; Rebeck, G. William; Green, Adam E.

2014-01-01

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root. PMID:25339884

Human effects on ecological connectivity in aquatic ecosystems: Integrating scientific approaches to support management and mitigation.

PubMed

Crook, David A; Lowe, Winsor H; Allendorf, Frederick W; Erős, Tibor; Finn, Debra S; Gillanders, Bronwyn M; Hadwen, Wade L; Harrod, Chris; Hermoso, Virgilio; Jennings, Simon; Kilada, Raouf W; Nagelkerken, Ivan; Hansen, Michael M; Page, Timothy J; Riginos, Cynthia; Fry, Brian; Hughes, Jane M

2015-11-15

Understanding the drivers and implications of anthropogenic disturbance of ecological connectivity is a key concern for the conservation of biodiversity and ecosystem processes. Here, we review human activities that affect the movements and dispersal of aquatic organisms, including damming of rivers, river regulation, habitat loss and alteration, human-assisted dispersal of organisms and climate change. Using a series of case studies, we show that the insight needed to understand the nature and implications of connectivity, and to underpin conservation and management, is best achieved via data synthesis from multiple analytical approaches. We identify four key knowledge requirements for progressing our understanding of the effects of anthropogenic impacts on ecological connectivity: autecology; population structure; movement characteristics; and environmental tolerance/phenotypic plasticity. Structuring empirical research around these four broad data requirements, and using this information to parameterise appropriate models and develop management approaches, will allow for mitigation of the effects of anthropogenic disturbance on ecological connectivity in aquatic ecosystems. Copyright © 2015 Elsevier B.V. All rights reserved.

From patterns to emerging processes in mechanistic urban ecology.

PubMed

Shochat, Eyal; Warren, Paige S; Faeth, Stanley H; McIntyre, Nancy E; Hope, Diane

2006-04-01

Rapid urbanization has become an area of crucial concern in conservation owing to the radical changes in habitat structure and loss of species engendered by urban and suburban development. Here, we draw on recent mechanistic ecological studies to argue that, in addition to altered habitat structure, three major processes contribute to the patterns of reduced species diversity and elevated abundance of many species in urban environments. These activities, in turn, lead to changes in animal behavior, morphology and genetics, as well as in selection pressures on animals and plants. Thus, the key to understanding urban patterns is to balance studying processes at the individual level with an integrated examination of environmental forces at the ecosystem scale.

Noise pollution alters ecological services: enhanced pollination and disrupted seed dispersal

PubMed Central

Francis, Clinton D.; Kleist, Nathan J.; Ortega, Catherine P.; Cruz, Alexander

2012-01-01

Noise pollution is a novel, widespread environmental force that has recently been shown to alter the behaviour and distribution of birds and other vertebrates, yet whether noise has cumulative, community-level consequences by changing critical ecological services is unknown. Herein, we examined the effects of noise pollution on pollination and seed dispersal and seedling establishment within a study system that isolated the effects of noise from confounding stimuli common to human-altered landscapes. Using observations, vegetation surveys and pollen transfer and seed removal experiments, we found that effects of noise pollution can reverberate through communities by disrupting or enhancing these ecological services. Specifically, noise pollution indirectly increased artificial flower pollination by hummingbirds, but altered the community of animals that prey upon and disperse Pinus edulis seeds, potentially explaining reduced P. edulis seedling recruitment in noisy areas. Despite evidence that some ecological services, such as pollination, may benefit indirectly owing to noise, declines in seedling recruitment for key-dominant species such as P. edulis may have dramatic long-term effects on ecosystem structure and diversity. Because the extent of noise pollution is growing, this study emphasizes that investigators should evaluate the ecological consequences of noise alongside other human-induced environmental changes that are reshaping human-altered landscapes worldwide. PMID:22438504

Noise pollution alters ecological services: enhanced pollination and disrupted seed dispersal.

PubMed

Francis, Clinton D; Kleist, Nathan J; Ortega, Catherine P; Cruz, Alexander

2012-07-22

Noise pollution is a novel, widespread environmental force that has recently been shown to alter the behaviour and distribution of birds and other vertebrates, yet whether noise has cumulative, community-level consequences by changing critical ecological services is unknown. Herein, we examined the effects of noise pollution on pollination and seed dispersal and seedling establishment within a study system that isolated the effects of noise from confounding stimuli common to human-altered landscapes. Using observations, vegetation surveys and pollen transfer and seed removal experiments, we found that effects of noise pollution can reverberate through communities by disrupting or enhancing these ecological services. Specifically, noise pollution indirectly increased artificial flower pollination by hummingbirds, but altered the community of animals that prey upon and disperse Pinus edulis seeds, potentially explaining reduced P. edulis seedling recruitment in noisy areas. Despite evidence that some ecological services, such as pollination, may benefit indirectly owing to noise, declines in seedling recruitment for key-dominant species such as P. edulis may have dramatic long-term effects on ecosystem structure and diversity. Because the extent of noise pollution is growing, this study emphasizes that investigators should evaluate the ecological consequences of noise alongside other human-induced environmental changes that are reshaping human-altered landscapes worldwide.

Hepatitis C virus envelope components alter localization of hepatocyte tight junction-associated proteins and promote occludin retention in the endoplasmic reticulum.

PubMed

Benedicto, Ignacio; Molina-Jiménez, Francisca; Barreiro, Olga; Maldonado-Rodríguez, Alejandra; Prieto, Jesús; Moreno-Otero, Ricardo; Aldabe, Rafael; López-Cabrera, Manuel; Majano, Pedro L

2008-10-01

Hepatocyte tight junctions (TJ) play key roles in characteristic liver functions, including bile formation and secretion. Infection by hepatitis C virus (HCV) may cause alterations of the liver architecture and disruption of the bile duct, which ultimately can lead to cholestasis. Herein, we employed the HCV replicon system to analyze the effect of HCV on TJ organization. TJ-associated proteins occludin, claudin-1, and Zonula Occludens protein-1 (ZO-1) disappeared from their normal localization at the border of adjacent cells in Huh7 clones harboring genomic but not subgenomic replicons expressing only the nonstructural proteins. Furthermore, cells containing genomic replicons showed a cytoplasmic accumulation of occludin in the endoplasmic reticulum (ER). TJ-associated function, measured as FITC-dextran paracellular permeability, of genomic replicon-containing cells, was also altered. Interestingly, clearance of the HCV replicon by interferon-alpha (IFN-alpha) treatment and by short hairpin RNA (shRNA) significantly restored the localization of TJ-associated proteins. Transient expression of all HCV structural proteins, but not core protein alone, altered the localization of TJ-associated proteins in Huh7 cells and in clones with subgenomic replicons. Confocal analysis showed that accumulation of occludin in the ER partially co-localized with HCV envelope glycoprotein E2. E2/occludin association was further confirmed by co-immunoprecipitation and pull-down assays. Additionally, using a cell culture model of HCV infection, we observed the cytoplasmic dot-like accumulation of occludin in infected Huh7 cells. We propose that HCV structural proteins, most likely those of the viral envelope, promote alterations of TJ-associated proteins, which may provide new insights for HCV-related pathogenesis.

Altered Expression of Genes Implicated in Xylan Biosynthesis Affects Penetration Resistance against Powdery Mildew.

PubMed

Chowdhury, Jamil; Lück, Stefanie; Rajaraman, Jeyaraman; Douchkov, Dimitar; Shirley, Neil J; Schwerdt, Julian G; Schweizer, Patrick; Fincher, Geoffrey B; Burton, Rachel A; Little, Alan

2017-01-01

Heteroxylan has recently been identified as an important component of papillae, which are formed during powdery mildew infection of barley leaves. Deposition of heteroxylan near the sites of attempted fungal penetration in the epidermal cell wall is believed to enhance the physical resistance to the fungal penetration peg and hence to improve pre-invasion resistance. Several glycosyltransferase (GT) families are implicated in the assembly of heteroxylan in the plant cell wall, and are likely to work together in a multi-enzyme complex. Members of key GT families reported to be involved in heteroxylan biosynthesis are up-regulated in the epidermal layer of barley leaves during powdery mildew infection. Modulation of their expression leads to altered susceptibility levels, suggesting that these genes are important for penetration resistance. The highest level of resistance was achieved when a GT43 gene was co-expressed with a GT47 candidate gene, both of which have been predicted to be involved in xylan backbone biosynthesis. Altering the expression level of several candidate heteroxylan synthesis genes can significantly alter disease susceptibility. This is predicted to occur through changes in the amount and structure of heteroxylan in barley papillae.

Neuroendocrine and neurotrophic signaling in Huntington's disease: Implications for pathogenic mechanisms and treatment strategies.

PubMed

Bartlett, Danielle M; Cruickshank, Travis M; Hannan, Anthony J; Eastwood, Peter R; Lazar, Alpar S; Ziman, Mel R

2016-12-01

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine tract in the huntingtin protein. Circadian, sleep and hypothalamic-pituitary-adrenal (HPA) axis disturbances are observed in HD as early as 15 years before clinical disease onset. Disturbances in these key processes result in increased cortisol and altered melatonin release which may negatively impact on brain-derived neurotrophic factor (BDNF) expression and contribute to documented neuropathological and clinical disease features. This review describes the normal interactions between neurotrophic factors, the HPA-axis and circadian rhythm, as indicated by levels of BDNF, cortisol and melatonin, and the alterations in these intricately balanced networks in HD. We also discuss the implications of these alterations on the neurobiology of HD and the potential to result in hypothalamic, circadian, and sleep pathologies. Measurable alterations in these pathways provide targets that, if treated early, may reduce degeneration of brain structures. We therefore focus here on the means by which multidisciplinary therapy could be utilised as a non-pharmaceutical approach to restore the balance of these pathways. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Engineering Biosynthesis of Non-ribosomal Peptides and Polyketides by Directed Evolution.

PubMed

Rui, Zhe; Zhang, Wenjun

2016-01-01

Non-ribosomal peptides (NRPs) and polyketides (PKs) play key roles in pharmaceutical industry due to their promising biological activities. The structural complexity of NRPs and PKs, however, creates significant synthetic challenges for producing these natural products and their analogues by purely chemical means. Alternatively, difficult syntheses can be achieved by using biosynthetic enzymes with improved efficiency and altered selectivity that are acquired from directed evolution. Key to the successful directed evolution is the methodology of screening/selection. This review summarizes the screening/selection strategies that have been employed to improve or modify the functions of non-ribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), in the hope of triggering the wide adoption of the directed evolution approaches in the engineered biosynthesis of NRPs and PKs for drug discovery.

A double-pulse approach for electrotransfection.

PubMed

Pasquet, L; Bellard, E; Golzio, M; Rols, M P; Teissie, J

2014-12-01

Gene transfer and expression can be obtained by delivering calibrated electric pulses on cells in the presence of plasmids coding for the activity of interest. The electric treatment affects the plasma membrane and induces the formation of a transient complex between nucleic acids and the plasma membrane. It results in a delivery of the plasmid in the cytoplasm. Expression is only obtained if the plasmid is translocated inside the nucleus. This is a key limit in the process. We previously showed that delivery of a high-field short-duration electric pulse was inducing a structural alteration of the nuclear envelope. This study investigates if the double-pulse approach (first pulse to transfer the plasmid to the cytoplasm, and second pulse to induce the structural alteration of the envelope) was a way to enhance the protein expression using the green fluorescent protein as a reporter. We observed that not only the double-pulse approach induced the transfection of a lower number of cells but moreover, these transfected cells were less fluorescent than the cells treated only with the first pulse.

Glycosylation potential of human prostate cancer cell lines

PubMed Central

Gao, Yin; Chachadi, Vishwanath B.; Cheng, Pi-Wan

2014-01-01

Altered glycosylation is a universal feature of cancer cells and altered glycans can help cancer cells escape immune surveillance, facilitate tumor invasion, and increase malignancy. The goal of this study was to identify specific glycoenzymes, which could distinguish prostate cancer cells from normal prostatic cells. We investigated enzymatic activities and gene expression levels of key glycosyl- and sulfotransferases responsible for the assembly of O- and N-glycans in several prostatic cells. These cells included immortalized RWPE-1 cells derived from normal prostatic tissues, and prostate cancer cells derived from metastasis in bone (PC-3), brain (DU145), lymph node (LNCaP), and vertebra (VCaP). We found that all cells were capable of synthesizing complex N-glycans and O-glycans with the core 1 structure, and each cell line had characteristic bio-synthetic pathways to modify these structures. The in vitro measured activities corresponded well to the mRNA levels of glycosyltransferases and sulfotransferases. Lectin and antibody binding to whole cells supported these results, which form the basis for the development of tumor cell-specific targeting strategies. PMID:22843320

Altered myofilament structure and function in dogs with Duchenne muscular dystrophy cardiomyopathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ait Mou, Younss; Lacampagne, Alain; Irving, Thomas

Aim Duchenne Muscular Dystrophy (DMD) is associated with progressive depressed left ventricular (LV) function. However, DMD effects on myofilament structure and function are poorly understood. Golden Retriever Muscular Dystrophy (GRMD) is a dog model of DMD recapitulating the human form of DMD. Objective The objective of this study is to evaluate myofilament structure and function alterations in GRMD model with spontaneous cardiac failure. Methods and results We have employed synchrotron X-rays diffraction to evaluate myofilament lattice spacing at various sarcomere lengths (SL) on permeabilized LV myocardium. We found a negative correlation between SL and lattice spacing in both sub-epicardium (EPI)more » and sub-endocardium (ENDO) LV layers in control dog hearts. In the ENDO of GRMD hearts this correlation is steeper due to higher lattice spacing at short SL (1.9 μm). Furthermore, cross-bridge cycling indexed by the kinetics of tension redevelopment (ktr) was faster in ENDO GRMD myofilaments at short SL. We measured post-translational modifications of key regulatory contractile proteins. S-glutathionylation of cardiac Myosin Binding Protein-C (cMyBP-C) was unchanged and PKA dependent phosphorylation of the cMyBP-C was significantly reduced in GRMD ENDO tissue and more modestly in EPI tissue. Conclusions We found a gradient of contractility in control dogs' myocardium that spreads across the LV wall, negatively correlated with myofilament lattice spacing. Chronic stress induced by dystrophin deficiency leads to heart failure that is tightly associated with regional structural changes indexed by increased myofilament lattice spacing, reduced phosphorylation of regulatory proteins and altered myofilament contractile properties in GRMD dogs.« less

Coastal urban lighting has ecological consequences for multiple trophic levels under the sea.

PubMed

Bolton, D; Mayer-Pinto, M; Clark, G F; Dafforn, K A; Brassil, W A; Becker, A; Johnston, E L

2017-01-15

Urban land and seascapes are increasingly exposed to artificial lighting at night (ALAN), which is a significant source of light pollution. A broad range of ecological effects are associated with ALAN, but the changes to ecological processes remain largely unstudied. Predation is a key ecological process that structures assemblages and responds to natural cycles of light and dark. We investigated the effect of ALAN on fish predatory behaviour, and sessile invertebrate prey assemblages. Over 21days fish and sessile assemblages were exposed to 3 light treatments (Day, Night and ALAN). An array of LED spotlights was installed under a wharf to create the ALAN treatments. We used GoPro cameras to film during the day and ALAN treatments, and a Dual frequency IDentification SONar (DIDSON) to film during the night treatments. Fish were most abundant during unlit nights, but were also relatively sedentary. Predatory behaviour was greatest during the day and under ALAN than at night, suggesting that fish are using structures for non-feeding purposes (e.g. shelter) at night, but artificial light dramatically increases their predatory behaviour. Altered predator behaviour corresponded with structural changes to sessile prey assemblages among the experimental lighting treatments. We demonstrate the direct effects of artificial lighting on fish behaviour and the concomitant indirect effects on sessile assemblage structure. Current and future projected use of artificial lights has the potential to significantly affect predator-prey interactions in marine systems by altering habitat use for both predators and prey. However, developments in lighting technology are a promising avenue for mitigation. This is among the first empirical evidence from the marine system on how ALAN can directly alter predation, a fundamental ecosystem process, and have indirect trophic consequences. Copyright © 2016 Elsevier B.V. All rights reserved.

Total Synthesis and Structure-Activity Investigation of the Marine Natural Product Neopeltolide

PubMed Central

Custar, Daniel W.; Zabawa, Thomas P.; Hines, John; Crews, Craig M.; Scheidt, Karl A.

2009-01-01

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity. PMID:19663512

EFFECTS OF OZONE ON ROOT PROCESSES

EPA Science Inventory

Ozone alters root growth and root processes by first reducing photosynthesis and altering foliar metabolic pathways. The alteration in foliar metabolism is reflected in lowered carbohydrate levels in the roots. This can reduce key metabolic processes such as mineral uptake and sy...

Domestication-driven Gossypium profilin 1 (GhPRF1) gene transduces early flowering phenotype in tobacco by spatial alteration of apical/floral-meristem related gene expression.

PubMed

Pandey, Dhananjay K; Chaudhary, Bhupendra

2016-05-13

Plant profilin genes encode core cell-wall structural proteins and are evidenced for their up-regulation under cotton domestication. Notwithstanding striking discoveries in the genetics of cell-wall organization in plants, little is explicit about the manner in which profilin-mediated molecular interplay and corresponding networks are altered, especially during cellular signalling of apical meristem determinacy and flower development. Here we show that the ectopic expression of GhPRF1 gene in tobacco resulted in the hyperactivation of apical meristem and early flowering phenotype with increased flower number in comparison to the control plants. Spatial expression alteration in CLV1, a key meristem-determinacy gene, is induced by the GhPRF1 overexpression in a WUS-dependent manner and mediates cell signalling to promote flowering. But no such expression alterations are recorded in the GhPRF1-RNAi lines. The GhPRF1 transduces key positive flowering regulator AP1 gene via coordinated expression of FT4, SOC1, FLC1 and FT1 genes involved in the apical-to-floral meristem signalling cascade which is consistent with our in silico profilin interaction data. Remarkably, these positive and negative flowering regulators are spatially controlled by the Actin-Related Protein (ARP) genes, specifically ARP4 and ARP6 in proximate association with profilins. This study provides a novel and systematic link between GhPRF1 gene expression and the flower primordium initiation via up-regulation of the ARP genes, and an insight into the functional characterization of GhPRF1 gene acting upstream to the flowering mechanism. Also, the transgenic plants expressing GhPRF1 gene show an increase in the plant height, internode length, leaf size and plant vigor. Overexpression of GhPRF1 gene induced early and increased flowering in tobacco with enhanced plant vigor. During apical meristem determinacy and flower development, the GhPRF1 gene directly influences key flowering regulators through ARP-genes, indicating for its role upstream in the apical-to-floral meristem signalling cascade.

Importance of doping, dopant distribution, and defects on electronic band structure alteration of metal oxide nanoparticles: Implications for reactive oxygen species.

PubMed

Saleh, Navid B; Milliron, Delia J; Aich, Nirupam; Katz, Lynn E; Liljestrand, Howard M; Kirisits, Mary Jo

2016-10-15

Metal oxide nanoparticles (MONPs) are considered to have the potency to generate reactive oxygen species (ROS), one of the key mechanisms underlying nanotoxicity. However, the nanotoxicology literature demonstrates a lack of consensus on the dominant toxicity mechanism(s) for a particular MONP. Moreover, recent literature has studied the correlation between band structure of pristine MONPs to their ability to introduce ROS and thus has downplayed the ROS-mediated toxicological relevance of a number of such materials. On the other hand, material science can control the band structure of these materials to engineer their electronic and optical properties and thereby is constantly modulating the pristine electronic structure. Since band structure is the fundamental material property that controls ROS-producing ability, band tuning via introduction of dopants and defects needs careful consideration in toxicity assessments. This commentary critically evaluates the existing material science and nanotoxicity literature and identifies the gap in our understanding of the role of important crystal structure features (i.e., dopants and defects) on MONPs' electronic structure alteration as well as their ROS-generation capability. Furthermore, this commentary provides suggestions on characterization techniques to evaluate dopants and defects on the crystal structure and identifies research needs for advanced theoretical predictions of their electronic band structures and ROS-generation abilities. Correlation of electronic band structure and ROS will not only aid in better mechanistic assessment of nanotoxicity but will be impactful in designing and developing ROS-based applications ranging from water disinfection to next-generation antibiotics and even cancer therapeutics. Copyright © 2016 Elsevier B.V. All rights reserved.

Tailoring Electronic Properties in Semiconducting Perovskite Materials through Octahedral Control

NASA Astrophysics Data System (ADS)

Choquette, Amber K.

Perovskite oxides, which take the chemical formula ABO 3, are a very versatile and interesting materials family, exhibiting properties that include ferroelectricity, ferromagnetism, mixed ionic/electronic conductivity, metal-insulator behavior and multiferroicity. Key to these functionalities is the network of BO6 corner-connected octahedra, which are known to distort and rotate, directly altering electronic and ferroic properties. By controlling the BO6 octahedral distortions and rotations through cationic substitutions, the use of strain engineering, or through the formation of superlattice structures, the functional properties of perovskites can be tuned. Motivating the use of structure-driven design in oxide heterostructures is the prediction of hybrid improper ferroelectricity in A'BO3/ABO3 superlattices. Two key design rules to realizing hybrid improper ferroelectricity are the growth of high quality superlattice structures with odd periodicities of the A / A' layers, and the control of the octahedral rotation pattern. My work explores the rotational response in perovskite oxides to strain and interface effects in thin films of RFeO3 ( R = La, Eu). I demonstrate a synchrotron x-ray diffraction technique to identify the rotation pattern that is present in the films. I then establish substrate imprinting as a key tool for controlling the rotation patterns in heterostructures, providing a means to realize the necessary structural variants of the predicted hybrid improper ferroelectricity in superlattices. In addition, by pairing measured diffraction data with a structure factor calculation, I demonstrate how one can extract both A-site and oxygen atomic positions in single crystal perovskite oxide films. Finally, I show results from (LaFeO 3)n/(EuFeO3)n superlattices (n = 1-5), synthesized to test the motivating predictions of hybrid improper ferroelectricity in oxide superlattices.

Tension Monitoring during Epithelial-to-Mesenchymal Transition Links the Switch of Phenotype to Expression of Moesin and Cadherins in NMuMG Cells

PubMed Central

Schneider, David; Baronsky, Thilo; Pietuch, Anna; Rother, Jan; Oelkers, Marieelen; Fichtner, Dagmar; Wedlich, Doris; Janshoff, Andreas

2013-01-01

Structural alterations during epithelial-to-mesenchymal transition (EMT) pose a substantial challenge to the mechanical response of cells and are supposed to be key parameters for an increased malignancy during metastasis. Herein, we report that during EMT, apical tension of the epithelial cell line NMuMG is controlled by cell-cell contacts and the architecture of the underlying actin structures reflecting the mechanistic interplay between cellular structure and mechanics. Using force spectroscopy we find that tension in NMuMG cells slightly increases 24 h after EMT induction, whereas upon reaching the final mesenchymal-like state characterized by a complete loss of intercellular junctions and a concerted down-regulation of the adherens junction protein E-cadherin, the overall tension becomes similar to that of solitary adherent cells and fibroblasts. Interestingly, the contribution of the actin cytoskeleton on apical tension increases significantly upon EMT induction, most likely due to the formation of stable and highly contractile stress fibers which dominate the elastic properties of the cells after the transition. The structural alterations lead to the formation of single, highly motile cells rendering apical tension a good indicator for the cellular state during phenotype switching. In summary, our study paves the way towards a more profound understanding of cellular mechanics governing fundamental morphological programs such as the EMT. PMID:24339870

DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes.

PubMed

Guha, Mithu; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Liiv, Ingrid; Haljasorg, Uku; Tasa, Tõnis; Metspalu, Andres; Milani, Lili; Peterson, Pärt

2017-04-21

The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

DNA breaks and chromatin structural changes enhance the transcription of autoimmune regulator target genes

PubMed Central

Guha, Mithu; Saare, Mario; Maslovskaja, Julia; Kisand, Kai; Liiv, Ingrid; Haljasorg, Uku; Tasa, Tõnis; Metspalu, Andres; Milani, Lili; Peterson, Pärt

2017-01-01

The autoimmune regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes. PMID:28242760

Structural basis for different phosphoinositide specificities of the PX domains of sorting nexins regulating G-protein signaling.

PubMed

Mas, Caroline; Norwood, Suzanne J; Bugarcic, Andrea; Kinna, Genevieve; Leneva, Natalya; Kovtun, Oleksiy; Ghai, Rajesh; Ona Yanez, Lorena E; Davis, Jasmine L; Teasdale, Rohan D; Collins, Brett M

2014-10-10

Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signaling. A subfamily of PX domain proteins possesses two unique PX-associated domains, as well as a regulator of G protein-coupled receptor signaling (RGS) domain that attenuates Gαs-coupled G protein-coupled receptor signaling. Here we delineate the structural organization of these RGS-PX proteins, revealing a protein family with a modular architecture that is conserved in all eukaryotes. The one exception to this is mammalian SNX19, which lacks the typical RGS structure but preserves all other domains. The PX domain is a sensor of membrane phosphoinositide lipids and we find that specific sequence alterations in the PX domains of the mammalian RGS-PX proteins, SNX13, SNX14, SNX19, and SNX25, confer differential phosphoinositide binding preferences. Although SNX13 and SNX19 PX domains bind the early endosomal lipid phosphatidylinositol 3-phosphate, SNX14 shows no membrane binding at all. Crystal structures of the SNX19 and SNX14 PX domains reveal key differences, with alterations in SNX14 leading to closure of the binding pocket to prevent phosphoinositide association. Our findings suggest a role for alternative membrane interactions in spatial control of RGS-PX proteins in cell signaling and trafficking. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Determination of antigenicity-altering patches on the major surface protein of human influenza A/H3N2 viruses

PubMed Central

Kratsch, Christina; Klingen, Thorsten R.; Mümken, Linda; Steinbrück, Lars; McHardy, Alice C.

2016-01-01

Human influenza viruses are rapidly evolving RNA viruses that cause short-term respiratory infections with substantial morbidity and mortality in annual epidemics. Uncovering the general principles of viral coevolution with human hosts is important for pathogen surveillance and vaccine design. Protein regions are an appropriate model for the interactions between two macromolecules, but the currently used epitope definition for the major antigen of influenza viruses, namely hemagglutinin, is very broad. Here, we combined genetic, evolutionary, antigenic, and structural information to determine the most relevant regions of the hemagglutinin of human influenza A/H3N2 viruses for interaction with human immunoglobulins. We estimated the antigenic weights of amino acid changes at individual sites from hemagglutination inhibition data using antigenic tree inference followed by spatial clustering of antigenicity-altering protein sites on the protein structure. This approach determined six relevant areas (patches) for antigenic variation that had a key role in the past antigenic evolution of the viruses. Previous transitions between successive predominating antigenic types of H3N2 viruses always included amino acid changes in either the first or second antigenic patch. Interestingly, there was only partial overlap between the antigenic patches and the patches under strong positive selection. Therefore, besides alterations of antigenicity, other interactions with the host may shape the evolution of human influenza A/H3N2 viruses. PMID:27774294

Alterations in the Ubiquitin Proteasome System in Persistent but Not Reversible Proteinuric Diseases

PubMed Central

Beeken, Maire; Lindenmeyer, Maja T.; Blattner, Simone M.; Radón, Victoria; Oh, Jun; Meyer, Tobias N.; Hildebrand, Diana; Schlüter, Hartmut; Reinicke, Anna T.; Knop, Jan-Hendrik; Vivekanandan-Giri, Anuradha; Münster, Silvia; Sachs, Marlies; Wiech, Thorsten; Pennathur, Subramaniam; Cohen, Clemens D.; Kretzler, Matthias; Stahl, Rolf A.K.

2014-01-01

Podocytes are the key cells affected in nephrotic glomerular kidney diseases, and they respond uniformly to injury with cytoskeletal rearrangement. In nephrotic diseases, such as membranous nephropathy and FSGS, persistent injury often leads to irreversible structural damage, whereas in minimal change disease, structural alterations are mostly transient. The factors leading to persistent podocyte injury are currently unknown. Proteolysis is an irreversible process and could trigger persistent podocyte injury through degradation of podocyte-specific proteins. We, therefore, analyzed the expression and functional consequence of the two most prominent proteolytic systems, the ubiquitin proteasome system (UPS) and the autophagosomal/lysosomal system, in persistent and transient podocyte injuries. We show that differential upregulation of both proteolytic systems occurs in persistent human and rodent podocyte injury. The expression of specific UPS proteins in podocytes differentiated children with minimal change disease from children with FSGS and correlated with poor clinical outcome. Degradation of the podocyte-specific protein α-actinin-4 by the UPS depended on oxidative modification in membranous nephropathy. Notably, the UPS was overwhelmed in podocytes during experimental glomerular disease, resulting in abnormal protein accumulation and compensatory upregulation of the autophagosomal/lysosomal system. Accordingly, inhibition of both proteolytic systems enhanced proteinuria in persistent nephrotic disease. This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome. PMID:24722446

The effects of osmotic stress on the structure and function of the cell nucleus.

PubMed

Finan, John D; Guilak, Farshid

2010-02-15

Osmotic stress is a potent regulator of the normal function of cells that are exposed to osmotically active environments under physiologic or pathologic conditions. The ability of cells to alter gene expression and metabolic activity in response to changes in the osmotic environment provides an additional regulatory mechanism for a diverse array of tissues and organs in the human body. In addition to the activation of various osmotically- or volume-activated ion channels, osmotic stress may also act on the genome via a direct biophysical pathway. Changes in extracellular osmolality alter cell volume, and therefore, the concentration of intracellular macromolecules. In turn, intracellular macromolecule concentration is a key physical parameter affecting the spatial organization and pressurization of the nucleus. Hyper-osmotic stress shrinks the nucleus and causes it to assume a convoluted shape, whereas hypo-osmotic stress swells the nucleus to a size that is limited by stretch of the nuclear lamina and induces a smooth, round shape of the nucleus. These behaviors are consistent with a model of the nucleus as a charged core/shell structure pressurized by uneven partition of macromolecules between the nucleoplasm and the cytoplasm. These osmotically-induced alterations in the internal structure and arrangement of chromatin, as well as potential changes in the nuclear membrane and pores are hypothesized to influence gene transcription and/or nucleocytoplasmic transport. A further understanding of the biophysical and biochemical mechanisms involved in these processes would have important ramifications for a range of fields including differentiation, migration, mechanotransduction, DNA repair, and tumorigenesis. (c) 2009 Wiley-Liss, Inc.

Effect of head group orientation on phospholipid assembly

NASA Astrophysics Data System (ADS)

Paul, Tanay; Saha, Jayashree

2017-06-01

The relationship between bilayer stability and lipid head group orientation is reported. In this work, molecular-dynamics simulations are performed to analyze the structure-property relationship of lipid biomembranes, taking into account coarse-grained model lipid interactions. The work explains the molecular scale mechanism of the phase behavior of lipid systems due to ion-lipid or anesthetic-lipid interactions, where reorientations of dipoles play a key role in modifying lipid phases and thereby alter biomembrane function. Our study demonstrates that simple dipolar reorientation is indeed sufficient in tuning a bilayer to a randomly flipped nonbilayer lamellar phase. This study may be used to assess the impact of changes in lipid phase characteristics on biomembrane structure due to the presence of anesthetics and ions.

Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

PubMed

Kutlu, Munir Gunes; Gould, Thomas J

2016-03-01

The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

Systematic review of the neural basis of social cognition in patients with mood disorders.

PubMed

Cusi, Andrée M; Nazarov, Anthony; Holshausen, Katherine; Macqueen, Glenda M; McKinnon, Margaret C

2012-05-01

This review integrates neuroimaging studies of 2 domains of social cognition--emotion comprehension and theory of mind (ToM)--in patients with major depressive disorder and bipolar disorder. The influence of key clinical and method variables on patterns of neural activation during social cognitive processing is also examined. Studies were identified using PsycINFO and PubMed (January 1967 to May 2011). The search terms were "fMRI," "emotion comprehension," "emotion perception," "affect comprehension," "affect perception," "facial expression," "prosody," "theory of mind," "mentalizing" and "empathy" in combination with "major depressive disorder," "bipolar disorder," "major depression," "unipolar depression," "clinical depression" and "mania." Taken together, neuroimaging studies of social cognition in patients with mood disorders reveal enhanced activation in limbic and emotion-related structures and attenuated activity within frontal regions associated with emotion regulation and higher cognitive functions. These results reveal an overall lack of inhibition by higher-order cognitive structures on limbic and emotion-related structures during social cognitive processing in patients with mood disorders. Critically, key variables, including illness burden, symptom severity, comorbidity, medication status and cognitive load may moderate this pattern of neural activation. Studies that did not include control tasks or a comparator group were included in this review. Further work is needed to examine the contribution of key moderator variables and to further elucidate the neural networks underlying altered social cognition in patients with mood disorders. The neural networks under lying higher-order social cognitive processes, including empathy, remain unexplored in patients with mood disorders.

Structure of the Mitochondrial Aminolevulinic Acid Synthase, a Key Heme Biosynthetic Enzyme.

PubMed

Brown, Breann L; Kardon, Julia R; Sauer, Robert T; Baker, Tania A

2018-04-03

5-Aminolevulinic acid synthase (ALAS) catalyzes the first step in heme biosynthesis. We present the crystal structure of a eukaryotic ALAS from Saccharomyces cerevisiae. In this homodimeric structure, one ALAS subunit contains covalently bound cofactor, pyridoxal 5'-phosphate (PLP), whereas the second is PLP free. Comparison between the subunits reveals PLP-coupled reordering of the active site and of additional regions to achieve the active conformation of the enzyme. The eukaryotic C-terminal extension, a region altered in multiple human disease alleles, wraps around the dimer and contacts active-site-proximal residues. Mutational analysis demonstrates that this C-terminal region that engages the active site is important for ALAS activity. Our discovery of structural elements that change conformation upon PLP binding and of direct contact between the C-terminal extension and the active site thus provides a structural basis for investigation of disruptions in the first step of heme biosynthesis and resulting human disorders. Copyright © 2018 Elsevier Ltd. All rights reserved.

High efficiency all-optical plasmonic diode based on a nonlinear side-coupled waveguide-cavity structure with broken symmetry

NASA Astrophysics Data System (ADS)

Liang, Hong-Qin; Liu, Bin; Hu, Jin-Feng; He, Xing-Dao

2018-05-01

An all-optical plasmonic diode, comprising a metal-insulator-metal waveguide coupled with a stub cavity, is proposed based on a nonlinear Fano structure. The key technique used is to break structural spatial symmetry by a simple reflector layer in the waveguide. The spatial asymmetry of the structure gives rise to the nonreciprocity of coupling efficiencies between the Fano cavity and waveguides on both sides of the reflector layer, leading to a nonreciprocal nonlinear response. Transmission properties and dynamic responses are numerically simulated and investigated by the nonlinear finite-difference time-domain method. In the proposed structure, high-efficiency nonreciprocal transmission can be achieved with a low power threshold and an ultrafast response time (subpicosecond level). A high maximum transmittance of 89.3% and an ultra-high transmission contrast ratio of 99.6% can also be obtained. The device can be flexibly adjusted for working wavebands by altering the stub cavity length.

Muscarinic receptors mediate the endocrine-disrupting effects of an organophosphorus insecticide in zebrafish.

PubMed

Santos da Rosa, João Gabriel; Alcântara Barcellos, Heloísa Helena de; Fagundes, Michele; Variani, Cristiane; Rossini, Mainara; Kalichak, Fabiana; Koakoski, Gessi; Acosta Oliveira, Thiago; Idalencio, Renan; Frandoloso, Rafael; Piato, Angelo L; José Gil Barcellos, Leonardo

2017-07-01

The glucocorticoid cortisol, the end product of hypothalamus-pituitary-interrenal axis in zebrafish (Danio rerio), is synthesized via steroidogenesis and promotes important physiological regulations in response to a stressor. The failure of this axis leads to inability to cope with environmental challenges preventing adaptive processes in order to restore homeostasis. Pesticides and agrichemicals are widely used, and may constitute an important class of environmental pollutants when reach aquatic ecosystems and nontarget species. These chemical compounds may disrupt hypothalamus-pituitary-interrenal axis by altering synthesis, structure or function of its constituents. We present evidence that organophosphorus exposure disrupts stress response by altering the expression of key genes of the neural steroidogenesis, causing downregulation of star, hsp70, and pomc genes. This appears to be mediated via muscarinic receptors, since the muscarinic antagonist scopolamine blocked these effects. © 2017 Wiley Periodicals, Inc.

Nutrient enrichment induces dormancy and decreases diversity of active bacteria in salt marsh sediments

PubMed Central

Kearns, Patrick J.; Angell, John H.; Howard, Evan M.; Deegan, Linda A.; Stanley, Rachel H. R.; Bowen, Jennifer L.

2016-01-01

Microorganisms control key biogeochemical pathways, thus changes in microbial diversity, community structure and activity can affect ecosystem response to environmental drivers. Understanding factors that control the proportion of active microbes in the environment and how they vary when perturbed is critical to anticipating ecosystem response to global change. Increasing supplies of anthropogenic nitrogen to ecosystems globally makes it imperative that we understand how nutrient supply alters active microbial communities. Here we show that nitrogen additions to salt marshes cause a shift in the active microbial community despite no change in the total community. The active community shift causes the proportion of dormant microbial taxa to double, from 45 to 90%, and induces diversity loss in the active portion of the community. Our results suggest that perturbations to salt marshes can drastically alter active microbial communities, however these communities may remain resilient by protecting total diversity through increased dormancy. PMID:27666199

Nutrient enrichment induces dormancy and decreases diversity of active bacteria in salt marsh sediments.

PubMed

Kearns, Patrick J; Angell, John H; Howard, Evan M; Deegan, Linda A; Stanley, Rachel H R; Bowen, Jennifer L

2016-09-26

Microorganisms control key biogeochemical pathways, thus changes in microbial diversity, community structure and activity can affect ecosystem response to environmental drivers. Understanding factors that control the proportion of active microbes in the environment and how they vary when perturbed is critical to anticipating ecosystem response to global change. Increasing supplies of anthropogenic nitrogen to ecosystems globally makes it imperative that we understand how nutrient supply alters active microbial communities. Here we show that nitrogen additions to salt marshes cause a shift in the active microbial community despite no change in the total community. The active community shift causes the proportion of dormant microbial taxa to double, from 45 to 90%, and induces diversity loss in the active portion of the community. Our results suggest that perturbations to salt marshes can drastically alter active microbial communities, however these communities may remain resilient by protecting total diversity through increased dormancy.

Stage structure alters how complexity affects stability of ecological networks

USGS Publications Warehouse

Rudolf, V.H.W.; Lafferty, Kevin D.

2011-01-01

Resolving how complexity affects stability of natural communities is of key importance for predicting the consequences of biodiversity loss. Central to previous stability analysis has been the assumption that the resources of a consumer are substitutable. However, during their development, most species change diets; for instance, adults often use different resources than larvae or juveniles. Here, we show that such ontogenetic niche shifts are common in real ecological networks and that consideration of these shifts can alter which species are predicted to be at risk of extinction. Furthermore, niche shifts reduce and can even reverse the otherwise stabilizing effect of complexity. This pattern arises because species with several specialized life stages appear to be generalists at the species level but act as sequential specialists that are hypersensitive to resource loss. These results suggest that natural communities are more vulnerable to biodiversity loss than indicated by previous analyses.

Phenotype-Based Screening of Small Molecules to Modify Plant Cell Walls Using BY-2 Cells.

PubMed

Okubo-Kurihara, Emiko; Matsui, Minami

2018-01-01

The plant cell wall is an important and abundant biomass with great potential for use as a modern recyclable resource. For effective utilization of this cellulosic biomass, its ability to degrade efficiently is key point. With the aim of modifying the cell wall to allow easy decomposition, we used chemical biological technology to alter its structure. As a first step toward evaluating the chemicals in the cell wall we employed a phenotype-based approach using high-throughput screening. As the plant cell wall is essential in determining cell morphology, phenotype-based screening is particularly effective in identifying compounds that bring about alterations in the cell wall. For rapid and reproducible screening, tobacco BY-2 cell is an excellent system in which to observe cell morphology. In this chapter, we provide a detailed chemical biological methodology for studying cell morphology using tobacco BY-2 cells.

The Pivotal Role of Airway Smooth Muscle in Asthma Pathophysiology

PubMed Central

Ozier, Annaïg; Allard, Benoit; Bara, Imane; Girodet, Pierre-Olivier; Trian, Thomas; Marthan, Roger; Berger, Patrick

2011-01-01

Asthma is characterized by the association of airway hyperresponsiveness (AHR), inflammation, and remodelling. The aim of the present article is to review the pivotal role of airway smooth muscle (ASM) in the pathophysiology of asthma. ASM is the main effector of AHR. The mechanisms of AHR in asthma may involve a larger release of contractile mediators and/or a lower release of relaxant mediators, an improved ASM cell excitation/contraction coupling, and/or an alteration in the contraction/load coupling. Beyond its contractile function, ASM is also involved in bronchial inflammation and remodelling. Whereas ASM is a target of the inflammatory process, it can also display proinflammatory and immunomodulatory functions, through its synthetic properties and the expression of a wide range of cell surface molecules. ASM remodelling represents a key feature of asthmatic bronchial remodelling. ASM also plays a role in promoting complementary airway structural alterations, in particular by its synthetic function. PMID:22220184

Changes of the nucleolus architecture in absence of the nuclear factor CTCF.

PubMed

Hernández-Hernández, A; Soto-Reyes, E; Ortiz, R; Arriaga-Canon, C; Echeverría-Martinez, O M; Vázquez-Nin, G H; Recillas-Targa, F

2012-01-01

CTCF is a multifunctional nuclear factor involved in many cellular processes like gene regulation, chromatin insulation and genomic organization. Recently, CTCF has been shown to be involved in the transcriptional regulation of ribosomal genes and nucleolar organization in Drosophila cells and different murine cell types, including embryonic stem cells. Moreover, it has been suggested that CTCF could be associated to the nucleolus of human erythroleukemic K562 cells. In the present work, we took advantage of efficient small hairpin RNA interference against human CTCF to analyze nucleolar organization in HeLa cells. We have found that key components of the nucleolar architecture are altered. As a consequence of such alterations, an upregulation of ribosomal gene transcription was observed. We propose that CTCF contributes to the structural organization of the nucleolus and, through epigenetic mechanisms, to the regulation of the ribosomal gene expression. Copyright © 2012 S. Karger AG, Basel.

Nutrient enrichment induces dormancy and decreases diversity of active bacteria in salt marsh sediments

NASA Astrophysics Data System (ADS)

Kearns, Patrick J.; Angell, John H.; Howard, Evan M.; Deegan, Linda A.; Stanley, Rachel H. R.; Bowen, Jennifer L.

2016-09-01

Microorganisms control key biogeochemical pathways, thus changes in microbial diversity, community structure and activity can affect ecosystem response to environmental drivers. Understanding factors that control the proportion of active microbes in the environment and how they vary when perturbed is critical to anticipating ecosystem response to global change. Increasing supplies of anthropogenic nitrogen to ecosystems globally makes it imperative that we understand how nutrient supply alters active microbial communities. Here we show that nitrogen additions to salt marshes cause a shift in the active microbial community despite no change in the total community. The active community shift causes the proportion of dormant microbial taxa to double, from 45 to 90%, and induces diversity loss in the active portion of the community. Our results suggest that perturbations to salt marshes can drastically alter active microbial communities, however these communities may remain resilient by protecting total diversity through increased dormancy.

The L530R variation associated with recurrent kidney stones impairs the structure and function of TRPV5.

PubMed

Wang, Lingyun; Holmes, Ross P; Peng, Ji-Bin

2017-10-21

TRPV5 is a Ca 2+ -selective channel that plays a key role in the reabsorption of Ca 2+ ions in the kidney. Recently, a rare L530R variation (rs757494578) of TRPV5 was found to be associated with recurrent kidney stones in a founder population. However, it was unclear to what extent this variation alters the structure and function of TRPV5. To evaluate the function and expression of the TRPV5 variant, Ca 2+ uptake in Xenopus oocytes and western blot analysis were performed. The L530R variation abolished the Ca 2+ uptake activity of TRPV5 in Xenopus oocytes. The variant protein was expressed with drastic reduction in complex glycosylation. To assess the structural effects of this L530R variation, TRPV5 was modeled based on the crystal structure of TRPV6 and molecular dynamics simulations were carried out. Simulation results showed that the L530R variation disrupts the hydrophobic interaction between L530 and L502, damaging the secondary structure of transmembrane domain 5. The variation also alters its interaction with membrane lipid molecules. Compared to the electroneutral L530, the positively charged R530 residue shifts the surface electrostatic potential towards positive. R530 is attracted to the negatively charged phosphate group rather than the hydrophobic carbon atoms of membrane lipids. This shifts the pore helix where R530 is located and the D542 residue in the Ca 2+ -selective filter towards the surface of the membrane. These alterations may lead to misfolding of TRPV5, reduction in translocation of the channel to the plasma membrane and/or impaired Ca 2+ transport function of the channel, and ultimately disrupt TRPV5-mediated Ca 2+ reabsorption. Copyright © 2017 Elsevier Inc. All rights reserved.

Dissecting structural and electronic effects in inducible nitric oxide synthase.

PubMed

Hannibal, Luciana; Page, Richard C; Haque, Mohammad Mahfuzul; Bolisetty, Karthik; Yu, Zhihao; Misra, Saurav; Stuehr, Dennis J

2015-04-01

Nitric oxide synthases (NOSs) are haem-thiolate enzymes that catalyse the conversion of L-arginine (L-Arg) into NO and citrulline. Inducible NOS (iNOS) is responsible for delivery of NO in response to stressors during inflammation. The catalytic performance of iNOS is proposed to rely mainly on the haem midpoint potential and the ability of the substrate L-Arg to provide a hydrogen bond for oxygen activation (O-O scission). We present a study of native iNOS compared with iNOS-mesohaem, and investigate the formation of a low-spin ferric haem-aquo or -hydroxo species (P) in iNOS mutant W188H substituted with mesohaem. iNOS-mesohaem and W188H-mesohaem were stable and dimeric, and presented substrate-binding affinities comparable to those of their native counterparts. Single turnover reactions catalysed by iNOSoxy with L-Arg (first reaction step) or N-hydroxy-L-arginine (second reaction step) showed that mesohaem substitution triggered higher rates of Fe(II)O₂ conversion and altered other key kinetic parameters. We elucidated the first crystal structure of a NOS substituted with mesohaem and found essentially identical features compared with the structure of iNOS carrying native haem. This facilitated the dissection of structural and electronic effects. Mesohaem substitution substantially reduced the build-up of species P in W188H iNOS during catalysis, thus increasing its proficiency towards NO synthesis. The marked structural similarities of iNOSoxy containing native haem or mesohaem indicate that the kinetic behaviour observed in mesohaem-substituted iNOS is most heavily influenced by electronic effects rather than structural alterations.

DISSECTING STRUCTURAL AND ELECTRONIC EFFECTS IN INDUCIBLE NITRIC OXIDE SYNTHASE

PubMed Central

Hannibal, Luciana; Page, Richard C.; Haque, Mohammad Mahfuzul; Bolisetty, Karthik; Yu, Zhihao; Misra, Saurav; Stuehr, Dennis J.

2015-01-01

Nitric oxide synthases (NOS) are haem-thiolate enzymes that catalyse the conversion of L-Arginine (LArg) into NO and citrulline. Inducible NOS (iNOS) is responsible for delivery of NO in response to stressors during inflammation. The catalytic performance of iNOS is proposed to rely mainly on the haem midpoint potential and the ability of the substrate L-Arg to provide an H-bond for oxygen activation (O-O scission). We present a comparative study of native iNOS versus iNOS-mesohaem, and investigate the formation of a low-spin ferric haem-aquo or -hydroxo species (P) in iNOS mutant W188H substituted with mesohaem. iNOS-mesohaem and W188H-mesohaem were stable and dimeric, and presented substrate-binding affinities comparable to their native counterparts. Single turnover reactions catalysed by iNOSoxy with LArg (first reaction step) or N-hydroxyarginine (second reaction step) showed that mesohaem substitution triggered faster rates of FeIIO2 conversion and altered other key kinetic parameters. We elucidated the first crystal structure of a NOS substituted with mesohaem and found essentially identical features compared to the structure of iNOS carrying native haem. This facilitated the dissection of structural and electronic effects. Mesohaem substitution substantially reduced the build-up of species P in W188H iNOS during catalysis, thus increasing its proficiency toward NO synthesis. The marked structural similarities of iNOSoxy containing native haem or mesohaem indicate that the kinetic behaviour observed in mesohaem-substituted iNOS is most heavily influenced by electronic effects rather than structural alterations. PMID:25608846

Epigenetic Regulation in Prostate Cancer Progression.

PubMed

Ruggero, Katia; Farran-Matas, Sonia; Martinez-Tebar, Adrian; Aytes, Alvaro

2018-01-01

An important number of newly identified molecular alterations in prostate cancer affect gene encoding master regulators of chromatin biology epigenetic regulation. This review will provide an updated view of the key epigenetic mechanisms underlying prostate cancer progression, therapy resistance, and potential actionable mechanisms and biomarkers. Key players in chromatin biology and epigenetic master regulators has been recently described to be crucially altered in metastatic CRPC and tumors that progress to AR independency. As such, epigenetic dysregulation represents a driving mechanism in the reprograming of prostate cancer cells as they lose AR-imposed identity. Chromatin integrity and accessibility for transcriptional regulation are key features altered in cancer progression, and particularly relevant in nuclear hormone receptor-driven tumors like prostate cancer. Understanding how chromatin remodeling dictates prostate development and how its deregulation contributes to prostate cancer onset and progression may improve risk stratification and treatment selection for prostate cancer patients.

Hypothalamic Alterations in Neurodegenerative Diseases and Their Relation to Abnormal Energy Metabolism

PubMed Central

Vercruysse, Pauline; Vieau, Didier; Blum, David; Petersén, Åsa; Dupuis, Luc

2018-01-01

Neurodegenerative diseases (NDDs) are disorders characterized by progressive deterioration of brain structure and function. Selective neuronal populations are affected leading to symptoms which are prominently motor in amyotrophic lateral sclerosis (ALS) or Huntington’s disease (HD), or cognitive in Alzheimer’s disease (AD) and fronto-temporal dementia (FTD). Besides the common existence of neuronal loss, NDDs are also associated with metabolic changes such as weight gain, weight loss, loss of fat mass, as well as with altered feeding behavior. Importantly, preclinical research as well as clinical studies have demonstrated that altered energy homeostasis influences disease progression in ALS, AD and HD, suggesting that identification of the pathways leading to perturbed energy balance might provide valuable therapeutic targets Signals from both the periphery and central inputs are integrated in the hypothalamus, a major hub for the control of energy balance. Recent research identified major hypothalamic changes in multiple NDDs. Here, we review these hypothalamic alterations and seek to identify commonalities and differences in hypothalamic involvement between the different NDDs. These hypothalamic defects could be key in the development of perturbations in energy homeostasis in NDDs and further understanding of the underlying mechanisms might open up new avenues to not only treat weight loss but also to ameliorate overall neurological symptoms. PMID:29403354

Human activities change marine ecosystems by altering predation risk.

PubMed

Madin, Elizabeth M P; Dill, Lawrence M; Ridlon, April D; Heithaus, Michael R; Warner, Robert R

2016-01-01

In ocean ecosystems, many of the changes in predation risk - both increases and decreases - are human-induced. These changes are occurring at scales ranging from global to local and across variable temporal scales. Indirect, risk-based effects of human activity are known to be important in structuring some terrestrial ecosystems, but these impacts have largely been neglected in oceans. Here, we synthesize existing literature and data to explore multiple lines of evidence that collectively suggest diverse human activities are changing marine ecosystems, including carbon storage capacity, in myriad ways by altering predation risk. We provide novel, compelling evidence that at least one key human activity, overfishing, can lead to distinct, cascading risk effects in natural ecosystems whose magnitude exceeds that of presumed lethal effects and may account for previously unexplained findings. We further discuss the conservation implications of human-caused indirect risk effects. Finally, we provide a predictive framework for when human alterations of risk in oceans should lead to cascading effects and outline a prospectus for future research. Given the speed and extent with which human activities are altering marine risk landscapes, it is crucial that conservation and management policy considers the indirect effects of these activities in order to increase the likelihood of success and avoid unfortunate surprises. © 2015 John Wiley & Sons Ltd.

Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report

PubMed Central

Liu, Xiaolin; Silverman, Alan; Kern, Mark; Ward, B. Douglas; Li, Shi-Jiang; Shaker, Reza; Sood, Manu R.

2015-01-01

Background The neural network mechanisms underlying visceral hypersensitivity in irritable bowel syndrome (IBS) are incompletely understood. It has been proposed that an intrinsic salience network plays an important role in chronic pain and IBS symptoms. Using neuroimaging, we examined brain responses to rectal distension in adolescent IBS patients, focusing on determining the alteration of salience network integrity in IBS and its functional implications in current theoretical frameworks. We hypothesized that (1) brain responses to visceral stimulation in adolescents are similar to those in adults, and (2) IBS is associated with an altered salience network interaction with other neurocognitive networks, particularly the default mode network (DMN) and executive control network (ECN), as predicted by the theoretical models. Methods IBS patients and controls received subliminal and liminal rectal distension during imaging. Stimulus-induced brain activations were determined. Salience network integrity was evaluated by functional connectivity of its seed regions activated by rectal distension in the insular and cingulate cortices. Key Results Compared with controls, IBS patients demonstrated greater activation to rectal distension in neural structures of the homeostatic afferent and emotional arousal networks, especially the anterior cingulate and insular cortices. Greater brain responses to liminal vs. subliminal distension were observed in both groups. Particularly, IBS is uniquely associated with an excessive coupling of the salience network with the DMN and ECN in their key frontal and parietal node areas. Conclusions & Inferences Our study provided consistent evidence supporting the theoretical predictions of altered salience network functioning as a neuropathological mechanism of IBS symptoms. PMID:26467966

Amyloid-β Homeostasis Bridges Inflammation, Synaptic Plasticity Deficits and Cognitive Dysfunction in Multiple Sclerosis.

PubMed

Stampanoni Bassi, Mario; Garofalo, Sara; Marfia, Girolama A; Gilio, Luana; Simonelli, Ilaria; Finardi, Annamaria; Furlan, Roberto; Sancesario, Giulia M; Di Giandomenico, Jonny; Storto, Marianna; Mori, Francesco; Centonze, Diego; Iezzi, Ennio

2017-01-01

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ 1-42 and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1β (IL-1β), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor α (TNFα), interferon γ (IFNγ)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of Aβ 1-42 were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered Aβ homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS.

Combining mutations at genes encoding key enzymes involved in starch synthesis affects the amylose content, carbohydrate allocation and hardness in the wheat grain.

PubMed

Botticella, Ermelinda; Sestili, Francesco; Sparla, Francesca; Moscatello, Stefano; Marri, Lucia; Cuesta-Seijo, Jose A; Falini, Giuseppe; Battistelli, Alberto; Trost, Paolo; Lafiandra, Domenico

2018-03-02

Modifications to the composition of starch, the major component of wheat flour, can have a profound effect on the nutritional and technological characteristics of the flour's end products. The starch synthesized in the grain of conventional wheats (Triticum aestivum) is a 3:1 mixture of the two polysaccharides amylopectin and amylose. Altering the activity of certain key starch synthesis enzymes (GBSSI, SSIIa and SBEIIa) has succeeded in generating starches containing a different polysaccharide ratio. Here, mutagenesis, followed by a conventional marker-assisted breeding exercise, has been used to generate three mutant lines that produce starch with an amylose contents of 0%, 46% and 79%. The direct and pleiotropic effects of the multiple mutation lines were identified at both the biochemical and molecular levels. Both the structure and composition of the starch were materially altered, changes which affected the functionality of the starch. An analysis of sugar and nonstarch polysaccharide content in the endosperm suggested an impact of the mutations on the carbon allocation process, suggesting the existence of cross-talk between the starch and carbohydrate synthesis pathways. © 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Structural alterations in rat liver proteins due to streptozotocin-induced diabetes and the recovery effect of selenium: Fourier transform infrared microspectroscopy and neural network study

NASA Astrophysics Data System (ADS)

Bozkurt, Ozlem; Haman Bayari, Sevgi; Severcan, Mete; Krafft, Christoph; Popp, Jürgen; Severcan, Feride

2012-07-01

The relation between protein structural alterations and tissue dysfunction is a major concern as protein fibrillation and/or aggregation due to structural alterations has been reported in many disease states. In the current study, Fourier transform infrared microspectroscopic imaging has been used to investigate diabetes-induced changes on protein secondary structure and macromolecular content in streptozotocin-induced diabetic rat liver. Protein secondary structural alterations were predicted using neural network approach utilizing the amide I region. Moreover, the role of selenium in the recovery of diabetes-induced alterations on macromolecular content and protein secondary structure was also studied. The results revealed that diabetes induced a decrease in lipid to protein and glycogen to protein ratios in diabetic livers. Significant alterations in protein secondary structure were observed with a decrease in α-helical and an increase in β-sheet content. Both doses of selenium restored diabetes-induced changes in lipid to protein and glycogen to protein ratios. However, low-dose selenium supplementation was not sufficient to recover the effects of diabetes on protein secondary structure, while a higher dose of selenium fully restored diabetes-induced alterations in protein structure.

Human genetic variation and the gut microbiome in disease.

PubMed

Hall, Andrew Brantley; Tolonen, Andrew C; Xavier, Ramnik J

2017-11-01

Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

Insights Into the Role of Collagen in Vocal Fold Health and Disease.

PubMed

Tang, Sharon S; Mohad, Vidisha; Gowda, Madhu; Thibeault, Susan L

2017-09-01

As one of the key fibrous proteins in the extracellular matrix, collagen plays a significant role in the structural and biomechanical characteristics of the vocal fold. Anchored fibrils of collagen create secure structural regions within the vocal folds and are strong enough to sustain vibratory impact and stretch during phonation. This contributes tensile strength, density, and organization to the vocal folds and influences health and pathogenesis. This review offers a comprehensive summary for a current understanding of collagen within normal vocal fold tissues throughout the life span as well as vocal pathology and wound repair. Further, collagen's molecular structure and biosynthesis are discussed. Finally, collagen alterations in tissue injury and repair and the incorporation of collagen-based biomaterials as a method of treating voice disorders are reviewed. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Molecular basis of thermal stability in truncated (2/2) hemoglobins.

PubMed

Bustamante, Juan P; Bonamore, Alessandra; Nadra, Alejandro D; Sciamanna, Natascia; Boffi, Alberto; Estrin, Darío A; Boechi, Leonardo

2014-07-01

Understanding the molecular mechanism through which proteins are functional at extreme high and low temperatures is one of the key issues in structural biology. To investigate this phenomenon, we have focused on two instructive truncated hemoglobins from Thermobifida fusca (Tf-trHbO) and Mycobacterium tuberculosis (Mt-trHbO); although the two proteins are structurally nearly identical, only the former is stable at high temperatures. We used molecular dynamics simulations at different temperatures as well as thermal melting profile measurements of both wild type proteins and two mutants designed to interchange the amino acid residue, either Pro or Gly, at E3 position. The results show that the presence of a Pro at the E3 position is able to increase (by 8°) or decrease (by 4°) the melting temperature of Mt-trHbO and Tf-trHbO, respectively. We observed that the ProE3 alters the structure of the CD loop, making it more flexible. This gain in flexibility allows the protein to concentrate its fluctuations in this single loop and avoid unfolding. The alternate conformations of the CD loop also favor the formation of more salt-bridge interactions, together augmenting the protein's thermostability. These results indicate a clear structural and dynamical role of a key residue for thermal stability in truncated hemoglobins. Copyright © 2014 Elsevier B.V. All rights reserved.

MicroCT angiography detects vascular formation and regression in skin wound healing

PubMed Central

Urao, Norifumi; Okonkwo, Uzoagu A.; Fang, Milie M.; Zhuang, Zhen W.; Koh, Timothy J.; DiPietro, Luisa A.

2016-01-01

Properly regulated angiogenesis and arteriogenesis are essential for effective wound healing. Tissue injury induces robust new vessel formation and subsequent vessel maturation, which involves vessel regression and remodeling. Although formation of functional vasculature is essential for healing, alterations in vascular structure over the time course of skin wound healing are not well understood. Here, using high-resolution ex vivo X-ray micro-computed tomography (microCT), we describe the vascular network during healing of skin excisional wounds with highly detailed three-dimensional (3D) reconstructed images and associated quantitative analysis. We found that relative vessel volume, surface area and branching number are significantly decreased in wounds from day 7 to day 14 and 21. Segmentation and skeletonization analysis of selected branches from high-resolution images as small as 2.5 μm voxel size show that branching orders are decreased in the wound vessels during healing. In histological analysis, we found that the contrast agent fills mainly arterioles, but not small capillaries nor large veins. In summary, high-resolution microCT revealed dynamic alterations of vessel structures during wound healing. This technique may be useful as a key tool in the study of the formation and regression of wound vessels. PMID:27009591

Stress, epigenetics, and alcoholism.

PubMed

Moonat, Sachin; Pandey, Subhash C

2012-01-01

Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker's dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity-for example, by modifying the structure of the DNA-protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism.

O-GlcNAc in cancer: An Oncometabolism-fueled vicious cycle.

PubMed

Hanover, John A; Chen, Weiping; Bond, Michelle R

2018-06-01

Cancer cells exhibit unregulated growth, altered metabolism, enhanced metastatic potential and altered cell surface glycans. Fueled by oncometabolism and elevated uptake of glucose and glutamine, the hexosamine biosynthetic pathway (HBP) sustains glycosylation in the endomembrane system. In addition, the elevated pools of UDP-GlcNAc drives the O-GlcNAc modification of key targets in the cytoplasm, nucleus and mitochondrion. These targets include transcription factors, kinases, key cytoplasmic enzymes of intermediary metabolism, and electron transport chain complexes. O-GlcNAcylation can thereby alter epigenetics, transcription, signaling, proteostasis, and bioenergetics, key 'hallmarks of cancer'. In this review, we summarize accumulating evidence that many cancer hallmarks are linked to dysregulation of O-GlcNAc cycling on cancer-relevant targets. We argue that onconutrient and oncometabolite-fueled elevation increases HBP flux and triggers O-GlcNAcylation of key regulatory enzymes in glycolysis, Kreb's cycle, pentose-phosphate pathway, and the HBP itself. The resulting rerouting of glucose metabolites leads to elevated O-GlcNAcylation of oncogenes and tumor suppressors further escalating elevation in HBP flux creating a 'vicious cycle'. Downstream, elevated O-GlcNAcylation alters DNA repair and cellular stress pathways which influence oncogenesis. The elevated steady-state levels of O-GlcNAcylated targets found in many cancers may also provide these cells with a selective advantage for sustained growth, enhanced metastatic potential, and immune evasion in the tumor microenvironment.

Intestinal Fluid Permeability in Atlantic Salmon (Salmo salar L.) Is Affected by Dietary Protein Source.

PubMed

Hu, Haibin; Kortner, Trond M; Gajardo, Karina; Chikwati, Elvis; Tinsley, John; Krogdahl, Åshild

2016-01-01

In Atlantic salmon (Salmo salar L.), and also in other fish species, certain plant protein ingredients can increase fecal water content creating a diarrhea-like condition which may impair gut function and reduce fish growth. The present study aimed to strengthen understanding of the underlying mechanisms by observing effects of various alternative plant protein sources when replacing fish meal on expression of genes encoding proteins playing key roles in regulation of water transport across the mucosa of the distal intestine (DI). A 48-day feeding trial was conducted with five diets: A reference diet (FM) in which fish meal (72%) was the only protein source; Diet SBMWG with a mix of soybean meal (30%) and wheat gluten (22%); Diet SPCPM with a mix of soy protein concentrate (30%) and poultry meal (6%); Diet GMWG with guar meal (30%) and wheat gluten (14.5%); Diet PM with 58% poultry meal. Compared to fish fed the FM reference diet, fish fed the soybean meal containing diet (SBMWG) showed signs of enteritis in the DI, increased fecal water content of DI chyme and higher plasma osmolality. Altered DI expression of a battery of genes encoding aquaporins, ion transporters, tight junction and adherens junction proteins suggested reduced transcellular transport of water as well as a tightening of the junction barrier in fish fed the SBMWG diet, which may explain the observed higher fecal water content and plasma osmolality. DI structure was not altered for fish fed the other experimental diets but alterations in target gene expression and fecal water content were observed, indicating that alterations in water transport components may take place without clear effects on intestinal structure.

Analysing and Manipulating the Nanostructure of Geopolymers

NASA Astrophysics Data System (ADS)

Provis, J. L.; Hajimohammadi, A.; Rees, C. A.; van Deventer, J. S. J.

Geopolymer concretes are currently being commercialised in Australia and elsewhere around the world, with a view towards enhancing the sustainability of the world’s construction industry. The fundamental geopolymer binder is an aluminosilicate gel which displays key structural features on every length scale from Ångstroms up to centimetres, meaning that multiscale analysis is key to the development of a detailed understanding of geopolymer formation and performance. Here, we present results from investigations of geopolymer nanostructure, focusing on the use of infrared spectroscopy as an analytical tool. The effects of different combinations of precursors in geopolymer formation provides critical information, in particular with regard to the rate of reaction and its impact on the final distribution of elements and structures within the geopolymer binder. Formulations are designed so that the same composition is obtained by the use of precursors which release their constituent elements at very different rates under alkaline attack during geopolymerisation, and this provides essential information regarding the role of different elements in forming strong and durable geopolymer structures. Seeding the geopolymer mixture with very low doses of oxide nanoparticles presents several unexpected effects, both in terms of reaction kinetics and also in altering the nature of the zeolitic crystallites formed within the predominantly X-ray amorphous geopolymer binder.

Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

NASA Astrophysics Data System (ADS)

Agarwal, Sonya; Döring, Kristina; Gierusz, Leszek A.; Iyer, Pooja; Lane, Fiona M.; Graham, James F.; Goldmann, Wilfred; Pinheiro, Teresa J. T.; Gill, Andrew C.

2015-10-01

The β2-α2 loop of PrPC is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrPC appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2-α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that ‘rigidity’ in the β2-α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region.

The position of a key tyrosine in dTDP-4-Keto-6-deoxy-D-glucose-5-epimerase (EvaD) alters the substrate profile for this RmlC-like enzyme.

PubMed

Merkel, Alexandra B; Major, Louise L; Errey, James C; Burkart, Michael D; Field, Robert A; Walsh, Christopher T; Naismith, James H

2004-07-30

Vancomycin, the last line of defense antibiotic, depends upon the attachment of the carbohydrate vancosamine to an aglycone skeleton for antibacterial activity. Vancomycin is a naturally occurring secondary metabolite that can be produced by bacterial fermentation. To combat emerging resistance, it has been proposed to genetically engineer bacteria to produce analogues of vancomycin. This requires a detailed understanding of the biochemical steps in the synthesis of vancomycin. Here we report the 1.4 A structure and biochemical characterization of EvaD, an RmlC-like protein that is required for the C-5' epimerization during synthesis of dTDP-epivancosamine. EvaD, although clearly belonging to the RmlC class of enzymes, displays very low activity in the archetypal RmlC reaction (double epimerization of dTDP-6-deoxy-4-keto-D-glucose at C-3' and C-5'). The high resolution structure of EvaD compared with the structures of authentic RmlC enzymes indicates that a subtle change in the enzyme active site repositions a key catalytic Tyr residue. A mutant designed to re-establish the normal position of the Tyr increases the RmlC-like activity of EvaD.

Design of tunable ultraviolet (UV) absorbance by controlling the Agsbnd Al co-sputtering deposition

NASA Astrophysics Data System (ADS)

Zhang, Xin-Yuan; Chen, Lei; Wang, Yaxin; Zhang, Yongjun; Yang, Jinghai; Choi, Hyun Chul; Jung, Young Mee

2018-05-01

Changing the structure and composition of a material can alter its properties; hence, the controlled fabrication of metal nanostructures plays a key role in a wide range of applications. In this study, the structure of Agsbnd Al ordered arrays fabricated by co-sputtering deposition onto a monolayer colloidal crystal significantly increased its ultraviolet (UV) absorbance owing to a tunable localized surface plasmon resonance (LSPR) effect. By increasing the spacing between two nanospheres and the content of aluminum, absorbance in the UV region could be changed from UVA (320-400 nm) to UVC (200-275 nm), and the LSPR peak in the visible region gradually shifted to the UV region. This provides the potential for surface-enhanced Raman scattering (SERS) in both the UV and visible regions.

Structural Alteration of the Dorsal Visual Network in DLB Patients with Visual Hallucinations: A Cortical Thickness MRI Study

PubMed Central

Delli Pizzi, Stefano; Franciotti, Raffaella; Tartaro, Armando; Caulo, Massimo; Thomas, Astrid; Onofrj, Marco; Bonanni, Laura

2014-01-01

Visual hallucinations (VH) represent one of the core features in discriminating dementia with Lewy bodies (DLB) from Alzheimer’s Disease (AD). Previous studies reported that in DLB patients functional alterations of the parieto-occipital regions were correlated with the presence of VH. The aim of our study was to assess whether morphological changes in specific cortical regions of DLB could be related to the presence and severity of VH. We performed a cortical thickness analysis on magnetic resonance imaging data in a cohort including 18 DLB patients, 15 AD patients and 14 healthy control subjects. Relatively to DLB group, correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores was also performed. Cortical thickness was reduced bilaterally in DLB compared to controls in the pericalcarine and lingual gyri, cuneus, precuneus, superior parietal gyrus. Cortical thinning was found bilaterally in AD compared to controls in temporal cortex including the superior and middle temporal gyrus, part of inferior temporal cortex, temporal pole and insula. Inferior parietal and supramarginal gyri were also affected bilaterally in AD as compared to controls. The comparison between DLB and AD evidenced cortical thinning in DLB group in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri. Furthermore, the correlation analysis between cortical thickness and NPI hallucination item scores showed that the structural alteration in the dorsal visual regions including superior parietal gyrus and precuneus closely correlated with the occurrence and severity of VH. We suggest that structural changes in key regions of the dorsal visual network may play a crucial role in the physiopathology of VH in DLB patients. PMID:24466177

Mining-caused changes to habitat structure affect amphibian and reptile population ecology more than metal pollution.

PubMed

Sasaki, Kiyoshi; Lesbarrères, David; Watson, Glen; Litzgus, Jacqueline

2015-12-01

Emissions from smelting not only contaminate water and soil with metals, but also induce extensive forest dieback and changes in resource availability and microclimate. The relative effects of such co-occurring stressors are often unknown, but this information is imperative in developing targeted restoration strategies. We assessed the role and relative effects of structural alterations of terrestrial habitat and metal pollution caused by century-long smelting operations on amphibian and reptile communities by collecting environmental and time- and area-standardized multivariate abundance data along three spatially replicated impact gradients. Overall, species richness, diversity, and abundance declined progressively with increasing levels of metals (As, Cu, and Ni) and soil temperature (T(s)) and decreasing canopy cover, amount of coarse woody debris (CWD), and relative humidity (RH). The composite habitat variable (which included canopy cover, CWD, T(s), and RH) was more strongly associated with most response metrics than the composite metal variable (As, Cu, and Ni), and canopy cover alone explained 19-74% of the variance. Moreover, species that use terrestrial habitat for specific behaviors (e.g., hibernation, dispersal), especially forest-dependent species, were more severely affected than largely aquatic species. These results suggest that structural alterations of terrestrial habitat and concomitant changes in the resource availability and microclimate have stronger effects than metal pollution per se. Furthermore, much of the variation in response metrics was explained by the joint action of several environmental variables, implying synergistic effects (e.g., exacerbation of metal toxicity by elevated temperatures in sites with reduced canopy cover). We thus argue that the restoration of terrestrial habitat conditions is a key to successful recovery of herpetofauna communities in smelting-altered landscapes.

A constitutively activating mutation alters the dynamics and energetics of a key conformational change in a ligand-free G protein-coupled receptor.

PubMed

Tsukamoto, Hisao; Farrens, David L

2013-09-27

G protein-coupled receptors (GPCRs) undergo dynamic transitions between active and inactive conformations. Usually, these conversions are triggered when the receptor detects an external signal, but some so-called constitutively activating mutations, or CAMs, induce a GPCR to bind and activate G proteins in the absence of external stimulation, in ways still not fully understood. Here, we investigated how a CAM alters the structure of a GPCR and the dynamics involved as the receptor transitions between different conformations. Our approach used site-directed fluorescence labeling (SDFL) spectroscopy to compare opsin, the ligand-free form of the GPCR rhodopsin, with opsin containing the CAM M257Y, focusing specifically on key movements that occur in the sixth transmembrane helix (TM6) during GPCR activation. The site-directed fluorescence labeling data indicate opsin is constrained to an inactive conformation both in detergent micelles and lipid membranes, but when it contains the M257Y CAM, opsin is more dynamic and can interact with a G protein mimetic. Further study of these receptors using tryptophan-induced quenching (TrIQ) methods indicates that in detergent, the CAM significantly increases the population of receptors in the active state, but not in lipids. Subsequent Arrhenius analysis of the TrIQ data suggests that, both in detergent and lipids, the CAM lowers the energy barrier for TM6 movement, a key transition required for conversion between the inactive and active conformations. Together, these data suggest that the lowered energy barrier is a primary effect of the CAM on the receptor dynamics and energetics.

Switching of the core structures of glycosphingolipids from globo- and lacto- to ganglio-series upon human embryonic stem cell differentiation.

PubMed

Liang, Yuh-Jin; Kuo, Huan-Hsien; Lin, Chi-Hung; Chen, Yen-Ying; Yang, Bei-Chia; Cheng, Yuan-Yuan; Yu, Alice L; Khoo, Kay-Hooi; Yu, John

2010-12-28

A systematic survey of expression profiles of glycosphingolipids (GSLs) in two hESC lines and their differentiated embryoid body (EB) outgrowth with three germ layers was carried out using immunofluorescence, flow cytometry, and MALDI-MS and MS/MS analyses. In addition to the well-known hESC-specific markers stage-specific embryonic antigen 3 (SSEA-3) and SSEA-4, we identified several globosides and lacto-series GSLs, previously unrevealed in hESCs, including Gb(4)Cer, Lc(4)Cer, fucosyl Lc(4)Cer, Globo H, and disialyl Gb(5)Cer. During hESC differentiation into EBs, MS analysis revealed a clear-cut switch in the core structures of GSLs from globo- and lacto- to ganglio-series, which was not as evident by immunostaining with antibodies against SSEA-3 and SSEA-4, owing to their cross-reactivities with various glycosphingolipids. Such a switch was attributable to altered expression of key glycosyltransferases (GTs) in the biosynthetic pathways by the up-regulation of ganglio-series-related GTs with simultaneous down-regulation of globo- and lacto-series-related GTs. Thus, these results provide insights into the unique stage-specific transition and mechanism for alterations of GSL core structures during hESC differentiation. In addition, unique glycan structures uncovered by MS analyses may serve as surface markers for further delineation of hESCs and help identify of their functional roles not only in hESCs but also in cancers.

Interpreting histopathology in the epididymis

PubMed Central

De Grava Kempinas, Wilma; Klinefelter, Gary Robert

2014-01-01

While most of this Special Issue is devoted to the testis (which is where most drug and chemically induced toxicity of the male reproductive tract is identified), being able to recognize and understand the potential effects of toxicants on the epididymis is immensely important and an area that is often overlooked. The epididymis is the organ where the post-testicular sperm differentiation occurs, through a complex and still not completely understood sperm maturation process, allowing them to fertilize the oocyte. Also in the epididymis, sperm are stored until ejaculation, while being protected from immunogenic reaction by a blood-epididymis barrier. From a toxicologic perspective the epididymis is inherently complicated as its structure and function can be altered both indirectly and directly. In this review we will discuss the factors that must be considered when attempting to distinguish between indirect and direct epididymal toxicity and highlight what is currently known about mechanisms of epididymal toxicants, using the rat as a reference model. We identify 2 distinguishable signature lesions – one representing androgen deprivation (secondary to Leydig cell toxicity in the testis) and another representing a direct acting toxicant. Other commonly observed alterations will also be shown and discussed. Finally, we point out that many of the key functions of the epididymis can be altered in the absence of a detectable change in tissue structure. Collectively, we hope this will provide pathologists with increased confidence in identification of epididymal toxicity and enable more informed guidance as mechanism of action is considered. PMID:26413396

Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans.

PubMed

Tubbs, Emily; Chanon, Stéphanie; Robert, Maud; Bendridi, Nadia; Bidaux, Gabriel; Chauvin, Marie-Agnès; Ji-Cao, Jingwei; Durand, Christine; Gauvrit-Ramette, Daphné; Vidal, Hubert; Lefai, Etienne; Rieusset, Jennifer

2018-04-01

Modifications of the interactions between endoplasmic reticulum (ER) and mitochondria, defined as mitochondria-associated membranes (MAMs), were recently shown to be involved in the control of hepatic insulin action and glucose homeostasis, but with conflicting results. Whereas skeletal muscle is the primary site of insulin-mediated glucose uptake and the main target for alterations in insulin-resistant states, the relevance of MAM integrity in muscle insulin resistance is unknown. Deciphering the importance of MAMs on muscle insulin signaling could help to clarify this controversy. Here, we show in skeletal muscle of different mice models of obesity and type 2 diabetes (T2D) a marked disruption of ER-mitochondria interactions as an early event preceding mitochondrial dysfunction and insulin resistance. Furthermore, in human myotubes, palmitate-induced insulin resistance is associated with a reduction of structural and functional ER-mitochondria interactions. Importantly, experimental increase of ER-mitochondria contacts in human myotubes prevents palmitate-induced alterations of insulin signaling and action, whereas disruption of MAM integrity alters the action of the hormone. Lastly, we found an association between altered insulin signaling and ER-mitochondria interactions in human myotubes from obese subjects with or without T2D compared with healthy lean subjects. Collectively, our data reveal a new role of MAM integrity in insulin action of skeletal muscle and highlight MAM disruption as an essential subcellular alteration associated with muscle insulin resistance in mice and humans. Therefore, reduced ER-mitochondria coupling could be a common alteration of several insulin-sensitive tissues playing a key role in altered glucose homeostasis in the context of obesity and T2D. © 2018 by the American Diabetes Association.

How mammalian predation contributes to tropical tree community structure.

PubMed

Paine, C E Timothy; Beck, Harald; Terborgh, John

2016-12-01

The recruitment of seedlings from seeds is the key demographic transition for rain forest trees. Though tropical forest mammals are known to consume many seeds, their effects on tree community structure remain little known. To evaluate their effects, we monitored 8,000 seeds of 24 tree species using exclosure cages that were selectively permeable to three size classes of mammals for up to 4.4 years. Small and medium-bodied mammals removed many more seeds than did large mammals, and they alone generated beta diversity and negative density dependence, whereas all mammals reduced diversity and shaped local species composition. Thus, small and medium-bodied mammals more strongly contributed to community structure and promoted species coexistence than did large mammals. Given that seedling recruitment is seed limited for most species, alterations to the composition of the community of mammalian seed predators is expected to have long-term consequences for tree community structure in tropical forests. © 2016 by the Ecological Society of America.

Alpha-synuclein: relating metals to structure, function and inhibition.

PubMed

McDowall, J S; Brown, D R

2016-04-01

Alpha-synuclein has long been studied due to its involvement in the progression of Parkinson's disease (PD), a common neurodegenerative disorder, although a consensus on the exact function of this protein is elusive. This protein shows remarkable structural plasticity and this property is important for both correct cellular function and pathological progression of PD. Formation of intracellular oligomeric species within the substantia nigra correlates with disease progression and it has been proposed that formation of a partially folded intermediate is key to the initiation of the fibrillisation process. Many factors can influence changes in the structure of alpha-synuclein such as disease mutations and interaction with metals and neurotransmitters. High concentrations of both dopamine and metals are present in the substantia nigra making this an ideal location for both the structural alteration of alpha-synuclein and the production of toxic oxygen species. The recent proposal that alpha-synuclein is a ferrireductase is important as it can possibly catalyse the formation of such reactive species and as a result exacerbate neurodegeneration.

Seed dispersal increases local species richness and reduces spatial turnover of tropical tree seedlings

PubMed Central

Dunham, Amy E.; Duncan, Richard P.; Rogers, Haldre S.

2017-01-01

Dispersal is thought to be a key process underlying the high spatial diversity of tropical forests. Just how important dispersal is in structuring plant communities is nevertheless an open question because it is very difficult to isolate dispersal from other processes, and thereby measure its effect. Using a unique situation, the loss of vertebrate seed dispersers on the island of Guam and their presence on the neighboring islands of Saipan and Rota, we quantify the contribution of vertebrate seed dispersal to spatial patterns of diversity of tree seedlings in treefall gaps. The presence of vertebrate seed dispersers approximately doubled seedling species richness within canopy gaps and halved species turnover among gaps. Our study demonstrates that dispersal plays a key role in maintaining local and regional patterns of diversity, and highlights the potential for ongoing declines in vertebrate seed dispersers to profoundly alter tropical forest composition. PMID:28847937

Seed dispersal increases local species richness and reduces spatial turnover of tropical tree seedlings.

PubMed

Wandrag, Elizabeth M; Dunham, Amy E; Duncan, Richard P; Rogers, Haldre S

2017-10-03

Dispersal is thought to be a key process underlying the high spatial diversity of tropical forests. Just how important dispersal is in structuring plant communities is nevertheless an open question because it is very difficult to isolate dispersal from other processes, and thereby measure its effect. Using a unique situation, the loss of vertebrate seed dispersers on the island of Guam and their presence on the neighboring islands of Saipan and Rota, we quantify the contribution of vertebrate seed dispersal to spatial patterns of diversity of tree seedlings in treefall gaps. The presence of vertebrate seed dispersers approximately doubled seedling species richness within canopy gaps and halved species turnover among gaps. Our study demonstrates that dispersal plays a key role in maintaining local and regional patterns of diversity, and highlights the potential for ongoing declines in vertebrate seed dispersers to profoundly alter tropical forest composition.

Music is Beneficial for Awake Craniotomy Patients: A Qualitative Study.

PubMed

Jadavji-Mithani, Radhika; Venkatraghavan, Lashmi; Bernstein, Mark

2015-01-01

Patients undergoing awake craniotomy may experience high levels of stress. Minimizing anxiety benefits patients and surgeons. Music has many therapeutic effects in altering human mood and emotion. Tonality of music as conveyed by composition in major or minor keys can have an impact on patients' emotions and thoughts. Assessing the effects of listening to major and minor key musical pieces on patients undergoing awake craniotiomy could help in the design of interventions to alleviate anxiety, stress and tension. Twenty-nine patients who were undergoing awake craniotomy were recruited and randomly assigned into two groups: Group 1 subjects listened to major key music and Group 2 listened to minor key compositions. Subjects completed a demographics questionnaire, a pre- and post-operative Beck Anxiety Inventory (BAI) and a semi-structured open-ended interview. RESULTS were analyzed using modified thematic analysis through open and axial coding. Overall, patients enjoyed the music regardless of the key distinctions and stated they benefitted from listening to the music. No adverse reactions to the music were found. Subjects remarked that the music made them feel more at ease and less anxious before, during and after their procedure. Patients preferred either major key or minor key music but not a combination of both. Those who preferred major key pieces said it was on the basis of tonality while the individuals who selected minor key pieces stated that tempo of the music was the primary factor. Overall, listening to music selections was beneficial for the patients. Future work should further investigate the effects of audio interventions in awake surgery through narrative means.

Spatiotemporal and Long Lasting Modulation of 11 Key Nogo Signaling Genes in Response to Strong Neuroexcitation

PubMed Central

Karlsson, Tobias E.; Wellfelt, Katrin; Olson, Lars

2017-01-01

Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-Myelin glycoprotein (OMgp), Nogo receptor 1 (NgR1), NgR2, NgR3, Lingo-1, TNF receptor orphan Y (Troy), Olfactomedin, Lateral olfactory tract usher substance (Lotus) and membrane-type matrix metalloproteinase-3 (MT3-MPP)), as well as BDNF and GAPDH. Expression was analyzed in nine different brain areas before, and at eight time points during the first 3 days after a strong neuroexcitatory stimulation, caused by one kainic acid injection. A temporo-spatial pattern of orderly transcriptional regulations emerges that strengthens the role of Nogo-signaling mechanisms for synaptic plasticity in synchrony with transcriptional increases of BDNF mRNA. For most Nogo-type signaling genes, the largest alterations of mRNA levels occur in the dentate gyrus, with marked alterations also in the CA1 region. Changes occurred somewhat later in several areas of the cerebral cortex. The detailed spatio-temporal pattern of mRNA presence and kainic acid-induced transcriptional response is gene-specific. We reveal that several different gene alterations combine to decrease (and later increase) Nogo-like signaling, as expected to allow structural plasticity responses. Other genes are altered in the opposite direction, suggesting that the system prepares in advance in order to rapidly restore balance. However, the fact that Lingo-1 shows a seemingly opposite, plasticity inhibiting response to kainic acid (strong increase of mRNA in the dentate gyrus), may instead suggest a plasticity-enhancing intracellular function of this presumed NgR1 co-receptor. PMID:28442990

Correlation Between Structural, Spectroscopic, and Reactivity Properties Within a Series of Structurally Analogous Metastable Manganese(III)-Alkylperoxo Complexes

PubMed Central

Coggins, Michael K.; Martin-Diaconescu, Vlad; DeBeer, Serena; Kovacs, Julie A.

2013-01-01

Manganese–peroxos are proposed as key intermediates in a number of important biochemical and synthetic transformations. Our understanding of the structural, spectroscopic, and reactivity properties of these metastable species is limited, however, and correlations between these properties have yet to be established experimentally. Herein we report the crystallographic structures of a series of structurally related metastable Mn(III)–OOR compounds, and examine their spectroscopic and reactivity properties. The four reported Mn(III)–OOR compounds extend the number of known end-on Mn(III)–(η1-peroxos) to six. The ligand backbone is shown to alter the metal–ligand distances and modulate the electronic properties key to bonding and activation of the peroxo. The mechanism of thermal decay of these metastable species is examined via variable-temperature kinetics. Strong correlations between structural (O–O and Mn⋯Npy,quin distances), spectroscopic (E(πv*(O–O) → Mn CT band), νO–O), and kinetic (ΔH‡ and ΔS‡) parameters for these complexes provide compelling evidence for rate-limiting O–O bond cleavage. Products identified in the final reaction mixtures of Mn(III)–OOR decay are consistent with homolytic O–O bond scission. The N-heterocyclic amines and ligand backbone (Et vs Pr) are found to modulate structural and reactivity properties, and O–O bond activation is shown, both experimentally and theoretically, to track with metal ion Lewis acidity. The peroxo O–O bond is shown to gradually become more activated as the N-heterocyclic amines move closer to the metal ion causing a decrease in π-donation from the peroxo πv*(O–O) orbital. The reported work represents one of very few examples of experimentally verified relationships between structure and function. PMID:23432090

Correlation between structural, spectroscopic, and reactivity properties within a series of structurally analogous metastable manganese(III)-alkylperoxo complexes.

PubMed

Coggins, Michael K; Martin-Diaconescu, Vlad; DeBeer, Serena; Kovacs, Julie A

2013-03-20

Manganese-peroxos are proposed as key intermediates in a number of important biochemical and synthetic transformations. Our understanding of the structural, spectroscopic, and reactivity properties of these metastable species is limited, however, and correlations between these properties have yet to be established experimentally. Herein we report the crystallographic structures of a series of structurally related metastable Mn(III)-OOR compounds, and examine their spectroscopic and reactivity properties. The four reported Mn(III)-OOR compounds extend the number of known end-on Mn(III)-(η(1)-peroxos) to six. The ligand backbone is shown to alter the metal-ligand distances and modulate the electronic properties key to bonding and activation of the peroxo. The mechanism of thermal decay of these metastable species is examined via variable-temperature kinetics. Strong correlations between structural (O-O and Mn···N(py,quin) distances), spectroscopic (E(πv*(O-O) → Mn CT band), ν(O-O)), and kinetic (ΔH(‡) and ΔS(‡)) parameters for these complexes provide compelling evidence for rate-limiting O-O bond cleavage. Products identified in the final reaction mixtures of Mn(III)-OOR decay are consistent with homolytic O-O bond scission. The N-heterocyclic amines and ligand backbone (Et vs Pr) are found to modulate structural and reactivity properties, and O-O bond activation is shown, both experimentally and theoretically, to track with metal ion Lewis acidity. The peroxo O-O bond is shown to gradually become more activated as the N-heterocyclic amines move closer to the metal ion causing a decrease in π-donation from the peroxo πv*(O-O) orbital. The reported work represents one of very few examples of experimentally verified relationships between structure and function.

In Silico Analysis of Single Nucleotide Polymorphism (SNPs) in Human β-Globin Gene

PubMed Central

Alanazi, Mohammed; Abduljaleel, Zainularifeen; Khan, Wajahatullah; Warsy, Arjumand S.; Elrobh, Mohamed; Khan, Zahid; Amri, Abdullah Al; Bazzi, Mohammad D.

2011-01-01

Single amino acid substitutions in the globin chain are the most common forms of genetic variations that produce hemoglobinopathies- the most widespread inherited disorders worldwide. Several hemoglobinopathies result from homozygosity or compound heterozygosity to beta-globin (HBB) gene mutations, such as that producing sickle cell hemoglobin (HbS), HbC, HbD and HbE. Several of these mutations are deleterious and result in moderate to severe hemolytic anemia, with associated complications, requiring lifelong care and management. Even though many hemoglobinopathies result from single amino acid changes producing similar structural abnormalities, there are functional differences in the generated variants. Using in silico methods, we examined the genetic variations that can alter the expression and function of the HBB gene. Using a sequence homology-based Sorting Intolerant from Tolerant (SIFT) server we have searched for the SNPs, which showed that 200 (80%) non-synonymous polymorphism were found to be deleterious. The structure-based method via PolyPhen server indicated that 135 (40%) non-synonymous polymorphism may modify protein function and structure. The Pupa Suite software showed that the SNPs will have a phenotypic consequence on the structure and function of the altered protein. Structure analysis was performed on the key mutations that occur in the native protein coded by the HBB gene that causes hemoglobinopathies such as: HbC (E→K), HbD (E→Q), HbE (E→K) and HbS (E→V). Atomic Non-Local Environment Assessment (ANOLEA), Yet Another Scientific Artificial Reality Application (YASARA), CHARMM-GUI webserver for macromolecular dynamics and mechanics, and Normal Mode Analysis, Deformation and Refinement (NOMAD-Ref) of Gromacs server were used to perform molecular dynamics simulations and energy minimization calculations on β-Chain residue of the HBB gene before and after mutation. Furthermore, in the native and altered protein models, amino acid residues were determined and secondary structures were observed for solvent accessibility to confirm the protein stability. The functional study in this investigation may be a good model for additional future studies. PMID:22028795

Altered nutrition during hot droughts will impair forest functions in the future

NASA Astrophysics Data System (ADS)

Grossiord, C.; Gessler, A.; Reed, S.; Dickman, L. T.; Collins, A.; Schönbeck, L.; Sevanto, S.; Vilagrosa, A.; McDowell, N. G.

2017-12-01

Rising greenhouse gas emissions will increase atmospheric temperature globally and alter hydrological cycles resulting in more extreme and recurrent droughts in the coming century. Nutrition is a key component affecting the vulnerability of forests to extreme climate. Models typically assume that global warming will enhance nitrogen cycling in terrestrial ecosystems and lead to improved plant functions. Drought on the other hand is expected to weaken the same processes, leading to a clear conflict and inability to predict how nutrition and plant functions will be impacted by a simultaneously warming and drying climate. We used a unique setup consisting of long-term manipulation of climate on mature trees to examine how individual vs. combined warming and drought would alter soil N cycling and tree functions. The site consists of the longest record of tree responses to experimental warming and precipitation reduction in natural conditions.Changes in soil nitrogen cycling (e.g. microbial activity, nitrification and ammonification rates, N concentration) occurred in response to the treatments. In addition, temperature rise and precipitation reduction altered the ability of trees to take up nitrogen and modified nitrogen allocation patterns between aboveground and belowground compartments. Although no additive effect of warming and drying were found for the two studied species, contrasting responses to warming and droughts were observed between the two functional types. Overall, our results show that higher temperature and reduced precipitation will alter the nutrition of forest ecosystems in the future with potentially large consequences for forest functions, structure and biodiversity.

Poor Brain Growth in Extremely Preterm Neonates Long Before the Onset of Autism Spectrum Disorder Symptoms.

PubMed

Padilla, Nelly; Eklöf, Eva; Mårtensson, Gustaf E; Bölte, Sven; Lagercrantz, Hugo; Ådén, Ulrika

2017-02-01

Preterm infants face an increased risk of autism spectrum disorder (ASD). The relationship between autism during childhood and early brain development remains unexplored. We studied 84 preterm children born at <27 weeks of gestation, who underwent neonatal magnetic resonance imaging (MRI) at term and were screened for ASD at 6.5 years. Full-scale intelligence quotient was measured and neonatal morbidities were recorded. Structural brain morphometric studies were performed in 33 infants with high-quality MRI and no evidence of focal brain lesions. Twenty-three (27.4%) of the children tested ASD positive and 61 (72.6%) tested ASD negative. The ASD-positive group had a significantly higher frequency of neonatal complications than the ASD-negative group. In the subgroup of 33 children, the ASD infants had reduced volumes in the temporal, occipital, insular, and limbic regions and in the brain areas involved in social/behavior and salience integration. This study shows that the neonatal MRI scans of extremely preterm children, subsequently diagnosed with ASD at 6.5 years, showed brain structural alterations, localized in the regions that play a key role in the core features of autism. Early detection of these structural alterations may allow the early identification and intervention of children at risk of ASD. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Molecular investigation on the interaction of spermine with proteinase K by multispectroscopic techniques and molecular simulation studies.

PubMed

Hosseini-Koupaei, Mansoore; Shareghi, Behzad; Saboury, Ali Akbar; Davar, Fateme

2017-01-01

The alteration in structure, function and stability of proteinase K in the presence of spermine was investigated using spectroscopic methods and simulation techniques. The stability and enzyme activity of proteinase K-spermine complex were significantly enhanced as compared to that of the pure enzyme. The increase in the value of V max and the catalytic efficiency of Proteinase K in presence of spermine confirmed that the polyamine could bring the enzyme hyperactivation. UV-vis spectroscopy, intrinsic fluorescence and circular dichroism methods demonstrated that the binding of spermine changed the microenvironment and structure of proteinase K. The fluorescence studies, showing that spermine quenched the intensity of proteinase K with static mechanism. Thermodynamic parameters analysis suggested that hydrogen bond and van der Waals forces play a key role in complex stability which is in agreement with modeling studies. The CD spectra represented the secondary structure alteration of proteinase K with an increase in α-helicity and a decrease in β-sheet of proteinase K upon spermine conjugation. The molecular simulation results proposed that spermine could interact with proteinase K spontaneously at single binding site, which is in agreement with spectroscopic results. This agreement between experimental and theoretical results may be a worth method for protein-ligand complex studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Quantitative analysis of nanoscale intranuclear structural alterations in hippocampal cells in chronic alcoholism via transmission electron microscopy imaging.

PubMed

Sahay, Peeyush; Shukla, Pradeep K; Ghimire, Hemendra M; Almabadi, Huda M; Tripathi, Vibha; Mohanty, Samarendra K; Rao, Radhakrishna; Pradhan, Prabhakar

2017-03-01

Chronic alcoholism is known to alter the morphology of the hippocampus, an important region of cognitive function in the brain. Therefore, to understand the effect of chronic alcoholism on hippocampal neural cells, we employed a mouse model of chronic alcoholism and quantified intranuclear nanoscale structural alterations in these cells. Transmission electron microscopy (TEM) images of hippocampal neurons were obtained, and the degree of structural alteration in terms of mass density fluctuation was determined using the light-localization properties of optical media generated from TEM imaging. The results, which were obtained at length scales ranging from ~30 to 200 nm, show that 10-12 week-old mice fed a Lieber-DeCarli liquid (alcoholic) diet had a higher degree of structural alteration than control mice fed a normal diet without alcohol. The degree of structural alteration became significantly distinguishable at a sample length of ~100 nm, which is the typical length scale of the building blocks of cells, such as DNA, RNA, proteins and lipids. Interestingly, different degrees of structural alteration at such length scales suggest possible structural rearrangement of chromatin inside the nuclei in chronic alcoholism.

Quantitative analysis of nanoscale intranuclear structural alterations in hippocampal cells in chronic alcoholism via transmission electron microscopy imaging

NASA Astrophysics Data System (ADS)

Sahay, Peeyush; Shukla, Pradeep K.; Ghimire, Hemendra M.; Almabadi, Huda M.; Tripathi, Vibha; Mohanty, Samarendra K.; Rao, Radhakrishna; Pradhan, Prabhakar

2017-04-01

Chronic alcoholism is known to alter the morphology of the hippocampus, an important region of cognitive function in the brain. Therefore, to understand the effect of chronic alcoholism on hippocampal neural cells, we employed a mouse model of chronic alcoholism and quantified intranuclear nanoscale structural alterations in these cells. Transmission electron microscopy (TEM) images of hippocampal neurons were obtained, and the degree of structural alteration in terms of mass density fluctuation was determined using the light-localization properties of optical media generated from TEM imaging. The results, which were obtained at length scales ranging from ~30 to 200 nm, show that 10-12 week-old mice fed a Lieber-DeCarli liquid (alcoholic) diet had a higher degree of structural alteration than control mice fed a normal diet without alcohol. The degree of structural alteration became significantly distinguishable at a sample length of ~100 nm, which is the typical length scale of the building blocks of cells, such as DNA, RNA, proteins and lipids. Interestingly, different degrees of structural alteration at such length scales suggest possible structural rearrangement of chromatin inside the nuclei in chronic alcoholism.

TCGA and Its Vital Role in Understanding the Landscape of Somatic Alterations in Cancer - TCGA

Cancer.gov

Dr. Stephen Chanock, M.D., Director of the Division of Cancer Epidemiology & Genetics at the NCI, discusses how TCGA provides a strong foundation for understanding key biological alterations in cancer.

Alterations of CNS structure & function by charged particle radiation & resultant oxidative stress

NASA Astrophysics Data System (ADS)

Nelson, Gregory; Chang, Polly; Favre, Cecile; Fike, John; Komarova, Natalia; Limoli, Charles; Mao, Xiao-Wen; Obenaus, Andre; Raber, Jacob; Spigelman, Igor; Soltesz, Ivan; Song, Sheng-Kwei; Stampanoni, Marco; Vlkolinsky, Roman; Wodarz, Dominik

The NSCOR program project is transitioning from establishing the existence of CNS responses to low doses of charged particles, to an investigation of mechanisms underlying these changes and extending the irradiation paradigm to more space-like exposures. In earlier experiments we examined radiation responses of the mouse brain (hippocampus) following exposure to 250 MeV protons and 600 MeV/n iron ions. Our key findings on structural changes were: 1) Significant dose and time dependent loss of en-dothelial cells and microvessel network remodeling occurs suggesting that vascular insufficiency is produced. 2) Significant dose dependent losses of neural precursor cells were observed in a lineage specific pattern which may be associated with cognitive impairment. 3) Evaluation of DNA damage showed dose and time dependent accumulation of mutations with region-specific mutation structures and gene expression profiling demonstrated activation of neurotrophic and adhesion factors as well as chemokine receptors associated with inflammation. Our key find-ings on functional changes were: 1) Time and dose dependent modifications to neural output expressed as enhanced excitability but reduced synaptic efficacy and plasticity (including long term potentiation). 2) Intrinsic membrane properties of neurons were not significantly modi-fied by radiation exposure but pharmacological treatments demonstrated changes in inhibitory synapses. 3) MRI imaging visualized brain structural changes based on altered water diffu-sion properties and patterns were consistent with demyelination or gliosis. Our key findings on neurodegeneration and fidelity of homeostasis were: 1) APP23 transgenic mice exhibited accelerated APP-type electrophysiological pathology over several months. 2) Microvessel net-work changes following irradiation were suggestive of poor tissue oxygenation. 3) The ability of the brain to respond a controlled septic shock was altered by irradiation; the septic shock reactions were complex and suggested continuous remodeling of the brain for up to 6 months. Thus we demonstrated a suite of CNS structural and functional changes after proton and iron ion exposure in the low dose regime. Based on these findings we will now test whether oxidative stress mediates the reactions of CNS to radiation exposure and what role radiation quality and dose rate play in the responses. We will use cultured neural precursor cells (mouse human) to detect changes in oxidative status and differentiation as functions of charged particle charge and velocity. These results will inform the selection of particles for many in vivo measurements that will compare wild type mice to a transgenic strain that over-expresses a human catalase gene (which inactivates hydrogen peroxide) in the mitochondrial compartment. This will explicitly test the role of reactive oxygen species in mediating the mechanisms underlying the CNS endpoints that we will measure. We will extend the electrophysiological measurements on individual nerves in hippocampal slices to characterize both inhibitory and excitatory synapses. Further, multi-electrode arrays will be used to follow correlated electrical activity in different hippocampal regions in order to understand network-level function as well as synaptic efficacy and plasticity. Controlled oxidative stress on irradiated samples will explore whether response mechanisms are shared. To link alterations in neurogenesis to performance we will explore behavioral changes mediated by the hippocampus simultaneously with measures of expression of the Arc gene in newly-born neurons. This will test whether decrements in performance correlate with loss of new cells and whether behavior properly stimulates functional integration of the new cells; the behavioral paradigm will be contextual fear conditioning. We will develop mathematical frameworks for CNS responses to radiation in order to inform risk estimates. Finally, we will couple a high-fidelity hippocampus network model to modified patterns of neuron activity along simulated charged particle tracks to probe the potential effects on network function.

Structures of Rotavirus Reassortants Demonstrate Correlation of Altered Conformation of the VP4 Spike and Expression of Unexpected VP4-Associated Phenotypes

PubMed Central

Pesavento, Joseph B.; Billingsley, Angela M.; Roberts, Ed J.; Ramig, Robert F.; Prasad, B. V. Venkataram

2003-01-01

Numerous prior studies have indicated that viable rotavirus reassortants containing structural proteins of heterologous parental origin may express unexpected phenotypes, such as changes in infectivity and immunogenicity. To provide a structural basis for alterations in phenotypic expression, a three-dimensional structural analysis of these reassortants was conducted. The structures of the reassortants show that while VP4 generally maintains the parental structure when moved to a heterologous protein background, in certain reassortants, there are subtle alterations in the conformation of VP4. The alterations in VP4 conformation correlated with expression of unexpected VP4-associated phenotypes. Interactions between heterologous VP4 and VP7 in reassortants expressing unexpected phenotypes appeared to induce the conformational alterations seen in VP4. PMID:12584352

Impacts of past climate and sea level change on Everglades wetlands: placing a century of anthropogenic change into a late-Holocene context

USGS Publications Warehouse

Willard, D.A.; Bernhardt, C.E.

2011-01-01

We synthesize existing evidence on the ecological history of the Florida Everglades since its inception ~7 ka (calibrated kiloannum) and evaluate the relative impacts of sea level rise, climate variability, and human alteration of Everglades hydrology on wetland plant communities. Initial freshwater peat accumulation began between 6 and 7 ka on the platform underlying modern Florida Bay when sea level was ~6.2 m below its current position. By 5 ka, sawgrass and waterlily peats covered the area bounded by Lake Okeechobee to the north and the Florida Keys to the south. Slower rates of relative sea level rise ~3 ka stabilized the south Florida coastline and initiated transitions from freshwater to mangrove peats near the coast. Hydrologic changes in freshwater marshes also are indicated ~3 ka. During the last ~2 ka, the Everglades wetland was affected by a series of hydrologic fluctuations related to regional to global-scale fluctuations in climate and sea level. Pollen evidence indicates that regional-scale droughts lasting two to four centuries occurred ~1 ka and ~0.4 ka, altering wetland community composition and triggering development of characteristic Everglades habitats such as sawgrass ridges and tree islands. Intercalation of mangrove peats with estuarine muds ~1 ka indicates a temporary slowing or stillstand of sea level. Although sustained droughts and Holocene sea level rise played large roles in structuring the greater Everglades ecosystem, twentieth century reductions in freshwater flow, compartmentalization of the wetland, and accelerated rates of sea level rise had unprecedented impacts on oxidation and subsidence of organic soils, changes/loss of key Everglades habitats, and altered distribution of coastal vegetation.

Amyloid-β Homeostasis Bridges Inflammation, Synaptic Plasticity Deficits and Cognitive Dysfunction in Multiple Sclerosis

PubMed Central

Stampanoni Bassi, Mario; Garofalo, Sara; Marfia, Girolama A.; Gilio, Luana; Simonelli, Ilaria; Finardi, Annamaria; Furlan, Roberto; Sancesario, Giulia M.; Di Giandomenico, Jonny; Storto, Marianna; Mori, Francesco; Centonze, Diego; Iezzi, Ennio

2017-01-01

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ1–42 and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1β (IL-1β), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor α (TNFα), interferon γ (IFNγ)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of Aβ1–42 were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered Aβ homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS. PMID:29209169

How do Changes in Hydro-Climate Conditions Alter the Risk of Infection With Fasciolosis?

NASA Astrophysics Data System (ADS)

Beltrame, L.; Dunne, T.; Rose, H.; Walker, J.; Morgan, E.; Vickerman, P.; Wagener, T.

2017-12-01

Fasciolosis is a widespread parasitic disease of livestock and is emerging as a major zoonosis. Since the parasite and its intermediate host live and develop in the environment, risk of infection is directly affected by climatic-environmental conditions. Changes in disease prevalence, seasonality and distribution have been reported in recent years and attributed to altered temperature and rainfall patterns, raising concerns about the effects of climate change in the future. Therefore, it is urgent to understand how changes in climate-environmental drivers may alter the dynamics of disease risk in a quantitative way, to guide parasite control strategies and interventions in the coming decades. In a previous work, we developed and tested a novel mechanistic hydro-epidemiological model for Fasciolosis, which explicitly represents the parasite life-cycle in connection with key environmental processes, allowing to capture the impact of previously unseen conditions. In this study, we use the new mechanistic model to assess the sensitivity of infection rates to changes in climate-environmental factors. This is challenging as processes underlying disease transmission are complex and interacting, and may have contrasting effects on the parasite life-cycle stages. To this end, we set up a sensitivity analysis framework to investigate in a structured way which factors play a key role in controlling the magnitude, timing and spread of infection, and how the sensitivity of disease risk varies in time and space. Moreover, we define synthetic scenarios to explore the space of possible variability of the hydro-climate drivers and investigate conditions that lead to critical levels of infection. The study shows how the new model combined with the sensitivity analysis framework can support decision-making, providing useful information for disease management.

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

NASA Astrophysics Data System (ADS)

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.; Ryan, Joseph V.; McCloy, John S.; Wall, Nathalie A.

2017-07-01

In order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only. For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

DOE PAGES

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.; ...

2017-07-01

Here, in order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe 0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only.more » For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe 0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.« less

The use of positrons to survey alteration layers on synthetic nuclear waste glasses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reiser, Joelle T.; Parruzot, Benjamin; Weber, Marc H.

Here, in order to safeguard society and the environment, understanding radioactive waste glass alteration mechanisms in interactions with solutions and near-field materials, such as Fe, is essential to nuclear waste repository performance assessments. Alteration products are formed at the surface of glasses after reaction with solution. In this study, glass altered in the presence of Fe 0 in aqueous solution formed two alteration layers: one embedded with Fe closer to the surface and one without Fe found deeper in the sample. Both layers were found to be thinner than the alteration layer found in glass altered in aqueous solution only.more » For the first time, Doppler Broadening Positron Annihilation Spectroscopy (DB-PAS) is used to non-destructively characterize the pore structures of glass altered in the presence of Fe 0. Advantages and disadvantages of DB-PAS compared to other techniques used to analyze pore structures for altered glass samples are discussed. Ultimately, DB-PAS has shown to be an excellent choice for pore structure characterization for glasses with multiple alteration layers. Monte Carlo modeling predicted positron trajectories through the layers, and helped explain DB-PAS data, which showed that the deeper alteration layer without Fe had a similar composition and pore structure to layers on glass altered in water only.« less

Chemical and structural biology of protein lysine deacetylases

PubMed Central

YOSHIDA, Minoru; KUDO, Norio; KOSONO, Saori; ITO, Akihiro

2017-01-01

Histone acetylation is a reversible posttranslational modification that plays a fundamental role in regulating eukaryotic gene expression and chromatin structure/function. Key enzymes for removing acetyl groups from histones are metal (zinc)-dependent and NAD+-dependent histone deacetylases (HDACs). The molecular function of HDACs have been extensively characterized by various approaches including chemical, molecular, and structural biology, which demonstrated that HDACs regulate cell proliferation, differentiation, and metabolic homeostasis, and that their alterations are deeply involved in various human disorders including cancer. Notably, drug discovery efforts have achieved success in developing HDAC-targeting therapeutics for treatment of several cancers. However, recent advancements in proteomics technology have revealed much broader aspects of HDACs beyond gene expression control. Not only histones but also a large number of cellular proteins are subject to acetylation by histone acetyltransferases (HATs) and deacetylation by HDACs. Furthermore, some of their structures can flexibly accept and hydrolyze other acyl groups on protein lysine residues. This review mainly focuses on structural aspects of HDAC enzymatic activity regulated by interaction with substrates, co-factors, small molecule inhibitors, and activators. PMID:28496053

Simultaneous Drug Targeting of the Promoter MYC G-Quadruplex and BCL2 i-Motif in Diffuse Large B-Cell Lymphoma Delays Tumor Growth.

PubMed

Kendrick, Samantha; Muranyi, Andrea; Gokhale, Vijay; Hurley, Laurence H; Rimsza, Lisa M

2017-08-10

Secondary DNA structures are uniquely poised as therapeutic targets due to their molecular switch function in turning gene expression on or off and scaffold-like properties for protein and small molecule interaction. Strategies to alter gene transcription through these structures thus far involve targeting single DNA conformations. Here we investigate the feasibility of simultaneously targeting different secondary DNA structures to modulate two key oncogenes, cellular-myelocytomatosis (MYC) and B-cell lymphoma gene-2 (BCL2), in diffuse large B-cell lymphoma (DLBCL). Cotreatment with previously identified ellipticine and pregnanol derivatives that recognize the MYC G-quadruplex and BCL2 i-motif promoter DNA structures lowered mRNA levels and subsequently enhanced sensitivity to a standard chemotherapy drug, cyclophosphamide, in DLBCL cell lines. In vivo repression of MYC and BCL2 in combination with cyclophosphamide also significantly slowed tumor growth in DLBCL xenograft mice. Our findings demonstrate concurrent targeting of different DNA secondary structures offers an effective, precise, medicine-based approach to directly impede transcription and overcome aberrant pathways in aggressive malignancies.

The role of immune dysfunction in the pathophysiology of autism

PubMed Central

Onore, Charity; Careaga, Milo; Ashwood, Paul

2012-01-01

Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD. PMID:21906670

From Molecular Biology to Clinical Trials: Toward Personalized Colorectal Cancer Therapy.

PubMed

Palma, Sabina; Zwenger, Ariel O; Croce, María V; Abba, Martín C; Lacunza, Ezequiel

2016-06-01

During the past years, molecular studies through high-throughput technologies have led to the confirmation of critical alterations in colorectal cancer (CRC) and the discovery of some new ones, including mutations, DNA methylations, and structural chromosomal changes. These genomic alterations might act in concert to dysregulate specific signaling pathways that normally exert their functions on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Targeted therapy against key components of altered signaling pathways has allowed an improvement in CRC treatment. However, a significant percentage of patients with CRC and metastatic CRC will not benefit from these targeted therapies and will be restricted to systemic chemotherapy. Mechanisms of resistance have been associated with specific gene alterations. To fully understand the nature and significance of the genetic and epigenetic defects in CRC that might favor a tumor evading a given therapy, much work remains. Therefore, a dynamic link between basic molecular research and preclinical studies, which ultimately constitute the prelude to standardized therapies, is very important to provide better and more effective treatments against CRC. We present an updated revision of the main molecular features of CRC and their associated therapies currently under study in clinical trials. Moreover, we performed an unsupervised classification of CRC clinical trials with the aim of obtaining an overview of the future perspectives of preclinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

24 CFR 3285.903 - Permits, alterations, and on-site structures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... HOUSING AND URBAN DEVELOPMENT MODEL MANUFACTURED HOME INSTALLATION STANDARDS Optional Information for... from property lines and public roads are met. (b) Alterations. Prior to making any alteration to a home...) Installation of on-site structures. Each accessory building and structure is designed to support all of its own...

Perinatal Risk Factors Altering Regional Brain Structure in the Preterm Infant

ERIC Educational Resources Information Center

Thompson, Deanne K.; Warfield, Simon K.; Carlin, John B.; Pavlovic, Masa; Wang, Hong X.; Bear, Merilyn; Kean, Michael J.; Doyle, Lex W.; Egan, Gary F.; Inder, Terrie E.

2007-01-01

Neuroanatomical structure appears to be altered in preterm infants, but there has been little insight into the major perinatal risk factors associated with regional cerebral structural alterations. MR images were taken to quantitatively compare regional brain tissue volumes between term and preterm infants and to investigate associations between…

Gaining qualitative insight into the subjective experiences of adherers to an exercise referral scheme: A thematic analysis.

PubMed

Eynon, Michael John; O'Donnell, Christopher; Williams, Lynn

2016-07-01

Nine adults who had completed an exercise referral scheme participated in a semi-structured interview to uncover the key psychological factors associated with adherence to the scheme. Through thematic analysis, an exercise identity emerged to be a major factor associated with adherence to the scheme, which was formed of a number of underpinning constructs including changes in self-esteem, changes in self-efficacy and changes in self-regulatory strategies. Also, an additional theme of transitions in motivation to exercise was identified, showing participants' motivation to alter from extrinsic to intrinsic reasons to exercise during the scheme.

The multisensory brain and its ability to learn music.

PubMed

Zimmerman, Emily; Lahav, Amir

2012-04-01

Playing a musical instrument requires a complex skill set that depends on the brain's ability to quickly integrate information from multiple senses. It has been well documented that intensive musical training alters brain structure and function within and across multisensory brain regions, supporting the experience-dependent plasticity model. Here, we argue that this experience-dependent plasticity occurs because of the multisensory nature of the brain and may be an important contributing factor to musical learning. This review highlights key multisensory regions within the brain and discusses their role in the context of music learning and rehabilitation. © 2012 New York Academy of Sciences.

Structural correlates of psychopathological symptom dimensions in schizophrenia: a voxel-based morphometric study.

PubMed

Koutsouleris, Nikolaos; Gaser, Christian; Jäger, Markus; Bottlender, Ronald; Frodl, Thomas; Holzinger, Silvia; Schmitt, Gisela J E; Zetzsche, Thomas; Burgermeister, Bernhard; Scheuerecker, Johanna; Born, Christine; Reiser, Maximilian; Möller, Hans-Jürgen; Meisenzahl, Eva M

2008-02-15

Structural neuroimaging has substantially advanced the neurobiological research of schizophrenia by describing a range of focal brain alterations as possible neuroanatomical underpinnings of the disease. Despite this progress, a considerable heterogeneity of structural findings persists that may reflect the phenomenological diversity of schizophrenia. It is unclear whether the range of possible clinical disease manifestations relates to a core structural brain deficit or to distinct structural correlates. Therefore, gray matter density (GMD) differences between 175 schizophrenic patients (SZ) and 177 matched healthy control subjects (HC) were examined in a three-step approach using cross-sectional and conjunctional voxel-based morphometry (VBM): (1) analysis of structural alterations irrespective of symptomatology; (2) subdivision of the patient sample according to a three-dimensional factor model of the PANSS and investigation of structural differences between these subsamples and healthy controls; (3) analysis of a common pattern of structural alterations present in all patient subsamples compared to healthy controls. Significant GMD reductions in patients compared to controls were identified within the prefrontal, limbic, paralimbic, temporal and thalamic regions. The disorganized symptom dimension was associated with bilateral alterations in temporal, insular and medial prefrontal cortices. Positive symptoms were associated with left-pronounced alterations in perisylvian regions and extended thalamic GMD losses. Negative symptoms were linked to the most extended alterations within orbitofrontal, medial prefrontal, lateral prefrontal and temporal cortices as well as limbic and subcortical structures. Thus, structural heterogeneity in schizophrenia may relate to specific patterns of GMD reductions that possibly share a common prefrontal-perisylvian pattern of structural brain alterations.

Hydrothermal Alteration Products as Key to Formation of Duricrust and Rock Coatings on Mars

NASA Astrophysics Data System (ADS)

Bishop, J. L.

1999-03-01

A model is presented for the formation of duricrust and rock coatings on Mars. Hydrothermal alteration of volcanic tephra may produce a corrosive agent that attacks rock surfaces and binds dust particles to form duricrust.

Steroidogenic Factor-1 and Human Disease

PubMed Central

El-Khairi, Ranna; Achermann, John C.

2016-01-01

Steroidogenic factor-1 (SF-1) (Ad4BP, NR5A1) is a nuclear receptor that plays a key role in adrenal and reproductive development and function. Deletion of the gene encoding Sf-1 (Nr5a1) in mice results in severe developmental defects of the adrenal gland and gonad. Consequently, initial work on the potential effects of SF-1 disruption in humans focused on individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis, and Müllerian structures. This is a rare phenotype, but has been reported on two occasions, because of alterations that affect key DNA-binding domains of SF-1. Attention then turned to a potential wider role of SF-1 in human adrenal and reproductive disorders. Although changes in SF-1 only very rarely cause isolated adrenal failure, it is emerging that variations in SF-1 are a surprisingly frequent cause of reproductive dysfunction in humans. In 46,XY disorders of sex development, a spectrum of phenotypes has been reported including severe and partial forms of gonadal (testicular) dysgenesis, hypospadias, anorchia with microphallus, and even male factor infertility. In 46,XX females, alterations in SF-1 are associated with primary ovarian insufficiency. Thus, SF-1 seems be a more significant factor in human reproductive health than was first envisioned, with implications for adults as well as children. PMID:23044873

The physiological determinants of drug-induced lysosomal stress resistance

PubMed Central

Woldemichael, Tehetina; Rosania, Gus R.

2017-01-01

Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs. PMID:29117253

Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications

PubMed Central

2011-01-01

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. PMID:21251296

Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites, and Metabolic Pathways.

PubMed

Gao, Bei; Chi, Liang; Mahbub, Ridwan; Bian, Xiaoming; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

2017-04-17

Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied. The aim of this study is to define gut microbiome toxicity induced by lead exposure in C57BL/6 mice using multiomics approaches, including 16S rRNA sequencing, whole genome metagenomics sequencing, and gas chromatography-mass spectrometry (GC-MS) metabolomics. 16S rRNA sequencing revealed that lead exposure altered the gut microbiome trajectory and phylogenetic diversity. Metagenomics sequencing and metabolomics profiling showed that numerous metabolic pathways, including vitamin E, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and the defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications for lead toxicity in the host. Taken together, these results demonstrated that lead exposure not only altered the gut microbiome community structures/diversity but also greatly affected metabolic functions, leading to gut microbiome toxicity.

Nogo receptor 1 regulates formation of lasting memories.

PubMed

Karlén, Alexandra; Karlsson, Tobias E; Mattsson, Anna; Lundströmer, Karin; Codeluppi, Simone; Pham, Therese M; Bäckman, Cristina M; Ogren, Sven Ove; Aberg, Elin; Hoffman, Alexander F; Sherling, Michael A; Lupica, Carl R; Hoffer, Barry J; Spenger, Christian; Josephson, Anna; Brené, Stefan; Olson, Lars

2009-12-01

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.

Nogo receptor 1 regulates formation of lasting memories

PubMed Central

Karlén, Alexandra; Karlsson, Tobias E.; Mattsson, Anna; Lundströmer, Karin; Codeluppi, Simone; Pham, Therese M.; Bäckman, Cristina M.; Ögren, Sven Ove; Åberg, Elin; Hoffman, Alexander F.; Sherling, Michael A.; Lupica, Carl R.; Hoffer, Barry J.; Spenger, Christian; Josephson, Anna; Brené, Stefan; Olson, Lars

2009-01-01

Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction. PMID:19915139

Population-level coordination of pigment response in individual cyanobacterial cells under altered nitrogen levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murton, Jaclyn; Nagarajan, Aparna; Nguyen, Amelia Y.

Cyanobacterial phycobilisome (PBS) pigment-protein complexes harvest light and transfer the energy to reaction centers. Previous ensemble studies have shown that cyanobacteria respond to changes in nutrient availability by modifying the structure of PBS complexes, but this process has not been visualized for individual pigments at the single-cell level due to spectral overlap. We characterized the response of four key photosynthetic pigments to nitrogen depletion and repletion at the subcellular level in individual, live Synechocystis sp. PCC 6803 cells using hyperspectral confocal fluorescence microscopy and multivariate image analysis. Our results revealed that PBS degradation and re-synthesis comprise a rapid response tomore » nitrogen fluctuations, with coordinated populations of cells undergoing pigment modifications. Chlorophyll fluorescence originating from photosystem I and II decreased during nitrogen starvation, but no alteration in subcellular chlorophyll localization was found. Lastly, we observed differential rod and core pigment responses to nitrogen deprivation, suggesting that PBS complexes undergo a stepwise degradation process.« less

Pedophilia is linked to reduced activation in hypothalamus and lateral prefrontal cortex during visual erotic stimulation.

PubMed

Walter, Martin; Witzel, Joachim; Wiebking, Christine; Gubka, Udo; Rotte, Michael; Schiltz, Kolja; Bermpohl, Felix; Tempelmann, Claus; Bogerts, Bernhard; Heinze, Hans Jochen; Northoff, Georg

2007-09-15

Although pedophilia is of high public concern, little is known about underlying neural mechanisms. Although pedophilic patients are sexually attracted to prepubescent children, they show no sexual interest toward adults. This study aimed to investigate the neural correlates of deficits of sexual and emotional arousal in pedophiles. Thirteen pedophilic patients and 14 healthy control subjects were tested for differential neural activity during visual stimulation with emotional and erotic pictures with functional magnetic resonance imaging. Regions showing differential activations during the erotic condition comprised the hypothalamus, the periaqueductal gray, and dorsolateral prefrontal cortex, the latter correlating with a clinical measure. Alterations of emotional processing concerned the amygdala-hippocampus and dorsomedial prefrontal cortex. Hypothesized regions relevant for processing of erotic stimuli in healthy individuals showed reduced activations during visual erotic stimulation in pedophilic patients. This suggests an impaired recruitment of key structures that might contribute to an altered sexual interest of these patients toward adults.

Implementing International Health Regulation (2005) in the Brazilian legal-administrative system.

PubMed

Lima, Yara Oyram Ramos; Costa, Ediná Alves

2015-06-01

The scope of this study was to analyze how the International Sanitary Regulation (ISR 2005)has been incorporated into the Brazilian legal-administrative system, in relation to sanitary control measures involving freight, means of transportation and travelers and possible alterations to health surveillance activities, competencies and procedures. This case study has been undertaken using a qualitative approach, of a descriptive and exploratory nature, using institutional data sources and interviews with key-informants involved in implementing ISR (2005). Alterations to the Brazilian legal-administrative system resulting from ISR (2005) were identified, in relation to standards, special competencies and procedures relating to sanitary controls for freight, modes of transportation and travelers. In its present form, the International Sanitary Regulation is an instrument that, in addition to introducing new international and national sanitary control concepts and elements, also helps to clarify questions that are helpful on a national level, relating to the specific competencies and procedures which will, to a certain extent, put pressure on administrative structures in the areas of sanitary control and surveillance.

Measurement of the Mechanical Properties of Intact Collagen Fibrils

NASA Astrophysics Data System (ADS)

Mercedes, H.; Heim, A.; Matthews, W. G.; Koob, T.

2006-03-01

Motivated by the genetic disorder Ehlers-Danlos syndrome (EDS), in which proper collagen synthesis is interrupted, we are investigating the structural and mechanical properties of collagen fibrils. The fibrous glycoprotein collagen is the most abundant protein found in the human body and plays a key role in the extracellular matrix of the connective tissue, the properties of which are altered in EDS. We have selected as our model system the collagen fibrils of the sea cucumber dermis, a naturally mutable tissue. This system allows us to work with native fibrils which have their proteoglycan complement intact, something that is not possible with reconstituted mammalian collagen fibrils. Using atomic force microscopy, we measure, as a function of the concentration of divalent cations, the fibril diameter, its response to force loading, and the changes in its rigidity. Through these experiments, we will shed light on the mechanisms which control the properties of the sea cucumber dermis and hope to help explain the altered connective tissue extracellular matrix properties associated with EDS.

Exploiting the Gastric Epithelial Barrier: Helicobacter pylori's Attack on Tight and Adherens Junctions.

PubMed

Backert, Steffen; Schmidt, Thomas P; Harrer, Aileen; Wessler, Silja

2017-01-01

Highly organized intercellular tight and adherens junctions are crucial structural components for establishing and maintenance of epithelial barrier functions, which control the microbiota and protect against intruding pathogens in humans. Alterations in these complexes represent key events in the development and progression of multiple infectious diseases as well as various cancers. The gastric pathogen Helicobacter pylori exerts an amazing set of strategies to manipulate these epithelial cell-to-cell junctions, which are implicated in changing cell polarity, migration and invasive growth as well as pro-inflammatory and proliferative responses. This chapter focuses on the H. pylori pathogenicity factors VacA, CagA, HtrA and urease, and how they can induce host cell signaling involved in altering cell-to-cell permeability. We propose a stepwise model for how H. pylori targets components of tight and adherens junctions in order to disrupt the gastric epithelial cell layer, giving fresh insights into the pathogenesis of this important bacterium.

Population-level coordination of pigment response in individual cyanobacterial cells under altered nitrogen levels

DOE PAGES

Murton, Jaclyn; Nagarajan, Aparna; Nguyen, Amelia Y.; ...

2017-07-21

Cyanobacterial phycobilisome (PBS) pigment-protein complexes harvest light and transfer the energy to reaction centers. Previous ensemble studies have shown that cyanobacteria respond to changes in nutrient availability by modifying the structure of PBS complexes, but this process has not been visualized for individual pigments at the single-cell level due to spectral overlap. We characterized the response of four key photosynthetic pigments to nitrogen depletion and repletion at the subcellular level in individual, live Synechocystis sp. PCC 6803 cells using hyperspectral confocal fluorescence microscopy and multivariate image analysis. Our results revealed that PBS degradation and re-synthesis comprise a rapid response tomore » nitrogen fluctuations, with coordinated populations of cells undergoing pigment modifications. Chlorophyll fluorescence originating from photosystem I and II decreased during nitrogen starvation, but no alteration in subcellular chlorophyll localization was found. Lastly, we observed differential rod and core pigment responses to nitrogen deprivation, suggesting that PBS complexes undergo a stepwise degradation process.« less

Tackling the ‘dyslexia paradox’: reading brain and behavior for early markers of developmental dyslexia

PubMed Central

Ozernov-Palchik, Ola; Gaab, Nadine

2016-01-01

Developmental dyslexia is an unexplained inability to acquire accurate or fluent reading that affects approximately 5–17% of children. Dyslexia is associated with structural and functional alterations in various brain regions that support reading. Neuroimaging studies in infants and pre-reading children suggest that these alterations predate reading instruction and reading failure, supporting the hypothesis that variant function in dyslexia susceptibility genes lead to atypical neural migration and/or axonal growth during early, most likely in utero, brain development. Yet, dyslexia is typically not diagnosed until a child has failed to learn to read as expected (usually in second grade or later). There is emerging evidence that neuroimaging measures, when combined with key behavioral measures, can enhance the accuracy of identification of dyslexia risk in prereading children but its sensitivity, specificity, and cost-efficiency is still unclear. Early identification of dyslexia risk carries important implications for dyslexia remediation and the amelioration of the psychosocial consequences commonly associated with reading failure. PMID:26836227

The fate of silicon during glass corrosion under alkaline conditions: A mechanistic and kinetic study with the International Simple Glass

NASA Astrophysics Data System (ADS)

Gin, Stéphane; Jollivet, Patrick; Fournier, Maxime; Berthon, Claude; Wang, Zhaoying; Mitroshkov, Alexandre; Zhu, Zihua; Ryan, Joseph V.

2015-02-01

International Simple Glass - a six oxide borosilicate glass selected by the international nuclear glass community to improve the understanding of glass corrosion mechanisms and kinetics - was altered at 90 °C in a solution initially saturated with respect to amorphous 29SiO2. The pH90°C, was fixed at 9 at the start of the experiment and raised to 11.5 after 209 d by the addition of KOH. Isotope sensitive analytical techniques were used to analyze the solution and altered glass samples, helping to understand the driving forces and rate limiting processes controlling long-term glass alteration. At pH 9, the corrosion rate continuously drops and the glass slowly transforms into a uniform, homogeneous amorphous alteration layer. The mechanisms responsible for this transformation are water penetration through the growing alteration layer and ion exchange. We demonstrate that this amorphous alteration layer is not a precipitate resulting from the hydrolysis of the silicate network; it is mostly inherited from the glass structure from which the most weakly bonded cations (Na, Ca and B) have been released. At pH 11.5, the alteration process is very different: the high solubility of glass network formers (Si, Al, Zr) triggers the rapid and complete dissolution of the glass (dissolution becomes congruent) and precipitation of amorphous and crystalline phases. Unlike at pH 9 where glass corrosion rate decreased by 3 orders of magnitude likely due to the retroaction of the alteration layer on water dynamics/reactivity at the reaction front, the rate at pH 11.5 is maintained at a value close to the forward rate due to both the hydrolysis of the silicate network promoted by OH- and the precipitation of CSH and zeolites. This study provides key information for a unified model for glass dissolution.

Role of organic matter on aggregate stability and related mechanisms through organic amendments

NASA Astrophysics Data System (ADS)

Zaher, Hafida

2010-05-01

To date, only a few studies have tried to simultaneously compare the role of neutral and uronic sugars and lipids on soil structural stability. Moreover, evidence for the mechanisms involved has often been established following wetting of moist aggregates after various pre-treatments thus altering aggregate structure and resulting in manipulations on altered aggregates on which the rapid wetting process may not be involved anymore. To the best of our knowledge, the objective of this work was to study the role of neutral and uronic sugars and lipids in affecting key mechanisms (swelling rate, pressure evolution) involved in the stabilization of soil structure. A long-term incubation study (48-wk) was performed on a clay loam and a silty-clay loam amended with de-inking-secondary sludge mix at three rates (8, 16 and 24 Mg dry matter ha-1), primary-secondary sludge mix at one rate (18 Mg oven-dry ha-1) and composted de-inking sludge at one rate (24 Mg ha-1). Different structural stability indices (stability of moist and dry aggregates, the amount of dispersible clay and loss of soil material following sudden wetting) were measured on a regular basis during the incubation, along with CO2 evolved, neutral and uronic sugar, and lipid contents. During the course of the incubations, significant increases in all stability indices were measured for both soil types. In general, the improvements in stability were proportional to the amount of C added as organic amendments. These improvements were linked to a very intense phase of C mineralization and associated with increases in neutral and uronic sugars as well as lipid contents. The statistical relationships found between the different carbonaceous fractions and stability indices were all highly significant and indicated no clear superiority of one fraction over another. Paper sludge amendments also resulted in significant decreases in maximum internal pressure of aggregate and aggregate swelling following immersion in water, two mechanisms affecting structural stability. Overall, the results suggest that reduction in maximum internal pressure induced by organic amendments most likely resulted from increases in pore surface roughness and pore occlusion rather than by increase in surface wetting angles. This study also supports the view of a non specific action of the lipids, neutral and uronic sugars on aggregate stability to rapid wetting. Key words: soil aggregate stability, polysaccharides, lipids, mechanisms, organic matter

A quest for macroinvertebrate indicators of flow conditions in small, suburban stream

EPA Science Inventory

Alteration of hydrologic variability is considered a key pathway by which urbanization affects stream assemblages; however, understanding the mechanisms of alteration remains a challenge. One approach is to identify biological metrics that show distinct responses to flows, which ...

Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder

DTIC Science & Technology

2015-06-01

Tsc1-deficient astrocytes on neuronal morphology and neuronal activity associated with seizures . 2. KEY WORDS epilepsy , seizure , tuberous sclerosis...AWARD NUMBER: W81XWH-12-1-0196 TITLE: Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder PRINCIPAL...TITLE AND SUBTITLE Altered Astrocyte-Neuron Interactions and Epileptogenesis in Tuberous Sclerosis Complex Disorder 5a. CONTRACT NUMBER 5b. GRANT

A Constitutively Activating Mutation Alters the Dynamics and Energetics of a Key Conformational Change in a Ligand-free G Protein-coupled Receptor*

PubMed Central

Tsukamoto, Hisao; Farrens, David L.

2013-01-01

G protein-coupled receptors (GPCRs) undergo dynamic transitions between active and inactive conformations. Usually, these conversions are triggered when the receptor detects an external signal, but some so-called constitutively activating mutations, or CAMs, induce a GPCR to bind and activate G proteins in the absence of external stimulation, in ways still not fully understood. Here, we investigated how a CAM alters the structure of a GPCR and the dynamics involved as the receptor transitions between different conformations. Our approach used site-directed fluorescence labeling (SDFL) spectroscopy to compare opsin, the ligand-free form of the GPCR rhodopsin, with opsin containing the CAM M257Y, focusing specifically on key movements that occur in the sixth transmembrane helix (TM6) during GPCR activation. The site-directed fluorescence labeling data indicate opsin is constrained to an inactive conformation both in detergent micelles and lipid membranes, but when it contains the M257Y CAM, opsin is more dynamic and can interact with a G protein mimetic. Further study of these receptors using tryptophan-induced quenching (TrIQ) methods indicates that in detergent, the CAM significantly increases the population of receptors in the active state, but not in lipids. Subsequent Arrhenius analysis of the TrIQ data suggests that, both in detergent and lipids, the CAM lowers the energy barrier for TM6 movement, a key transition required for conversion between the inactive and active conformations. Together, these data suggest that the lowered energy barrier is a primary effect of the CAM on the receptor dynamics and energetics. PMID:23940032

Role of Hypoxia-Induced Brain Derived Neurotrophic Factor in Human Pulmonary Artery Smooth Muscle

PubMed Central

Hartman, William; Helan, Martin; Smelter, Dan; Sathish, Venkatachalem; Thompson, Michael; Pabelick, Christina M.; Johnson, Bruce; Prakash, Y. S.

2015-01-01

Background Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). Methods and Results 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. Conclusions Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy. PMID:26192455

A Systems Biology-Based Approach to Uncovering Molecular Mechanisms Underlying Effects of Traditional Chinese Medicine Qingdai in Chronic Myelogenous Leukemia, Involving Integration of Network Pharmacology and Molecular Docking Technology.

PubMed

Zhou, Chao; Liu, LiJuan; Zhuang, Jing; Wei, JunYu; Zhang, TingTing; Gao, ChunDi; Liu, Cun; Li, HuaYao; Si, HongZong; Sun, ChangGang

2018-06-23

BACKGROUND The method of multiple targets overall control is increasingly used to predict the main active ingredient and potential target group of Chinese traditional medicines and to determine the mechanisms involved in their curative effects. Qingdai is the main traditional Chinese medicine used in the treatment of chronic myelogenous leukemia (CML), but the complex active ingredients and antitumor targets in treatment of CML have not been clearly defined in previous studies. MATERIAL AND METHODS We constructed a protein-protein interaction network diagram of CML with 638 nodes (proteins) and 1830 edges, based on the biological function of chronic myelocytic leukemia by use of Cytoscape, and we determined 19 key gene nodes in the CML molecule by network topological properties analysis in a data bank. Then, we used the Surflex-dock plugin in SYBYL7.3 docking and acquired the protein crystal structures of key genes involved in CML from the chemical composition of the traditional Chinese medicine Qingdai with key proteins in CML networks. RESULTS According to the score and the spatial structure, the pharmacodynamically active ingredients of Qingdai are Isdirubin, Isoindigo, N-phenyl-2-naphthylamine, and Isatin, among which Isdirubin is the most important. We further screened the most effective activity key protein structures of CML to find the best pharmacodynamically active ingredients of Qingdai, according to the binding interactions of the inhibitors at the catalytic site performed in best docking combinations. CONCLUSIONS The results suggest that Isdirubin plays a role in resistance to CML by altering the expressions of PIK3CA, MYC, JAK2, and TP53 target proteins. Network pharmacology and molecular docking technology can be used to search for possible reactive molecules in traditional chinese medicines (TCM) and to elucidate their molecular mechanisms.

Mass coral bleaching causes biotic homogenization of reef fish assemblages.

PubMed

Richardson, Laura E; Graham, Nicholas A J; Pratchett, Morgan S; Eurich, Jacob G; Hoey, Andrew S

2018-04-06

Global climate change is altering community composition across many ecosystems due to nonrandom species turnover, typically characterized by the loss of specialist species and increasing similarity of biological communities across spatial scales. As anthropogenic disturbances continue to alter species composition globally, there is a growing need to identify how species responses influence the establishment of distinct assemblages, such that management actions may be appropriately assigned. Here, we use trait-based analyses to compare temporal changes in five complementary indices of reef fish assemblage structure among six taxonomically distinct coral reef habitats exposed to a system-wide thermal stress event. Our results revealed increased taxonomic and functional similarity of previously distinct reef fish assemblages following mass coral bleaching, with changes characterized by subtle, but significant, shifts toward predominance of small-bodied, algal-farming habitat generalists. Furthermore, while the taxonomic or functional richness of fish assemblages did not change across all habitats, an increase in functional originality indicated an overall loss of functional redundancy. We also found that prebleaching coral composition better predicted changes in fish assemblage structure than the magnitude of coral loss. These results emphasize how measures of alpha diversity can mask important changes in the structure and functioning of ecosystems as assemblages reorganize. Our findings also highlight the role of coral species composition in structuring communities and influencing the diversity of responses of reef fishes to disturbance. As new coral species configurations emerge, their desirability will hinge upon the composition of associated species and their capacity to maintain key ecological processes in spite of ongoing disturbances. © 2018 John Wiley & Sons Ltd.

Maternal folic acid-deficient diet causes congenital malformations in the mouse eye.

PubMed

Maestro-de-las-Casas, Carmen; Pérez-Miguelsanz, Juliana; López-Gordillo, Yamila; Maldonado, Estela; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Martínez-Álvarez, Concepción

2013-09-01

The eye is a very complex structure derived from the neural tube, surface ectoderm, and migratory mesenchyme from a neural crest origin. Because structures that evolve from the neural tube may be affected by a folate/folic acid (FA) deficiency, the aim of this work was to investigate whether a maternal folic acid-deficient diet may cause developmental alterations in the mouse eye. Female C57BL/6J mice (8 weeks old) were assigned into two different folic acid groups for periods ranging between 2 and 16 weeks. Animals were killed at gestation day 17. Hepatic folate was analyzed, and the eyes from 287 fetuses were macroscopically studied, sectioned and immunolabeled with anti-transforming growth factor (TGF)-β2 and anti-TGF-βRII. Mice exposed to a FA-deficient diet exhibited numerous eye macroscopic anomalies, such as anophthalmia and microphthalmia. Microscopically, the eye was the most affected organ (43.7% of the fetuses). The highest incidence of malformations occurred from the 8th week onward. A statistically significant linear association between the number of maternal weeks on the FA-deficient diet and embryonic microscopic eye malformations was observed. The optic cup derivatives and structures forming the eye anterior segment showed severe abnormalities. In addition, TGF-β2 and TGF-βRII expression in the eye was also altered. This study suggests that an adequate folic acid/folate status plays a key role in the formation of ocular tissues and structures, whereas a vitamin deficiency is negatively associated with a normal eye development even after a short-term exposure. Copyright © 2013 Wiley Periodicals, Inc.

High resolution three‐dimensional reconstruction of fibrotic skeletal muscle extracellular matrix

PubMed Central

Gillies, Allison R.; Chapman, Mark A.; Bushong, Eric A.; Deerinck, Thomas J.; Ellisman, Mark H.

2016-01-01

Key points Fibrosis occurs secondary to many skeletal muscle diseases and injuries, and can alter muscle function.It is unknown how collagen, the most abundant extracellular structural protein, alters its organization during fibrosis.Quantitative and qualitative high‐magnification electron microscopy shows that collagen is organized into perimysial cables which increase in number in a model of fibrosis, and cables have unique interactions with collagen‐producing cells.Fibrotic muscles are stiffer and have a higher concentration of collagen‐producing cells.These results improve our understanding of the organization of fibrotic skeletal muscle extracellular matrix and identify novel structures that might be targeted by antifibrotic therapy. Abstract Skeletal muscle extracellular matrix (ECM) structure and organization are not well understood, yet the ECM plays an important role in normal tissue homeostasis and disease processes. Fibrosis is common to many muscle diseases and is typically quantified based on an increase in ECM collagen. Through the use of multiple imaging modalities and quantitative stereology, we describe the structure and composition of wild‐type and fibrotic ECM, we show that collagen in the ECM is organized into large bundles of fibrils, or collagen cables, and the number of these cables (but not their size) increases in desmin knockout muscle (a fibrosis model). The increase in cable number is accompanied by increased muscle stiffness and an increase in the number of collagen producing cells. Unique interactions between ECM cells and collagen cables were also observed and reconstructed by serial block face scanning electron microscopy. These results demonstrate that the muscle ECM is more highly organized than previously reported. Therapeutic strategies for skeletal muscle fibrosis should consider the organization of the ECM to target the structures and cells contributing to fibrotic muscle function. PMID:27859324

Pulsed flows, tributary inputs, and food web structure in a highly regulated river

USGS Publications Warehouse

Sabo, John; Caron, Melanie; Doucett, Richard R.; Dibble, Kimberly L.; Ruhi, Albert; Marks, Jane; Hungate, Bruce; Kennedy, Theodore A.

2018-01-01

1.Dams disrupt the river continuum, altering hydrology, biodiversity, and energy flow. Although research indicates that tributary inputs have the potential to dilute these effects, knowledge at the food web level is still scarce.2.Here we examined the riverine food web structure of the Colorado River below Glen Canyon Dam, focusing on organic matter sources, trophic diversity, and food chain length. We asked how these components respond to pulsed flows from tributaries following monsoon thunderstorms that seasonally increase streamflow in the American Southwest.3.Tributaries increased the relative importance of terrestrial organic matter, particularly during the wet season below junctures of key tributaries. This contrasted with the algal-based food web present immediately below Glen Canyon Dam.4.Tributary inputs during the monsoon also increased trophic diversity and food chain length: food chain length peaked below the confluence with the largest tributary (by discharge) in Grand Canyon, increasing by >1 trophic level over a 4-5 kilometre reach possibly due to aquatic prey being flushed into the mainstem during heavy rain events.5.Our results illustrate that large tributaries can create seasonal discontinuities, influencing riverine food web structure in terms of allochthony, food web diversity, and food chain length.6.Synthesis and applications. Pulsed flows from unregulated tributaries following seasonal monsoon rains increase the importance of terrestrially-derived organic matter in large, regulated river food webs, increasing food chain length and trophic diversity downstream of tributary inputs. Protecting unregulated tributaries within hydropower cascades may be important if we are to mitigate food web structure alteration due to flow regulation by large dams. This is critical in the light of global hydropower development, especially in megadiverse, developing countries where dam placement (including completed and planned structures) is in tributaries.

Variations in protein/flavin hydrogen bonding in a LOV domain produce non-Arrhenius kinetics of adduct decay†

PubMed Central

Zoltowski, Brian D.; Nash, Abigail I.; Gardner, Kevin H.

2011-01-01

Light Oxygen Voltage (LOV) domains utilize a conserved blue light-dependent mechanism to control a diverse array of effector domains in biological and engineered proteins. Variations in the kinetics and efficiency of LOV photochemistry fine tune various aspects of the photic response. Characterization of the kinetics of a key aspect of this photochemical mechanism in EL222, a blue-light responsive DNA binding protein from Erythrobacter litoralis HTCC2594, reveals unique non-Arrhenius behavior in the rate of dark state cleavage of the photochemically-generated adduct. Sequence analysis and mutagenesis studies establish that this effect stems from a Gln to Ala mutation unique to EL222 and homologous proteins from marine bacteria. Kinetic and spectroscopic analyses reveal that hydrogen bonding interactions between the FMN N1, O2 and ribityl hydroxyls with the surrounding protein regulate photocycle kinetics and stabilize the LOV active site from temperature-induced alteration in local structure. Substitution of residues interacting with the N1-O2 locus modulates adduct stability, structural flexibility and sequestration of the active site from bulk solvent without perturbation of light-activated DNA binding. Together, these variants link non-Arrhenius behavior to specific alteration of an H-bonding network, while affording tunability of photocycle kinetics. PMID:21923139

Variations in protein-flavin hydrogen bonding in a light, oxygen, voltage domain produce non-Arrhenius kinetics of adduct decay.

PubMed

Zoltowski, Brian D; Nash, Abigail I; Gardner, Kevin H

2011-10-18

Light, oxygen, voltage (LOV) domains utilize a conserved blue light-dependent mechanism to control a diverse array of effector domains in biological and engineered proteins. Variations in the kinetics and efficiency of LOV photochemistry fine-tune various aspects of the photic response. Characterization of the kinetics of a key aspect of this photochemical mechanism in EL222, a blue light responsive DNA binding protein from Erythrobacter litoralis HTCC2594, reveals unique non-Arrhenius behavior in the rate of dark-state cleavage of the photochemically generated adduct. Sequence analysis and mutagenesis studies establish that this effect stems from a Gln to Ala mutation unique to EL222 and homologous proteins from marine bacteria. Kinetic and spectroscopic analyses reveal that hydrogen bonding interactions between the FMN N1, O2, and ribityl hydroxyls and the surrounding protein regulate photocycle kinetics and stabilize the LOV active site from temperature-induced alteration in local structure. Substitution of residues interacting with the N1-O2 locus modulates adduct stability, structural flexibility, and sequestration of the active site from bulk solvent without perturbation of light-activated DNA binding. Together, these variants link non-Arrhenius behavior to specific alteration of an H-bonding network, while affording tunability of photocycle kinetics. © 2011 American Chemical Society

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

PubMed Central

Hernández-Rivas, Jesús María

2018-01-01

The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease. PMID:29642462

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update.

PubMed

Montaño, Adrián; Forero-Castro, Maribel; Marchena-Mendoza, Darnel; Benito, Rocío; Hernández-Rivas, Jesús María

2018-04-07

The identification and study of genetic alterations involved in various signaling pathways associated with the pathogenesis of acute lymphoblastic leukemia (ALL) and the application of recent next-generation sequencing (NGS) in the identification of these lesions not only broaden our understanding of the involvement of various genetic alterations in the pathogenesis of the disease but also identify new therapeutic targets for future clinical trials. The present review describes the main deletions, amplifications, sequence mutations, epigenetic lesions, and new structural DNA rearrangements detected by NGS in B-ALL and T-ALL and their clinical importance for therapeutic procedures. We reviewed the molecular basis of pathways including transcriptional regulation, lymphoid differentiation and development, TP53 and the cell cycle, RAS signaling, JAK/STAT, NOTCH, PI3K/AKT/mTOR, Wnt/β-catenin signaling, chromatin structure modifiers, and epigenetic regulators. The implementation of NGS strategies has enabled important mutated genes in each pathway, their associations with the genetic subtypes of ALL, and their outcomes, which will be described further. We also discuss classic and new cryptic DNA rearrangements in ALL identified by mRNA-seq strategies. Novel cooperative abnormalities in ALL could be key prognostic and/or predictive biomarkers for selecting the best frontline treatment and for developing therapies after the first relapse or refractory disease.

The effect of noise exposure during the developmental period on the function of the auditory system.

PubMed

Bureš, Zbyněk; Popelář, Jiří; Syka, Josef

2017-09-01

Recently, there has been growing evidence that development and maturation of the auditory system depends substantially on the afferent activity supplying inputs to the developing centers. In cases when this activity is altered during early ontogeny as a consequence of, e.g., an unnatural acoustic environment or acoustic trauma, the structure and function of the auditory system may be severely affected. Pathological alterations may be found in populations of ribbon synapses of the inner hair cells, in the structure and function of neuronal circuits, or in auditory driven behavioral and psychophysical performance. Three characteristics of the developmental impairment are of key importance: first, they often persist to adulthood, permanently influencing the quality of life of the subject; second, their manifestations are different and sometimes even contradictory to the impairments induced by noise trauma in adulthood; third, they may be 'hidden' and difficult to diagnose by standard audiometric procedures used in clinical practice. This paper reviews the effects of early interventions to the auditory system, in particular, of sound exposure during ontogeny. We summarize the results of recent morphological, electrophysiological, and behavioral experiments, discuss the putative mechanisms and hypotheses, and draw possible consequences for human neonatal medicine and noise health. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of Radiographic Contrast Media on the Micromorphology of the Junctional Complex of Erythrocytes Visualized by Immunocytology

PubMed Central

Franke, Ralf-Peter; Krüger, Anne; Scharnweber, Tim; Wenzel, Folker; Jung, Friedrich

2014-01-01

Effects of radiographic contrast media (RCM) application were demonstrated in vitro and in vivo where the injection of RCM into the A. axillaris of patients with coronary artery disease was followed by a significant and RCM-dependent decrease of erythrocyte velocity in downstream skin capillaries. Another study in pigs revealed that the deceleration of erythrocytes coincided with a significant reduction of the oxygen partial pressure in the myocardium—supplied by the left coronary artery—after the administration of RCM into this artery. Further reports showed RCM dependent alterations of erythrocytes like echinocyte formation and exocytosis, sequestration of actin or band 3 and the buckling of endothelial cells coinciding with a formation of interendothelial fenestrations leading to areas devoid of endothelial cells. Key to morphological alterations of erythrocytes is the membrane cytoskeleton, which is linked to the band 3 in the erythrocyte membrane via the junctional complex. Fundamental observations regarding the cell biological and biochemical aspects of the structure and function of the cell membrane and the membrane cytoskeleton of erythrocytes have been reported. This review focuses on recent results gained, e.g., by advanced confocal laser scanning microscopy of different double-stained structural elements of the erythrocyte membrane cytoskeleton. PMID:25222553

Small-molecule inducers of Aβ-42 peptide production share a common mechanism of action.

PubMed

Bettayeb, Karima; Oumata, Nassima; Zhang, Yuanyuan; Luo, Wenjie; Bustos, Victor; Galons, Hervé; Greengard, Paul; Meijer, Laurent; Flajolet, Marc

2012-12-01

The pathways leading specifically to the toxic Aβ42 peptide production, a key event in Alzheimer's disease (AD), are unknown. While searching for pathways that mediate pathological increases of Aβ42, we identified Aftin-4, a new compound that selectively and potently increases Aβ42 compared to DMSO (N2a cells: 7-fold; primary neurons: 4-fold; brain lysates: 2-fold) with an EC(50) of 30 μM. These results were confirmed by ELISA and IP-WB. Using affinity chromatography and mass spectrometry, we identified 3 proteins (VDAC1, prohibitin, and mitofilin) relevant to AD that interact with Aftin-4, but not with a structurally similar but inactive molecule. Electron microscopy studies demonstrated that Aftin-4 induces a reversible mitochondrial phenotype reminiscent of the one observed in AD brains. Sucrose gradient fractionation showed that Aftin-4 perturbs the subcellular localization of γ-secretase components and could, therefore, modify γ-secretase specificity by locally altering its membrane environment. Remarkably, Aftin-4 shares all these properties with two other "AD accelerator" compounds. In summary, treatment with three Aβ42 raising agents induced similar biochemical alterations that lead to comparable cellular phenotypes in vitro, suggesting a common mechanism of action involving three structural cellular targets.

Stress, Epigenetics, and Alcoholism

PubMed Central

Moonat, Sachin; Pandey, Subhash C.

2012-01-01

Acute and chronic stressors have been associated with alterations in mood and increased anxiety that may eventually result in the development of stress-related psychiatric disorders. Stress and associated disorders, including anxiety, are key factors in the development of alcoholism because alcohol consumption can temporarily reduce the drinker’s dysphoria. One molecule that may help mediate the relationship between stress and alcohol consumption is brain-derived neurotrophic factor (BDNF), a protein that regulates the structure and function of the sites where two nerve cells interact and exchange nerve signals (i.e., synapses) and which is involved in numerous physiological processes. Aberrant regulation of BDNF signaling and alterations in synapse activity (i.e., synaptic plasticity) have been associated with the pathophysiology of stress-related disorders and alcoholism. Mechanisms that contribute to the regulation of genetic information without modification of the DNA sequence (i.e., epigenetic mechanisms) may play a role in the complex control of BDNF signaling and synaptic plasticity—for example, by modifying the structure of the DNA–protein complexes (i.e., chromatin) that make up the chromosomes and thereby modulating the expression of certain genes. Studies regarding the epigenetic control of BDNF signaling and synaptic plasticity provide a promising direction to understand the mechanisms mediating the interaction between stress and alcoholism. PMID:23584115

Basidiomycete fungal communities in Australian sclerophyll forest soil are altered by repeated prescribed burning.

PubMed

Anderson, Ian C; Bastias, Brigitte A; Genney, David R; Parkin, Pamela I; Cairney, John W G

2007-04-01

Soil basidiomycetes play key roles in forest nutrient and carbon cycling processes, yet the diversity and structure of below ground basidiomycete communities remain poorly understood. Prescribed burning is a commonly used forest management practice and there is evidence that single fire events can have an impact on soil fungal communities but little is known about the effects of repeated prescribed burning. We have used internal transcribed spacer (ITS) terminal restriction fragment length polymorphism (T-RFLP) analysis to investigate the impacts of repeated prescribed burning every two or four years over a period of 30 years on soil basidiomycete communities in an Australian wet sclerophyll forest. Detrended correspondence analysis of ITS T-RFLP profiles separated basidiomycete communities in unburned control plots from those in burned plots, with those burned every two years being the most different from controls. Burning had no effect on basidiomycete species richness, thus these differences appear to be due to changes in community structure. Basidiomycete communities in the unburned control plots were vertically stratified in the upper 20 cm of soil, but no evidence was found for stratification in the burned plots, suggesting that repeated prescribed burning results in more uniform basidiomycete communities. Overall, the results demonstrate that repeated prescribed burning alters soil basidiomycete communities, with the effect being greater with more frequent burning.

MicroCT angiography detects vascular formation and regression in skin wound healing.

PubMed

Urao, Norifumi; Okonkwo, Uzoagu A; Fang, Milie M; Zhuang, Zhen W; Koh, Timothy J; DiPietro, Luisa A

2016-07-01

Properly regulated angiogenesis and arteriogenesis are essential for effective wound healing. Tissue injury induces robust new vessel formation and subsequent vessel maturation, which involves vessel regression and remodeling. Although formation of functional vasculature is essential for healing, alterations in vascular structure over the time course of skin wound healing are not well understood. Here, using high-resolution ex vivo X-ray micro-computed tomography (microCT), we describe the vascular network during healing of skin excisional wounds with highly detailed three-dimensional (3D) reconstructed images and associated quantitative analysis. We found that relative vessel volume, surface area and branching number are significantly decreased in wounds from day 7 to days 14 and 21. Segmentation and skeletonization analysis of selected branches from high-resolution images as small as 2.5μm voxel size show that branching orders are decreased in the wound vessels during healing. In histological analysis, we found that the contrast agent fills mainly arterioles, but not small capillaries nor large veins. In summary, high-resolution microCT revealed dynamic alterations of vessel structures during wound healing. This technique may be useful as a key tool in the study of the formation and regression of wound vessels. Copyright © 2016 Elsevier Inc. All rights reserved.

Systematic review of the neural basis of social cognition in patients with mood disorders

PubMed Central

Cusi, Andrée M.; Nazarov, Anthony; Holshausen, Katherine; MacQueen, Glenda M.; McKinnon, Margaret C.

2012-01-01

Background This review integrates neuroimaging studies of 2 domains of social cognition — emotion comprehension and theory of mind (ToM) — in patients with major depressive disorder and bipolar disorder. The influence of key clinical and method variables on patterns of neural activation during social cognitive processing is also examined. Methods Studies were identified using PsycINFO and PubMed (January 1967 to May 2011). The search terms were “fMRI,” “emotion comprehension,” “emotion perception,” “affect comprehension,” “affect perception,” “facial expression,” “prosody,” “theory of mind,” “mentalizing” and “empathy” in combination with “major depressive disorder,” “bipolar disorder,” “major depression,” “unipolar depression,” “clinical depression” and “mania.” Results Taken together, neuroimaging studies of social cognition in patients with mood disorders reveal enhanced activation in limbic and emotion-related structures and attenuated activity within frontal regions associated with emotion regulation and higher cognitive functions. These results reveal an overall lack of inhibition by higher-order cognitive structures on limbic and emotion-related structures during social cognitive processing in patients with mood disorders. Critically, key variables, including illness burden, symptom severity, comorbidity, medication status and cognitive load may moderate this pattern of neural activation. Limitations Studies that did not include control tasks or a comparator group were included in this review. Conclusion Further work is needed to examine the contribution of key moderator variables and to further elucidate the neural networks underlying altered social cognition in patients with mood disorders. The neural networks underlying higher-order social cognitive processes, including empathy, remain unexplored in patients with mood disorders. PMID:22297065

Nanoscale analysis of caspofungin-induced cell surface remodelling in Candida albicans

NASA Astrophysics Data System (ADS)

El-Kirat-Chatel, Sofiane; Beaussart, Audrey; Alsteens, David; Jackson, Desmond N.; Lipke, Peter N.; Dufrêne, Yves F.

2013-01-01

The advent of fungal pathogens that are resistant to the classic repertoire of antifungal drugs has increased the need for new therapeutic agents. A prominent example of such a novel compound is caspofungin, known to alter cell wall biogenesis by inhibiting β-1,3-d-glucan synthesis. Although much progress has been made in understanding the mechanism of action of caspofungin, little is known about its influence on the biophysical properties of the fungal cells. Here, we use atomic force microscopy (AFM) to demonstrate that caspofungin induces major remodelling of the cell surface properties of Candida albicans. Caspofungin causes major morphological and structural alterations of the cells, which correlate with a decrease of the cell wall mechanical strength. Moreover, we find that the drug induces the massive exposure of the cell adhesion protein Als1 on the cell surface and leads to increased cell surface hydrophobicity, two features that trigger cell aggregation. This behaviour is not observed in yeast species lacking Als1, demonstrating the key role that the protein plays in determining the aggregation phenotype of C. albicans. The results show that AFM opens up new avenues for understanding the molecular bases of microbe-drug interactions and for developing new therapeutic agents.The advent of fungal pathogens that are resistant to the classic repertoire of antifungal drugs has increased the need for new therapeutic agents. A prominent example of such a novel compound is caspofungin, known to alter cell wall biogenesis by inhibiting β-1,3-d-glucan synthesis. Although much progress has been made in understanding the mechanism of action of caspofungin, little is known about its influence on the biophysical properties of the fungal cells. Here, we use atomic force microscopy (AFM) to demonstrate that caspofungin induces major remodelling of the cell surface properties of Candida albicans. Caspofungin causes major morphological and structural alterations of the cells, which correlate with a decrease of the cell wall mechanical strength. Moreover, we find that the drug induces the massive exposure of the cell adhesion protein Als1 on the cell surface and leads to increased cell surface hydrophobicity, two features that trigger cell aggregation. This behaviour is not observed in yeast species lacking Als1, demonstrating the key role that the protein plays in determining the aggregation phenotype of C. albicans. The results show that AFM opens up new avenues for understanding the molecular bases of microbe-drug interactions and for developing new therapeutic agents. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr33215a

Structurally altered capsular polysaccharides produced by mutant bacteria

NASA Technical Reports Server (NTRS)

Petersen, Gene R. (Inventor); Kern, Roger G. (Inventor); Richards, Gil F. (Inventor)

1995-01-01

Structurally altered capsular polysaccharides are produced by mutant bacteria. These polysaccharides are isolated by selecting a wild type bacterial strain and a phage producing degradative enzymes that have substrate specificity for the capsular polysaccharides produced by the wild type bacteria. Phage-resistant mutants producing capsular polysaccharides are selected and the structurally altered capsular polysaccharide is isolated therefrom.

The role of strong electrostatic interactions at the dimer interface of human glutathione synthetase.

PubMed

De Jesus, Margarita C; Ingle, Brandall L; Barakat, Khaldoon A; Shrestha, Bisesh; Slavens, Kerri D; Cundari, Thomas R; Anderson, Mary E

2014-10-01

The obligate homodimer human glutathione synthetase (hGS) provides an ideal system for exploring the role of protein-protein interactions in the structural stability, activity and allostery of enzymes. The two active sites of hGS, which are 40 Å apart, display allosteric modulation by the substrate γ-glutamylcysteine (γ-GC) during the synthesis of glutathione, a key cellular antioxidant. The two subunits interact at a relatively small dimer interface dominated by electrostatic interactions between S42, R221, and D24. Alanine scans of these sites result in enzymes with decreased activity, altered γ-GC affinity, and decreased thermal stability. Molecular dynamics simulations indicate these mutations disrupt interchain bonding and impact the tertiary structure of hGS. While the ionic hydrogen bonds and salt bridges between S42, R221, and D24 do not mediate allosteric communication in hGS, these interactions have a dramatic impact on the activity and structural stability of the enzyme.

Bidirectional synaptic structural plasticity after chronic cocaine administration occurs through Rap1 small GTPase signaling

PubMed Central

Cahill, Michael E.; Bagot, Rosemary C.; Gancarz, Amy M.; Walker, Deena M.; Sun, HaoSheng; Wang, Zi-Jun; Heller, Elizabeth A.; Feng, Jian; Kennedy, Pamela J.; Koo, Ja Wook; Cates, Hannah M.; Neve, Rachael L.; Shen, Li; Dietz, David M.

2016-01-01

Summary Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens, a primary brain reward region, are seen at early vs. late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local-synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce “metaplasticity” in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner. PMID:26844834

Robust excitons inhabit soft supramolecular nanotubes

PubMed Central

Eisele, Dörthe M.; Arias, Dylan H.; Fu, Xiaofeng; Bloemsma, Erik A.; Steiner, Colby P.; Jensen, Russell A.; Rebentrost, Patrick; Eisele, Holger; Tokmakoff, Andrei; Lloyd, Seth; Nelson, Keith A.; Nicastro, Daniela; Knoester, Jasper; Bawendi, Moungi G.

2014-01-01

Nature's highly efficient light-harvesting antennae, such as those found in green sulfur bacteria, consist of supramolecular building blocks that self-assemble into a hierarchy of close-packed structures. In an effort to mimic the fundamental processes that govern nature’s efficient systems, it is important to elucidate the role of each level of hierarchy: from molecule, to supramolecular building block, to close-packed building blocks. Here, we study the impact of hierarchical structure. We present a model system that mirrors nature’s complexity: cylinders self-assembled from cyanine-dye molecules. Our work reveals that even though close-packing may alter the cylinders’ soft mesoscopic structure, robust delocalized excitons are retained: Internal order and strong excitation-transfer interactions—prerequisites for efficient energy transport—are both maintained. Our results suggest that the cylindrical geometry strongly favors robust excitons; it presents a rational design that is potentially key to nature’s high efficiency, allowing construction of efficient light-harvesting devices even from soft, supramolecular materials. PMID:25092336

Structure-activity relationship studies of the lipophilic tail region of sphingosine kinase 2 inhibitors.

PubMed

Congdon, Molly D; Childress, Elizabeth S; Patwardhan, Neeraj N; Gumkowski, James; Morris, Emily A; Kharel, Yugesh; Lynch, Kevin R; Santos, Webster L

2015-11-01

Sphingosine-1-phosphate (S1P) is a ubiquitous, endogenous small molecule that is synthesized by two isoforms of sphingosine kinase (SphK1 and 2). Intervention of the S1P signaling pathway has attracted significant attention because alteration of S1P levels is linked to several disease states including cancer, fibrosis, and sickle cell disease. While intense investigations have focused on developing SphK1 inhibitors, only a limited number of SphK2-selective agents have been reported. Herein, we report our investigations on the structure-activity relationship studies of the lipophilic tail region of SLR080811, a SphK2-selective inhibitor. Our studies demonstrate that the internal phenyl ring is a key structural feature that is essential in the SLR080811 scaffold. Further, we show the dependence of SphK2 activity and selectivity on alkyl tail length, suggesting a larger lipid binding pocket in SphK2 compared to SphK1. Copyright © 2015 Elsevier Ltd. All rights reserved.

Lanosterol reverses protein aggregation in cataracts.

PubMed

Zhao, Ling; Chen, Xiang-Jun; Zhu, Jie; Xi, Yi-Bo; Yang, Xu; Hu, Li-Dan; Ouyang, Hong; Patel, Sherrina H; Jin, Xin; Lin, Danni; Wu, Frances; Flagg, Ken; Cai, Huimin; Li, Gen; Cao, Guiqun; Lin, Ying; Chen, Daniel; Wen, Cindy; Chung, Christopher; Wang, Yandong; Qiu, Austin; Yeh, Emily; Wang, Wenqiu; Hu, Xun; Grob, Seanna; Abagyan, Ruben; Su, Zhiguang; Tjondro, Harry Christianto; Zhao, Xi-Juan; Luo, Hongrong; Hou, Rui; Jefferson, J; Perry, P; Gao, Weiwei; Kozak, Igor; Granet, David; Li, Yingrui; Sun, Xiaodong; Wang, Jun; Zhang, Liangfang; Liu, Yizhi; Yan, Yong-Bin; Zhang, Kang

2015-07-30

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Androgen receptor: structure, role in prostate cancer and drug discovery

PubMed Central

Tan, MH Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

2015-01-01

Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

Key ecological responses to nitrogen are altered by climate change

USGS Publications Warehouse

Greaver, T.L.; Clark, C.M.; Compton, J.E.; Vallano, D.; Talhelm, A. F.; Weaver, C.P.; Band, L.E.; Baron, Jill S.; Davidson, E.A.; Tague, C.L.; Felker-Quinn, E.; Lynch, J.A.; Herrick, J.D.; Liu, L.; Goodale, C.L.; Novak, K. J.; Haeuber, R. A.

2016-01-01

Climate change and anthropogenic nitrogen deposition are both important ecological threats. Evaluating their cumulative effects provides a more holistic view of ecosystem vulnerability to human activities, which would better inform policy decisions aimed to protect the sustainability of ecosystems. Our knowledge of the cumulative effects of these stressors is growing, but we lack an integrated understanding. In this Review, we describe how climate change alters key processes in terrestrial and freshwater ecosystems related to nitrogen cycling and availability, and the response of ecosystems to nitrogen addition in terms of carbon cycling, acidification and biodiversity.

Key ecological responses to nitrogen are altered by climate change

NASA Astrophysics Data System (ADS)

Greaver, T. L.; Clark, C. M.; Compton, J. E.; Vallano, D.; Talhelm, A. F.; Weaver, C. P.; Band, L. E.; Baron, J. S.; Davidson, E. A.; Tague, C. L.; Felker-Quinn, E.; Lynch, J. A.; Herrick, J. D.; Liu, L.; Goodale, C. L.; Novak, K. J.; Haeuber, R. A.

2016-09-01

Climate change and anthropogenic nitrogen deposition are both important ecological threats. Evaluating their cumulative effects provides a more holistic view of ecosystem vulnerability to human activities, which would better inform policy decisions aimed to protect the sustainability of ecosystems. Our knowledge of the cumulative effects of these stressors is growing, but we lack an integrated understanding. In this Review, we describe how climate change alters key processes in terrestrial and freshwater ecosystems related to nitrogen cycling and availability, and the response of ecosystems to nitrogen addition in terms of carbon cycling, acidification and biodiversity.

Tectono-metallogenetic evolution of the Fe-Cu deposit of Dominga, northern Chile

NASA Astrophysics Data System (ADS)

Veloso, E.; Cembrano, J.; Arancibia, G.; Heuser, G.; Neira, S.; Siña, A.; Garrido, I.; Vermeesch, P.; Selby, D.

2017-04-01

The Dominga district in northern Chile (2082 Mt at 23.3 % Fe, 0.07 % Cu) shows a spatial and genetic affinity among distinctive structural elements and Fe-Cu-rich paragenetic mineral assemblages. Deep seated, NE-to-E striking structural elements form a right-lateral duplex-like structural system (early structural system, ESS) that cuts a regionally extensive alteration (stage I) zone. The EES system served as a locus and as path for the emplacement of biotite-magnetite alteration/mineralization (stage IIa) as veins and Fe-bearing layers following altered volcano sedimentary strata. NW-striking actinolite-magnetite hydrothermal breccias, coeval with and part of the ESS, include apatite (stage IIb) crystallized at 127 ± 15 Ma (U-Pb, 2σ). The ESS was also the locus of subsequent alteration/mineralization represented by K-feldspar, epidote, and albite (stage IIIa) and Fe-Cu-rich (vermiculite-anhydrite-chalcopyrite, stage IIIb) mineral associations. Shallowly developed, NNE-striking, left-lateral structural elements defining the El Tofo Structural System (ETSS)—probably part of the Atacama Fault System—clearly crosscut the ESS. Minerals associated with alteration/mineralization stage IIIb also occur as veins and as part of hydrothermal breccias of the ETSS, marking the transition from the ESS to ETSS. Molybdenite associated with alteration/mineralization stage IIIb yielded a Re-Os age of 127.1 ± 0.7 Ma (2σ). Both the ESS and ETSS were cut by left-lateral, NW- to E-striking shallowly developed structural elements (Intermediate Structural System, ISS) on which a hematite-calcite assemblage (stage IV) occurs mostly as infill material of veins and fault veins. The ISS is cut by N-striking, left-lateral, and shallowly developed structural elements (Late Structural System, LSS) showing no evidence of alteration/mineralization. Estimated strain and stress fields indicate an overall NW-trending shortening/compression and NE-trending stretching/tension strike-slip regime probably due to oblique subduction during the Mesozoic. However, the orientations of the stress and strain fields calculated for each structural system suggest a back-and-forth rotation pattern during transition from one structural system to the other—as they change between transtension and transpression—and between alteration/mineralization stages.

Engineering Metallic Nanoparticles for Enhancing and Probing Catalytic Reactions.

PubMed

Collins, Gillian; Holmes, Justin D

2016-07-01

Recent developments in tailoring the structural and chemical properties of colloidal metal nanoparticles (NPs) have led to significant enhancements in catalyst performance. Controllable colloidal synthesis has also allowed tailor-made NPs to serve as mechanistic probes for catalytic processes. The innovative use of colloidal NPs to gain fundamental insights into catalytic function will be highlighted across a variety of catalytic and electrocatalytic applications. The engineering of future heterogenous catalysts is also moving beyond size, shape and composition considerations. Advancements in understanding structure-property relationships have enabled incorporation of complex features such as tuning surface strain to influence the behavior of catalytic NPs. Exploiting plasmonic properties and altering colloidal surface chemistry through functionalization are also emerging as important areas for rational design of catalytic NPs. This news article will highlight the key developments and challenges to the future design of catalytic NPs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nitrogen-Doped Carbon Nanotube/Graphite Felts as Advanced Electrode Materials for Vanadium Redox Flow Batteries.

PubMed

Wang, Shuangyin; Zhao, Xinsheng; Cochell, Thomas; Manthiram, Arumugam

2012-08-16

Nitrogen-doped carbon nanotubes have been grown, for the first time, on graphite felt (N-CNT/GF) by a chemical vapor deposition approach and examined as an advanced electrode for vanadium redox flow batteries (VRFBs). The unique porous structure and nitrogen doping of N-CNT/GF with increased surface area enhances the battery performance significantly. The enriched porous structure of N-CNTs on graphite felt could potentially facilitate the diffusion of electrolyte, while the N-doping could significantly contribute to the enhanced electrode performance. Specifically, the N-doping (i) modifies the electronic properties of CNT and thereby alters the chemisorption characteristics of the vanadium ions, (ii) generates defect sites that are electrochemically more active, (iii) increases the oxygen species on CNT surface, which is a key factor influencing the VRFB performance, and (iv) makes the N-CNT electrochemically more accessible than the CNT.

Hydrothermal temperature effect on crystal structures, optical properties and electrical conductivity of ZnO nanostructures

NASA Astrophysics Data System (ADS)

Dhafina, Wan Almaz; Salleh, Hasiah; Daud, Mohd Zalani; Ghazali, Mohd Sabri Mohd; Ghazali, Salmah Mohd

2017-09-01

ZnO is an wide direct band gap semiconductor and possess rich family of nanostructures which turned to be a key role in the nanotechnology field of applications. Hydrothermal method was proven to be simple, robust and low cost among the reported methods to synthesize ZnO nanostructures. In this work, the properties of ZnO nanostructures were altered by varying temperatures of hydrothermal process. The changes in term of morphological, crystal structures, optical properties and electrical conductivity were investigated. A drastic change of ZnO nanostructures morphology and decreases of 002 diffraction peak were observed as the hydrothermal temperature increased. The band gap of samples decreased as the size of ZnO nanostructure increased, whereas the electrical conductivity had no influence on the band gap value but more on the morphology of ZnO nanostructures instead.

Getting Things Sorted With Lagrangian Coherent Structures

NASA Astrophysics Data System (ADS)

Atis, Severine; Peacock, Thomas; Environmental Dynamics Laboratory Team

2014-11-01

The dispersion of a tracer in a fluid flow is influenced by the Lagrangian motion of fluid elements. Even in laminar regimes, the irregular chaotic behavior of a fluid flow can lead to effective stirring that rapidly redistributes a tracer throughout the domain. For flows with arbitrary time-dependence, the modern approach of Lagrangian Coherent Structures (LCSs) provide a method for identifying the key material lines that organize flow transport. When the advected tracer particles possess a finite size and nontrivial shape, however, their dynamics can differ markedly from passive tracers, thus affecting the dispersion phenomena. We present details of numerical simulations and laboratory experiments that investigate the behavior of finite size particles in 2-dimensional chaotic flows. We show that the shape and the size of the particles alter the underlying LCSs, facilitating segregation between tracers of different shape in the same flow field.

Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite.

PubMed

Das, Pronay; Babbar, Palak; Malhotra, Nipun; Sharma, Manmohan; Jachak, Gorakhnath R; Gonnade, Rajesh G; Shanmugam, Dhanasekaran; Harlos, Karl; Yogavel, Manickam; Sharma, Amit; Reddy, D Srinivasa

2018-05-21

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme- and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

Effect of mutation at the interface of Trp-repressor dimeric protein: a steered molecular dynamics simulation.

PubMed

Miño, German; Baez, Mauricio; Gutierrez, Gonzalo

2013-09-01

The strength of key interfacial contacts that stabilize protein-protein interactions have been studied by computer simulation. Experimentally, changes in the interface are evaluated by generating specific mutations at one or more points of the protein structure. Here, such an evaluation is performed by means of steered molecular dynamics and use of a dimeric model of tryptophan repressor and in-silico mutants as a test case. Analysis of four particular cases shows that, in principle, it is possible to distinguish between wild-type and mutant forms by examination of the total energy and force-extension profiles. In particular, detailed atomic level structural analysis indicates that specific mutations at the interface of the dimeric model (positions 19 and 39) alter interactions that appear in the wild-type form of tryptophan repressor, reducing the energy and force required to separate both subunits.

Zooplankton and the Ocean Carbon Cycle.

PubMed

Steinberg, Deborah K; Landry, Michael R

2017-01-03

Marine zooplankton comprise a phylogenetically and functionally diverse assemblage of protistan and metazoan consumers that occupy multiple trophic levels in pelagic food webs. Within this complex network, carbon flows via alternative zooplankton pathways drive temporal and spatial variability in production-grazing coupling, nutrient cycling, export, and transfer efficiency to higher trophic levels. We explore current knowledge of the processing of zooplankton food ingestion by absorption, egestion, respiration, excretion, and growth (production) processes. On a global scale, carbon fluxes are reasonably constrained by the grazing impact of microzooplankton and the respiratory requirements of mesozooplankton but are sensitive to uncertainties in trophic structure. The relative importance, combined magnitude, and efficiency of export mechanisms (mucous feeding webs, fecal pellets, molts, carcasses, and vertical migrations) likewise reflect regional variability in community structure. Climate change is expected to broadly alter carbon cycling by zooplankton and to have direct impacts on key species.

Optimization of a growth process for as-grown 2D materials-based devices

NASA Astrophysics Data System (ADS)

Lindquist, Miles; Khadka, Sudiksha; Aleithan, Shrouq; Blumer, Ari; Wickramasinghe, Thushan; Thorat, Ruhi; Kordesch, Martin; Stinaff, Eric

We will present the effects of varying key parameters of a deterministic growth method for producing self-contacted 2D transition metal dichalcogenides. Chemical vapor deposition is used to grow a film of 2D material nucleated around and seeded from metallic features prepared by photolithography and sputtering on a Si/SiO2 substrate prior to growth. We will focus on a particular method of growing variable MoS2 based device structures. The goal of this work is to arrive at robust platform for growing a variety of device structures by systematically altering parameters such as the amount of reactants used, the heat of the substrate and oxide powder, and the flow rate of argon gas used. These results will help advance a comprehensive process for the scalable production of as-grown, complex, 2D materials-based device architectures.

General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

DOE PAGES

Brinkmann-Chen, Sabine; Flock, Tilman; Cahn, Jackson K. B.; ...

2013-06-17

To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymesmore » having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. As a result, high-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch.« less

Eavesdropping on altered cell-to-cell signaling in cancer by secretome profiling.

PubMed

Klinke, David J

2016-01-01

In the past decade, cumulative clinical experiences with molecular targeted therapies and immunotherapies for cancer have promoted a shift in our conceptual understanding of cancer. This view shifted from viewing solid tumors as a homogeneous mass of malignant cells to viewing tumors as heterogeneous structures that are dynamically shaped by intercellular interactions among the variety of stromal, immune, and malignant cells present within the tumor microenvironment. As in any dynamic system, identifying how cells communicate to maintain homeostasis and how this communication is altered during oncogenesis are key hurdles for developing therapies to restore normal tissue homeostasis. Here, I discuss tissues as dynamic systems, using the mammary gland as an example, and the evolutionary concepts applied to oncogenesis. Drawing from these concepts, I present 2 competing hypotheses for how intercellular communication might be altered during oncogenesis. As an initial test of these competing hypotheses, a recent secretome comparison between normal human mammary and HER2+ breast cancer cell lines suggested that the particular proteins secreted by the malignant cells reflect a convergent evolutionary path associated with oncogenesis in a specific anatomical niche, despite arising in different individuals. Overall, this study illustrates the emerging power of secretome proteomics to probe, in an unbiased way, how intercellular communication changes during oncogenesis.

Eavesdropping on altered cell-to-cell signaling in cancer by secretome profiling

PubMed Central

Klinke, David J

2016-01-01

In the past decade, cumulative clinical experiences with molecular targeted therapies and immunotherapies for cancer have promoted a shift in our conceptual understanding of cancer. This view shifted from viewing solid tumors as a homogeneous mass of malignant cells to viewing tumors as heterogeneous structures that are dynamically shaped by intercellular interactions among the variety of stromal, immune, and malignant cells present within the tumor microenvironment. As in any dynamic system, identifying how cells communicate to maintain homeostasis and how this communication is altered during oncogenesis are key hurdles for developing therapies to restore normal tissue homeostasis. Here, I discuss tissues as dynamic systems, using the mammary gland as an example, and the evolutionary concepts applied to oncogenesis. Drawing from these concepts, I present 2 competing hypotheses for how intercellular communication might be altered during oncogenesis. As an initial test of these competing hypotheses, a recent secretome comparison between normal human mammary and HER2+ breast cancer cell lines suggested that the particular proteins secreted by the malignant cells reflect a convergent evolutionary path associated with oncogenesis in a specific anatomical niche, despite arising in different individuals. Overall, this study illustrates the emerging power of secretome proteomics to probe, in an unbiased way, how intercellular communication changes during oncogenesis. PMID:27308541

Model of the Students' Key Competences Development through Interactive Whiteboard in the Subject of Technology

ERIC Educational Resources Information Center

Brecka, Peter; Valentová, Monika

2017-01-01

The basis of the submitted study are the continuously rising demands to alter the curricula with the aim to develop students' key competences in order to increase their professional versatility. The lack of scientific research and discussions show that little investigation has been done on the issue of development of key competences. Therefore,…

Mechanisms of stress in the brain.

PubMed

McEwen, Bruce S; Bowles, Nicole P; Gray, Jason D; Hill, Matthew N; Hunter, Richard G; Karatsoreos, Ilia N; Nasca, Carla

2015-10-01

The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a sign of successful adaptation, whereas persistence of these changes when stress ends indicates failed resilience. Excitatory amino acids and glucocorticoids have key roles in these processes, along with a growing list of extra- and intracellular mediators that includes endocannabinoids and brain-derived neurotrophic factor (BDNF). The result is a continually changing pattern of gene expression mediated by epigenetic mechanisms involving histone modifications and CpG methylation and hydroxymethylation as well as by the activity of retrotransposons that may alter genomic stability. Elucidation of the underlying mechanisms of plasticity and vulnerability of the brain provides a basis for understanding the efficacy of interventions for anxiety and depressive disorders as well as age-related cognitive decline.

Nucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming.

PubMed

West, Jason A; Cook, April; Alver, Burak H; Stadtfeld, Matthias; Deaton, Aimee M; Hochedlinger, Konrad; Park, Peter J; Tolstorukov, Michael Y; Kingston, Robert E

2014-08-27

Chromatin structure determines DNA accessibility. We compare nucleosome occupancy in mouse and human embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs) and differentiated cell types using MNase-seq. To address variability inherent in this technique, we developed a bioinformatic approach to identify regions of difference (RoD) in nucleosome occupancy between pluripotent and somatic cells. Surprisingly, most chromatin remains unchanged; a majority of rearrangements appear to affect a single nucleosome. RoDs are enriched at genes and regulatory elements, including enhancers associated with pluripotency and differentiation. RoDs co-localize with binding sites of key developmental regulators, including the reprogramming factors Klf4, Oct4/Sox2 and c-Myc. Nucleosomal landscapes in ESC enhancers are extensively altered, exhibiting lower nucleosome occupancy in pluripotent cells than in somatic cells. Most changes are reset during reprogramming. We conclude that changes in nucleosome occupancy are a hallmark of cell differentiation and reprogramming and likely identify regulatory regions essential for these processes.

Relating Nanoscale Accessibility within Plant Cell Walls to Improved Enzyme Hydrolysis Yields in Corn Stover Subjected to Diverse Pretreatments.

PubMed

Crowe, Jacob D; Zarger, Rachael A; Hodge, David B

2017-10-04

Simultaneous chemical modification and physical reorganization of plant cell walls via alkaline hydrogen peroxide or liquid hot water pretreatment can alter cell wall structural properties impacting nanoscale porosity. Nanoscale porosity was characterized using solute exclusion to assess accessible pore volumes, water retention value as a proxy for accessible water-cell walls surface area, and solute-induced cell wall swelling to measure cell wall rigidity. Key findings concluded that delignification by alkaline hydrogen peroxide pretreatment decreased cell wall rigidity and that the subsequent cell wall swelling resulted increased nanoscale porosity and improved enzyme binding and hydrolysis compared to limited swelling and increased accessible surface areas observed in liquid hot water pretreated biomass. The volume accessible to a 90 Å dextran probe within the cell wall was found to be correlated to both enzyme binding and glucose hydrolysis yields, indicating cell wall porosity is a key contributor to effective hydrolysis yields.

Depletion of key protein components of the RISC pathway impairs pre-ribosomal RNA processing.

PubMed

Liang, Xue-Hai; Crooke, Stanley T

2011-06-01

Little is known about whether components of the RNA-induced silencing complex (RISC) mediate the biogenesis of RNAs other than miRNA. Here, we show that depletion of key proteins of the RISC pathway by antisense oligonucleotides significantly impairs pre-rRNA processing in human cells. In cells depleted of Drosha or Dicer, different precursors to 5.8S rRNA strongly accumulated, without affecting normal endonucleolytic cleavages. Moderate yet distinct processing defects were also observed in Ago2-depleted cells. Physical links between pre-rRNA and these proteins were identified by co-immunoprecipitation analyses. Interestingly, simultaneous depletion of Dicer and Drosha led to a different processing defect, causing slower production of 28S rRNA and its precursor. Both Dicer and Ago2 were detected in the nuclear fraction, and reduction of Dicer altered the structure of the nucleolus, where pre-rRNA processing occurs. Together, these results suggest that Drosha and Dicer are implicated in rRNA biogenesis.

Salicylic acid induces vanillin synthesis through the phospholipid signaling pathway in Capsicum chinense cell cultures

PubMed Central

Rodas-Junco, Beatriz A; Cab-Guillen, Yahaira; Muñoz-Sanchez, J Armando; Vázquez-Flota, Felipe; Monforte-Gonzalez, Miriam; Hérnandez-Sotomayor, S M Teresa

2013-01-01

Signal transduction via phospholipids is mediated by phospholipases such as phospholipase C (PLC) and D (PLD), which catalyze hydrolysis of plasma membrane structural phospholipids. Phospholipid signaling is also involved in plant responses to phytohormones such as salicylic acid (SA). The relationships between phospholipid signaling, SA, and secondary metabolism are not fully understood. Using a Capsicum chinense cell suspension as a model, we evaluated whether phospholipid signaling modulates SA-induced vanillin production through the activation of phenylalanine ammonia lyase (PAL), a key enzyme in the biosynthetic pathway. Salicylic acid was found to elicit PAL activity and consequently vanillin production, which was diminished or reversed upon exposure to the phosphoinositide-phospholipase C (PI-PLC) signaling inhibitors neomycin and U73122. Exposure to the phosphatidic acid inhibitor 1-butanol altered PLD activity and prevented SA-induced vanillin production. Our results suggest that PLC and PLD-generated secondary messengers may be modulating SA-induced vanillin production through the activation of key biosynthetic pathway enzymes.

Membrane alterations induced by nonstructural proteins of human norovirus

PubMed Central

White, Peter A.; Hansman, Grant S.

2017-01-01

Human noroviruses (huNoV) are the most frequent cause of non-bacterial acute gastroenteritis worldwide, particularly genogroup II genotype 4 (GII.4) variants. The viral nonstructural (NS) proteins encoded by the ORF1 polyprotein induce vesical clusters harboring the viral replication sites. Little is known so far about the ultrastructure of these replication organelles or the contribution of individual NS proteins to their biogenesis. We compared the ultrastructural changes induced by expression of norovirus ORF1 polyproteins with those induced upon infection with murine norovirus (MNV). Characteristic membrane alterations induced by ORF1 expression resembled those found in MNV infected cells, consisting of vesicle accumulations likely built from the endoplasmic reticulum (ER) which included single membrane vesicles (SMVs), double membrane vesicles (DMVs) and multi membrane vesicles (MMVs). In-depth analysis using electron tomography suggested that MMVs originate through the enwrapping of SMVs with tubular structures similar to mechanisms reported for picornaviruses. Expression of GII.4 NS1-2, NS3 and NS4 fused to GFP revealed distinct membrane alterations when analyzed by correlative light and electron microscopy. Expression of NS1-2 induced proliferation of smooth ER membranes forming long tubular structures that were affected by mutations in the active center of the putative NS1-2 hydrolase domain. NS3 was associated with ER membranes around lipid droplets (LDs) and induced the formation of convoluted membranes, which were even more pronounced in case of NS4. Interestingly, NS4 was the only GII.4 protein capable of inducing SMV and DMV formation when expressed individually. Our work provides the first ultrastructural analysis of norovirus GII.4 induced vesicle clusters and suggests that their morphology and biogenesis is most similar to picornaviruses. We further identified NS4 as a key factor in the formation of membrane alterations of huNoV and provide models of the putative membrane topologies of NS1-2, NS3 and NS4 to guide future studies. PMID:29077760

High-salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system.

PubMed

Mao, Caiping; Liu, Rong; Bo, Le; Chen, Ningjing; Li, Shigang; Xia, Shuixiu; Chen, Jie; Li, Dawei; Zhang, Lubo; Xu, Zhice

2013-07-01

Intrauterine environments are related to fetal renal development and postnatal health. Influence of salty diets during pregnancy on renal functions and renin-angiotensin system (RAS) was determined in the ovine fetuses and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for 2 months during middle-to-late gestation. Fetal renal functions, plasma hormones, and mRNA and protein expressions of the key elements of renal RAS were measured in the fetuses and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in the HSD group. Fetal blood urea nitrogen was increased, while kidney weight:body weight ratio decreased in the HSD group. The altered ratio was also observed in the offspring aged 15 and 90 days. Maternal and fetal plasma antidiuretic hormone was elevated without changes in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, angiotensin converting enzyme (ACE), ACE2, AT1, and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that high intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases.

Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto-Kakizaki rats.

PubMed

Sárközy, Márta; Szűcs, Gergő; Fekete, Veronika; Pipicz, Márton; Éder, Katalin; Gáspár, Renáta; Sója, Andrea; Pipis, Judit; Ferdinandy, Péter; Csonka, Csaba; Csont, Tamás

2016-08-05

There is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats. Fasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein-protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM. Fasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up-regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein-protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM. Non-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM.

Functional diversity of the superfamily of K⁺ transporters to meet various requirements.

PubMed

Diskowski, Marina; Mikusevic, Vedrana; Stock, Charlott; Hänelt, Inga

2015-09-01

The superfamily of K+ transporters unites proteins from plants, fungi, bacteria, and archaea that translocate K+ and/or Na+ across membranes. These proteins are key components in osmotic regulation, pH homeostasis, and resistance to high salinity and dryness. The members of the superfamily are closely related to K+ channels such as KcsA but also show several striking differences that are attributed to their altered functions. This review highlights these functional differences, focusing on the bacterial superfamily members KtrB, TrkH, and KdpA. The functional variations within the family and comparison to MPM-type K+ channels are discussed in light of the recently solved structures of the Ktr and Trk systems.

Exercise and ankle sprain injuries: a comprehensive review.

PubMed

Calatayud, Joaquin; Borreani, Sebastien; Colado, Juan Carlos; Flandez, Jorge; Page, Phil; Andersen, Lars L

2014-02-01

Ankle sprains are common in team sports and sports played on courts, and often result in structural and functional alterations that lead to a greater reinjury risk. Specific exercises are often used to promote neuromuscular improvements in the prevention and rehabilitation of ankle injuries. This literature review summarizes the neuromuscular characteristics of common ankle sprains and the effectiveness of exercise as an intervention for improving neuromuscular function and preventing reinjury. Our review found that appropriate exercise prescription can increase static and dynamic balance and decrease injury recurrence. In particular, the addition of dynamic activities in the exercise program can be beneficial because of the anticipatory postural adjustments identified as a key factor in the injury mechanism.

Expanding the Scope of Site-Specific Recombinases for Genetic and Metabolic Engineering

PubMed Central

Gaj, Thomas; Sirk, Shannon J.; Barbas, Carlos F.

2014-01-01

Site-specific recombinases are tremendously valuable tools for basic research and genetic engineering. By promoting high-fidelity DNA modifications, site-specific recombination systems have empowered researchers with unprecedented control over diverse biological functions, enabling countless insights into cellular structure and function. The rigid target specificities of many sites-specific recombinases, however, have limited their adoption in fields that require highly flexible recognition abilities. As a result, intense effort has been directed toward altering the properties of site-specific recombination systems by protein engineering. Here, we review key developments in the rational design and directed molecular evolution of site-specific recombinases, highlighting the numerous applications of these enzymes across diverse fields of study. PMID:23982993

The role of genes and environment on brain alterations in Major Depressive Disorder: A review of twin studies: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders.

PubMed

Pigoni, A; Delvecchio, G; Altamura, A C; Soares, J C; Fagnani, C; Brambilla, P

2018-07-01

Although it has been consistently reported the important role of genetic and environmental risk factors on structural and functional alterations in Major Depressive Disorder (MDD), the mechanism and the magnitude of the interactions between specific genetic and/or environmental risk factors on brain structures in this disabling disorder are still elusive. Therefore, in the last two decades an increased interest has been devoted to neuroimaging investigations on monozygotic and dizygotic twin samples mainly because their intrinsic characteristics may help to separate the effects of genetic and environmental risk factors on clinical phenotypes, including MDD. In this context, the present review summarizes results from structural and functional Magnetic Resonance Imaging studies that investigated twin samples in correlation with MDD. Overall the results confirmed that a) MDD is characterized by significant alterations in selective brain areas presiding over emotion recognition and evaluation, including amygdala, insula and prefrontal cortices, and b) both genetic and environmental risk factors play a key role in the pathophysiology of this disorder. Few MRI studies exploring MDD in twin samples. The specific contribution of both aspects is still not fully elucidated especially because genes and environment have an impact on the same brain areas, which are particularly vulnerable in MDD. Expansion of the current twin sample sizes would help to clearly establish the potential relationship between risk factors and the development of MDD. Copyright © 2017 Elsevier B.V. All rights reserved.

Subjects harboring presenilin familial Alzheimer’s disease mutations exhibit diverse white matter biochemistry alterations

PubMed Central

Roher, Alex E; Maarouf, Chera L; Malek-Ahmadi, Michael; Wilson, Jeffrey; Kokjohn, Tyler A; Daugs, Ian D; Whiteside, Charisse M; Kalback, Walter M; Macias, MiMi P; Jacobson, Sandra A; Sabbagh, Marwan N; Ghetti, Bernardino; Beach, Thomas G

2013-01-01

Alzheimer’s disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined. PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (Aβ) peptides compared to SAD, which may play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce uniform increases in the relative proportions of Aβ42 and exhibited substantial variability in total Aβ levels. These observations suggest that neurodegeneration and dementia do not depend solely on enhanced Aβ42 levels. Our data revealed additional complexities in PSEN-FAD individuals. Some direct substrates of γ-secretase, such as Notch, N-cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types. Proteins that were not direct γ-secretase substrates, but play key structural and functional roles in the WM, likewise exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of effective therapeutic interventions for both SAD and FAD. PMID:24093083

Molecular modeling and structural analysis of nAChR variants uncovers the mechanism of resistance to snake toxins.

PubMed

Gunasekaran, D; Sridhar, J; Suryanarayanan, V; Manimaran, N C; Singh, Sanjeev Kumar

2017-06-01

Nicotinic acetylcholine receptors (nAChRs) are neuromuscular proteins responsible for muscle contraction upon binding with chemical stimulant acetylcholine (ACh). The α-neurotoxins of snake mimic the structure of ACh and attacks nAChRs, which block the flow of ACh and leads to numbness and paralysis. The toxin-binding site of alpha subunit in the nAChRs is highly conserved throughout chordate lineages with few exceptions in resistance organisms. In this study, we have analyzed the sequence and structures of toxin-binding/resistant nAChRs and their interaction stability with toxins through molecular docking and molecular dynamics simulation (MDS). We have reported the potential glycosylation residues within the toxin-binding cleft adding sugar moieties through N-linked glycosylation in resistant organisms. Residue variations at key positions alter the secondary structure of binding cleft, which might interfere with toxin binding and it could be one of the possible explanations for the resistance to snake venoms. Analysis of nAChR-α-neurotoxin complexes has confirmed the key interacting residues. In addition, drastic variation in the binding stability of Mongoose nAChR-α-Bungarotoxin (α-BTX) and human nAChR-α-BTX complexes were found at specific phase of MDS. Our findings suggest that specific mutations in the binding site of toxin are potentially preventing the formation of stable complex of receptor-toxin, which might lead to mechanism of resistance. This in silico study on the binding cleft of nAChR and the findings of interacting residues will assist in designing potential inhibitors as therapeutic targets.

Brain structures and functional connectivity associated with individual differences in Internet tendency in healthy young adults.

PubMed

Li, Weiwei; Li, Yadan; Yang, Wenjing; Zhang, Qinglin; Wei, Dongtao; Li, Wenfu; Hitchman, Glenn; Qiu, Jiang

2015-04-01

Internet addiction (IA) incurs significant social and financial costs in the form of physical side-effects, academic and occupational impairment, and serious relationship problems. The majority of previous studies on Internet addiction disorders (IAD) have focused on structural and functional abnormalities, while few studies have simultaneously investigated the structural and functional brain alterations underlying individual differences in IA tendencies measured by questionnaires in a healthy sample. Here we combined structural (regional gray matter volume, rGMV) and functional (resting-state functional connectivity, rsFC) information to explore the neural mechanisms underlying IAT in a large sample of 260 healthy young adults. The results showed that IAT scores were significantly and positively correlated with rGMV in the right dorsolateral prefrontal cortex (DLPFC, one key node of the cognitive control network, CCN), which might reflect reduced functioning of inhibitory control. More interestingly, decreased anticorrelations between the right DLPFC and the medial prefrontal cortex/rostral anterior cingulate cortex (mPFC/rACC, one key node of the default mode network, DMN) were associated with higher IAT scores, which might be associated with reduced efficiency of the CCN and DMN (e.g., diminished cognitive control and self-monitoring). Furthermore, the Stroop interference effect was positively associated with the volume of the DLPFC and with the IA scores, as well as with the connectivity between DLPFC and mPFC, which further indicated that rGMV variations in the DLPFC and decreased anticonnections between the DLPFC and mPFC may reflect addiction-related reduced inhibitory control and cognitive efficiency. These findings suggest the combination of structural and functional information can provide a valuable basis for further understanding of the mechanisms and pathogenesis of IA. Copyright © 2015 Elsevier Ltd. All rights reserved.

How protein materials balance strength, robustness, and adaptability

PubMed Central

Buehler, Markus J.; Yung, Yu Ching

2010-01-01

Proteins form the basis of a wide range of biological materials such as hair, skin, bone, spider silk, or cells, which play an important role in providing key functions to biological systems. The focus of this article is to discuss how protein materials are capable of balancing multiple, seemingly incompatible properties such as strength, robustness, and adaptability. To illustrate this, we review bottom-up materiomics studies focused on the mechanical behavior of protein materials at multiple scales, from nano to macro. We focus on alpha-helix based intermediate filament proteins as a model system to explain why the utilization of hierarchical structural features is vital to their ability to combine strength, robustness, and adaptability. Experimental studies demonstrating the activation of angiogenesis, the growth of new blood vessels, are presented as an example of how adaptability of structure in biological tissue is achieved through changes in gene expression that result in an altered material structure. We analyze the concepts in light of the universality and diversity of the structural makeup of protein materials and discuss the findings in the context of potential fundamental evolutionary principles that control their nanoscale structure. We conclude with a discussion of multiscale science in biology and de novo materials design. PMID:20676305

Comprehensive Peptide Ion Structure Studies Using Ion Mobility Techniques: Part 3. Relating Solution-Phase to Gas-Phase Structures.

PubMed

Kondalaji, Samaneh Ghassabi; Khakinejad, Mahdiar; Valentine, Stephen J

2018-06-01

Molecular dynamics (MD) simulations have been utilized to study peptide ion conformer establishment during the electrospray process. An explicit water model is used for nanodroplets containing a model peptide and hydronium ions. Simulations are conducted at 300 K for two different peptide ion charge configurations and for droplets containing varying numbers of hydronium ions. For all conditions, modeling has been performed until production of the gas-phase ions and the resultant conformers have been compared to proposed gas-phase structures. The latter species were obtained from previous studies in which in silico candidate structures were filtered according to ion mobility and hydrogen-deuterium exchange (HDX) reactivity matches. Results from the present study present three key findings namely (1) the evidence from ion production modeling supports previous structure refinement studies based on mobility and HDX reactivity matching, (2) the modeling of the electrospray process is significantly improved by utilizing initial droplets existing below but close to the calculated Rayleigh limit, and (3) peptide ions in the nanodroplets sample significantly different conformers than those in the bulk solution due to altered physicochemical properties of the solvent. Graphical Abstract ᅟ.

Calcium-independent metal-ion catalytic mechanism of anthrax edema factor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Yuequan; Zhukovskaya, Natalia L.; Guo, Qing

2009-11-18

Edema factor (EF), a key anthrax exotoxin, has an anthrax protective antigen-binding domain (PABD) and a calmodulin (CaM)-activated adenylyl cyclase domain. Here, we report the crystal structures of CaM-bound EF, revealing the architecture of EF PABD. CaM has N- and C-terminal domains and each domain can bind two calcium ions. Calcium binding induces the conformational change of CaM from closed to open. Structures of the EF-CaM complex show how EF locks the N-terminal domain of CaM into a closed conformation regardless of its calcium-loading state. This represents a mechanism of how CaM effector alters the calcium affinity of CaM andmore » uncouples the conformational change of CaM from calcium loading. Furthermore, structures of EF-CaM complexed with nucleotides show that EF uses two-metal-ion catalysis, a prevalent mechanism in DNA and RNA polymerases. A histidine (H351) further facilitates the catalysis of EF by activating a water to deprotonate 3'OH of ATP. Mammalian adenylyl cyclases share no structural similarity with EF and they also use two-metal-ion catalysis, suggesting the catalytic mechanism-driven convergent evolution of two structurally diverse adenylyl cyclases.« less

Investigation of Plant Cell Wall Properties: A Study of Contributions from the Nanoscale to the Macroscale Impacting Cell Wall Recalcitrance

NASA Astrophysics Data System (ADS)

Crowe, Jacob Dillon

Biochemical conversion of lignocellulosic biomass to fuel ethanol is one of a few challenging, yet opportune technologies that can reduce the consumption of petroleum-derived transportation fuels, while providing parallel reductions in greenhouse gas emissions. Biomass recalcitrance, or resistance to deconstruction, is a major technical challenge that limits effective conversion of biomass to fermentable sugars, often requiring a costly thermochemical pretreatment step to improve biomass deconstruction. Biomass recalcitrance is imparted largely by the secondary cell wall, a complex polymeric matrix of cell wall polysaccharides and aromatic heteropolymers, that provides structural stability to cells and enables plant upright growth. Polymers within the cell wall can vary both compositionally and structurally depending upon plant species and anatomical fraction, and have varied responses to thermochemical pretreatments. Cell wall properties impacting recalcitrance are still not well understood, and as a result, the goal of this dissertation is to investigate structural features of the cell wall contributing to recalcitrance (1) in diverse anatomical fractions of a single species, (2) in response to diverse pretreatments, and (3) resulting from genetic modification. In the first study, feedstock cell wall heterogeneity was investigated in anatomical (stem, leaf sheaths, and leaf blades) and internode fractions of switchgrass at varying tissue maturities. Lignin content was observed as the key contributor to recalcitrance in maturing stem tissues only, with non-cellulosic substituted glucuronoarabinoxylans and pectic polysaccharides contributing to cell wall recalcitrance in leaf sheath and leaf blades. Hydroxycinnamate (i.e., saponifiable p-coumarate and ferulate) content along with xylan and pectin extractability decreased with tissue maturity, suggesting lignification is only one component imparting maturity specific cell wall recalcitrance. In the second study, alkaline hydrogen peroxide and liquid hot water pretreatments were shown to alter structural properties impacting nanoscale porosity in corn stover. Delignification by alkaline hydrogen peroxide pretreatment decreased cell wall rigidity, with subsequent cell wall swelling resulting in increased nanoscale porosity and improved enzymatic hydrolysis compared to limited swelling and increased accessible surface areas observed in liquid hot water pretreated biomass. The volume accessible to a 90 A dextran probe within the cell wall was found to be positively correlated to both enzyme binding and glucose hydrolysis yields, indicating cell wall porosity is a key contributor to effective hydrolysis yields. In the third study, the effect of altered xylan content and structure was investigated in irregular xylem (irx) Arabidopsis thaliana mutants to understand the role xylan plays in secondary cell wall development and organization. Higher xylan extractability and lower cellulose crystallinity observed in irx9 and irx15 irx15-L mutants compared to wild type indicated altered xylan integration into the secondary cell wall. Nanoscale cell wall organization observed using multiple microscopy techniques was impacted to some extent in all irx mutants, with disorganized cellulose microfibril layers in sclerenchyma secondary cell walls likely resulting from irregular xylan structure and content. Irregular secondary cell wall microfibril layers showed heterogeneous nanomechanical properties compared to wild type, which translated to mechanical deficiencies observed in stem tensile tests. These results suggest nanoscale defects in cell wall strength can correspond to macroscale phenotypes.

Resource-driven changes to host population stability alter the evolution of virulence and transmission.

PubMed

Hite, Jessica L; Cressler, Clayton E

2018-05-05

What drives the evolution of parasite life-history traits? Recent studies suggest that linking within- and between-host processes can provide key insight into both disease dynamics and parasite evolution. Still, it remains difficult to understand how to pinpoint the critical factors connecting these cross-scale feedbacks, particularly under non-equilibrium conditions; many natural host populations inherently fluctuate and parasites themselves can strongly alter the stability of host populations. Here, we develop a general model framework that mechanistically links resources to parasite evolution across a gradient of stable and unstable conditions. First, we dynamically link resources and between-host processes (host density, stability, transmission) to virulence evolution, using a 'non-nested' model. Then, we consider a 'nested' model where population-level processes (transmission and virulence) depend on resource-driven changes to individual-level (within-host) processes (energetics, immune function, parasite production). Contrary to 'non-nested' model predictions, the 'nested' model reveals complex effects of host population dynamics on parasite evolution, including regions of evolutionary bistability; evolution can push parasites towards strongly or weakly stabilizing strategies. This bistability results from dynamic feedbacks between resource-driven changes to host density, host immune function and parasite production. Together, these results highlight how cross-scale feedbacks can provide key insights into the structuring role of parasites and parasite evolution.This article is part of the theme issue 'Anthropogenic resource subsidies and host-parasite dynamics in wildlife'. © 2018 The Author(s).

Ecological consequences of human niche construction: Examining long-term anthropogenic shaping of global species distributions

PubMed Central

Boivin, Nicole L.; Zeder, Melinda A.; Fuller, Dorian Q.; Crowther, Alison; Larson, Greger; Erlandson, Jon M.; Denham, Tim; Petraglia, Michael D.

2016-01-01

The exhibition of increasingly intensive and complex niche construction behaviors through time is a key feature of human evolution, culminating in the advanced capacity for ecosystem engineering exhibited by Homo sapiens. A crucial outcome of such behaviors has been the dramatic reshaping of the global biosphere, a transformation whose early origins are increasingly apparent from cumulative archaeological and paleoecological datasets. Such data suggest that, by the Late Pleistocene, humans had begun to engage in activities that have led to alterations in the distributions of a vast array of species across most, if not all, taxonomic groups. Changes to biodiversity have included extinctions, extirpations, and shifts in species composition, diversity, and community structure. We outline key examples of these changes, highlighting findings from the study of new datasets, like ancient DNA (aDNA), stable isotopes, and microfossils, as well as the application of new statistical and computational methods to datasets that have accumulated significantly in recent decades. We focus on four major phases that witnessed broad anthropogenic alterations to biodiversity—the Late Pleistocene global human expansion, the Neolithic spread of agriculture, the era of island colonization, and the emergence of early urbanized societies and commercial networks. Archaeological evidence documents millennia of anthropogenic transformations that have created novel ecosystems around the world. This record has implications for ecological and evolutionary research, conservation strategies, and the maintenance of ecosystem services, pointing to a significant need for broader cross-disciplinary engagement between archaeology and the biological and environmental sciences. PMID:27274046

Ecological consequences of human niche construction: Examining long-term anthropogenic shaping of global species distributions.

PubMed

Boivin, Nicole L; Zeder, Melinda A; Fuller, Dorian Q; Crowther, Alison; Larson, Greger; Erlandson, Jon M; Denham, Tim; Petraglia, Michael D

2016-06-07

The exhibition of increasingly intensive and complex niche construction behaviors through time is a key feature of human evolution, culminating in the advanced capacity for ecosystem engineering exhibited by Homo sapiens A crucial outcome of such behaviors has been the dramatic reshaping of the global biosphere, a transformation whose early origins are increasingly apparent from cumulative archaeological and paleoecological datasets. Such data suggest that, by the Late Pleistocene, humans had begun to engage in activities that have led to alterations in the distributions of a vast array of species across most, if not all, taxonomic groups. Changes to biodiversity have included extinctions, extirpations, and shifts in species composition, diversity, and community structure. We outline key examples of these changes, highlighting findings from the study of new datasets, like ancient DNA (aDNA), stable isotopes, and microfossils, as well as the application of new statistical and computational methods to datasets that have accumulated significantly in recent decades. We focus on four major phases that witnessed broad anthropogenic alterations to biodiversity-the Late Pleistocene global human expansion, the Neolithic spread of agriculture, the era of island colonization, and the emergence of early urbanized societies and commercial networks. Archaeological evidence documents millennia of anthropogenic transformations that have created novel ecosystems around the world. This record has implications for ecological and evolutionary research, conservation strategies, and the maintenance of ecosystem services, pointing to a significant need for broader cross-disciplinary engagement between archaeology and the biological and environmental sciences.

Exploring the potential of a conditional cash transfer intervention to reduce HIV risk among young women in Iringa, Tanzania.

PubMed

Kennedy, Caitlin E; Brahmbhatt, Heena; Likindikoki, Samuel; Beckham, Sarah W; Mbwambo, Jessie K; Kerrigan, Deanna

2014-01-01

Cash transfer programs seek to alter structural determinants of HIV risk such as poverty and gender inequality. We sought to explore the feasibility and potential effectiveness of a cash transfer intervention for young women as part of combination HIV prevention in Iringa, Tanzania. Qualitative, in-depth interviews were conducted with 116 stakeholders and residents from the region, including key informants, service delivery users, and members of key populations. Most respondents felt a cash transfer program would assist young women in Iringa to have more control over sexual decision-making and reduce poverty-driven transactional sex. Respondents were divided on who should receive funds: young women themselves, their parents/guardians, or community leaders. Cash amounts and suggested target groups varied, and several respondents suggested providing microcredit or small business capital instead of cash. Potential concerns included jealousy, dependency, and corruption. However, most respondents felt that some intervention was needed to address underlying poverty driving some sexual risk behavior. A cash transfer program could fill this role, ultimately reducing HIV, sexually transmitted infections, and unintended pregnancies. As increased attention is given to economic and structural interventions for HIV prevention, local input and knowledge should be considered in a program design.

Bridging the Divide: Linking Genomics to Ecosystem Responses to Climate Change: Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Melinda D.

2014-03-15

Over the project period, we have addressed the following objectives: 1) assess the effects of altered precipitation patterns (i.e., increased variability in growing season precipitation) on genetic diversity of the dominant C4 grass species, Andropogon gerardii, and 2) experimentally assess the impacts of extreme climatic events (heat wave, drought) on responses of the dominant C4 grasses, A. gerardii and Sorghastrum nutans, and the consequences of these response for community and ecosystem structure and function. Below is a summary of how we have addressed these objectives. Objective 1 After ten years of altered precipitation, we found the number of genotypes ofmore » A. gerardii was significantly reduced compared to the ambient precipitation treatments (Avolio et al., 2013a). Although genotype number was reduced, the remaining genotypes were less related to one another indicating that the altered precipitation treatment was selecting for increasingly dissimilar genomes (based on mean pairwise Dice distance among individuals). For the four key genotypes that displayed differential abundances depending on the precipitation treatment (G1, G4, and G11 in the altered plots and G2 in the ambient plots), we identified phenotypic differences in the field that could account for ecological sorting (Avolio & Smith, 2013a). The three altered rainfall genotypes also have very different phenotypic traits in the greenhouse in response to different soil moisture availabilities (Avolio and Smith, 2013c). Two of the genotypes that increased in abundance in the altered precipitation plots had greater allocation to root biomass (G4 and G11), while G1 allocated more biomass aboveground. These phenotypic differences among genotypes suggests that changes in genotypic structure between the altered and the ambient treatments has likely occurred via niche differentiation, driven by changes in soil moisture dynamics (reduced mean, increased variability and changes in the depth distribution of soil moisture) under a more variable precipitation regime, rather than reduced population numbers (A. gerardii tiller densities did not differ between altered and ambient treatments; p = 0.505) or a priori differences in genotype richness (Avolio et al.2013a). This ecological sorting of genotypes, which accounts for 40% of all sampled individuals in the altered plots, is an important legacy of the press chronic climate changes in the RaMPs experiment. Objective 2 In May 2010, we established the Climate Extremes Experiment at the Konza Prairie Biological Station. For the experiment, a gradient of temperatures, ranging from ambient to extreme, were imposed in 2010 and 2011 as a mid-season heat wave under well-watered or severe drought conditions. This study allowed us for the first time to examine species-specific thresholds of responses to climate extremes and assess how these phenotypic responses may impact selection of particular genotypes, with the ultimate goal of linking alterations in individual performance and genetic diversity to ecosystem structure and functioning. We found that tallgrass prairie was resistant to heat waves, but it was not resistant to extreme drought, which reduced aboveground net primary productivity (ANPP) below the lowest level measured in this grassland in almost thirty years (Hoover et al. in press(a)). This extreme reduction in ecosystem function was a consequence of reduced productivity of both C4 grasses and C3 forbs. This reduction in biomass of the C4 grasses (Andropogon gerardii and Sorghastrum nutans) was, in part, due to significant reductions in photosynthesis, leaf water potential and productivity with drought in the dominant grasses species, with S. nutans was more sensitive than A. gerardii to drought (Hoover et al. in press(b)). However, the dominant forb was negatively impacted by the drought more than the dominant grasses, and this led to a reordering of species abundances within the plant community. Although this change in community composition persisted post-drought, ANPP recovered completely the year after drought due to rapid demographic responses by the dominant grass, compensating for loss of the dominant forb. Overall, our results show that an extreme reduction in ecosystem function attributable to a climate extreme (e.g., low resistance) does not preclude rapid ecosystem recovery. Given that dominance by a few species is characteristic of most ecosystems, knowledge of the traits of these species and their responses to climate extremes will be key for predicting future ecosystem dynamics and function. In addition, our research suggests that water stress will dominate photosynthetic and productivity responses caused by discrete drought and heat wave events, rather than direct or additive effects of heat stress, with differential sensitivity in these grasses altering future ecosystem function.« less

Correlation of Factor IXa Subsite Modulations with Effects on Substrate Discrimination

PubMed Central

Neuenschwander, Pierre F.; Deadmond, Kimberly J.; Zepeda, Karla; Rutland, Joshua

2012-01-01

Summary Background A key feature of factor IXa (fIXa) is its allosteric transformation from an enzymatically latent form into a potent procoagulant. Whilst several small molecules have been found capable of partially effecting fIXa function (i.e. ethylene glycol, calcium ion and LMWH), the resulting modest changes in peptidolytic activity have made the study of their mechanisms of action challenging. Since these effects yield hints into potential regulatory forces that may be operational in full expression of fIXa coagulant activity, their description remains of high interest. Studies of crystal structures have yielded insight into structural changes induced by these effectors, but there remains a paucity of information to correlate any given structural change with specific consequences on fIXa function. Objectives To correlate structural changes induced by these modulators with defined consequences in fIXa substrate discrimination and function. Methods A peptidomics-based MS approach was used to examine patterns of hydrolysis of four combinatorial chemistry-derived pentapeptide libraries by fIXa under various conditions in a soluble, active enzyme system. Results Ethylene glycol specifically alters the S3 subsite of fIXa to render it more tolerant to side chains at the P3 substrate position, while calcium enhances tolerance at the S2 subsite. In contrast, LMWH alters both S2 and S1' subsites. Conclusions These results demonstrate the role of plasticity in regulating fIXa function with respect to discrimination of extended substrate sequences, as well as provide crucial insight into active site modulations that may be capitalized upon by various physiological cofactors of fIXa and in future drug design. PMID:22212890

Change in emotional self-concept following socio-cognitive training relates to structural plasticity of the prefrontal cortex.

PubMed

Lumma, Anna-Lena; Valk, Sofie L; Böckler, Anne; Vrtička, Pascal; Singer, Tania

2018-04-01

Self-referential processing is a key component of the emotional self-concept. Previous studies have shown that emotional self-referential processing is related to structure and function of cortical midline areas such as medial prefrontal cortex (mPFC), and that it can be altered on a behavioral level by specific mental training practices. However, it remains unknown how behavioral training-related change in emotional self-concept content relates to structural plasticity. To address this issue, we examined the relationship between training-induced change in participant's emotional self-concept measured through emotional word use in the Twenty Statement Test and change in cortical thickness in the context of a large-scale longitudinal mental training study called the ReSource Project . Based on prior behavioral findings showing increased emotional word use particularly after socio-cognitive training targeting perspective-taking capacities, this study extended these results by revealing that individual differences in the degree to which participants changed their emotional self-concept after training was positively related to cortical thickness change in right mPFC extending to dorsolateral PFC (dlPFC). Furthermore, increased self-related negative emotional word use after training was positively associated with cortical thickness change in left pars orbitalis and bilateral dlPFC. Our findings reveal training-related structural brain change in regions known to be involved in self-referential processing and cognitive control, and could indicate a relationship between restructuring of the emotional self-concept content as well as reappraisal of negative aspects and cortical thickness change. As such, our findings can guide the development of psychological interventions targeted to alter specific facets of the self-concept.

Self-Disturbances as a Possible Premorbid Indicator of Schizophrenia Risk: A Neurodevelopmental Perspective

PubMed Central

Brent, Benjamin K.; Seidman, Larry J.; Thermenos, Heidi W.; Holt, Daphne J.; Keshavan, Matcheri S.

2013-01-01

Self-disturbances (SDs) are increasingly identified in schizophrenia and are theorized to confer vulnerability to psychosis. Neuroimaging research has shed some light on the neural correlates of SDs in schizophrenia. But, the onset and trajectory of the neural alterations underlying SDs in schizophrenia remain incompletely understood. We hypothesize that the aberrant structure and function of brain areas (e.g., prefrontal, lateral temporal, and parietal cortical structures) comprising the “neural circuitry of self” may represent an early, premorbid (i.e., pre-prodromal) indicator of schizophrenia risk. Consistent with neurodevelopmental models, we argue that “early” (i.e., perinatal) dysmaturational processes (e.g., abnormal cortical neural cell migration and mini-columnar formation) affecting key prefrontal (e.g., medial prefrontal cortex), lateral temporal cortical (e.g., superior temporal sulcus), parietal (e.g., inferior parietal lobule) structures involved in self-processing may lead to subtle disruptions of “self” during childhood in persons at risk for schizophrenia. During adolescence, progressive neurodevelopmental alterations (e.g., aberrant synaptic pruning) affecting the neural circuitry of self may contribute to worsening of SDs. This could result in the emergence of prodromal symptoms and, eventually, full-blown psychosis. To highlight why adolescence may be a period of heightened risk for SDs, we first summarize the literature regarding the neural correlates of self in typically developing children. Next, we present evidence from neuroimaging studies in genetic high-risk youth suggesting that fronto-temporal-parietal structures mediating self-reflection may be abnormal in the premorbid period. Our goal is that the ideas presented here might provide future directions for research into the neurobiology of SDs during the pre-psychosis development of youth at risk for schizophrenia. PMID:23932148

Pathophysiology of hypertension: interactions between macro and microvascular alterations through endothelial dysfunction.

PubMed

Yannoutsos, Alexandra; Levy, Bernard I; Safar, Michel E; Slama, Gerard; Blacher, Jacques

2014-02-01

Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.

Effects of Aging on the Respiratory System.

ERIC Educational Resources Information Center

Levitzky, Michael G.

1984-01-01

Relates alterations in respiratory system functions occurring with aging to changes in respiratory system structure during the course of life. Main alterations noted include loss of alveolar elastic recoil, alteration in chest wall structure and decreased respiratory muscle strength, and loss of surface area and changes in pulmonary circulation.…

Resting State Brain Entropy Alterations in Relapsing Remitting Multiple Sclerosis.

PubMed

Zhou, Fuqing; Zhuang, Ying; Gong, Honghan; Zhan, Jie; Grossman, Murray; Wang, Ze

2016-01-01

Brain entropy (BEN) mapping provides a novel approach to characterize brain temporal dynamics, a key feature of human brain. Using resting state functional magnetic resonance imaging (rsfMRI), reliable and spatially distributed BEN patterns have been identified in normal brain, suggesting a potential use in clinical populations since temporal brain dynamics and entropy may be altered in disease conditions. The purpose of this study was to characterize BEN in multiple sclerosis (MS), a neurodegenerative disease that affects millions of people. Since currently there is no cure for MS, developing treatment or medication that can slow down its progression represents a high research priority, for which validating a brain marker sensitive to disease and the related functional impairments is essential. Because MS can start long time before any measurable symptoms and structural deficits, assessing the dynamic brain activity and correspondingly BEN may provide a critical way to study MS and its progression. Because BEN is new to MS, we aimed to assess BEN alterations in the relapsing-remitting MS (RRMS) patients using a patient versus control design, to examine the correlation of BEN to clinical measurements, and to check the correlation of BEN to structural brain measures which have been more often used in MS studies. As compared to controls, RRMS patients showed increased BEN in motor areas, executive control area, spatial coordinating area, and memory system. Increased BEN was related to greater disease severity as measured by the expanded disability status scale (EDSS) and greater tissue damage as indicated by the mean diffusivity. Patients also showed decreased BEN in other places, which was associated with less disability or fatigue, indicating a disease-related BEN re-distribution. Our results suggest BEN as a novel and useful tool for characterizing RRMS.

Consequences of plant invasions on compartmentalization and species’ roles in plant–pollinator networks

PubMed Central

Albrecht, Matthias; Padrón, Benigno; Bartomeus, Ignasi; Traveset, Anna

2014-01-01

Compartmentalization—the organization of ecological interaction networks into subsets of species that do not interact with other subsets (true compartments) or interact more frequently among themselves than with other species (modules)—has been identified as a key property for the functioning, stability and evolution of ecological communities. Invasions by entomophilous invasive plants may profoundly alter the way interaction networks are compartmentalized. We analysed a comprehensive dataset of 40 paired plant–pollinator networks (invaded versus uninvaded) to test this hypothesis. We show that invasive plants have higher generalization levels with respect to their pollinators than natives. The consequences for network topology are that—rather than displacing native species from the network—plant invaders attracting pollinators into invaded modules tend to play new important topological roles (i.e. network hubs, module hubs and connectors) and cause role shifts in native species, creating larger modules that are more connected among each other. While the number of true compartments was lower in invaded compared with uninvaded networks, the effect of invasion on modularity was contingent on the study system. Interestingly, the generalization level of the invasive plants partially explains this pattern, with more generalized invaders contributing to a lower modularity. Our findings indicate that the altered interaction structure of invaded networks makes them more robust against simulated random secondary species extinctions, but more vulnerable when the typically highly connected invasive plants go extinct first. The consequences and pathways by which biological invasions alter the interaction structure of plant–pollinator communities highlighted in this study may have important dynamical and functional implications, for example, by influencing multi-species reciprocal selection regimes and coevolutionary processes. PMID:24943368

Animal responses to natural disturbance and climate extremes: a review

NASA Astrophysics Data System (ADS)

Sergio, Fabrizio; Blas, Julio; Hiraldo, Fernando

2018-02-01

Natural disturbances, such as droughts, fires or hurricanes, are key drivers of ecological heterogeneity and ecosystem function. The frequency and severity of these episodes is unequivocally expected to increase in the coming decades, through the concerted action of climate change and anthropogenic pressures. This will impose severe challenges for many biota through exposure to rapidly changing conditions never experienced in the preceding millennia. Thus, it is urgently needed to gain a thorough understanding of animal responses and adaptations to disturbances in order to better estimate potential future impacts. Here, we review such adjustments and find that animals may respond to disturbances through changes in: (1) behaviour, such as altered mobility, emigration, resource-switching, refuge use, suspended animation, or biotic interactions; (2) life history traits, such as survival, aging, longevity, recruitment, reproductive restraint, breeding output, phenology and bet-hedging tactics; (3) morphology, such as rapid evolution through size-dependent mortality or facultative metamorphosis; (4) physiology, such as altered body condition, pathogen prevalence and transmission, or adrenocortical modulation of stress responses to emergency conditions; (5) genetic structure, such as changes in frequency of polymorphic variants or diversity-modulation through mortality bottlenecks. Individual-level responses scale up to population and community responses, such as altered density, population dynamics, distribution, local extinction and colonization, or assemblage structure and diversity. Overall, disturbances have pervasive effects on individuals, populations and communities of vertebrates and invertebrates of all realms, biomes, continents and ecosystems. Their rapidly increasing incidence and severity will bring unique study opportunities for researchers and novel, unpredictable challenges for managers, while demanding tougher choices and more proactive crisis-preparation for conservationists, as well as mentality changes for all. Under all conditions, disturbances may soon become the defining signatures of most ecosystems and the dynamic leitmotif of modern ecology.

Systematic identification of an integrative network module during senescence from time-series gene expression.

PubMed

Park, Chihyun; Yun, So Jeong; Ryu, Sung Jin; Lee, Soyoung; Lee, Young-Sam; Yoon, Youngmi; Park, Sang Chul

2017-03-15

Cellular senescence irreversibly arrests growth of human diploid cells. In addition, recent studies have indicated that senescence is a multi-step evolving process related to important complex biological processes. Most studies analyzed only the genes and their functions representing each senescence phase without considering gene-level interactions and continuously perturbed genes. It is necessary to reveal the genotypic mechanism inferred by affected genes and their interaction underlying the senescence process. We suggested a novel computational approach to identify an integrative network which profiles an underlying genotypic signature from time-series gene expression data. The relatively perturbed genes were selected for each time point based on the proposed scoring measure denominated as perturbation scores. Then, the selected genes were integrated with protein-protein interactions to construct time point specific network. From these constructed networks, the conserved edges across time point were extracted for the common network and statistical test was performed to demonstrate that the network could explain the phenotypic alteration. As a result, it was confirmed that the difference of average perturbation scores of common networks at both two time points could explain the phenotypic alteration. We also performed functional enrichment on the common network and identified high association with phenotypic alteration. Remarkably, we observed that the identified cell cycle specific common network played an important role in replicative senescence as a key regulator. Heretofore, the network analysis from time series gene expression data has been focused on what topological structure was changed over time point. Conversely, we focused on the conserved structure but its context was changed in course of time and showed it was available to explain the phenotypic changes. We expect that the proposed method will help to elucidate the biological mechanism unrevealed by the existing approaches.

Nicergoline inhibits human platelet Ca2+ signalling through triggering a microtubule‐dependent reorganization of the platelet ultrastructure

PubMed Central

Walford, T; Musa, F I

2015-01-01

Background and Purpose Recently, we demonstrated that a pericellular Ca2+ recycling system potentiates agonist‐evoked Ca2+ signalling and granule secretion in human platelets and hypothesized a role for the membrane complex (MC) in orchestrating the accumulation of Ca2+ in the pericellular region. Previous work has demonstrated that treatment with high concentrations of nicergoline may disrupt the MC through an ability to trigger a re‐organization of the dense tubular system. Experiments were therefore performed to assess whether nicergoline‐induced changes in platelet ultrastructure affects thrombin‐evoked Ca2+ fluxes and dense granule secretion. Experimental Approach Thrombin‐evoked Ca2+ fluxes were monitored in Fura‐2‐ or Fluo‐5N‐loaded human platelets, or using platelet suspensions containing Fluo‐4 or Rhod‐5N K+ salts. Fluorescence microscopy was utilized to monitor microtubule structure and intracellular Ca2+ store distribution in TubulinTracker‐ and Fluo‐5N‐loaded platelets respectively. Dense granule secretion was monitored using luciferin–luciferase. Key Results Nicergoline treatment inhibited thrombin‐evoked Ca2+ signalling and induced alterations in the microtubule structure and the distribution of intracellular Ca2+ stores in platelets. Nicergoline altered the generation and spreading of thrombin‐induced pericellular Ca2+ signals and almost completely prevented dense granule secretion. Stabilization of microtubules using taxol reversed most effects of nicergoline on platelet Ca2+ signalling and partially reversed its effects on dense granule secretion. Conclusions and Implications Nicergoline‐induced alterations to platelet ultrastructure disrupt platelet Ca2+ signalling in a manner that would be predicted if the MC had been disrupted. These data suggest that nicergoline may be a useful prototype for the discovery of novel MC‐disrupting anti‐thrombotics. PMID:26450366

Biomechanical properties of predator-induced body armour in the freshwater crustacean Daphnia.

PubMed

Kruppert, Sebastian; Horstmann, Martin; Weiss, Linda C; Witzel, Ulrich; Schaber, Clemens F; Gorb, Stanislav N; Tollrian, Ralph

2017-08-29

The freshwater crustacean Daphnia is known for its ability to develop inducible morphological defences that thwart predators. These defences are developed only in the presence of predators and are realized as morphological shape alterations e.g. 'neckteeth' in D. pulex and 'crests' in D. longicephala. Both are discussed to hamper capture, handling or consumption by interfering with the predator's prey capture devices. Additionally, D. pulex and some other daphniids were found to armour-up and develop structural alterations resulting in increased carapace stiffness. We used scanning transmission electron microscopy (STEM) and confocal laser scanning microscopy (CLSM) to identify predator-induced structural and shape alterations. We found species specific structural changes accompanying the known shape alterations. The cuticle becomes highly laminated (i.e. an increased number of layers) in both species during predator exposure. Using nano- and micro-indentation as well as finite element analysis (FEA) we determined both: the structure's and shape's contribution to the carapace's mechanical resistance. From our results we conclude that only structural alterations are responsible for increased carapace stiffness, whereas shape alterations appear to pose handling difficulties during prey capture. Therefore, these defences act independently at different stages during predation.

ALTERATIONS IN A11 TRANS RETINOIC ACID METABOLISM IN LIVER MICROSOMES FROM MICE TREATED WITH HEPATOTUMORIGENIC AND NON-HEPATOTUMORIGENIC CONAZOLES

EPA Science Inventory

Conazoles are fungicides used in crop protection and as pharmaceuticals. Triadimefon and propiconazole are hepatotumorigenic in mice, while myclobutanil is not. Previous toxicogenomic studies suggest that alteration of the retinoic acid metabolism pathway may be a key event in co...

β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

PubMed Central

Gill, Andrew C.

2014-01-01

Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies. PMID:24498083

The microbial perspective of organic matter turnover and nutrient cycling in tropical soils

NASA Astrophysics Data System (ADS)

Rasche, Frank

2017-04-01

A primary goal of low-input small-holder farming systems in the tropics is the appropriate management of organic matter (OM) turnover and nutrient cycling via adapted agricultural practices. These emphasize the promotion of soil organic matter (SOM) turnover and carbon (C) sequestration, nutrient use efficiency and soil microbial activity. Since soil microbial communities are acknowledged as key players in the terrestrial C and nutrient (e.g., nitrogen (N), phosphorus (P)) cycles, they may respond sensitively to agricultural management with shifts in their community structure as well as functional traits (i.e., decomposition, mineralization). This may be in particular evident for tropical, agricultural soils which show an accelerated microbial decomposition activity induced by favourable climatic and unique physico-chemical soil conditions. While modern molecular techniques advanced primarily the understanding about the microbiome and their functional traits interacting closely with SOM dynamics in temperate soils, tropical soils under agricultural use have been still neglected to a great extent. The majority of available studies revealed mainly descriptive data on the structural composition of microbial communities rather than questioning if detected structural alterations of the soil microbiome influenced key processes in N and P cycling which actually maintain ecosystem functioning and soil productivity. This talk highlights latest efforts in deploying molecular techniques to study the compositional status of soil microbial decomposer communities and their functional attributes in response to land use change and OM management in tropical agro-ecosystems.

Nutritional effects on T-cell immunometabolism

PubMed Central

Cohen, Sivan; Danzaki, Keiko; MacIver, Nancie J.

2017-01-01

T cells are highly influenced by nutrient uptake from their environment, and changes in overall nutritional status, such as malnutrition or obesity, can result in altered T-cell metabolism and behavior. In states of severe malnutrition or starvation, T-cell survival, proliferation, and inflammatory cytokine production are all decreased, as is T-cell glucose uptake and metabolism. The altered T-cell function and metabolism seen in malnutrition is associated with altered adipokine levels, most particularly decreased leptin. Circulating leptin levels are low in malnutrition, and leptin has been shown to be a key link between nutrition and immunity. The current view is that leptin signaling is required to upregulate activated T-cell glucose metabolism and thereby fuel T-cell activation. In the setting of obesity, T cells have been found to have a key role in promoting the recruitment of inflammatory macrophages to adipose depots along with the production of inflammatory cytokines that promote the development of insulin resistance leading to diabetes. Deletion of T cells, key T-cell transcription factors, or pro-inflammatory T-cell cytokines prevents insulin resistance in obesity and underscores the importance of T cells in obesity-associated inflammation and metabolic disease. Altogether, T cells have a critical role in nutritional immunometabolism. PMID:28054344

24 CFR 3285.903 - Permits, alterations, and on-site structures.

Code of Federal Regulations, 2013 CFR

2013-04-01

... live and dead loads, unless the structure, including any attached garage, carport, deck, and porch, is... structures. 3285.903 Section 3285.903 Housing and Urban Development Regulations Relating to Housing and Urban... Manufacturer's Installation Instructions § 3285.903 Permits, alterations, and on-site structures. It is...

24 CFR 3285.903 - Permits, alterations, and on-site structures.

Code of Federal Regulations, 2012 CFR

2012-04-01

... live and dead loads, unless the structure, including any attached garage, carport, deck, and porch, is... structures. 3285.903 Section 3285.903 Housing and Urban Development Regulations Relating to Housing and Urban... Manufacturer's Installation Instructions § 3285.903 Permits, alterations, and on-site structures. It is...

24 CFR 3285.903 - Permits, alterations, and on-site structures.

Code of Federal Regulations, 2011 CFR

2011-04-01

... live and dead loads, unless the structure, including any attached garage, carport, deck, and porch, is... structures. 3285.903 Section 3285.903 Housing and Urban Development Regulations Relating to Housing and Urban... Manufacturer's Installation Instructions § 3285.903 Permits, alterations, and on-site structures. It is...

24 CFR 3285.903 - Permits, alterations, and on-site structures.

Code of Federal Regulations, 2014 CFR

2014-04-01

... live and dead loads, unless the structure, including any attached garage, carport, deck, and porch, is... structures. 3285.903 Section 3285.903 Housing and Urban Development Regulations Relating to Housing and Urban... Manufacturer's Installation Instructions § 3285.903 Permits, alterations, and on-site structures. It is...

Chromatographic analysis of age-related changes in mucosal serotonin transmission in the murine distal ileum

PubMed Central

2012-01-01

Background In the upper bowel, alterations in motility and absorption of key nutrients have been observed as part of the normal ageing process. Serotonin (5-HT) is a key signalling molecule in the gastrointestinal tract and is known to influence motility, however little is known of how the ageing process alters 5-HT signalling processes in the bowel. Results An isocratic chromatographic method was able to detect all 5-HT precursors and metabolites. Using extracellular and intracellular sampling approaches, we were able to monitor all key parameters associated with the transmission process. There was no alteration in the levels of tryptophan and 5-HTP between 3 and 18 month old animals. There was a significant increase in the ratio of 5-HT:5-HTP and an increase in intracellular 5-HT between 3 and 18 month old animals suggesting an increase in 5-HT synthesis. There was also a significant increase in extracellular 5-HT with age, suggesting increased 5-HT release. There was an age-related decrease in the ratio of intracellular 5-HIAA:extracellular 5-HT, whilst the amount of 5-HIAA did not change with age. In the presence of an increase in extracellular 5-HT, the lack of an age-related change in 5-HIAA is suggestive of a decrease in re-uptake via the serotonin transporter (SERT). Conclusions We have used intracellular and extracellular sampling to provide more insight into alterations in the neurotransmission process of 5-HT during normal ageing. We observed elevated 5-HT synthesis and release and a possible decrease in the activity of SERT. Taken together these changes lead to increased 5-HT availability and may alter motility function and could lead to the changes in adsorption observed in the elderly. PMID:22494644

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents.

PubMed

Erazo-Oliveras, Alfredo; Fuentes, Natividad R; Wright, Rachel C; Chapkin, Robert S

2018-06-02

The cell plasma membrane serves as a nexus integrating extra- and intracellular components, which together enable many of the fundamental cellular signaling processes that sustain life. In order to perform this key function, plasma membrane components assemble into well-defined domains exhibiting distinct biochemical and biophysical properties that modulate various signaling events. Dysregulation of these highly dynamic membrane domains can promote oncogenic signaling. Recently, it has been demonstrated that select membrane-targeted dietary bioactives (MTDBs) have the ability to remodel plasma membrane domains and subsequently reduce cancer risk. In this review, we focus on the importance of plasma membrane domain structural and signaling functionalities as well as how loss of membrane homeostasis can drive aberrant signaling. Additionally, we discuss the intricacies associated with the investigation of these membrane domain features and their associations with cancer biology. Lastly, we describe the current literature focusing on MTDBs, including mechanisms of chemoprevention and therapeutics in order to establish a functional link between these membrane-altering biomolecules, tuning of plasma membrane hierarchal organization, and their implications in cancer prevention.

Airborne Astronomy Program

NASA Technical Reports Server (NTRS)

Butner, Harold M.

1999-01-01

Our understanding about the inter-relationship between the collapsing cloud envelope and the disk has been greatly altered. While the dominant star formation models invoke free fall collapse and r(sup -1.5) density profile, other star formation models are possible. These models invoke either different cloud starting conditions or the mediating effects of magnetic fields to alter the cloud geometry during collapse. To test these models, it is necessary to understand the envelope's physical structure. The discovery of disks, based on millimeter observations around young stellar objects, however makes a simple interpretation of the emission complicated. Depending on the wavelength, the disk or the envelope could dominate emission from a star. In addition, the discovery of planets around other stars has made understanding the disks in their own right quite important. Many star formation models predict disks should form naturally as the star is forming. In many cases, the information we derive about disk properties depends implicitly on the assumed envelope properties. How to understand the two components and their interaction with each other is a key problem of current star formation.

Protein glycosylation in gastric and colorectal cancers: Toward cancer detection and targeted therapeutics.

PubMed

Ferreira, José Alexandre; Magalhães, Ana; Gomes, Joana; Peixoto, Andreia; Gaiteiro, Cristiana; Fernandes, Elisabete; Santos, Lúcio Lara; Reis, Celso A

2017-02-28

Glycosylation is the most frequent and structurally complex posttranslational modification in cell-surface and secreted proteins. Glycans are major orchestrators of biological processes, namely, by controlling protein folding and key biological functions such as cell adhesion, migration, signaling and immune recognition. Altered glycosylation is considered a hallmark of malignant transformations that decisively contributes to disease outcome. This review comprehensively summarizes the main findings related with gastrointestinal cancers and the decisive impact of aberrant glycosylation on tumor biology toward more aggressive phenotypes. Particular emphasis is given to alterations in O-glycosylation, namely, the overexpression of immature O-glycans, and the sialylated Lewis antigens sialyl-LeA and sialyl-LeX, frequently implicated in lymphohematogenous metastasis. We further discuss how recent contributions from glycoproteomics and glycoengineering fields have broadened our understanding of the human O-glycoproteome and its implications for cancer research. Finally, we address the tremendous potential of glycans in the context of targeted therapeutics (selective inhibition of glycosylation pathways, immunotherapy) and discuss the need to include glycomics/glycoproteomics in holistic panomics models toward true precision medicine settings. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genetics of pancreatic neuroendocrine tumors: implications for the clinic

PubMed Central

Pea, Antonio; Hruban, Ralph H.; Wood, Laura D.

2016-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID:26413978

Structural characterization and mutational assessment of podocin - a novel drug target to nephrotic syndrome - an in silico approach.

PubMed

Tabassum, Asra; Rajeshwari, Tadigadapa; Soni, Nidhi; Raju, D S B; Yadav, Mukesh; Nayarisseri, Anuraj; Jahan, Parveen

2014-03-01

Non-synonymous single nucleotide changes (nSNC) are coding variants that introduce amino acid changes in their corresponding proteins. They can affect protein function; they are believed to have the largest impact on human health compared with SNCs in other regions of the genome. Such a sequence alteration directly affects their structural stability through conformational changes. Presence of these conformational changes near catalytic site or active site may alter protein function and as a consequence receptor-ligand complex interactions. The present investigation includes assessment of human podocin mutations (G92C, P118L, R138Q, and D160G) on its structure. Podocin is an important glomerular integral membrane protein thought to play a key role in steroid resistant nephrotic syndrome. Podocin has a hairpin like structure with 383 amino acids, it is an integral protein homologous to stomatin, and acts as a molecular link in a stretch-sensitive system. We modeled 3D structure of podocin by means of Modeller and validated via PROCHECK to get a Ramachandran plot (88.5% in most favored region), main chain, side chain, bad contacts, gauche and pooled standard deviation. Further, a protein engineering tool Triton was used to induce mutagenesis corresponding to four variants G92C, P118L, R138Q and D160G in the wild type. Perusal of energies of wild and mutated type of podocin structures confirmed that mutated structures were thermodynamically more stable than wild type and therefore biological events favored synthesis of mutated forms of podocin than wild type. As a conclusive part, two mutations G92C (-8179.272 kJ/mol) and P118L (-8136.685 kJ/mol) are more stable and probable to take place in podocin structure over wild podocin structure (-8105.622 kJ/mol). Though there is lesser difference in mutated and wild type (approximately, 74 and 35 kJ/mol), it may play a crucial role in deciding why mutations are favored and occur at the genetic level.

The Epidermis of Grhl3-Null Mice Displays Altered Lipid Processing and Cellular Hyperproliferation

PubMed Central

Ting, Stephen B; Caddy, Jacinta; Wilanowski, Tomasz; Auden, Alana; Cunningham, John M; Elias, Peter M; Holleran, Walter M

2005-01-01

The presence of an impermeable surface barrier is an essential homeostatic mechanism in almost all living organisms. We have recently described a novel gene that is critical for the developmental instruction and repair of the integument in mammals. This gene, Grainy head-like 3 (Grhl3) is a member of a large family of transcription factors that are homologs of the Drosophila developmental gene grainy head (grh). Mice lacking Grhl3 fail to form an adequate skin barrier, and die at birth due to dehydration. These animals are also unable to repair the epidermis, exhibiting failed wound healing in both fetal and adult stages of development. These defects are due, in part, to diminished expression of a Grhl3 target gene, Transglutaminase 1 (TGase 1), which encodes a key enzyme involved in cross-linking of epidermal structural proteins and lipids into the cornified envelope (CE). Remarkably, the Drosophila grh gene plays an analogous role, regulating enzymes involved in the generation of quinones, which are essential for cross-linking structural components of the fly epidermis. In an extension of our initial analyses, we focus this report on additional defects observed in the Grhl3-null epidermis, namely defective extra-cellular lipid processing, altered lamellar lipid architecture and cellular hyperproliferation. These abnormalities suggest that Grhl3 plays diverse mechanistic roles in maintaining homeostasis in the skin. PMID:19521564

The epidermis of grhl3-null mice displays altered lipid processing and cellular hyperproliferation.

PubMed

Ting, Stephen B; Caddy, Jacinta; Wilanowski, Tomasz; Auden, Alana; Cunningham, John M; Elias, Peter M; Holleran, Walter M; Jane, Stephen M

2005-04-01

The presence of an impermeable surface barrier is an essential homeostatic mechanism in almost all living organisms. We have recently described a novel gene that is critical for the developmental instruction and repair of the integument in mammals. This gene, Grainy head-like 3 (Grhl3) is a member of a large family of transcription factors that are homologs of the Drosophila developmental gene grainy head (grh). Mice lacking Grhl3 fail to form an adequate skin barrier, and die at birth due to dehydration. These animals are also unable to repair the epidermis, exhibiting failed wound healing in both fetal and adult stages of development. These defects are due, in part, to diminished expression of a Grhl3 target gene, Transglutaminase 1 (TGase 1), which encodes a key enzyme involved in cross-linking of epidermal structural proteins and lipids into the cornified envelope (CE). Remarkably, the Drosophila grh gene plays an analogous role, regulating enzymes involved in the generation of quinones, which are essential for cross-linking structural components of the fly epidermis. In an extension of our initial analyses, we focus this report on additional defects observed in the Grhl3-null epidermis, namely defective extra-cellular lipid processing, altered lamellar lipid architecture and cellular hyperproliferation. These abnormalities suggest that Grhl3 plays diverse mechanistic roles in maintaining homeostasis in the skin.

Understanding the role of hydrogen bonding in the aggregation of fumed silica particles in triglyceride solvents.

PubMed

Whitby, Catherine P; Krebsz, Melinda; Booty, Samuel J

2018-10-01

Fumed silica particles are thought to thicken organic solvents into gels by aggregating to form networks. Hydrogen bonding between silanol groups on different particle surfaces causes the aggregation. The gel structure and hence flow behaviour is altered by varying the proportion of silanol groups on the particle surfaces. However, characterising the gel using rheology measurements alone is not sufficient to optimise the aggregation. We have used confocal microscopy to characterise the changes in the network microstructure caused by altering the particle surface chemistry. Organogels were formed by dispersing fumed silica nanoparticles in a triglyceride solvent. The particle surface chemistry was systematically varied from oleophobic to oleophilic by functionalisation with hydrocarbons. We directly visualised the particle networks using confocal scanning laser microscopy and investigated the correlations between the network structure and the shear response of the organogels. Our key finding is that the sizes of the pore spaces in the networks depend on the fraction of silanol groups available to form hydrogen bonds. The reduction in the network elasticity of gels formed by methylated particles can be accounted for by the increasing pore size and tenuous nature of the networks. This is the first report that characterises the changes in the microstructure of fumed silica particle networks in non-polar solvents caused by manipulating the particle surface chemistry. Copyright © 2018 Elsevier Inc. All rights reserved.

Insights into molecular mechanisms of drug metabolism dysfunction of human CYP2C9*30

PubMed Central

Louet, Maxime; Labbé, Céline M.; Aono, Cassiano M.; Homem-de-Mello, Paula; Villoutreix, Bruno O.

2018-01-01

Cytochrome P450 2C9 (CYP2C9) metabolizes about 15% of clinically administrated drugs. The allelic variant CYP2C9*30 (A477T) is associated to diminished response to the antihypertensive effects of the prodrug losartan and affected metabolism of other drugs. Here, we investigated molecular mechanisms involved in the functional consequences of this amino-acid substitution. Molecular dynamics (MD) simulations performed for the active species of the enzyme (heme in the Compound I state), in the apo or substrate-bound state, and binding energy analyses gave insights into altered protein structure and dynamics involved in the defective drug metabolism of human CYP2C9.30. Our data revealed an increased rigidity of the key Substrate Recognition Sites SRS1 and SRS5 and shifting of the β turn 4 of SRS6 toward the helix F in CYP2C9.30. Channel and binding substrate dynamics analyses showed altered substrate channel access and active site accommodation. These conformational and dynamic changes are believed to be involved in the governing mechanism of the reduced catalytic activity. An ensemble of representative conformations of the WT and A477T mutant properly accommodating drug substrates were identified, those structures can be used for prediction of new CYP2C9 and CYP2C9.30 substrates and drug-drug interactions. PMID:29746595

Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin

PubMed Central

Argyropoulos, Angela J.; Robichaud, Patrick; Balimunkwe, Rebecca Mutesi; Fisher, Gary J.; Hammerberg, Craig; Yan, Yan

2016-01-01

Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels of MMP-1 and MMP-2. Laser capture microdissection (LCM) coupled real-time PCR indicated that elevated MMPs in diabetic skin were primarily expressed in the dermis. Furthermore, diabetic skin shows increased lysyl oxidase (LOX) expression and higher cross-linked collagens. Atomic force microscopy (AFM) further indicated that collagen fibrils were fragmented/disorganized, and key mechanical properties of traction force and tensile strength were increased in diabetic skin, compared to intact/well-organized collagen fibrils in non-diabetic skin. In in vitro tissue culture system, multiple MMPs including MMP-1 and MM-2 were induced by high glucose (25 mM) exposure to isolated primary human skin dermal fibroblasts, the major cells responsible for collagen homeostasis in skin. The elevation of MMPs and LOX over the years is thought to result in the accumulation of fragmented and cross-linked collagen, and thus impairs dermal collagen structural integrity and mechanical properties in diabetes. Our data partially explain why old-looking skin is more common in diabetic patients. PMID:27104752

Anatomical study of minor alterations in neonate vocal folds.

PubMed

Silva, Adriano Rezende; Machado, Almiro José; Crespo, Agrício Nubiato

2014-01-01

Minor structural alterations of the vocal fold cover are frequent causes of voice abnormalities. They may be difficult to diagnose, and are expressed in different manners. Cases of intracordal cysts, sulcus vocalis, mucosal bridge, and laryngeal micro-diaphragm form the group of minor structural alterations of the vocal fold cover investigated in the present study. The etiopathogenesis and epidemiology of these alterations are poorly known. To evaluate the existence and anatomical characterization of minor structural alterations in the vocal folds of newborns. 56 larynxes excised from neonates of both genders were studied. They were examined fresh, or defrosted after conservation via freezing, under a microscope at magnifications of 25× and 40×. The vocal folds were inspected and palpated by two examiners, with the aim of finding minor structural alterations similar to those described classically, and other undetermined minor structural alterations. Larynges presenting abnormalities were submitted to histological examination. Six cases of abnormalities were found in different larynges: one (1.79%) compatible with a sulcus vocalis and five (8.93%) compatible with a laryngeal micro-diaphragm. No cases of cysts or mucosal bridges were found. The observed abnormalities had characteristics similar to those described in other age groups. Abnormalities similar to sulcus vocalis or micro-diaphragm may be present at birth. Copyright © 2014 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Protein analysis: key to the future.

PubMed

Boodhun, Nawsheen

2018-05-01

Protein analysis is crucial to elucidating the function of proteins and understanding the impact of their presence, absence and alteration. This is key to advancing knowledge about diseases, providing the opportunity for biomarker discovery and development of therapeutics. In this issue of Tech News, Nawsheen Boodhun explores the various means of protein analysis.

Intestinal microbiota composition is altered according to nutritional biorhythms in the leopard coral grouper (Plectropomus leopardus).

PubMed

Mekuchi, Miyuki; Asakura, Taiga; Sakata, Kenji; Yamaguchi, Tomofumi; Teruya, Kazuhisa; Kikuchi, Jun

2018-01-01

Aquaculture is currently a major source of fish and has the potential to become a major source of protein in the future. These demands require efficient aquaculture. The intestinal microbiota plays an integral role that benefits the host, providing nutrition and modulating the immune system. Although our understanding of microbiota in fish gut has increased, comprehensive studies examining fish microbiota and host metabolism remain limited. Here, we investigated the microbiota and host metabolism in the coral leopard grouper, which is traded in Asian markets as a superior fish and has begun to be produced via aquaculture. We initially examined the structural changes of the gut microbiota using next-generation sequencing and found that the composition of microbiota changed between fasting and feeding conditions. The dominant phyla were Proteobacteria in fasting and Firmicutes in feeding; interchanging the dominant bacteria required 12 hours. Moreover, microbiota diversity was higher under feeding conditions than under fasting conditions. Multivariate analysis revealed that Proteobacteria are the key bacteria in fasting and Firmicutes and Fusobacteria are the key bacteria in feeding. Subsequently, we estimated microbiota functional capacity. Microbiota functional structure was relatively stable throughout the experiment; however, individual function activity changed according to feeding conditions. Taken together, these findings indicate that the gut microbiota could be a key factor to understanding fish feeding conditions and play a role in interactions with host metabolism. In addition, the composition of microbiota in ambient seawater directly affects the fish; therefore, it is important to monitor the microbiota in rearing tanks and seawater circulating systems.

Mineralogical, crystallographic and redox features of the earliest stages of fluid alteration in CM chondrites

NASA Astrophysics Data System (ADS)

Pignatelli, Isabella; Marrocchi, Yves; Mugnaioli, Enrico; Bourdelle, Franck; Gounelle, Matthieu

2017-07-01

The CM chondrites represent the largest group of hydrated meteorites and span a wide range of conditions, from less altered (i.e., CM2) down to heavily altered (i.e., CM1). The Paris chondrite is considered the least altered CM and thus enables the earliest stages of aqueous alteration processes to be deciphered. Here, we report results from a nanoscale study of tochilinite/cronstedtite intergrowths (TCIs) in Paris-TCIs being the emblematic secondary mineral assemblages of CM chondrites, formed from the alteration of Fe-Ni metal beads (type-I TCIs) and anhydrous silicates (type-II TCIs). We combined high-resolution transmission electron microscopy, scanning transmission X-ray microscopy and electron diffraction tomography to characterize the crystal structure, crystal chemistry and redox state of TCIs. The data obtained are useful to reconstruct the alteration conditions of Paris and to compare them with those of other meteorites. Our results show that tochilinite in Paris is characterized by a high hydroxide layer content (n = 2.1-2.2) regardless of the silicate precursors. When examined alongside other CMs, it appears that the hydroxide layer and iron contents of tochilinites correlate with the degree of alteration experienced by the chondrites. The Fe3+/ΣFe ratios of TCIs are high: 8-15% in tochilinite, 33-60% in cronstedtite and 70-80% in hydroxides. These observations suggest that alteration of CM chondrites took place under oxidizing conditions that could have been induced by significant H2 release during serpentinization. Similar results were recently reported in CR chondrites (Le Guillou et al., 2015), suggesting that the process(es) controlling the redox state of the secondary mineral assemblages were quite similar in the CM and CR parent bodies despite the different alteration conditions. According to our mineralogical and crystallographic survey, the formation of TCIs in Paris occurred at temperatures lower than 100 °C, under neutral, slightly alkaline conditions that favored the formation of both tochilinite and cronstedtite. During the course of alteration, the reduction in sulfur activity and/or the decrease of temperature prevented tochilinite crystallization and favoured the formation of cronstedtite and iron hydroxides. We suggest that iron hydroxides probably formed as ferrihydrite and then progressively converted to goethite between 50° and 80 °C, a temperature range that is also favorable for cronstedtite formation. The presence of cronstedtite plays a key role in the reconstruction of the alteration history, demonstrating that the alteration of Paris took place by way of serpentinization processes similar to those described on the Earth.

Epigenetic regulation of hematopoietic stem cell aging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu; Department of Pediatrics, Harvard Medical School, Boston, MA 02115; Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children's Hospital, MA 02116

2014-12-10

Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and playmore » a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.« less

Structural and functional alterations in the colonic microbiome of the rat in a model of stress induced irritable bowel syndrome

PubMed Central

Fourie, Nicolaas H.; Wang, Dan; Abey, Sarah K.; Creekmore, Amy L.; Hong, Shuangsong; Martin, Christiana G.; Wiley, John W.

2017-01-01

ABSTRACT Stress is known to perturb the microbiome and exacerbate irritable bowel syndrome (IBS) associated symptoms. Characterizing structural and functional changes in the microbiome is necessary to understand how alterations affect the biomolecular environment of the gut in IBS. Repeated water avoidance (WA) stress was used to induce IBS-like symptoms in rats. The colon-mucosa associated microbiome was characterized in 13 stressed and control animals by 16S sequencing. In silico analysis of the functional domains of microbial communities was done by inferring metagenomic profiles from 16S data. Microbial communities and functional profiles were compared between conditions. WA animals exhibited higher α-diversity and moderate divergence in community structure (β-diversity) compared with controls. Specific clades and taxa were consistently and significantly modified in the WA animals. The WA microbiome was particularly enriched in Proteobacteria and depleted in several beneficial taxa. A decreased capacity in metabolic domains, including energy- and lipid-metabolism, and an increased capacity for fatty acid and sulfur metabolism was inferred for the WA microbiome. The stressed condition favored the proliferation of a greater diversity of microbes that appear to be functionally similar, resulting in a functionally poorer microbiome with implications for epithelial health. Taxa, with known beneficial effects, were found to be depleted, which supports their relevance as therapeutic agents to restore microbial health. Microbial sulfur metabolism may form a key component of visceral nerve sensitization pathways and is therefore of interest as a target metabolic domain in microbial ecological restoration. PMID:28059627

Chronic amphetamine enhances visual input to and suppresses visual output from the superior colliculus in withdrawal.

PubMed

Turner, Amy C; Kraev, Igor; Stewart, Michael G; Stramek, Agata; Overton, Paul G; Dommett, Eleanor J

2018-06-04

Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10 mg/kg) or a vehicle for one month after which local field potential and multiunit recordings were made from the superficial layers of the SC in response to whole-field light flashes in withdrawal. Rapid Golgi staining was also used to assess dendritic spines, and synaptophysin staining was used to assess synaptic integrity. Chronic amphetamine increased local field potential responses at higher doses, and increased synaptophysin expression, suggesting enhanced visual input involving presynaptic remodelling. No comparable increases in multiunit activity were found suggesting amphetamine suppresses collicular output activity, counterbalancing the increased input. We also report, for the first time, five different dendritic spine types in the superficial layers and show these to be unaffected by amphetamine, indicating that suppression does not involve gross postsynaptic structural alterations. In conclusion, we suggest that amphetamine produces changes at the collicular level that potentially stabilise the structure and may prevent the worsening of symptoms in disorders like ADHD. Copyright © 2018. Published by Elsevier Ltd.

Toward a Rational Design of Bioactive Glasses with Optimal Structural Features: Composition–Structure Correlations Unveiled by Solid-State NMR and MD Simulations

PubMed Central

2013-01-01

The physiological responses of silicate-based bioactive glasses (BGs) are known to depend critically on both the P content (nP) of the glass and its silicate network connectivity (N̅BOSi). However, while the bioactivity generally displays a nonmonotonic dependence on nP itself, recent work suggest that it is merely the net orthophosphate content that directly links to the bioactivity. We exploit molecular dynamics (MD) simulations combined with 31P and 29Si solid-state nuclear magnetic resonance (NMR) spectroscopy to explore the quantitative relationships between N̅BOSi, nP, and the silicate and phosphate speciations in a series of Na2O–CaO–SiO2–P2O5 glasses spanning 2.1 ≤ N̅BOSi ≤ 2.9 and variable P2O5 contents up to 6.0 mol %. The fractional population of the orthophosphate groups remains independent of nP at a fixed N̅BOSi-value, but is reduced slightly as N̅BOSi increases. Nevertheless, P remains predominantly as readily released orthophosphate ions, whose content may be altered essentially independently of the network connectivity, thereby offering a route to optimize the glass bioactivity. We discuss the observed composition-structure links in relation to known composition-bioactivity correlations, and define how Na2O–CaO–SiO2–P2O5 compositions exhibiting an optimal bioactivity can be designed by simultaneously altering three key parameters: the silicate network connectivity, the (ortho)phosphate content, and the nNa/nCa molar ratio. PMID:24364818

Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

NASA Astrophysics Data System (ADS)

Zrelli, K.; Galy, O.; Latour-Lambert, P.; Kirwan, L.; Ghigo, J. M.; Beloin, C.; Henry, N.

2013-12-01

Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms.

The 1.3 A resolution structure of the RNA tridecamer r(GCGUUUGAAACGC): metal ion binding correlates with base unstacking and groove contraction.

PubMed

Timsit, Youri; Bombard, Sophie

2007-12-01

Metal ions play a key role in RNA folding and activity. Elucidating the rules that govern the binding of metal ions is therefore an essential step for better understanding the RNA functions. High-resolution data are a prerequisite for a detailed structural analysis of ion binding on RNA and, in particular, the observation of monovalent cations. Here, the high-resolution crystal structures of the tridecamer duplex r(GCGUUUGAAACGC) crystallized under different conditions provides new structural insights on ion binding on GAAA/UUU sequences that exhibit both unusual structural and functional properties in RNA. The present study extends the repertory of RNA ion binding sites in showing that the two first bases of UUU triplets constitute a specific site for sodium ions. A striking asymmetric pattern of metal ion binding in the two equivalent halves of the palindromic sequence demonstrates that sequence and its environment act together to bind metal ions. A highly ionophilic half that binds six metal ions allows, for the first time, the observation of a disodium cluster in RNA. The comparison of the equivalent halves of the duplex provides experimental evidences that ion binding correlates with structural alterations and groove contraction.

Authenticity techniques for PACS images and records

NASA Astrophysics Data System (ADS)

Wong, Stephen T. C.; Abundo, Marco; Huang, H. K.

1995-05-01

Along with the digital radiology environment supported by picture archiving and communication systems (PACS) comes a new problem: How to establish trust in multimedia medical data that exist only in the easily altered memory of a computer. Trust is characterized in terms of integrity and privacy of digital data. Two major self-enforcing techniques can be used to assure the authenticity of electronic images and text -- key-based cryptography and digital time stamping. Key-based cryptography associates the content of an image with the originator using one or two distinct keys and prevents alteration of the document by anyone other than the originator. A digital time stamping algorithm generates a characteristic `digital fingerprint' for the original document using a mathematical hash function, and checks that it has not been modified. This paper discusses these cryptographic algorithms and their appropriateness for a PACS environment. It also presents experimental results of cryptographic algorithms on several imaging modalities.

Altered resting brain function and structure in professional badminton players.

PubMed

Di, Xin; Zhu, Senhua; Jin, Hua; Wang, Pin; Ye, Zhuoer; Zhou, Ke; Zhuo, Yan; Rao, Hengyi

2012-01-01

Neuroimaging studies of professional athletic or musical training have demonstrated considerable practice-dependent plasticity in various brain structures, which may reflect distinct training demands. In the present study, structural and functional brain alterations were examined in professional badminton players and compared with healthy controls using magnetic resonance imaging (MRI) and resting-state functional MRI. Gray matter concentration (GMC) was assessed using voxel-based morphometry (VBM), and resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity. Results showed that the athlete group had greater GMC and ALFF in the right and medial cerebellar regions, respectively. The athlete group also demonstrated smaller ALFF in the left superior parietal lobule and altered functional connectivity between the left superior parietal and frontal regions. These findings indicate that badminton expertise is associated with not only plastic structural changes in terms of enlarged gray matter density in the cerebellum, but also functional alterations in fronto-parietal connectivity. Such structural and functional alterations may reflect specific experiences of badminton training and practice, including high-capacity visuo-spatial processing and hand-eye coordination in addition to refined motor skills.

Voice and Valence-Altering Operations in Falam Chin: A Role and Reference Grammar Approach

ERIC Educational Resources Information Center

King, Deborah

2010-01-01

This dissertation describes and analyzes voice and valence-altering operations in Falam Chin, a Tibeto-Burman language of Burma. The data is explained within the framework of Role and Reference Grammar (RRG), which supplies several key concepts particularly useful for generalizing the behavior of the Falam Chin operations. The first is RRG's…

Are Amygdalar Volume Alterations in Children with Tourette Syndrome Due to ADHD Comorbidity?

ERIC Educational Resources Information Center

Ludolph, Andrea G.; Pinkhardt, Elmar H.; van Elst, Ludger Tebartz; Libal, Gerhard; Ludolph, Albert C.; Fegert, Jorg M.; Kassubek, Jan

2008-01-01

Recent studies have shown that changes in the basal ganglia circuitry and limbic loops may play an important role both in Tourette syndrome (TS) and attention-deficit-hyperactivity disorder (ADHD). This study aimed to investigate in vivo possible morphological alterations of the amygdala as a key component of the limbic system. Amygdalar and total…

Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.

PubMed

Depetris-Chauvin, Ana; Fernández-Gamba, Agata; Gorostiza, E Axel; Herrero, Anastasia; Castaño, Eduardo M; Ceriani, M Fernanda

2014-10-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons

PubMed Central

Depetris-Chauvin, Ana; Fernández-Gamba, Ágata; Gorostiza, E. Axel; Herrero, Anastasia; Castaño, Eduardo M.; Ceriani, M. Fernanda

2014-01-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior. PMID:25356918

Rebels with a cause: molecular features and physiological consequences of yeast prions.

PubMed

Garcia, David M; Jarosz, Daniel F

2014-02-01

Prions are proteins that convert between structurally and functionally distinct states, at least one of which is self-perpetuating. The prion fold templates the conversion of native protein, altering its structure and function, and thus serves as a protein-based element of inheritance. Molecular chaperones ensure that these prion aggregates are divided and faithfully passed from mother cells to their daughters. Prions were originally identified as the cause of several rare neurodegenerative diseases in mammals, but the last decade has brought great progress in understanding their broad importance in biology and evolution. Most prion proteins regulate information flow in signaling networks, or otherwise affect gene expression. Consequently, switching into and out of prion states creates diverse new traits – heritable changes based on protein structure rather than nucleic acid. Despite intense study of the molecular mechanisms of this paradigm-shifting, epigenetic mode of inheritance, many key questions remain. Recent studies in yeast that support the view that prions are common, often beneficial elements of inheritance that link environmental stress to the appearance of new traits.

Transient oligomerization of the SARS-CoV N protein--implication for virus ribonucleoprotein packaging.

PubMed

Chang, Chung-ke; Chen, Chia-Min Michael; Chiang, Ming-hui; Hsu, Yen-lan; Huang, Tai-huang

2013-01-01

The nucleocapsid (N) phosphoprotein of the severe acute respiratory syndrome coronavirus (SARS-CoV) packages the viral genome into a helical ribonucleocapsid and plays a fundamental role during viral self-assembly. The N protein consists of two structural domains interspersed between intrinsically disordered regions and dimerizes through the C-terminal structural domain (CTD). A key activity of the protein is the ability to oligomerize during capsid formation by utilizing the dimer as a building block, but the structural and mechanistic bases of this activity are not well understood. By disulfide trapping technique we measured the amount of transient oligomers of N protein mutants with strategically located cysteine residues and showed that CTD acts as a primary transient oligomerization domain in solution. The data is consistent with the helical oligomer packing model of N protein observed in crystal. A systematic study of the oligomerization behavior revealed that altering the intermolecular electrostatic repulsion through changes in solution salt concentration or phosphorylation-mimicking mutations affects oligomerization propensity. We propose a biophysical mechanism where electrostatic repulsion acts as a switch to regulate N protein oligomerization.

Living in the branches: population dynamics and ecological processes in dendritic networks

USGS Publications Warehouse

Grant, E.H.C.; Lowe, W.H.; Fagan, W.F.

2007-01-01

Spatial structure regulates and modifies processes at several levels of ecological organization (e.g. individual/genetic, population and community) and is thus a key component of complex systems, where knowledge at a small scale can be insufficient for understanding system behaviour at a larger scale. Recent syntheses outline potential applications of network theory to ecological systems, but do not address the implications of physical structure for network dynamics. There is a specific need to examine how dendritic habitat structure, such as that found in stream, hedgerow and cave networks, influences ecological processes. Although dendritic networks are one type of ecological network, they are distinguished by two fundamental characteristics: (1) both the branches and the nodes serve as habitat, and (2) the specific spatial arrangement and hierarchical organization of these elements interacts with a species' movement behaviour to alter patterns of population distribution and abundance, and community interactions. Here, we summarize existing theory relating to ecological dynamics in dendritic networks, review empirical studies examining the population- and community-level consequences of these networks, and suggest future research integrating spatial pattern and processes in dendritic systems.

Structural analysis of the Quaking homodimerization interface

PubMed Central

Beuck, Christine; Qu, Song; Fagg, W. Samuel; Ares, Manuel; Williamson, James R.

2012-01-01

Quaking is a prototypical member of the STAR protein family, which plays key roles in posttranscriptional gene regulation by controlling mRNA translation, stability and splicing. QkI-5 has been shown to regulate mRNA expression in the central nervous system, but little is known about its roles in other tissues. STAR proteins function as dimers and bind to bipartite RNA sequences, however, the structural and functional roles of homo- and hetero-dimerization are still unclear. Here, we present the crystal structure of the QkI dimerization domain, which adopts a similar stacked helix-turn-helix arrangement as its homologs GLD-1 and Sam68, but differs by an additional helix inserted in the dimer interface. Variability of the dimer interface residues likely ensures selective homodimerization by preventing association with non-cognate STAR family proteins in the cell. Mutations that inhibit dimerization also significantly impair RNA binding in vitro, alter QkI-5 protein levels, and impair QkI function in a splicing assay in vivo. Together our results indicate that a functional Qua1 homodimerization domain is required for QkI-5 function in mammalian cells. PMID:22982292

An extreme climatic event alters marine ecosystem structure in a global biodiversity hotspot

NASA Astrophysics Data System (ADS)

Wernberg, Thomas; Smale, Dan A.; Tuya, Fernando; Thomsen, Mads S.; Langlois, Timothy J.; de Bettignies, Thibaut; Bennett, Scott; Rousseaux, Cecile S.

2013-01-01

Extreme climatic events, such as heat waves, are predicted to increase in frequency and magnitude as a consequence of global warming but their ecological effects are poorly understood, particularly in marine ecosystems. In early 2011, the marine ecosystems along the west coast of Australia--a global hotspot of biodiversity and endemism--experienced the highest-magnitude warming event on record. Sea temperatures soared to unprecedented levels and warming anomalies of 2-4°C persisted for more than ten weeks along >2,000km of coastline. We show that biodiversity patterns of temperate seaweeds, sessile invertebrates and demersal fish were significantly different after the warming event, which led to a reduction in the abundance of habitat-forming seaweeds and a subsequent shift in community structure towards a depauperate state and a tropicalization of fish communities. We conclude that extreme climatic events are key drivers of biodiversity patterns and that the frequency and intensity of such episodes have major implications for predictive models of species distribution and ecosystem structure, which are largely based on gradual warming trends.

Geology of the Göçükdibi Cu-Pb-Zn Mineralization, Gökçedoǧan, Çorum (Turkey): Preliminary Findings on Its Formation

NASA Astrophysics Data System (ADS)

Yalçin, Cihan; Hanilçi, Nurullah; Kumral, Mustafa; Abdelnasser, Amr

2016-04-01

Göçükdibi Cu-Pb-Zn mineralization is located 3 km north west of Gökçedoǧan village where is 30 km east of the Kargı, Çorum. The geology of the mineralization area is represented by Mesozoic and Upper Pliocene lithostratigraphic units in different origin. These units with respect to their structural locations have identified as autochthonous and allachtonous. The autochthonous units which are the basement of the region are represented by Bekirli Metamorphites (Triassic-Liassic) and Beşpınar formation (Upper Cretaceous-Lower Eocene) which overlies the Bekirli Metamorphites as angular discordance. The allachtonous units are represented by Saraycık formation belongs to Kargı Ophioltic Melange, and located on the autochthonous units as tectonically. These allocthonous units are the product of the Neotethyan Ocean. The autochthonous and allachtonous units are overlaid by Upper Pliocene Ilgaz Formation and Plio-Quaternary stream sediments. The Cu-Pb-Zn mineralization is located in northwest of the Gökçedoǧan village within the Bekirli Metamorphites. The ore zone has N80E direction, 5 m wide and 120 m in length. The mineralizations which follow NE-SW trending structural line occurred as alternation with quartz-chlorite schists of the Bekirli Metamorphites. The mineralization is generally concordant to the foliation of schist's and also occurred as disseminated in the wall rocks. The ore paragenesis comprises with pyrite, chalcopyrite, sphalerite and galenit as the main sulphide minerals, and the malachite, azurite and limonite as the production of the oxidation. Preliminary data such as relationship between the ore and host rock, inner-structure of the ore and indicate that the Gökçedoǧan Cu-Pb-Zn mineralization was likely to have originated syngenetic. In addition, the geochemical behaviour of rare earth elements (REE) of the altered and mineralized samples collected from the alteration zone show that light REE enrichment with fair depletion of heavy REE during the alteration processes with positive Eu anomalies. As well as there is a positive correlation between K2O index and LREE that reveal the addition of K and La and the sericitization is the main alteration associated with the studied deposit. Key Words: Cu-Pb-Zn mineralization, Syngenetic, Bekirli Metamorphites, Gökçedoǧan.

Controlling Pickering Emulsion Destabilisation: A Route to Fabricating New Materials by Phase Inversion

PubMed Central

Whitby, Catherine P.; Wanless, Erica J.

2016-01-01

The aim of this paper is to review the key findings about how particle-stabilised (or Pickering) emulsions respond to stress and break down. Over the last ten years, new insights have been gained into how particles attached to droplet (and bubble) surfaces alter the destabilisation mechanisms in emulsions. The conditions under which chemical demulsifiers displace, or detach, particles from the interface were established. Mass transfer between drops and the continuous phase was shown to disrupt the layers of particles attached to drop surfaces. The criteria for causing coalescence by applying physical stress (shear or compression) to Pickering emulsions were characterised. These findings are being used to design the structures of materials formed by breaking Pickering emulsions. PMID:28773747

Scratching the surface: the processing of pain from deep tissues.

PubMed

Sikandar, Shafaq; Aasvang, Eske Kvanner; Dickenson, Anthony H

2016-04-01

Although most pain research focuses on skin, muscles, joints and viscerae are major sources of pain. We discuss the mechanisms of deep pains arising from somatic and visceral structures and how this can lead to widespread manifestations and chronification. We include how both altered peripheral and central sensory neurotransmission lead to deep pain states and comment on key areas such as top-down modulation where little is known. It is vital that the clinical characterization of deep pain in patients is improved to allow for back translation to preclinical models so that the missing links can be ascertained. The contribution of deeper somatic and visceral tissues to various chronic pain syndromes is common but there is much we need to know.

Expanding the scope of site-specific recombinases for genetic and metabolic engineering.

PubMed

Gaj, Thomas; Sirk, Shannon J; Barbas, Carlos F

2014-01-01

Site-specific recombinases are tremendously valuable tools for basic research and genetic engineering. By promoting high-fidelity DNA modifications, site-specific recombination systems have empowered researchers with unprecedented control over diverse biological functions, enabling countless insights into cellular structure and function. The rigid target specificities of many sites-specific recombinases, however, have limited their adoption in fields that require highly flexible recognition abilities. As a result, intense effort has been directed toward altering the properties of site-specific recombination systems by protein engineering. Here, we review key developments in the rational design and directed molecular evolution of site-specific recombinases, highlighting the numerous applications of these enzymes across diverse fields of study. © 2013 Wiley Periodicals, Inc.

The synthesis of new oxazoline-containing bifunctional catalysts and their application in the addition of diethylzinc to aldehydes.

PubMed

Coeffard, Vincent; Müller-Bunz, Helge; Guiry, Patrick J

2009-04-21

The straightforward preparation of new modular oxazoline-containing bifunctional catalysts is reported employing a microwave-assisted Buchwald-Hartwig aryl amination as the key step. Covalent attachment of 2-(o-aminophenyl)oxazolines and pyridine derivatives generated in good-to-high yields a series of ligands in two or three steps in which each part was altered independently to tune the activity and the selectivity of the corresponding catalysts. These catalysts prepared in situ were subsequently applied in the asymmetric addition of diethylzinc to various aldehydes, producing the corresponding alcohols with enantioselectivities of up to 68%. A transition state model, based on relevant X-ray crystal structures, has also been proposed to explain the observed stereoselectivities.

Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning.

PubMed

Ma, Di; Feng, Liangshu; Deng, Fang; Feng, Jia-Chun

2017-01-01

Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and inhibition of calcium overload, as well as the release of endogenous active substances, alterations in membrane channel function, and activation of protein kinases. Here we review the novel discovery, mechanism, key factors, and clinical application of ischemic postconditioning and discuss its implications for future research and problem of clinical practice.

Water: a responsive small molecule.

PubMed

Shultz, Mary Jane; Vu, Tuan Hoang; Meyer, Bryce; Bisson, Patrick

2012-01-17

Unique among small molecules, water forms a nearly tetrahedral yet flexible hydrogen-bond network. In addition to its flexibility, this network is dynamic: bonds are formed or broken on a picosecond time scale. These unique features make probing the local structure of water challenging. Despite the challenges, there is intense interest in developing a picture of the local water structure due to water's fundamental importance in many fields of chemistry. Understanding changes in the local network structure of water near solutes likely holds the key to unlock problems from analyzing parameters that determine the three dimensional structure of proteins to modeling the fate of volatile materials released into the atmosphere. Pictures of the local structure of water are heavily influenced by what is known about the structure of ice. In hexagonal I(h) ice, the most stable form of solid water under ordinary conditions, water has an equal number of donor and acceptor bonds; a kind of symmetry. This symmetric tetrahedral coordination is only approximately preserved in the liquid. The most obvious manifestation of this altered tetrahedral bonding is the greater density in the liquid compared with the solid. Formation of an interface or addition of solutes further modifies the local bonding in water. Because the O-H stretching frequency is sensitive to the environment, vibrational spectroscopy provides an excellent probe for the hydrogen-bond structure in water. In this Account, we examine both local interactions between water and small solutes and longer range interactions at the aqueous surface. Locally, the results suggest that water is not a symmetric donor or acceptor, but rather has a propensity to act as an acceptor. In interactions with hydrocarbons, action is centered at the water oxygen. For soluble inorganic salts, interaction is greater with the cation than the anion. The vibrational spectrum of the surface of salt solutions is altered compared with that of neat water. Studies of local salt-water interactions suggest that the picture of the local water structure and the ion distribution at the surface deduced from the surface vibrational spectrum should encompass both ions of the salt.

Large area, label-free imaging of extracellular matrix using telecentricity

NASA Astrophysics Data System (ADS)

Visbal Onufrak, Michelle A.; Konger, Raymond L.; Kim, Young L.

2017-02-01

Subtle alterations in stromal tissue structures and organizations within the extracellular matrix (ECM) have been observed in several types of tissue abnormalities, including early skin cancer and wounds. Current microscopic imaging methods often lack the ability to accurately determine the extent of malignancy over a large area, due to their limited field of view. In this research we focus on the development of simple mesoscopic (i.e. between microscopic and macroscopic) biomedical imaging device for non-invasive assessment of ECM alterations over a large, heterogeneous area. In our technology development, a telecentric lens, commonly used in machine vision systems but rarely used in biomedical imaging, serves as a key platform to visualize alterations in tissue microenvironments in a label-free manner over a clinically relevant area. In general, telecentric imaging represents a simple, alternative method for reducing unwanted scattering or diffuse light caused by the highly anisotropic scattering properties of biological tissue. In particular, under telecentric imaging the light intensity backscattered from biological tissue is mainly sensitive to the scattering anisotropy factor, possibly associated with the ECM. We demonstrate the inherent advantages of combining telecentric lens systems with hyperspectral imaging for providing optical information of tissue scattering in biological tissue of murine models, as well as light absorption of hemoglobin in blood vessel tissue phantoms. Thus, we envision that telecentric imaging could potentially serve for simple site-specific, tissue-based assessment of stromal alterations over a clinically relevant field of view in a label-free manner, for studying diseases associated with disruption of homeostasis in ECM.

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation

PubMed Central

Pagliaccio, David; Luby, Joan L.; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S.; Belden, Andrew C.; Botteron, Kelly N.; Harms, Michael P.; Barch, Deanna M.

2015-01-01

Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. PMID:26595470

Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation.

PubMed

Pagliaccio, David; Luby, Joan L; Bogdan, Ryan; Agrawal, Arpana; Gaffrey, Michael S; Belden, Andrew C; Botteron, Kelly N; Harms, Michael P; Barch, Deanna M

2015-11-01

Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N = 120). Whole-brain regression analyses indicated that increasing genetic "risk" predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic "risk" and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. (c) 2015 APA, all rights reserved).

Bio-inspired device: a novel smart MR spring featuring tendril structure

NASA Astrophysics Data System (ADS)

Kaluvan, Suresh; Park, Chun-Yong; Choi, Seung-Bok

2016-01-01

Smart materials such as piezoelectric patches, shape memory alloy, electro and magneto rheological fluid, magnetostrictive materials, etc are involved by far to design intelligent and high performance smart devices like injectors, dental braces, dampers, actuators and sensors. In this paper, an interesting smart device is proposed by inspiring on the structure of the bio climber plant. The key enabling concept of this proposed work is to design the smart spring damper as a helical shaped tendril structure using magneto-rheological (MR) fluid. The proposed smart spring consists of a hollow helical structure filled with MR fluid. The viscosity of the MR fluid decides the damping force of helical shaped smart spring, while the fluid intensity in the vine decides the strength of the tendril in the climber plant. Thus, the proposed smart spring can provide a new concept design of the damper which can be applicable to various damping system industries with tuneable damping force. The proposed smart spring damper has several advantageous such as cost effective, easy implementation compared with the conventional damper. In addition, the proposed spring damper can be easily designed to adapt different damping force levels without any alteration.

Efficacy of atmospheric pressure dielectric barrier discharge for inactivating airborne pathogens

DOE PAGES

Romero-Mangado, Jaione; Dey, Avishek; Diaz-Cartagena, Diana C.; ...

2017-07-05

Atmospheric pressure plasmas have gained attention in recent years for several environmental applications. This technology could potentially be used to deactivate airborne microorganisms, surface-bound microorganisms, and biofilms. Here, the authors explore the efficacy of the atmospheric pressure dielectric barrier discharge (DBD) to inactivate airborne Staphylococcus epidermidis and Aspergillus niger that are opportunistic pathogens associated with nosocomial infections. This technology uses air as the source of gas and does not require any process gas such as helium, argon, nitrogen, or hydrogen. Moreover, the effect of DBD was studied on aerosolized S. epidermidis and aerosolized A. niger spores via scanning electron microscopymore » (SEM). The morphology observed on the SEM micrographs showed deformations in the cellular structure of both microorganisms. Cell structure damage upon interaction with the DBD suggests leakage of vital cellular materials, which is a key mechanism for microbial inactivation. The chemical structure of the cell surface of S. epidermidis was also analyzed by near edge x-ray absorption fine structure spectroscopy before and after DBD exposure. Our results from surface analysis revealed that reactive oxygen species from the DBD discharge contributed to alterations on the chemistry of the cell membrane/cell wall of S. epidermidis.« less

Structural basis for regulation of rhizobial nodulation and symbiosis gene expression by the regulatory protein NolR.

PubMed

Lee, Soon Goo; Krishnan, Hari B; Jez, Joseph M

2014-04-29

The symbiosis between rhizobial microbes and host plants involves the coordinated expression of multiple genes, which leads to nodule formation and nitrogen fixation. As part of the transcriptional machinery for nodulation and symbiosis across a range of Rhizobium, NolR serves as a global regulatory protein. Here, we present the X-ray crystal structures of NolR in the unliganded form and complexed with two different 22-base pair (bp) double-stranded operator sequences (oligos AT and AA). Structural and biochemical analysis of NolR reveals protein-DNA interactions with an asymmetric operator site and defines a mechanism for conformational switching of a key residue (Gln56) to accommodate variation in target DNA sequences from diverse rhizobial genes for nodulation and symbiosis. This conformational switching alters the energetic contributions to DNA binding without changes in affinity for the target sequence. Two possible models for the role of NolR in the regulation of different nodulation and symbiosis genes are proposed. To our knowledge, these studies provide the first structural insight on the regulation of genes involved in the agriculturally and ecologically important symbiosis of microbes and plants that leads to nodule formation and nitrogen fixation.

Efficacy of atmospheric pressure dielectric barrier discharge for inactivating airborne pathogens

DOE Office of Scientific and Technical Information (OSTI.GOV)

Romero-Mangado, Jaione; Dey, Avishek; Diaz-Cartagena, Diana C.

Atmospheric pressure plasmas have gained attention in recent years for several environmental applications. This technology could potentially be used to deactivate airborne microorganisms, surface-bound microorganisms, and biofilms. Here, the authors explore the efficacy of the atmospheric pressure dielectric barrier discharge (DBD) to inactivate airborne Staphylococcus epidermidis and Aspergillus niger that are opportunistic pathogens associated with nosocomial infections. This technology uses air as the source of gas and does not require any process gas such as helium, argon, nitrogen, or hydrogen. Moreover, the effect of DBD was studied on aerosolized S. epidermidis and aerosolized A. niger spores via scanning electron microscopymore » (SEM). The morphology observed on the SEM micrographs showed deformations in the cellular structure of both microorganisms. Cell structure damage upon interaction with the DBD suggests leakage of vital cellular materials, which is a key mechanism for microbial inactivation. The chemical structure of the cell surface of S. epidermidis was also analyzed by near edge x-ray absorption fine structure spectroscopy before and after DBD exposure. Our results from surface analysis revealed that reactive oxygen species from the DBD discharge contributed to alterations on the chemistry of the cell membrane/cell wall of S. epidermidis.« less

Long-Term Alterations in Neural and Endocrine Processes Induced by Motherhood

PubMed Central

Bridges, Robert S.

2015-01-01

The reproductive experience of pregnancy, lactation and motherhood can significantly remodel the female’s biological state, affecting endocrine, neuroendocrine, neural, and immunological processes. The brain, pituitary gland, liver, thymus, and mammary tissue are among the structures that are modified by reproductive experience. The present review that focuses on rodent research, but also includes pertinent studies in sheep and other species, identifies specific changes in these processes brought about by the biological states of pregnancy, parturition, and lactation and how the components of reproductive experience contribute to the remodeling of the maternal brain and organ systems. Findings indicate that prior parity alters key circulating hormone levels and neural receptor gene expression. Moreover, reproductive experience results in modifications in neural processes and glial support. The possible role of pregnancy-induced neurogenesis is considered in the context of neuroplasticity and behavior, and the effects of reproductive experience on maternal memory, i.e. the retention of maternal behavior, together with anxiety and learning are presented. Together, these sets of findings support the concept that the neural and biological state of the adult female is significantly and dramatically altered on a long-term basis by the experiences of parity and motherhood. Remodeling of the maternal brain and other biological systems is posited to help facilitate adaptations to environmental/ecological challenges as the female raises young and ages. PMID:26388065

The Role of Trabecular Microarchitecture in the Formation, Accumulation, and Morphology of Microdamage in Human Cancellous Bone

PubMed Central

Karim, Lamya; Vashishth, Deepak

2011-01-01

Alterations in microdamage morphology and accumulation are typically attributed to impaired remodeling, but may also result from changes in microdamage initiation and propagation. Such alterations are relevant for cancellous bone with high metabolic activity and numerous bone quality changes. This study investigates the role of trabecular microarchitecture on morphology and accumulation of microdamage in human cancellous bone. Trabecular bone cores from donors of varying ages and bone volume fraction (BV/TV) were separated into high and low BV/TV groups. Samples were subjected to no load or uniaxial compression to 0.6% (pre-yield) or 1.1% (post-yield) strain. Microdamage was stained with lead uranyl acetate and specimens were imaged via microcomputed tomography to quantify microdamage and determine its morphology in three-dimensions (3D). Donors with high BV/TV had greater post yield strain and were tougher than low BV/TV donors. High BV/TV bone had less microdamage than low BV/TV bone under post- but not pre-yield loading. Microdamage under both loading conditions showed significant correlations with microarchitecture and BV/TV, but the key predictor was structure model index (SMI). As SMI increased (more trabecular rods), microdamage morphology became crack-like. Thus, low BV/TV and increased SMI have strong influences on microdamage accumulation in bone through altered initiation. PMID:21538510

Myeloperoxidase-dependent Inactivation of Surfactant Protein D in Vitro and in Vivo*

PubMed Central

Crouch, Erika C.; Hirche, Tim O.; Shao, Baohai; Boxio, Rachel; Wartelle, Julien; Benabid, Rym; McDonald, Barbara; Heinecke, Jay; Matalon, Sadis; Belaaouaj, Azzaq

2010-01-01

Surfactant protein D (SP-D) plays diverse and important roles in innate immunity and pulmonary homeostasis. Neutrophils and myeloperoxidase (MPO) colocalized with SP-D in a murine bacterial pneumonia model of acute inflammation, suggesting that MPO-derived reactive species might alter the function of SP-D. Exposure of SP-D to the complete MPO-H2O2-halide system caused loss of SP-D-dependent aggregating activity. Hypochlorous acid (HOCl), the major oxidant generated by MPO, caused a similar loss of aggregating activity, which was accompanied by the generation of abnormal disulfide-cross-linked oligomers. A full-length SP-D mutant lacking N-terminal cysteine residues and truncation mutants lacking the N-terminal domains were resistant to the oxidant-induced alterations in disulfide bonding. Mass spectroscopy of HOCl-treated human SP-D demonstrated several modifications, but none involved key ligand binding residues. There was detectable oxidation of cysteine 15, but no HOCl-induced cysteine modifications were observed in the C-terminal lectin domain. Together, the findings localize abnormal disulfide cross-links to the N-terminal domain. MPO-deficient mice showed decreased cross-linking of SP-D and increased SP-D-dependent aggregating activity in the pneumonia model. Thus, MPO-derived oxidants can lead to modifications of SP-D structure with associated alterations in its characteristic aggregating activity. PMID:20228064

Sperm with fibrous sheath dysplasia and anomalies in head-neck junction: focus on centriole and centrin 1.

PubMed

Moretti, E; Pascarelli, N A; Belmonte, G; Renieri, T; Collodel, G

2017-09-01

Spermatozoa with a rare combination of two monomorphic sperm defects, dysplasia of the fibrous sheath (DFS) and alterations in head-mid-piece junction were analysed. The main focus was to explore the status of the centriole, a key organisation during fertilisation, using the centrin 1, a calcium-binding protein linked to this structure. The sperm quality was examined by light, scanning and transmission electron microscopy (SEM, TEM); immunocytochemistry was performed for tubulin, A-kinase anchor protein 4 (AKAP4) and centrin 1. Spermatozoa showed DFS defect associated with anomalies in head-tail attachment detected by SEM and TEM. Immunolocalisation of tubulin, AKAP4 and centrin 1 confirmed these alterations. Centrin 1 was visible in 67% of spermatozoa (in only 13% centrin localised in a normal position); in the majority of sperm centrin 1's location was altered, sometimes bent; often four spots, indicating the presence of two implantation fossae, were detected. At the centriolar level, immunoreactive fragments, frequently invading the entire short and thick tail, were observed. Centrin 1 is an essential component of the spermatozoa connecting piece and plays a role in centrosome dynamics during sperm morphogenesis and in zygotes and early embryos during spindle assembly. It is important to shed light on these rare conditions in order to better manage the patients during assisted reproductive technology. © 2016 Blackwell Verlag GmbH.

Balancing Authority Cooperation Concepts - Intra-Hour Scheduling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hunsaker, Matthew; Samaan, Nader; Milligan, Michael

2013-03-29

The overall objective of this study was to understand, on an Interconnection-wide basis, the effects intra-hour scheduling compared to hourly scheduling. Moreover, the study sought to understand how the benefits of intra-hour scheduling would change by altering the input assumptions in different scenarios. This report describes results of three separate scenarios with differing key assumptions and comparing the production costs between hourly scheduling and 10-minute scheduling performance. The different scenarios were chosen to provide insight into how the estimated benefits might change by altering input assumptions. Several key assumptions were different in the three scenarios, however most assumptions were similarmore » and/or unchanged among the scenarios.« less

Mitochondrial Dynamics: Coupling Mitochondrial Fitness with Healthy Aging.

PubMed

Sebastián, David; Palacín, Manuel; Zorzano, Antonio

2017-03-01

Aging is associated with a decline in mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these mitochondrial alterations and the role of the latter in aging are still not fully understood. Mitochondrial dynamics is a key process regulating mitochondrial function and quality. Altered expression of some mitochondrial dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans, mice, and humans. Here, we review the link between alterations in mitochondrial dynamics, aging, and age-related impairment. We propose that the dysregulation of mitochondrial dynamics leads to age-induced accumulation of unhealthy mitochondria and contributes to alterations linked to aging, such as diabetes and neurodegeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bioturbating shrimp alter the structure and diversity of bacterial communities in coastal marine sediments.

PubMed

Laverock, Bonnie; Smith, Cindy J; Tait, Karen; Osborn, A Mark; Widdicombe, Steve; Gilbert, Jack A

2010-12-01

Bioturbation is a key process in coastal sediments, influencing microbially driven cycling of nutrients as well as the physical characteristics of the sediment. However, little is known about the distribution, diversity and function of the microbial communities that inhabit the burrows of infaunal macroorganisms. In this study, terminal-restriction fragment length polymorphism analysis was used to investigate variation in the structure of bacterial communities in sediment bioturbated by the burrowing shrimp Upogebia deltaura or Callianassa subterranea. Analyses of 229 sediment samples revealed significant differences between bacterial communities inhabiting shrimp burrows and those inhabiting ambient surface and subsurface sediments. Bacterial communities in burrows from both shrimp species were more similar to those in surface-ambient than subsurface-ambient sediment (R=0.258, P<0.001). The presence of shrimp was also associated with changes in bacterial community structure in surrounding surface sediment, when compared with sediments uninhabited by shrimp. Bacterial community structure varied with burrow depth, and also between individual burrows, suggesting that the shrimp's burrow construction, irrigation and maintenance behaviour affect the distribution of bacteria within shrimp burrows. Subsequent sequence analysis of bacterial 16S rRNA genes from surface sediments revealed differences in the relative abundance of bacterial taxa between shrimp-inhabited and uninhabited sediments; shrimp-inhabited sediment contained a higher proportion of proteobacterial sequences, including in particular a twofold increase in Gammaproteobacteria. Chao1 and ACE diversity estimates showed that taxon richness within surface bacterial communities in shrimp-inhabited sediment was at least threefold higher than that in uninhabited sediment. This study shows that bioturbation can result in significant structural and compositional changes in sediment bacterial communities, increasing bacterial diversity in surface sediments and resulting in distinct bacterial communities even at depth within the burrow. In an area of high macrofaunal abundance, this could lead to alterations in the microbial transformations of important nutrients at the sediment-water interface.

18 CFR 1304.209 - Land-based structures/alterations.

Code of Federal Regulations, 2014 CFR

2014-04-01

..., satellite antennas, septic tanks, and septic drainfields shall not be allowed on TVA land. (c) Utility lines... APPROVAL OF CONSTRUCTION IN THE TENNESSEE RIVER SYSTEM AND REGULATION OF STRUCTURES AND OTHER ALTERATIONS...

18 CFR 1304.209 - Land-based structures/alterations.

Code of Federal Regulations, 2013 CFR

2013-04-01

..., satellite antennas, septic tanks, and septic drainfields shall not be allowed on TVA land. (c) Utility lines... APPROVAL OF CONSTRUCTION IN THE TENNESSEE RIVER SYSTEM AND REGULATION OF STRUCTURES AND OTHER ALTERATIONS...

Preservation of flavor in freeze dried green beans

NASA Technical Reports Server (NTRS)

Huber, C. S.; Heidelbaugh, N. D.; Davis, D.

1973-01-01

Before freeze drying, green beans are heated to point at which their cell structure is altered. Beans freeze dried with altered cell structure have improved rehydration properties and retain color, flavor, and texture.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure.

PubMed

Gavin, David P; Grayson, Dennis R; Varghese, Sajoy P; Guizzetti, Marina

2017-05-11

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

PubMed Central

Gavin, David P.; Grayson, Dennis R.; Varghese, Sajoy P.; Guizzetti, Marina

2017-01-01

Prenatal alcohol exposure causes persistent neuropsychiatric deficits included under the term fetal alcohol spectrum disorders (FASD). Cellular identity emerges from a cascade of intrinsic and extrinsic (involving cell-cell interactions and signaling) processes that are partially initiated and maintained through changes in chromatin structure. Prenatal alcohol exposure influences neuronal and astrocyte development, permanently altering brain connectivity. Prenatal alcohol exposure also alters chromatin structure through histone and DNA modifications. However, the data linking alcohol-induced differentiation changes with developmental alterations in chromatin structure remain to be elucidated. In the first part of this review, we discuss the sequence of chromatin structural changes involved in neural cell differentiation during normal development. We then discuss the effects of prenatal alcohol on developmental histone modifications and DNA methylation in the context of neurogenesis and astrogliogenesis. We attempt to synthesize the developmental literature with the FASD literature, proposing that alcohol-induced changes to chromatin structure account for altered neurogenesis and astrogliogenesis as well as altered neuron and astrocyte differentiation. Together these changes may contribute to the cognitive and behavioral abnormalities in FASD. Future studies using standardized alcohol exposure paradigms at specific developmental stages will advance the understanding of how chromatin structural changes impact neural cell fate and maturation in FASD. PMID:28492482

Element speciation during nuclear glass alteration

NASA Astrophysics Data System (ADS)

Galoisy, L.; Calas, G.; Bergeron, B.; Jollivet, P.; Pelegrin, E.

2011-12-01

Assessing the long-term behavior of nuclear glasses implies the prediction of their long-term performance. An important controlling parameter is their evolution during interaction with water under conditions simulating geological repositories. After briefly recalling the major characteristics of the local and medium-range structure of borosilicate glasses of nuclear interest, we will present some structural features of this evolution. Specific structural tools used to determine the local structure of glass surfaces include synchrotron-radiation x-ray absorption spectroscopy with total electron yield detection. The evolution of the structure of glass surface has been determined at the Zr-, Fe-, Si- and Al-K edges and U-LIII edge. During alteration in near- or under-saturated conditions, some elements such as Fe change coordination, as other elements such as Zr only suffer structural modifications in under-saturated conditions. Uranium exhibits a modification of its speciation from an hexa-coordinated U(VI) in the borosilicate glass to an uranyl group in the gel. These structural modifications may explain the chemical dependence of the initial alteration rate and the transition to the residual regime. They also illustrate the molecular-scale origin of the processes at the origin of the glass-to-gel transformation. Eventually, they explain the provisional trapping of U by the alteration gel: the uranium retention factors in the gel depend on the alteration conditions, and thus on the nature of the resulting gel and on the trapping conditions.

Influence of the segmentation on the characterization of cerebral networks of structural damage for patients with disorders of consciousness

NASA Astrophysics Data System (ADS)

Martínez, Darwin; Mahalingam, Jamuna J.; Soddu, Andrea; Franco, Hugo; Lepore, Natasha; Laureys, Steven; Gómez, Francisco

2015-01-01

Disorders of consciousness (DOC) are a consequence of a variety of severe brain injuries. DOC commonly results in anatomical brain modifications, which can affect cortical and sub-cortical brain structures. Postmortem studies suggest that severity of brain damage correlates with level of impairment in DOC. In-vivo studies in neuroimaging mainly focus in alterations on single structures. Recent evidence suggests that rather than one, multiple brain regions can be simultaneously affected by this condition. In other words, DOC may be linked to an underlying cerebral network of structural damage. Recently, geometrical spatial relationships among key sub-cortical brain regions, such as left and right thalamus and brain stem, have been used for the characterization of this network. This approach is strongly supported on automatic segmentation processes, which aim to extract regions of interests without human intervention. Nevertheless, patients with DOC usually present massive structural brain changes. Therefore, segmentation methods may highly influence the characterization of the underlying cerebral network structure. In this work, we evaluate the level of characterization obtained by using the spatial relationships as descriptor of a sub-cortical cerebral network (left and right thalamus) in patients with DOC, when different segmentation approaches are used (FSL, Free-surfer and manual segmentation). Our results suggest that segmentation process may play a critical role for the construction of robust and reliable structural characterization of DOC conditions.

Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.

PubMed

Vannini, Alessandro; Volpari, Cinzia; Filocamo, Gessica; Casavola, Elena Caroli; Brunetti, Mirko; Renzoni, Debora; Chakravarty, Prasun; Paolini, Chantal; De Francesco, Raffaele; Gallinari, Paola; Steinkühler, Christian; Di Marco, Stefania

2004-10-19

Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single alpha/beta domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.

A thermosensitive hydrogel based on biodegradable amphiphilic poly(ethylene glycol) polycaprolactone poly(ethylene glycol) block copolymers

NASA Astrophysics Data System (ADS)

Gong, Chang Yang; Qian, Zhi Yong; Liu, Cai Bing; Juan Huang, Mei; Gu, Ying Chun; Wen, Yan Jun; Kan, Bing; Wang, Ke; Dai, Mei; Li, Xing Yi; Gou, Ma Ling; Tu, Ming Jing; Wei, Yu Quan

2007-06-01

A series of low molecular weight poly(ethylene glycol)-polycaprolactone-poly(ethylene glycol) (PEG-PCL-PEG) biodegradable block copolymers were successfully synthesized using isophorone diisocyanate (IPDI) as the coupling agent, and were characterized using 1H NMR and Fourier transform infrared spectroscopy. The aqueous solutions of the PEG-PCL-PEG copolymers displayed a special thermosensitive gel-sol transition when the concentration was above the corresponding critical gel concentration. Gel-sol phase diagrams were recorded using the test-tube-inversion method; they depended on the hydrophilic/hydrophobic balance in the macromolecular structure, as well as some other factors, including the heating history, volume, and the ageing time of the copolymer aqueous solutions and dissolution temperature of the copolymers. As a result, the gel-sol transition temperature range could be altered, which might be very useful for application in injectable drug delivery systems. This work was financially supported by the Chinese Key Basic Research Program (2004CB518800 and 2004CB518807), and the Sichuan Key Project of Science and Technology (06(05SG022-021-02)).

Altered Resting Brain Function and Structure in Professional Badminton Players

PubMed Central

Di, Xin; Zhu, Senhua; Wang, Pin; Ye, Zhuoer; Zhou, Ke; Zhuo, Yan

2012-01-01

Abstract Neuroimaging studies of professional athletic or musical training have demonstrated considerable practice-dependent plasticity in various brain structures, which may reflect distinct training demands. In the present study, structural and functional brain alterations were examined in professional badminton players and compared with healthy controls using magnetic resonance imaging (MRI) and resting-state functional MRI. Gray matter concentration (GMC) was assessed using voxel-based morphometry (VBM), and resting-brain functions were measured by amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity. Results showed that the athlete group had greater GMC and ALFF in the right and medial cerebellar regions, respectively. The athlete group also demonstrated smaller ALFF in the left superior parietal lobule and altered functional connectivity between the left superior parietal and frontal regions. These findings indicate that badminton expertise is associated with not only plastic structural changes in terms of enlarged gray matter density in the cerebellum, but also functional alterations in fronto-parietal connectivity. Such structural and functional alterations may reflect specific experiences of badminton training and practice, including high-capacity visuo-spatial processing and hand-eye coordination in addition to refined motor skills. PMID:22840241

Induced mutations in tomato SlExp1 alter cell wall metabolism and delay fruit softening.

PubMed

Minoia, Silvia; Boualem, Adnane; Marcel, Fabien; Troadec, Christelle; Quemener, Bernard; Cellini, Francesco; Petrozza, Angelo; Vigouroux, Jacqueline; Lahaye, Marc; Carriero, Filomena; Bendahmane, Abdelhafid

2016-01-01

Fruit ripening and softening are key traits for many fleshy fruit. Since cell walls play a key role in the softening process, expansins have been investigated to control fruit over ripening and deterioration. In tomato, expression of Expansin 1 gene, SlExp1, during fruit ripening was associated with fruit softening. To engineer tomato plants with long shelf life, we screened for mutant plants impaired in SlExp1 function. Characterization of two induced mutations, Slexp1-6_W211S, and Slexp1-7_Q213Stop, showed that SlExp1 loss of function leads to enhanced fruit firmness and delayed fruit ripening. Analysis of cell wall polysaccharide composition of Slexp1-7_Q213Stop mutant pointed out significant differences for uronic acid, neutral sugar and total sugar contents. Hemicelluloses chemistry analysis by endo-β-1,4-d-glucanase hydrolysis and MALDI-TOF spectrometry revealed that xyloglucan structures were affected in the fruit pericarp of Slexp1-7_Q213Stop mutant. Altogether, these results demonstrated that SlExp1 loss of function mutants yield firmer and late ripening fruits through modification of hemicellulose structure. These SlExp1 mutants represent good tools for breeding long shelf life tomato lines with contrasted fruit texture as well as for the understanding of the cell wall polysaccharide assembly dynamics in fleshy fruits. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Effect of Age and Proteoglycan Deficiency on Collagen Fiber Re-Alignment and Mechanical Properties in Mouse Supraspinatus Tendon

PubMed Central

Connizzo, Brianne K.; Sarver, Joseph J.; Iozzo, Renato V.; Birk, David E.; Soslowsky, Louis J.

2013-01-01

Collagen fiber realignment is one mechanism by which tendon responds to load. Re-alignment is altered when the structure of tendon is altered, such as in the natural process of aging or with alterations of matrix proteins, such as proteoglycan expression. While changes in re-alignment and mechanical properties have been investigated recently during development, they have not been studied in (1) aged tendons, or (2) in the absence of key proteoglycans. Collagen fiber re-alignment and the corresponding mechanical properties are quantified throughout tensile mechanical testing in both the insertion site and the midsubstance of mouse supraspinatus tendons in wild type (WT), decorin-null (Dcn-/-), and biglycan-null (Bgn-/-) mice at three different ages (90 days, 300 days, and 570 days). Percent relaxation was significantly decreased with age in the WT and Dcn-/- tendons, but not in the Bgn-/- tendons. Changes with age were found in the linear modulus at the insertion site where the 300 day group was greater than the 90 day and 570 day group in the Bgn-/- tendons and the 90 day group was smaller than the 300 day and 570 day groups in the Dcn-/- tendons. However, no changes in modulus were found across age in WT tendons were found. The midsubstance fibers of the WT and Bgn-/- tendons were initially less aligned with increasing age. The re-alignment was significantly altered with age in the WT tendons, with older groups responding to load later in the mechanical test. This was also seen in the Dcn-/- midsubstance and the Bgn-/- insertion, but not in the other locations. Although some studies have found changes in the WT mechanical properties with age, this study did not support those findings. However, it did show fiber re-alignment changes at both locations with age, suggesting a breakdown of tendon′s ability to respond to load in later ages. In the proteoglycan-null tendons however, there were changes in the mechanical properties, accompanied only by location-dependent re-alignment changes, suggesting a site-specific role for these molecules in loading. Finally, changes in the mechanical properties did not occur in concert with changes in re-alignment, suggesting that typical mechanical property measurements alone are insufficient to describe how structural alterations affect tendon′s response to load. PMID:23445064

Side-binding proteins modulate actin filament dynamics

PubMed Central

Crevenna, Alvaro H; Arciniega, Marcelino; Dupont, Aurélie; Mizuno, Naoko; Kowalska, Kaja; Lange, Oliver F; Wedlich-Söldner, Roland; Lamb, Don C

2015-01-01

Actin filament dynamics govern many key physiological processes from cell motility to tissue morphogenesis. A central feature of actin dynamics is the capacity of filaments to polymerize and depolymerize at their ends in response to cellular conditions. It is currently thought that filament kinetics can be described by a single rate constant for each end. In this study, using direct visualization of single actin filament elongation, we show that actin polymerization kinetics at both filament ends are strongly influenced by the binding of proteins to the lateral filament surface. We also show that the pointed-end has a non-elongating state that dominates the observed filament kinetic asymmetry. Estimates of flexibility as well as effects on fragmentation and growth suggest that the observed kinetic diversity arises from structural alteration. Tuning elongation kinetics by exploiting the malleability of the filament structure may be a ubiquitous mechanism to generate a rich variety of cellular actin dynamics. DOI: http://dx.doi.org/10.7554/eLife.04599.001 PMID:25706231

Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase

PubMed Central

Jiang, Tao; Yu, Kuai

2017-01-01

From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase. PMID:28917060

Computational Design of Thermostabilizing d-Amino Acid Substitutions

PubMed Central

Rodriguez-Granillo, Agustina; Annavarapu, Srinivas; Zhang, Lei; Koder, Ronald L.; Nanda, Vikas

2012-01-01

Judicious incorporation of d-amino acids in engineered proteins confer many advantages such as preventing degradation by endogenous proteases, and designing novel structures and functions not accessible to homochiral polypeptides. Glycine to d-alanine substitutions at the carboxy-termini can stabilize α-helices by reducing conformational entropy. Beyond alanine, we propose additional side chain effects on the degree of stabilization conferred by d-amino acid substitutions. A detailed, molecular understanding of backbone and side chain interactions is important for developing rational, broadly applicable strategies in using d-amino acids to increase protein thermostability. Insight from structural bioinformatics combined with computational protein design can successfully guide the selection of stabilizing d-amino acid mutations. Substituting a key glycine in the Trp-Cage mini-protein with d-Gln dramatically stabilizes the fold without altering the protein backbone. Stabilities of individual substitutions can be understood in terms of the balance of intramolecular forces at both the α-helix C-terminus and throughout the protein. PMID:21978298

Energetics and Structural Characterization of the large-scale Functional Motion of Adenylate Kinase

PubMed Central

Formoso, Elena; Limongelli, Vittorio; Parrinello, Michele

2015-01-01

Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins. PMID:25672826

Matrix metalloproteinase-9 involvement in the structural plasticity of dendritic spines

PubMed Central

Stawarski, Michal; Stefaniuk, Marzena; Wlodarczyk, Jakub

2014-01-01

Dendritic spines are the locus for excitatory synaptic transmission in the brain and thus play a major role in neuronal plasticity. The ability to alter synaptic connections includes volumetric changes in dendritic spines that are driven by scaffolds created by the extracellular matrix (ECM). Here, we review the effects of the proteolytic activity of ECM proteases in physiological and pathological structural plasticity. We use matrix metalloproteinase-9 (MMP-9) as an example of an ECM modifier that has recently emerged as a key molecule in regulating the morphology and dysmorphology of dendritic spines that underlie synaptic plasticity and neurological disorders, respectively. We summarize the influence of MMP-9 on the dynamic remodeling of the ECM via the cleavage of extracellular substrates. We discuss its role in the formation, modification, and maintenance of dendritic spines in learning and memory. Finally, we review research that implicates MMP-9 in aberrant synaptic plasticity and spine dysmorphology in neurological disorders, with a focus on morphological abnormalities of dendritic protrusions that are associated with epilepsy. PMID:25071472

Respiratory Muscle Plasticity

PubMed Central

Gransee, Heather M.; Mantilla, Carlos B.; Sieck, Gary C.

2014-01-01

Muscle plasticity is defined as the ability of a given muscle to alter its structural and functional properties in accordance with the environmental conditions imposed on it. As such, respiratory muscle is in a constant state of remodeling, and the basis of muscle’s plasticity is its ability to change protein expression and resultant protein balance in response to varying environmental conditions. Here, we will describe the changes of respiratory muscle imposed by extrinsic changes in mechanical load, activity, and innervation. Although there is a large body of literature on the structural and functional plasticity of respiratory muscles, we are only beginning to understand the molecular-scale protein changes that contribute to protein balance. We will give an overview of key mechanisms regulating protein synthesis and protein degradation, as well as the complex interactions between them. We suggest future application of a systems biology approach that would develop a mathematical model of protein balance and greatly improve treatments in a variety of clinical settings related to maintaining both muscle mass and optimal contractile function of respiratory muscles. PMID:23798306

2.0 Angstrom Structure of Prostaglandin H2 Synthase-1 Reconstituted with a Manganese Porphyrin Cofactor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta,K.; Selinsky, B.; Loll, P.

2006-01-01

Prostaglandin H{sub 2} synthase (EC 1.14.99.1) is a clinically important drug target that catalyzes two key steps in the biosynthesis of the eicosanoid hormones. The enzyme contains spatially distinct cyclooxygenase and peroxidase active sites, both of which require a heme cofactor. Substitution of ferric heme by Mn{sup III} protoporphyrin IX greatly diminishes the peroxidase activity, but has little effect on the cyclooxygenase activity. Here, the 2.0 Angstrom resolution crystal structure of the Mn{sup III} form of ovine prostaglandin H{sub 2} synthase-1 is described (R = 21.8%, R{sub free} = 23.7%). Substitution of Mn{sup III} for Fe{sup III} causes no structuralmore » perturbations in the protein. However, the out-of-plane displacement of the manganese ion with respect to the porphyrin is greater than that of the iron by approximately 0.2 Angstroms. This perturbation may help to explain the altered catalytic properties of the manganese enzyme.« less

Energetics and Structural Characterization of the large-scale Functional Motion of Adenylate Kinase

NASA Astrophysics Data System (ADS)

Formoso, Elena; Limongelli, Vittorio; Parrinello, Michele

2015-02-01

Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins.

Molecular structures guide the engineering of chromatin

PubMed Central

Tekel, Stefan J.

2017-01-01

Abstract Chromatin is a system of proteins, RNA, and DNA that interact with each other to organize and regulate genetic information within eukaryotic nuclei. Chromatin proteins carry out essential functions: packing DNA during cell division, partitioning DNA into sub-regions within the nucleus, and controlling levels of gene expression. There is a growing interest in manipulating chromatin dynamics for applications in medicine and agriculture. Progress in this area requires the identification of design rules for the chromatin system. Here, we focus on the relationship between the physical structure and function of chromatin proteins. We discuss key research that has elucidated the intrinsic properties of chromatin proteins and how this information informs design rules for synthetic systems. Recent work demonstrates that chromatin-derived peptide motifs are portable and in some cases can be customized to alter their function. Finally, we present a workflow for fusion protein design and discuss best practices for engineering chromatin to assist scientists in advancing the field of synthetic epigenetics. PMID:28609787

Engineered jadomycin analogues with altered sugar moieties revealing JadS as a substrate flexible O-glycosyltransferase.

PubMed

Li, Liyuan; Pan, Guohui; Zhu, Xifen; Fan, Keqiang; Gao, Wubin; Ai, Guomin; Ren, Jinwei; Shi, Mingxin; Olano, Carlos; Salas, José A; Yang, Keqian

2017-07-01

Glycosyltransferases (GTs)-mediated glycodiversification studies have drawn significant attention recently, with the goal of generating bioactive compounds with improved pharmacological properties by diversifying the appended sugars. The key to achieving glycodiversification is to identify natural and/or engineered flexible GTs capable of acting upon a broad range of substrates. Here, we report the use of a combinatorial biosynthetic approach to probe the substrate flexibility of JadS, the GT in jadomycin biosynthesis, towards different non-native NDP-sugar substrates, enabling us to identify six jadomycin B analogues with different sugar moieties. Further structural engineering by precursor-directed biosynthesis allowed us to obtain 11 new jadomycin analogues. Our results for the first time show that JadS is a flexible O-GT that can utilize both L- and D- sugars as donor substrates, and tolerate structural changes at the C2, C4 and C6 positions of the sugar moiety. JadS may be further exploited to generate novel glycosylated jadomycin molecules in future glycodiversification studies.

The impact of an anti-gravity treadmill (AlterG) training on walking capacity and corticospinal tract structure in children with cerebral palsy.

PubMed

Azizi, Sh; Marzbani, H; Raminfard, S; Birgani, P M; Rasooli, A H; Mirbagheri, M M

2017-07-01

We studied the effects of an anti-gravity treadmill (AlterG) training on walking capacity and corticospinal tract structure in children with Cerebral Palsy (CP). AlterG can help CP children walk on the treadmill by reducing their weights up to 80% and maintain their balance during locomotion. AlterG training thus has the potential to improve walking capacity permanently as it can provide systematic and intense locomotor training for sufficiently long period of time and produce brain neuroplasticity. AlterG training was given for 45 minutes, three times a week for two months. The neuroplasticity of corticospinal tract was evaluated using Diffusion Tensor Imaging (DTI). The fractional Anisotropy (FA) feature was extracted to quantify structural changes of the corticospinal tract. Walking capacity was evaluated using popular clinical measurements of gait; i.e., walking speed, mobility and balance. The evaluations were done before and after training. Our results revealed that AlterG training resulted in an increase in average FA value of the corticospinal tract following the training. The outcome measures of clinical assessments of gait presented enhanced walking capacity of the CP subjects. Our findings indicated that the improved walking capacity was concurrent with the enhancement of the corticospinal tract structure. The clinical implication is that AlterG training may be considered as a therapeutic tool for permanent gait improvement in CP children.

Microwave moisture sensing of seedcotton: Part 1: Seedcotton microwave material properties

USDA-ARS?s Scientific Manuscript database

Moisture content at harvest is a key parameter that impacts quality and how well the cotton crop can be stored without degrading before processing. It is also a key parameter of interest for harvest time field trials as it can directly influence the quality of the harvested crop as well as alter the...

Decorin expression is important for age-related changes in tendon structure and mechanical properties

PubMed Central

Dunkman, Andrew A.; Buckley, Mark R.; Mienaltowski, Michael J.; Adams, Sheila M.; Thomas, Stephen J.; Satchell, Lauren; Kumar, Akash; Pathmanathan, Lydia; Beason, David P.; Iozzo, Renato V.; Birk, David E.; Soslowsky, Louis J.

2013-01-01

The aging population is at an increased risk of tendon injury and tendinopathy. Elucidating the molecular basis of tendon aging is crucial to understanding the age-related changes in structure and function in this vulnerable tissue. In this study, the structural and functional features of tendon aging are investigated. In addition, the roles of decorin and biglycan in the aging process were analyzed using transgenic mice at both mature and aged time points. Our hypothesis is that the increase in tendon injuries in the aging population is the result of altered structural properties that reduce the biomechanical function of the tendon and consequently increase susceptibility to injury. Decorin and biglycan are important regulators of tendon structure and therefore, we further hypothesized that decreased function in aged tendons is partly the result of altered decorin and biglycan expression. Biomechanical analyses of mature (day 150) and aged (day 570) patellar tendons revealed deteriorating viscoelastic properties with age. Histology and polarized light microscopy demonstrated decreased cellularity, alterations in tenocyte shape, and reduced collagen fiber alignment in the aged tendons. Ultrastructural analysis of fibril diameter distributions indicated an altered distribution in aged tendons with an increase of large diameter fibrils. Aged wild type tendons maintained expression of decorin which was associated with the structural and functional changes seen in aged tendons. Aged patellar tendons exhibited altered and generally inferior properties across multiple assays. However, decorin-null tendons exhibited significantly decreased effects of aging compared to the other genotypes. The amelioration of the functional deficits seen in the absence of decorin in aged tendons was associated with altered tendon fibril structure. Fibril diameter distributions in the decorin-null aged tendons were comparable to those observed in the mature wild type tendon with the absence of the subpopulation containing large diameter fibrils. Collectively, our findings provide evidence for age-dependent alterations in tendon architecture and functional activity, and further show that lack of stromal decorin attenuates these changes. PMID:23178232

Molecular determinants of caste differentiation in the highly eusocial honeybee Apis mellifera.

PubMed

Barchuk, Angel R; Cristino, Alexandre S; Kucharski, Robert; Costa, Luciano F; Simões, Zilá L P; Maleszka, Ryszard

2007-06-18

In honeybees, differential feeding of female larvae promotes the occurrence of two different phenotypes, a queen and a worker, from identical genotypes, through incremental alterations, which affect general growth, and character state alterations that result in the presence or absence of specific structures. Although previous studies revealed a link between incremental alterations and differential expression of physiometabolic genes, the molecular changes accompanying character state alterations remain unknown. By using cDNA microarray analyses of >6,000 Apis mellifera ESTs, we found 240 differentially expressed genes (DEGs) between developing queens and workers. Many genes recorded as up-regulated in prospective workers appear to be unique to A. mellifera, suggesting that the workers' developmental pathway involves the participation of novel genes. Workers up-regulate more developmental genes than queens, whereas queens up-regulate a greater proportion of physiometabolic genes, including genes coding for metabolic enzymes and genes whose products are known to regulate the rate of mass-transforming processes and the general growth of the organism (e.g., tor). Many DEGs are likely to be involved in processes favoring the development of caste-biased structures, like brain, legs and ovaries, as well as genes that code for cytoskeleton constituents. Treatment of developing worker larvae with juvenile hormone (JH) revealed 52 JH responsive genes, specifically during the critical period of caste development. Using Gibbs sampling and Expectation Maximization algorithms, we discovered eight overrepresented cis-elements from four gene groups. Graph theory and complex networks concepts were adopted to attain powerful graphical representations of the interrelation between cis-elements and genes and objectively quantify the degree of relationship between these entities. We suggest that clusters of functionally related DEGs are co-regulated during caste development in honeybees. This network of interactions is activated by nutrition-driven stimuli in early larval stages. Our data are consistent with the hypothesis that JH is a key component of the developmental determination of queen-like characters. Finally, we propose a conceptual model of caste differentiation in A. mellifera based on gene-regulatory networks.

Molecular determinants of caste differentiation in the highly eusocial honeybee Apis mellifera

PubMed Central

Barchuk, Angel R; Cristino, Alexandre S; Kucharski, Robert; Costa, Luciano F; Simões, Zilá LP; Maleszka, Ryszard

2007-01-01

Background In honeybees, differential feeding of female larvae promotes the occurrence of two different phenotypes, a queen and a worker, from identical genotypes, through incremental alterations, which affect general growth, and character state alterations that result in the presence or absence of specific structures. Although previous studies revealed a link between incremental alterations and differential expression of physiometabolic genes, the molecular changes accompanying character state alterations remain unknown. Results By using cDNA microarray analyses of >6,000 Apis mellifera ESTs, we found 240 differentially expressed genes (DEGs) between developing queens and workers. Many genes recorded as up-regulated in prospective workers appear to be unique to A. mellifera, suggesting that the workers' developmental pathway involves the participation of novel genes. Workers up-regulate more developmental genes than queens, whereas queens up-regulate a greater proportion of physiometabolic genes, including genes coding for metabolic enzymes and genes whose products are known to regulate the rate of mass-transforming processes and the general growth of the organism (e.g., tor). Many DEGs are likely to be involved in processes favoring the development of caste-biased structures, like brain, legs and ovaries, as well as genes that code for cytoskeleton constituents. Treatment of developing worker larvae with juvenile hormone (JH) revealed 52 JH responsive genes, specifically during the critical period of caste development. Using Gibbs sampling and Expectation Maximization algorithms, we discovered eight overrepresented cis-elements from four gene groups. Graph theory and complex networks concepts were adopted to attain powerful graphical representations of the interrelation between cis-elements and genes and objectively quantify the degree of relationship between these entities. Conclusion We suggest that clusters of functionally related DEGs are co-regulated during caste development in honeybees. This network of interactions is activated by nutrition-driven stimuli in early larval stages. Our data are consistent with the hypothesis that JH is a key component of the developmental determination of queen-like characters. Finally, we propose a conceptual model of caste differentiation in A. mellifera based on gene-regulatory networks. PMID:17577409

Dam busy: beavers and their influence on the structure and function of river systems

NASA Astrophysics Data System (ADS)

Larsen, J.; Larsen, A.; Lane, S. N.

2017-12-01

Beavers (Castor fiber, Castor canadensis) are the most influential mammalian ecosystem engineer, heavily modifying rivers and floodplains and influencing the hydrology, geomorphology, carbon and nutrient cycling, and ecology. They do this by constructing dams, digging canals and burrows, felling trees and introducing wood into streams, which in turn impounds water, raises shallow water tables, and alters the partitioning of the water balance, sediment transport and channel patters, biogeochemical cycling, and aquatic and terrestrial habitats. However, largely in the absence of predators, beaver numbers have been rapidly increasing throughout Europe since the 1980s, but also in parts of the US and South America, prompting a need to comprehensively review the current state of knowledge on how beavers influence the structure and function of river systems. Here, we synthesize the overall impacts on hydrology, geomorphology, biogeochemistry, and aquatic and terrestrial ecosystems. We then examine the key feedbacks and overlaps between these changes induced by beavers, finding that modifications to the longitudinal connectivity drive many key process feedbacks. However, the magnitude of these feedbacks is also heavily dependent on the landscape and climatic context, with the ability to promote lateral connectivity determining the extent of beaver impacts as stream order increases. Crucially, beavers shape a river corridor, introducing distinct processes and feedbacks that would have existed prior to the historical collapse of beaver populations. There is thus a need to adapt current river management and restoration practices such that they can accommodate and enhance the ecosystem engineering services provided by beavers. We summarize key knowledge gaps that remain in our understanding of beaver impacts, which help map an interdisciplinary future research agenda.

The molecular bases of the suicidal brain

PubMed Central

Turecki, Gustavo

2017-01-01

Suicide ranks among the leading causes of death around the world, and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors — such as familial and genetic predisposition, as well as early-life adversity — increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors associate with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes associated with suicidality, and presents some promising avenues for future research. PMID:25354482

Epigenetics, obesity and early-life cadmium or lead exposure.

PubMed

Park, Sarah S; Skaar, David A; Jirtle, Randy L; Hoyo, Cathrine

2017-01-01

Obesity is a complex and multifactorial disease, which likely comprises multiple subtypes. Emerging data have linked chemical exposures to obesity. As organismal response to environmental exposures includes altered gene expression, identifying the regulatory epigenetic changes involved would be key to understanding the path from exposure to phenotype and provide new tools for exposure detection and risk assessment. In this report, we summarize published data linking early-life exposure to the heavy metals, cadmium and lead, to obesity. We also discuss potential mechanisms, as well as the need for complete coverage in epigenetic screening to fully identify alterations. The keys to understanding how metal exposure contributes to obesity are improved assessment of exposure and comprehensive establishment of epigenetic profiles that may serve as markers for exposures.

Alterations of resting state networks and structural connectivity in relation to the prefrontal and anterior cingulate cortices in late prematurity.

PubMed

Degnan, Andrew J; Wisnowski, Jessica L; Choi, SoYoung; Ceschin, Rafael; Bhushan, Chitresh; Leahy, Richard M; Corby, Patricia; Schmithorst, Vincent J; Panigrahy, Ashok

2015-01-07

Late preterm birth is increasingly recognized as a risk factor for cognitive and social deficits. The prefrontal cortex is particularly vulnerable to injury in late prematurity because of its protracted development and extensive cortical connections. Our study examined children born late preterm without access to advanced postnatal care to assess structural and functional connectivity related to the prefrontal cortex. Thirty-eight preadolescents [19 born late preterm (34-36 /7 weeks gestational age) and 19 at term] were recruited from a developing community in Brazil. Participants underwent neuropsychological testing. Individuals underwent three-dimensional T1-weighted, diffusion-weighted, and resting state functional MRI. Probabilistic tractography and functional connectivity analyses were carried out using unilateral seeds combining the medial prefrontal cortex and the anterior cingulate cortex. Late preterm children showed increased functional connectivity within regions of the default mode, salience, and central-executive networks from both right and left frontal cortex seeds. Decreased functional connectivity was observed within the right parahippocampal region from left frontal seeding. Probabilistic tractography showed a pattern of decreased streamlines in frontal white matter pathways and the corpus callosum, but also increased streamlines in the left orbitofrontal white matter and the right frontal white matter when seeded from the right. Late preterm children and term control children scored similarly on neuropsychological testing. Prefrontal cortical connectivity is altered in late prematurity, with hyperconnectivity observed in key resting state networks in the absence of neuropsychological deficits. Abnormal structural connectivity indicated by probabilistic tractography suggests subtle changes in white matter development, implying disruption of normal maturation during the late gestational period.

The relevance of time series in molecular ecology and conservation biology.

PubMed

Habel, Jan C; Husemann, Martin; Finger, Aline; Danley, Patrick D; Zachos, Frank E

2014-05-01

The genetic structure of a species is shaped by the interaction of contemporary and historical factors. Analyses of individuals from the same population sampled at different points in time can help to disentangle the effects of current and historical forces and facilitate the understanding of the forces driving the differentiation of populations. The use of such time series allows for the exploration of changes at the population and intraspecific levels over time. Material from museum collections plays a key role in understanding and evaluating observed population structures, especially if large numbers of individuals have been sampled from the same locations at multiple time points. In these cases, changes in population structure can be assessed empirically. The development of new molecular markers relying on short DNA fragments (such as microsatellites or single nucleotide polymorphisms) allows for the analysis of long-preserved and partially degraded samples. Recently developed techniques to construct genome libraries with a reduced complexity and next generation sequencing and their associated analysis pipelines have the potential to facilitate marker development and genotyping in non-model species. In this review, we discuss the problems with sampling and available marker systems for historical specimens and demonstrate that temporal comparative studies are crucial for the estimation of important population genetic parameters and to measure empirically the effects of recent habitat alteration. While many of these analyses can be performed with samples taken at a single point in time, the measurements are more robust if multiple points in time are studied. Furthermore, examining the effects of habitat alteration, population declines, and population bottlenecks is only possible if samples before and after the respective events are included. © 2013 The Authors. Biological Reviews © 2013 Cambridge Philosophical Society.

Age-related differences in the topological efficiency of the brain structural connectome in amnestic mild cognitive impairment.

PubMed

Zhao, Tengda; Sheng, Can; Bi, Qiuhui; Niu, Weili; Shu, Ni; Han, Ying

2017-11-01

Amnestic mild cognitive impairment (aMCI) is accompanied by the accelerated cognitive decline and rapid brain degeneration with aging. However, the age-related alterations of the topological organization of the brain connectome in aMCI patients remained largely unknown. In this study, we constructed the brain structural connectome in 51 aMCI patients and 51 healthy controls by diffusion magnetic resonance imaging and deterministic tractography. The different age-related alteration patterns of the global and regional network metrics between aMCI patients and healthy controls were assessed by a linear regression model. Compared with healthy controls, significantly decreased global and local network efficiency in aMCI patients were found. When correlating network efficiency with age, we observed a significant decline in network efficiency with aging in the aMCI patients, while not in the healthy controls. The age-related decreases of nodal efficiency in aMCI patients were mainly distributed in the key regions of the default-mode network, such as precuneus, anterior cingulate gyrus, and parahippocampal gyrus. In addition, age-related decreases in the connection strength of the edges between peripheral nodes were observed in aMCI patients. Moreover, the decreased regional efficiency of the parahippocampal gyrus was correlated with impaired memory performances in patients. The present study suggests an age-related disruption of the topological organization of the brain structural connectome in aMCI patients, which may provide evidence for different neural mechanisms underlying aging in aMCI and may serve as a potential imaging marker for the early diagnosis of Alzheimer's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Xylem Development and Cell Wall Changes of Soybean Seedlings Grown in Space

PubMed Central

de Micco, Veronica; Aronne, Giovanna; Joseleau, Jean-Paul; Ruel, Katia

2008-01-01

Background and Aims Plants growing in altered gravity conditions encounter changes in vascular development and cell wall deposition. The aim of this study was to investigate xylem anatomy and arrangement of cellulose microfibrils in vessel walls of different organs of soybean seedlings grown in Space. Methods Seeds germinated and seedlings grew for 5 d in Space during the Foton-M2 mission. The environmental conditions, other than gravity, of the ground control repeated those experienced in orbit. The seedlings developed in space were compared with those of the control test on the basis of numerous anatomical and ultrastructural parameters such as number of veins, size and shape of vessel lumens, thickness of cell walls and deposition of cellulose microfibrils. Key Results Observations made with light, fluorescence and transmission electron microscopy, together with the quantification of the structural features through digital image analysis, showed that the alterations due to microgravity do not occur at the same level in the various organs of soybean seedlings. The modifications induced by microgravity or by the indirect effect of space-flight conditions, became conspicuous only in developing vessels at the ultrastructural level. The results suggested that the orientation of microfibrils and their assembly in developing vessels are perturbed by microgravity at the beginning of wall deposition, while they are still able to orient and arrange in thicker and ordered structures at later stages of secondary wall deposition. Conclusions The process of proper cell-wall building, although not prevented, is perturbed in Space at the early stage of development. This would explain the almost unaltered anatomy of mature structures, accompanied by a slower growth observed in seedlings grown in Space than on Earth. PMID:18252765

Cardiovascular Adaptations to Long Duration Head-Down Tilt Bed Rest

NASA Technical Reports Server (NTRS)

Platts, Steven H.; Martin, David S.; Perez, Sondar A.; Ribeiro, Christine; Stenger, Michael B.; Summers, Richard; Meck, Janice V.

2008-01-01

INTRODUCTION: Orthostatic hypotension is a serious risk for crewmembers returning from spaceflight. Numerous cardiovascular mechanisms have been proposed to account for this problem, including vascular and cardiac dysfunction, which we studied during bed rest. METHODS: Thirteen subjects were studied before and during bed rest. Statistical analysis was limited to the first 49-60 days of bed rest, and compared to pre-bed rest data. Ultrasound data were collected on vascular and cardiac structure and function. Tilt testing was conducted for 30 minutes or until presyncopal symptoms intervened. RESULTS: Plasma volume was significantly reduced by day 7 of bed rest. Flow-mediated dilation in the leg was significantly increased at bed rest day 49. Arterial responses to nitroglycerin differed in the arm and leg, but did not change as a result of bed rest. Intimal-medial thickness markedly decreased at bed rest days 21, 35 and 49. Several cardiac functional parameters including isovolumic relaxation time, ejection time and myocardial performance index were significantly increased (indicating a decrease in cardiac function) during bed rest. There was a trend for decreased orthostatic tolerance following 60 days of bed rest. DISCUSSION: These data suggest that 6 head-down tilt bed rest alters cardiovascular structure and function in a pattern similar to short duration spaceflight. Additionally, the vascular alterations are primarily seen in the lower body, while vessels of the upper body are unaffected. KEY WORDS: spaceflight, orthostatic intolerance, hypotension, fluid-shift, plasma volume

Sensory, Cognitive, and Sensorimotor Learning Effects in Recognition Memory for Music.

PubMed

Mathias, Brian; Tillmann, Barbara; Palmer, Caroline

2016-08-01

Recent research suggests that perception and action are strongly interrelated and that motor experience may aid memory recognition. We investigated the role of motor experience in auditory memory recognition processes by musicians using behavioral, ERP, and neural source current density measures. Skilled pianists learned one set of novel melodies by producing them and another set by perception only. Pianists then completed an auditory memory recognition test during which the previously learned melodies were presented with or without an out-of-key pitch alteration while the EEG was recorded. Pianists indicated whether each melody was altered from or identical to one of the original melodies. Altered pitches elicited a larger N2 ERP component than original pitches, and pitches within previously produced melodies elicited a larger N2 than pitches in previously perceived melodies. Cortical motor planning regions were more strongly activated within the time frame of the N2 following altered pitches in previously produced melodies compared with previously perceived melodies, and larger N2 amplitudes were associated with greater detection accuracy following production learning than perception learning. Early sensory (N1) and later cognitive (P3a) components elicited by pitch alterations correlated with predictions of sensory echoic and schematic tonality models, respectively, but only for the perception learning condition, suggesting that production experience alters the extent to which performers rely on sensory and tonal recognition cues. These findings provide evidence for distinct time courses of sensory, schematic, and motoric influences within the same recognition task and suggest that learned auditory-motor associations influence responses to out-of-key pitches.

Circuits of cancer drivers revealed by convergent misregulation of transcription factor targets across tumor types.

PubMed

Gonzalez-Perez, Abel

2016-01-20

Large tumor genome sequencing projects have now uncovered a few hundred genes involved in the onset of tumorigenesis, or drivers, in some two dozen malignancies. One of the main challenges emerging from this catalog of drivers is how to make sense of their heterogeneity in most cancer types. This is key not only to understand how carcinogenesis appears and develops in these malignancies to be able to early diagnose them, but also to open up the possibility to employ therapeutic strategies targeting a driver protein to counteract the alteration of another connected driver. Here, I focus on driver transcription factors and their connection to tumorigensis in several tumor types through the alteration of the expression of their targets. First, I explore their involvement in tumorigenesis as mutational drivers in 28 different tumor types. Then, I collect a list of downstream targets of the all driver transcription factors (TFs), and identify which of them exhibit a differential expression upon alterations of driver transcription factors. I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap. Furthermore, I am able to identify other driver genes that cause tumorigenesis through the alteration of very similar sets of targets. I thus uncover these circuits of connected drivers which cause tumorigenesis through the perturbation of overlapping cellular pathways in a pan-cancer manner across 15 malignancies. The systematic detection of these circuits may be key to propose novel therapeutic strategies indirectly targeting driver alterations in tumors.

Polarization-Modulated Second Harmonic Generation Microscopy in Collagen

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stoller, P C

Collagen is a key structural protein in the body; several pathological conditions lead to changes in collagen. Among imaging modalities that can be used in vivo, second harmonic generation (SHG) microscopy has a key advantage: it provides {approx}1 {micro}m resolution information about collagen structure as a function of depth. A new technique--polarization-modulated SHG--is presented: it permits simultaneous measurement of collagen orientation, of a lower bound on the magnitude of the second order nonlinear susceptibility tensor, and of the ratio of the two independent elements in this tensor. It is applied to characterizing SHG in collagen and to determining effects ofmore » biologically relevant changes in collagen structure. The magnitude of the second harmonic signal in two dimensional images varies with position even in structurally homogeneous tissue; this phenomenon is due to interference between second harmonic light generated by neighboring fibrils, which are randomly oriented parallel or anti-parallel to each other. Studies in which focal spot size was varied indicated that regions where fibrils are co-oriented are less than {approx}1.5 {micro}m in diameter. A quartz reference was used to determine the spot size as well as a lower limit (d{sub xxx} > 0.3 pm/V) for the magnitude of the second order nonlinear susceptibility. The ratio of the two independent tensor elements ranged between d{sub XYY}/d{sub XXX} = 0.60 and 0.75. SHG magnitude alone was not useful for identifying structural anomalies in collagenous tissue. Instead, changes in the polarization dependence of SHG were used to analyze biologically relevant perturbations in collagen structure. Changes in polarization dependence were observed in dehydrated samples, but not in highly crosslinked samples, despite significant alterations in packing structure. Complete thermal denaturation and collagenase digestion produced samples with no detectable SHG signal. Collagen orientation was measured in thin samples of several different tissues in transmission mode as well as at different depths (up to 200 {micro}m) in thick samples in reflection mode; birefringence had no effect on the measurement. These studies showed that SHG microscopy was capable of detecting pathophysiological changes in collagen structure, suggesting that this technique has potential clinical applications.« less

Experimental constrain of hydrogen production during early serpentinization stages

NASA Astrophysics Data System (ADS)

Clément, M.; Munoz, M.; Vidal, O.; Parra, T.

2009-04-01

Hydrothermal alteration of mantellic peridotites and ultramafic rocks along axial valleys of low spread oceanic ridges plays a key role in different fundamental domains like, 1) energetic gaz production (H2 and hydrocarbons) representing a potential source of energy for future generations, 2) formation of organic pre-biotic molecules in potential relation with the origin of life. Moreover, such complex volcanic-related alteration processes play fundamental role in economic geology, being widely associated to important polymetallic sulphides ore deposits. Recent researches proposed an initial hydrogen production due to the integration of ferric iron in Fe,Mg-serpentine. To better understand the early stages of hydrogen production, a series of natural peridotite rocks have been experimentally exposed to hydrothermal conditions, up to 300°C, 300 bars during different time scales. Experiments have been performed in using autoclaves with a sampling gas system. A systematic mineralogical characterization of the new products was carried out using classical spectroscopic tools. In particular, we focused on the iron behaviour using a redox and structural micro-XANES investigation. Redox information has been accurately derived from the pre-peak features previously calibrated from model compounds, while structural information about short and medium range order around iron has been extracted from the XANES region of the spectra, based both on experimental standards and ab-initio theoretical calculations. Two processes of oxidation emerged. Before two month experiment duration, serpentine displays a not negligible oxidation of ferrous iron in his structure (up to 60%), while after two months, iron oxides and hydroxides appear in the system. These results seem to correspond to natural observations. The iron coordination decreases linearly with time. It means that iron also integrates the serpentine tetrahedral sites. Moreover, high resolution µ-XAS maps on experimental samples were collected on the iron K-edge (7712 eV). These maps give valuable information concerning both kinetic of mineral phases transformation and spatial speciation of iron through the altered part of the samples. Finally, these results allow us to define a non linear model of "Fe3+ in serpentine vs hydrogen production" as a function of time.

Dynamics of an Active-Site Flap Contributes to Catalysis in a JAMM Family Metallo Deubiquitinase.

PubMed

Bueno, Amy N; Shrestha, Rashmi K; Ronau, Judith A; Babar, Aditya; Sheedlo, Michael J; Fuchs, Julian E; Paul, Lake N; Das, Chittaranjan

2015-10-06

The endosome-associated deubiquitinase (DUB) AMSH is a member of the JAMM family of zinc-dependent metallo isopeptidases with high selectivity for Lys63-linked polyubiquitin chains, which play a key role in endosomal-lysosomal sorting of activated cell surface receptors. The catalytic domain of the enzyme features a flexible flap near the active site that opens and closes during its catalytic cycle. Structural analysis of its homologues, AMSH-LP (AMSH-like protein) and the fission yeast counterpart, Sst2, suggests that a conserved Phe residue in the flap may be critical for substrate binding and/or catalysis. To gain insight into the contribution of this flap in substrate recognition and catalysis, we generated mutants of Sst2 and characterized them using a combination of enzyme kinetics, X-ray crystallography, molecular dynamics simulations, and isothermal titration calorimetry (ITC). Our analysis shows that the Phe residue in the flap contributes key interactions during the rate-limiting step but not to substrate binding, since mutants of Phe403 exhibit a defect only in kcat but not in KM. Moreover, ITC studies show Phe403 mutants have similar KD for ubiquitin compared to the wild-type enzyme. The X-ray structures of both Phe403Ala and the Phe403Trp, in both the free and ubiquitin bound form, reveal no appreciable structural change that might impair substrate or alter product binding. We observed that the side chain of the Trp residue is oriented identically with respect to the isopeptide moiety of the substrate as the Phe residue in the wild-type enzyme, so the loss of activity seen in this mutant cannot be explained by the absence of a group with the ability to provide van der Waals interactions that facilitate the hyrdolysis of the Lys63-linked diubiquitin. Molecular dynamics simulations indicate that the flap in the Trp mutant is quite flexible, allowing almost free rotation of the indole side chain. Therefore, it is possible that these different dynamic properties of the flap in the Trp mutant, compared to the wild-type enzyme, manifest as a defect in interactions that facilitate the rate-limiting step. Consistent with this notion, the Trp mutant was able to cleave Lys48-linked and Lys11-linked diubiquitin better than the wild-type enzyme, indicating altered mobility and hence reduced selectivity.

Redox Regulation of Endothelial Cell Fate

PubMed Central

Song, Ping; Zou, Ming-Hui

2014-01-01

Endothelial cells (ECs) are present throughout blood vessels and have variable roles in both physiological and pathological settings. EC fate is altered and regulated by several key factors in physiological or pathological conditions. Reactive nitrogen species and reactive oxygen species derived from NAD(P)H oxidases, mitochondria, or nitric oxide-producing enzymes are not only cytotoxic but also compose a signaling network in the redox system. The formation, actions, key molecular interactions, and physiological and pathological relevance of redox signals in ECs remain unclear. We review the identities, sources, and biological actions of oxidants and reductants produced during EC function or dysfunction. Further, we discuss how ECs shape key redox sensors and examine the biological functions, transcriptional responses, and post-translational modifications evoked by the redox system in ECs. We summarize recent findings regarding the mechanisms by which redox signals regulate the fate of ECs and address the outcome of altered EC fate in health and disease. Future studies will examine if the redox biology of ECs can be targeted in pathophysiological conditions. PMID:24633153

Perinatal exposure to lead (Pb) induces ultrastructural and molecular alterations in synapses of rat offspring.

PubMed

Gąssowska, Magdalena; Baranowska-Bosiacka, Irena; Moczydłowska, Joanna; Frontczak-Baniewicz, Małgorzata; Gewartowska, Magdalena; Strużyńska, Lidia; Gutowska, Izabela; Chlubek, Dariusz; Adamczyk, Agata

2016-12-12

Lead (Pb), environmentally abundant heavy-metal pollutant, is a strong toxicant for the developing central nervous system. Pb intoxication in children, even at low doses, is found to affect learning and memorizing, with devastating effects on cognitive function and intellectual development. However, the precise mechanism by which Pb impairs synaptic plasticity is not fully elucidated. The purpose of this study was to investigate the effect of pre- and neonatal exposure to low dose of Pb (with Pb concentrations in whole blood below 10μg/dL) on the synaptic structure and the pre- and postsynaptic proteins expression in the developing rat brain. Furthermore, the level of brain-derived neurotrophic factor (BDNF) was analyzed. Pregnant female Wistar rats received 0.1% lead acetate (PbAc) in drinking water from the first day of gestation until weaning of the offspring, while the control animals received drinking water. During the feeding of pups, mothers from the Pb-group were continuously receiving PbAc. Pups of both groups were weaned at postnatal day 21 and then until postnatal day 28 received only drinking water. 28-day old pups were sacrificed and the ultrastructural changes as well as expression of presynaptic (VAMP1/2, synaptophysin, synaptotagmin-1, SNAP25, syntaxin-1) and postsynaptic (PSD-95) proteins were analyzed in: forebrain cortex, cerebellum and hippocampus. Our data revealed that pre- and neonatal exposure to low dose of Pb promotes pathological changes in synapses, including nerve endings swelling, blurred and thickened synaptic cleft structure as well as enhanced density of synaptic vesicles in the presynaptic area. Moreover, synaptic mitochondria were elongated, swollen or shrunken in Pb-treated animals. These structural abnormalities were accompanied by decrease in the level of key synaptic proteins: synaptotagmin-1 in cerebellum, SNAP25 in hippocampus and syntaxin-1 in cerebellum and hippocampus. In turn, increased level of synaptophysin was noticed in the cerebellum, while the expression of postsynaptic PSD-95 was significantly decreased in forebrain cortex and cerebellum, and raised in hippocampus. Additionally, we observed the lower level of BDNF in all brain structures in comparison to control animals. In conclusion, perinatal exposure to low doses of Pb caused pathological changes in nerve endings associated with the alterations in the level of key synaptic proteins. All these changes can lead to synaptic dysfunction, expressed by the impairment of the secretory mechanism and thereby to the abnormalities in neurotransmission as well as to the neuronal dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Conformational Toggling of Yeast Iso-1-Cytochrome c in the Oxidized and Reduced States

PubMed Central

Yang, Zhongzheng; Zhu, Jing; Ying, Tianlei; Jiang, Xianwang; Zhang, Xu; Wu, Houming; Liu, Maili; Tan, Xiangshi; Cao, Chunyang; Huang, Zhong-Xian

2011-01-01

To convert cyt c into a peroxidase-like metalloenzyme, the P71H mutant was designed to introduce a distal histidine. Unexpectedly, its peroxidase activity was found even lower than that of the native, and that the axial ligation of heme iron was changed to His71/His18 in the oxidized state, while to Met80/His18 in the reduced state, characterized by UV-visible, circular dichroism, and resonance Raman spectroscopy. To further probe the functional importance of Pro71 in oxidation state dependent conformational changes occurred in cyt c, the solution structures of P71H mutant in both oxidation states were determined. The structures indicate that the half molecule of cyt c (aa 50–102) presents a kind of “zigzag riveting ruler” structure, residues at certain positions of this region such as Pro71, Lys73 can move a big distance by altering the tertiary structure while maintaining the secondary structures. This finding provides a molecular insight into conformational toggling in different oxidation states of cyt c that is principle significance to its biological functions in electron transfer and apoptosis. Structural analysis also reveals that Pro71 functions as a key hydrophobic patch in the folding of the polypeptide of the region (aa 50–102), to prevent heme pocket from the solvent. PMID:22087268

Multiple conformations are a conserved and regulatory feature of the RB1 5′ UTR

PubMed Central

Kutchko, Katrina M.; Sanders, Wes; Ziehr, Ben; Phillips, Gabriela; Solem, Amanda; Halvorsen, Matthew; Weeks, Kevin M.; Moorman, Nathaniel

2015-01-01

Folding to a well-defined conformation is essential for the function of structured ribonucleic acids (RNAs) like the ribosome and tRNA. Structured elements in the untranslated regions (UTRs) of specific messenger RNAs (mRNAs) are known to control expression. The importance of unstructured regions adopting multiple conformations, however, is still poorly understood. High-resolution SHAPE-directed Boltzmann suboptimal sampling of the Homo sapiens Retinoblastoma 1 (RB1) 5′ UTR yields three distinct conformations compatible with the experimental data. Private single nucleotide variants (SNVs) identified in two patients with retinoblastoma each collapse the structural ensemble to a single but distinct well-defined conformation. The RB1 5′ UTRs from Bos taurus (cow) and Trichechus manatus latirostris (manatee) are divergent in sequence from H. sapiens (human) yet maintain structural compatibility with high-probability base pairs. SHAPE chemical probing of the cow and manatee RB1 5′ UTRs reveals that they also adopt multiple conformations. Luciferase reporter assays reveal that 5′ UTR mutations alter RB1 expression. In a traditional model of disease, causative SNVs disrupt a key structural element in the RNA. For the subset of patients with heritable retinoblastoma-associated SNVs in the RB1 5′ UTR, the absence of multiple structures is likely causative of the cancer. Our data therefore suggest that selective pressure will favor multiple conformations in eukaryotic UTRs to regulate expression. PMID:25999316

[Ambivalence--a key concept in gerontology? Elements of heuristics exemplified by identity formation in old age].

PubMed

Lüscher, Kurt; Haller, Miriam

2016-01-01

Ambivalence is a widely used concept in gerontology, mostly used in the common sense meaning. We propose that an elaborated notion based on the historical and systematic analysis, reveals important theoretical, methodological and practical potentials of the idea of ambivalence for the study of aging. We exemplify this view by proposing a heuristic perspective for the analysis of processes to constitute and reconstitute identities in old age using a model based on a multidimensional understanding of ambivalence. Ambivalence is defined as referring to the experiences of vacillating between polar contradictions of feeling, thinking, wanting and social structures in the search for the sense and meaning of social relationships, facts and texts, which are important for unfolding and altering facets of the self and agency.

Aging in the Brain: New Roles of Epigenetics in Cognitive Decline.

PubMed

Barter, Jolie D; Foster, Thomas C

2018-06-01

Gene expression in the aging brain depends on transcription signals generated by senescent physiology, interacting with genetic and epigenetic programs. In turn, environmental factors influence epigenetic mechanisms, such that an epigenetic-environmental link may contribute to the accumulation of cellular damage, susceptibility or resilience to stressors, and variability in the trajectory of age-related cognitive decline. Epigenetic mechanisms, DNA methylation and histone modifications, alter chromatin structure and the accessibility of DNA. Furthermore, small non-coding RNA, termed microRNA (miRNA) bind to messenger RNA (mRNA) to regulate translation. In this review, we examine key questions concerning epigenetic mechanisms in regulating the expression of genes associated with brain aging and age-related cognitive decline. In addition, we highlight the interaction of epigenetics with senescent physiology and environmental factors in regulating transcription.

Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL

PubMed Central

Scalvini, Laura; Vacondio, Federica; Bassi, Michele; Pala, Daniele; Lodola, Alessio; Rivara, Silvia; Jung, Kwang-Mook; Piomelli, Daniele; Mor, Marco

2016-01-01

The function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell’s redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favour closed conformations of the enzyme that do not permit the entry of substrate into the active site. PMID:27499063

Bacterial strategies of resistance to antimicrobial peptides.

PubMed

Joo, Hwang-Soo; Fu, Chih-Iung; Otto, Michael

2016-05-26

Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. © 2016 The Author(s).

Targetable genetic features of primary testicular and primary central nervous system lymphomas

PubMed Central

Chapuy, Bjoern; Roemer, Margaretha G. M.; Stewart, Chip; Tan, Yuxiang; Abo, Ryan P.; Zhang, Liye; Dunford, Andrew J.; Meredith, David M.; Thorner, Aaron R.; Jordanova, Ekaterina S.; Liu, Gang; Feuerhake, Friedrich; Ducar, Matthew D.; Illerhaus, Gerald; Gusenleitner, Daniel; Linden, Erica A.; Sun, Heather H.; Homer, Heather; Aono, Miyuki; Pinkus, Geraldine S.; Ligon, Azra H.; Ligon, Keith L.; Ferry, Judith A.; Freeman, Gordon J.; van Hummelen, Paul; Golub, Todd R.; Getz, Gad; Rodig, Scott J.; de Jong, Daphne; Monti, Stefano

2016-01-01

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL. PMID:26702065

Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease.

PubMed

Valles-Ortega, Jordi; Duran, Jordi; Garcia-Rocha, Mar; Bosch, Carles; Saez, Isabel; Pujadas, Lluís; Serafin, Anna; Cañas, Xavier; Soriano, Eduardo; Delgado-García, José M; Gruart, Agnès; Guinovart, Joan J

2011-11-01

Lafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin-positive (PV(+)) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some processes of PV(+) interneurons. This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function. Our results emphasize the relevance of the laforin-malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD. Copyright © 2011 EMBO Molecular Medicine.

Volcano electrical tomography unveils edifice collapse hazard linked to hydrothermal system structure and dynamics

NASA Astrophysics Data System (ADS)

Rosas-Carbajal, Marina; Komorowski, Jean-Christophe; Nicollin, Florence; Gibert, Dominique

2016-07-01

Catastrophic collapses of the flanks of stratovolcanoes constitute a major hazard threatening numerous lives in many countries. Although many such collapses occurred following the ascent of magma to the surface, many are not associated with magmatic reawakening but are triggered by a combination of forcing agents such as pore-fluid pressurization and/or mechanical weakening of the volcanic edifice often located above a low-strength detachment plane. The volume of altered rock available for collapse, the dynamics of the hydrothermal fluid reservoir and the geometry of incipient collapse failure planes are key parameters for edifice stability analysis and modelling that remain essentially hidden to current volcano monitoring techniques. Here we derive a high-resolution, three-dimensional electrical conductivity model of the La Soufrière de Guadeloupe volcano from extensive electrical tomography data. We identify several highly conductive regions in the lava dome that are associated to fluid saturated host-rock and preferential flow of highly acid hot fluids within the dome. We interpret this model together with the existing wealth of geological and geochemical data on the volcano to demonstrate the influence of the hydrothermal system dynamics on the hazards associated to collapse-prone altered volcanic edifices.

Volcano electrical tomography unveils edifice collapse hazard linked to hydrothermal system structure and dynamics

PubMed Central

Rosas-Carbajal, Marina; Komorowski, Jean-Christophe; Nicollin, Florence; Gibert, Dominique

2016-01-01

Catastrophic collapses of the flanks of stratovolcanoes constitute a major hazard threatening numerous lives in many countries. Although many such collapses occurred following the ascent of magma to the surface, many are not associated with magmatic reawakening but are triggered by a combination of forcing agents such as pore-fluid pressurization and/or mechanical weakening of the volcanic edifice often located above a low-strength detachment plane. The volume of altered rock available for collapse, the dynamics of the hydrothermal fluid reservoir and the geometry of incipient collapse failure planes are key parameters for edifice stability analysis and modelling that remain essentially hidden to current volcano monitoring techniques. Here we derive a high-resolution, three-dimensional electrical conductivity model of the La Soufrière de Guadeloupe volcano from extensive electrical tomography data. We identify several highly conductive regions in the lava dome that are associated to fluid saturated host-rock and preferential flow of highly acid hot fluids within the dome. We interpret this model together with the existing wealth of geological and geochemical data on the volcano to demonstrate the influence of the hydrothermal system dynamics on the hazards associated to collapse-prone altered volcanic edifices. PMID:27457494

The Role of Evolutionary Intermediates in the Host Adaptation of Canine Parvovirus

PubMed Central

Stucker, Karla M.; Pagan, Israel; Cifuente, Javier O.; Kaelber, Jason T.; Lillie, Tyler D.; Hafenstein, Susan; Holmes, Edward C.

2012-01-01

The adaptation of viruses to new hosts is a poorly understood process likely involving a variety of viral structures and functions that allow efficient replication and spread. Canine parvovirus (CPV) emerged in the late 1970s as a host-range variant of a virus related to feline panleukopenia virus (FPV). Within a few years of its emergence in dogs, there was a worldwide replacement of the initial virus strain (CPV type 2) by a variant (CPV type 2a) characterized by four amino acid differences in the capsid protein. However, the evolutionary processes that underlie the acquisition of these four mutations, as well as their effects on viral fitness, both singly and in combination, are still uncertain. Using a comprehensive experimental analysis of multiple intermediate mutational combinations, we show that these four capsid mutations act in concert to alter antigenicity, cell receptor binding, and relative in vitro growth in feline cells. Hence, host adaptation involved complex interactions among both surface-exposed and buried capsid mutations that together altered cell infection and immune escape properties of the viruses. Notably, most intermediate viral genotypes containing different combinations of the four key amino acids possessed markedly lower fitness than the wild-type viruses. PMID:22114336

Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics.

PubMed

ElRakaiby, Marwa; Dutilh, Bas E; Rizkallah, Mariam R; Boleij, Annemarie; Cole, Jason N; Aziz, Ramy K

2014-07-01

The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug-microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed.

Topological robustness analysis of protein interaction networks reveals key targets for overcoming chemotherapy resistance in glioma

NASA Astrophysics Data System (ADS)

Azevedo, Hátylas; Moreira-Filho, Carlos Alberto

2015-11-01

Biological networks display high robustness against random failures but are vulnerable to targeted attacks on central nodes. Thus, network topology analysis represents a powerful tool for investigating network susceptibility against targeted node removal. Here, we built protein interaction networks associated with chemoresistance to temozolomide, an alkylating agent used in glioma therapy, and analyzed their modular structure and robustness against intentional attack. These networks showed functional modules related to DNA repair, immunity, apoptosis, cell stress, proliferation and migration. Subsequently, network vulnerability was assessed by means of centrality-based attacks based on the removal of node fractions in descending orders of degree, betweenness, or the product of degree and betweenness. This analysis revealed that removing nodes with high degree and high betweenness was more effective in altering networks’ robustness parameters, suggesting that their corresponding proteins may be particularly relevant to target temozolomide resistance. In silico data was used for validation and confirmed that central nodes are more relevant for altering proliferation rates in temozolomide-resistant glioma cell lines and for predicting survival in glioma patients. Altogether, these results demonstrate how the analysis of network vulnerability to topological attack facilitates target prioritization for overcoming cancer chemoresistance.

Computerized image analysis for quantitative neuronal phenotyping in zebrafish.

PubMed

Liu, Tianming; Lu, Jianfeng; Wang, Ye; Campbell, William A; Huang, Ling; Zhu, Jinmin; Xia, Weiming; Wong, Stephen T C

2006-06-15

An integrated microscope image analysis pipeline is developed for automatic analysis and quantification of phenotypes in zebrafish with altered expression of Alzheimer's disease (AD)-linked genes. We hypothesize that a slight impairment of neuronal integrity in a large number of zebrafish carrying the mutant genotype can be detected through the computerized image analysis method. Key functionalities of our zebrafish image processing pipeline include quantification of neuron loss in zebrafish embryos due to knockdown of AD-linked genes, automatic detection of defective somites, and quantitative measurement of gene expression levels in zebrafish with altered expression of AD-linked genes or treatment with a chemical compound. These quantitative measurements enable the archival of analyzed results and relevant meta-data. The structured database is organized for statistical analysis and data modeling to better understand neuronal integrity and phenotypic changes of zebrafish under different perturbations. Our results show that the computerized analysis is comparable to manual counting with equivalent accuracy and improved efficacy and consistency. Development of such an automated data analysis pipeline represents a significant step forward to achieve accurate and reproducible quantification of neuronal phenotypes in large scale or high-throughput zebrafish imaging studies.

Cationic PAMAM dendrimers disrupt key platelet functions

PubMed Central

Jones, Clinton F.; Campbell, Robert A.; Franks, Zechariah; Gibson, Christopher C.; Thiagarajan, Giridhar; Vieira-de-Abreu, Adriana; Sukavaneshvar, Sivaprasad; Mohammad, S. Fazal; Li, Dean Y.; Ghandehari, Hamidreza; Weyrich, Andrew S.; Brooks, Benjamin D.; Grainger, David W.

2012-01-01

Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood. PMID:22497592

Volcano electrical tomography unveils edifice collapse hazard linked to hydrothermal system structure and dynamics.

PubMed

Rosas-Carbajal, Marina; Komorowski, Jean-Christophe; Nicollin, Florence; Gibert, Dominique

2016-07-26

Catastrophic collapses of the flanks of stratovolcanoes constitute a major hazard threatening numerous lives in many countries. Although many such collapses occurred following the ascent of magma to the surface, many are not associated with magmatic reawakening but are triggered by a combination of forcing agents such as pore-fluid pressurization and/or mechanical weakening of the volcanic edifice often located above a low-strength detachment plane. The volume of altered rock available for collapse, the dynamics of the hydrothermal fluid reservoir and the geometry of incipient collapse failure planes are key parameters for edifice stability analysis and modelling that remain essentially hidden to current volcano monitoring techniques. Here we derive a high-resolution, three-dimensional electrical conductivity model of the La Soufrière de Guadeloupe volcano from extensive electrical tomography data. We identify several highly conductive regions in the lava dome that are associated to fluid saturated host-rock and preferential flow of highly acid hot fluids within the dome. We interpret this model together with the existing wealth of geological and geochemical data on the volcano to demonstrate the influence of the hydrothermal system dynamics on the hazards associated to collapse-prone altered volcanic edifices.

Effect of smoking on gene expression profile - overall mechanism, impact on respiratory system function, and reference to electronic cigarettes.

PubMed

Kopa, Paulina Natalia; Pawliczak, Rafał

2018-07-01

Cigarette smoke has a crucial impact on transcriptome alteration by its effect on chromatin remodeling and DNA methylation status. The first mechanism is associated with the histone acetylation/deacetylation balance damage as a result of increased activity of NFĸB and lipid peroxidation products, which lead to an increased activity of HATs and DNMTs and reduced HDACs. The second mechanism is connected with direct damaging of DNA by smoke components, activation of downstream repair mechanism and recruitment of DNMTs into the breakage site, 'nicotine effect' and carbon monoxide (CO) activity on gene transcription and DNA methylation reduction. Cigarette smoking activates oxidative and inflammatory response and leads to uncontrolled structural changes in airways and alters gene expression. Such changes have a characteristic similar to that for COPD patients. Therefore, smoking is determined as a key risk factor for chronic respiratory disease development. Furthermore, electronic cigarettes, an alternative of tobacco cigarettes, also affect gene expression profile, which suggests some similarities in action mechanisms for both conventional and electronic cigarettes. However, there is only a limited number of trials discussing this issue and future investigations are needed.

Pharmacomicrobiomics: The Impact of Human Microbiome Variations on Systems Pharmacology and Personalized Therapeutics

PubMed Central

ElRakaiby, Marwa; Dutilh, Bas E.; Rizkallah, Mariam R.; Boleij, Annemarie; Cole, Jason N.

2014-01-01

Abstract The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra-individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug–microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed. PMID:24785449

Five Years of Experimental Warming Increases the Biodiversity and Productivity of Phytoplankton

PubMed Central

Yvon-Durocher, Gabriel; Allen, Andrew P.; Cellamare, Maria; Dossena, Matteo; Gaston, Kevin J.; Leitao, Maria; Montoya, José M.; Reuman, Daniel C.; Woodward, Guy; Trimmer, Mark

2015-01-01

Phytoplankton are key components of aquatic ecosystems, fixing CO2 from the atmosphere through photosynthesis and supporting secondary production, yet relatively little is known about how future global warming might alter their biodiversity and associated ecosystem functioning. Here, we explore how the structure, function, and biodiversity of a planktonic metacommunity was altered after five years of experimental warming. Our outdoor mesocosm experiment was open to natural dispersal from the regional species pool, allowing us to explore the effects of experimental warming in the context of metacommunity dynamics. Warming of 4°C led to a 67% increase in the species richness of the phytoplankton, more evenly-distributed abundance, and higher rates of gross primary productivity. Warming elevated productivity indirectly, by increasing the biodiversity and biomass of the local phytoplankton communities. Warming also systematically shifted the taxonomic and functional trait composition of the phytoplankton, favoring large, colonial, inedible phytoplankton taxa, suggesting stronger top-down control, mediated by zooplankton grazing played an important role. Overall, our findings suggest that temperature can modulate species coexistence, and through such mechanisms, global warming could, in some cases, increase the species richness and productivity of phytoplankton communities. PMID:26680314

Recognition of chromatin by the plant alkaloid, ellipticine as a dual binder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Banerjee, Amrita; Sanyal, Sulagna; Majumder, Parijat

Recognition of core histone components of chromatin along with chromosomal DNA by a class of small molecule modulators is worth examining to evaluate their intracellular mode of action. A plant alkaloid ellipticine (ELP) which is a putative anticancer agent has so far been reported to function via DNA intercalation, association with topoisomerase II and binding to telomere region. However, its effect upon the potential intracellular target, chromatin is hitherto unreported. Here we have characterized the biomolecular recognition between ELP and different hierarchical levels of chromatin. The significant result is that in addition to DNA, it binds to core histone(s) andmore » can be categorized as a ‘dual binder’. As a sequel to binding with histone(s) and core octamer, it alters post-translational histone acetylation marks. We have further demonstrated that it has the potential to modulate gene expression thereby regulating several key biological processes such as nuclear organization, transcription, translation and histone modifications. - Highlights: • Ellipticine acts a dual binder binding to both DNA and core histone(s). • It induces structural perturbations in chromatin, chromatosome and histone octamer. • It alters histones acetylation and affects global gene expression.« less

Phototropic growth in a reef flat acroporid branching coral species.

PubMed

Kaniewska, Paulina; Campbell, Paul R; Fine, Maoz; Hoegh-Guldberg, Ove

2009-03-01

Many terrestrial plants form complex morphological structures and will alter these growth patterns in response to light direction. Similarly reef building corals have high morphological variation across coral families, with many species also displaying phenotypic plasticity across environmental gradients. In particular, the colony geometry in branching corals is altered by the frequency, location and direction of branch initiation and growth. This study demonstrates that for the branching species Acropora pulchra, light plays a key role in axial polyp differentiation and therefore axial corallite development--the basis for new branch formation. A. pulchra branches exhibited a directional growth response, with axial corallites only developing when light was available, and towards the incident light. Field experimentation revealed that there was a light intensity threshold of 45 micromol m(-2) s(-1), below which axial corallites would not develop and this response was blue light (408-508 nm) dependent. There was a twofold increase in axial corallite growth above this light intensity threshold and a fourfold increase in axial corallite growth under the blue light treatment. These features of coral branch growth are highly reminiscent of the initiation of phototropic branch growth in terrestrial plants, which is directed by the blue light component of sunlight.

Focal expression of mutant huntingtin in the songbird basal ganglia disrupts cortico-basal ganglia networks and vocal sequences

PubMed Central

Tanaka, Masashi; Singh Alvarado, Jonnathan; Murugan, Malavika; Mooney, Richard

2016-01-01

The basal ganglia (BG) promote complex sequential movements by helping to select elementary motor gestures appropriate to a given behavioral context. Indeed, Huntington’s disease (HD), which causes striatal atrophy in the BG, is characterized by hyperkinesia and chorea. How striatal cell loss alters activity in the BG and downstream motor cortical regions to cause these disorganized movements remains unknown. Here, we show that expressing the genetic mutation that causes HD in a song-related region of the songbird BG destabilizes syllable sequences and increases overall vocal activity, but leave the structure of individual syllables intact. These behavioral changes are paralleled by the selective loss of striatal neurons and reduction of inhibitory synapses on pallidal neurons that serve as the BG output. Chronic recordings in singing birds revealed disrupted temporal patterns of activity in pallidal neurons and downstream cortical neurons. Moreover, reversible inactivation of the cortical neurons rescued the disorganized vocal sequences in transfected birds. These findings shed light on a key role of temporal patterns of cortico-BG activity in the regulation of complex motor sequences and show how a genetic mutation alters cortico-BG networks to cause disorganized movements. PMID:26951661

Glycation of human erythrocyte glutathione peroxidase: effect on the physical and kinetic properties.

PubMed

Suravajjala, Sreekanth; Cohenford, Menashi; Frost, Leslie R; Pampati, Praveen K; Dain, Joel A

2013-06-05

Glutathione peroxidase (GPx) is a significant antioxidant enzyme that plays a key role in protecting the body from reactive oxygen species (ROS) and their toxicity. As a biocatalyst, the enzyme has been shown to reduce hydrogen peroxide to water and lipid hydroperoxides to their respective alcohols. The increased levels of ROS in patients with diabetes have been speculated to arise, in part, from alterations in the activity of glutathione antioxidant enzymes, perhaps, by mechanisms such as the glycation of the protein, in vivo. Under physiological conditions of temperature and pH, we investigated the susceptibility of human glutathione peroxidase to glycation, determined the effects of glycation on the physical and kinetic properties of the enzyme, and identified the protein's vulnerable amino acid sites of glycation. Circular dichroism, UV and mass spectrometry studies revealed that methylglyoxal and DL-glyceraldehyde are potent glycators of glutathione peroxidase; destabilizing its structure, altering its pH activity and stability profiles and increasing its Km value. In comparison to DL-glyceraldehyde, methylglyxol was a more potent glycator of the enzyme and was found to nonenzymatically condense with Arg-177, located near the glutathione binding site of GPx. Copyright © 2013 Elsevier B.V. All rights reserved.

THYROID HORMONE DISRUPTION: FROM KINETICS TO DYNAMICS.

EPA Science Inventory

A wide range of chemicals with diverse structures act as thyroid disrupting chemicals (TDCs). Broadly defined, TDCs are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or t...

CREBBP mutations in relapsed acute lymphoblastic leukaemia

PubMed Central

Mullighan, Charles G.; Zhang, Jinghui; Kasper, Lawryn H.; Lerach, Stephanie; Payne-Turner, Debbie; Phillips, Letha A.; Heatley, Sue L.; Holmfeldt, Linda; Collins-Underwood, J. Racquel; Ma, Jing; Buetow, Kenneth H.; Pui, Ching-Hon; Baker, Sharyn D.; Brindle, Paul K.; Downing, James R.

2010-01-01

Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biologic determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways1,2, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse3. However, detailed analysis of sequence mutations in ALL has not been performed. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase (HAT) CREB-binding protein (CBP)4. The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the HAT domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL. PMID:21390130

Altered juvenile fish communities associated with invasive Halophila stipulacea seagrass habitats in the U.S. Virgin Islands.

PubMed

Olinger, Lauren K; Heidmann, Sarah L; Durdall, Allie N; Howe, Colin; Ramseyer, Tanya; Thomas, Sara G; Lasseigne, Danielle N; Brown, Elizabeth J; Cassell, John S; Donihe, Michele M; Duffing Romero, Mareike D; Duke, Mara A; Green, Damon; Hillbrand, Paul; Wilson Grimes, Kristin R; Nemeth, Richard S; Smith, Tyler B; Brandt, Marilyn

2017-01-01

Caribbean seagrass habitats provide food and protection for reef-associated juvenile fish. The invasive seagrass Halophila stipulacea is rapidly altering these seascapes. Since its arrival in the Caribbean in 2002, H. stipulacea has colonized and displaced native seagrasses, but the function of this invasive seagrass as a juvenile fish habitat remains unknown. To compare diversity, community structure, and abundance of juvenile fish between H. stipulacea and native seagrass beds, fish traps were deployed in four nearshore bays around St. Thomas, U.S. Virgin Islands. Traps were deployed in Frenchman, Lindbergh, and Sprat Bays for 24 h intervals in patches of bare sand, patches of H. stipulacea and patches of the native Caribbean seagrasses Thalassia testudinum and Syringodium filiforme. Traps were then deployed in Brewers Bay for 12 h intervals in stands of H. stipulacea and S. filiforme. Relative and total abundances of juvenile fish, identified at least to family, were compared across treatment habitats for each trap deployment period. The catch from H. stipulacea, compared to native seagrasses, comprised a greater abundance of nocturnal carnivores Lutjanus synagris (family Lutjanidae) and Haemulon flavolineatum (family Haemulidae). Additionally, the herbivore species Sparisoma aurofrenatum (family Labridae) and Acanthurus bahianus (family Acanthuridae) and the diurnal carnivore species Pseudopeneus maculatus (family Mullidae) were relatively scarce in H. stipulacea. The catch from sand was much smaller, compared to vegetated habitats, and comprised only L. synagris, H. flavolineatum, and H. aurolineatum. These results provide evidence of reduced family diversity and altered juvenile fish assemblages in H. stipulacea, driven by an abundance of some nocturnal carnivores and scarcity of herbivores and diurnal carnivores. The findings from the present work underpin the need for further investigation and mitigation of this invasion, particularly where H. stipulacea is driving seascape-alterations of key juvenile fish habitats.

Structural alterations in a component of cytochrome c oxidase and molecular evolution of pathogenic Neisseria in humans.

PubMed

Aspholm, Marina; Aas, Finn Erik; Harrison, Odile B; Quinn, Diana; Vik, Ashild; Viburiene, Raimonda; Tønjum, Tone; Moir, James; Maiden, Martin C J; Koomey, Michael

2010-08-19

Three closely related bacterial species within the genus Neisseria are of importance to human disease and health. Neisseria meningitidis is a major cause of meningitis, while Neisseria gonorrhoeae is the agent of the sexually transmitted disease gonorrhea and Neisseria lactamica is a common, harmless commensal of children. Comparative genomics have yet to yield clear insights into which factors dictate the unique host-parasite relationships exhibited by each since, as a group, they display remarkable conservation at the levels of nucleotide sequence, gene content and synteny. Here, we discovered two rare alterations in the gene encoding the CcoP protein component of cytochrome cbb(3) oxidase that are phylogenetically informative. One is a single nucleotide polymorphism resulting in CcoP truncation that acts as a molecular signature for the species N. meningitidis. We go on to show that the ancestral ccoP gene arose by a unique gene duplication and fusion event and is specifically and completely distributed within species of the genus Neisseria. Surprisingly, we found that strains engineered to express either of the two CcoP forms conditionally differed in their capacity to support nitrite-dependent, microaerobic growth mediated by NirK, a nitrite reductase. Thus, we propose that changes in CcoP domain architecture and ensuing alterations in function are key traits in successive, adaptive radiations within these metapopulations. These findings provide a dramatic example of how rare changes in core metabolic proteins can be connected to significant macroevolutionary shifts. They also show how evolutionary change at the molecular level can be linked to metabolic innovation and its reversal as well as demonstrating how genotype can be used to infer alterations of the fitness landscape within a single host.

Insights into Brain Glycogen Metabolism

PubMed Central

Mathieu, Cécile; de la Sierra-Gallay, Ines Li; Duval, Romain; Xu, Ximing; Cocaign, Angélique; Léger, Thibaut; Woffendin, Gary; Camadro, Jean-Michel; Etchebest, Catherine; Haouz, Ahmed; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2016-01-01

Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å) and in complex with its allosteric activator AMP (3.4 Å). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen. PMID:27402852

Structural Basis of the Heterodimer Formation between Cell Shape-Determining Proteins Csd1 and Csd2 from Helicobacter pylori.

PubMed

An, Doo Ri; Im, Ha Na; Jang, Jun Young; Kim, Hyoun Sook; Kim, Jieun; Yoon, Hye Jin; Hesek, Dusan; Lee, Mijoon; Mobashery, Shahriar; Kim, Soon-Jong; Suh, Se Won

2016-01-01

Colonization of the human gastric mucosa by Helicobacter pylori requires its high motility, which depends on the helical cell shape. In H. pylori, several genes (csd1, csd2, csd3/hdpA, ccmA, csd4, csd5, and csd6) play key roles in determining the cell shape by alteration of cross-linking or by trimming of peptidoglycan stem peptides. H. pylori Csd1, Csd2, and Csd3/HdpA are M23B metallopeptidase family members and may act as d,d-endopeptidases to cleave the d-Ala4-mDAP3 peptide bond of cross-linked dimer muropeptides. Csd3 functions also as the d,d-carboxypeptidase to cleave the d-Ala4-d-Ala5 bond of the muramyl pentapeptide. To provide a basis for understanding molecular functions of Csd1 and Csd2, we have carried out their structural characterizations. We have discovered that (i) Csd2 exists in monomer-dimer equilibrium and (ii) Csd1 and Csd2 form a heterodimer. We have determined crystal structures of the Csd2121-308 homodimer and the heterodimer between Csd1125-312 and Csd2121-308. Overall structures of Csd1125-312 and Csd2121-308 monomers are similar to each other, consisting of a helical domain and a LytM domain. The helical domains of both Csd1 and Csd2 play a key role in the formation of homodimers or heterodimers. The Csd1 LytM domain contains a catalytic site with a Zn2+ ion, which is coordinated by three conserved ligands and two water molecules, whereas the Csd2 LytM domain has incomplete metal ligands and no metal ion is bound. Structural knowledge of these proteins sheds light on the events that regulate the cell wall in H. pylori.

Structural Basis of the Heterodimer Formation between Cell Shape-Determining Proteins Csd1 and Csd2 from Helicobacter pylori

PubMed Central

An, Doo Ri; Im, Ha Na; Jang, Jun Young; Kim, Hyoun Sook; Kim, Jieun; Yoon, Hye Jin; Hesek, Dusan; Lee, Mijoon; Mobashery, Shahriar; Kim, Soon-Jong

2016-01-01

Colonization of the human gastric mucosa by Helicobacter pylori requires its high motility, which depends on the helical cell shape. In H. pylori, several genes (csd1, csd2, csd3/hdpA, ccmA, csd4, csd5, and csd6) play key roles in determining the cell shape by alteration of cross-linking or by trimming of peptidoglycan stem peptides. H. pylori Csd1, Csd2, and Csd3/HdpA are M23B metallopeptidase family members and may act as d,d-endopeptidases to cleave the d-Ala4-mDAP3 peptide bond of cross-linked dimer muropeptides. Csd3 functions also as the d,d-carboxypeptidase to cleave the d-Ala4-d-Ala5 bond of the muramyl pentapeptide. To provide a basis for understanding molecular functions of Csd1 and Csd2, we have carried out their structural characterizations. We have discovered that (i) Csd2 exists in monomer-dimer equilibrium and (ii) Csd1 and Csd2 form a heterodimer. We have determined crystal structures of the Csd2121–308 homodimer and the heterodimer between Csd1125–312 and Csd2121–308. Overall structures of Csd1125–312 and Csd2121–308 monomers are similar to each other, consisting of a helical domain and a LytM domain. The helical domains of both Csd1 and Csd2 play a key role in the formation of homodimers or heterodimers. The Csd1 LytM domain contains a catalytic site with a Zn2+ ion, which is coordinated by three conserved ligands and two water molecules, whereas the Csd2 LytM domain has incomplete metal ligands and no metal ion is bound. Structural knowledge of these proteins sheds light on the events that regulate the cell wall in H. pylori. PMID:27711177

Structural covariance of neostriatal and limbic regions in patients with obsessive-compulsive disorder.

PubMed

Subirà, Marta; Cano, Marta; de Wit, Stella J; Alonso, Pino; Cardoner, Narcís; Hoexter, Marcelo Q; Kwon, Jun Soo; Nakamae, Takashi; Lochner, Christine; Sato, João R; Jung, Wi Hoon; Narumoto, Jin; Stein, Dan J; Pujol, Jesus; Mataix-Cols, David; Veltman, Dick J; Menchón, José M; van den Heuvel, Odile A; Soriano-Mas, Carles

2016-03-01

Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive-compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored. We performed a mega-analysis pooling structural MRI scans from the Obsessive-compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software. Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex. This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres. Our results provide evidence for structural network-level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.

HUMAN LIVER FATTY ACID BINDING PROTEIN (L-FABP) T94A VARIANT ALTERS STRUCTURE, STABILITY, AND INTERACTION WITH FIBRATES

PubMed Central

Martin, Gregory G.; McIntosh, Avery L.; Huang, Huan; Gupta, Shipra; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

2014-01-01

Although the human L-FABP T94A variant arises from the most commonly occurring SNP in the entire FABP family, there is a complete lack of understanding regarding the role of this polymorphism in human disease. It has been hypothesized that the T94A substitution results in complete loss of ligand binding ability and function analogous to L-FABP gene ablation. This possibility was addressed using recombinant human WT T94T and T94A variant L-FABP and cultured primary human hepatocytes. Non-conservative replacement of the medium sized, polar, uncharged T residue by a smaller, nonpolar, aliphatic A residue at position 94 of human L-FABP significantly increased L-FABP protein α-helical structure at the expense of β-sheet and concomitantly decreased thermal stability. T94A did not alter binding affinities for PPARα agonist ligands (phytanic acid, fenofibrate, fenofibric acid). While T94A did not alter the impact of phytanic acid and only slightly altered that of fenofibrate on human L-FABP secondary structure, the active metabolite fenofibric acid altered T94A secondary structure much more than that of WT T94T L-FABP. Finally, in cultured primary human hepatocytes the T94A variant exhibited significantly reduced fibrate-mediated induction of PPARα-regulated proteins such as L-FABP, FATP5, and PPARα itself. Thus, while T94A substitution did not alter the affinity of human L-FABP for PPARα agonist ligands, it significantly altered human L-FABP structure, stability, as well as conformational and functional response to fibrate. PMID:24299557

[The value of double contrast arthrotomography combined with cinematography in the diagnosis of functional and structural TMJ alterations].

PubMed

Engelke, W; Grossniklaus, B; Sailer, H F

1991-01-01

Double contrast arthrotomography combined with cinematography as a diagnostic instrument establishing functional and structural TMJ alterations is evaluated for its diagnostic value and reliability within the chain of diagnostic measures applied. In 131 patients double-contrast arthrotomography was followed by a comprehensive history of joint problems, and verification of the clinical findings as well as the arthrographic diagnosis and the post-arthrographic TMJ alterations. Our interest was focussed, among others, on the question whether arthrography alone would have any therapeutic effect or produce an alteration in TMJ function.

Negotiating the new health system: purchasing publicly accountable managed care.

PubMed

Rosenbaum, S

1998-04-01

The transformation to managed care is one of the most important and complex changes ever to take place in the American health system. One key aspect of this transformation is its implications for public health policy and practice. Both public and private buyers purchase managed care; increasingly, public programs that used to act as their own insurers (i.e., Medicare, Medicaid and CHAMPUS) are purchasing large quantities of managed care insurance from private companies. The transformation to managed care is altering the manner in which public health policy makers conceive of and carry out public health activities (particularly activities that involve the provision of personal health services). The degree to which managed care changes public health and in turn is altered by public health will depend in great measure on the extent to which public and private policy makers understand the implications of their choices for various aspects of public health and take steps to address them. Because both publicly and privately managed care arrangements are relatively deregulated, much of the dialogue between public health and managed care purchasers can be expected to take place within the context of the large service agreements that are negotiated between buyers and sellers of managed care products. This is particularly true for Medicaid because of the importance of Medicaid coverage, payment and access policies to public health policy makers, and because of the public nature of the Medicaid contracting process. A nationwide study of Medicaid managed care contracts offers the first detailed analysis of the content and structure of managed care service agreements and the public health issues they raise. Four major findings emerge from a review of the contracts. First, most of the agreements fail to address key issues regarding which Medicaid-covered services and benefits are the contractor's responsibility and which remain the residual responsibility of the state agency. Second, most contracts fail to address the legal and structural issues arising from the relationship between the managed care service system and the public health system, including such key matters as access to care for communicable diseases and contractors' relationship to state public health laboratories. Third, many contracts are silent on health agencies' access to data for surveillance and community health measurement purposes. Finally, many contracts may be developed with only a limited understanding of the key public health-related issues facing the community from which the members will be drawn. The CDC and state and local public health agencies must expand their activities in the area of managed care contract specifications. For several years the CDC has been involved in an ongoing effort to develop quality of care measures to be collected from all companies through the HEDIS process. As important as this effort is, it represents only an attempt to measure what managed care does rather than an a priori effort to shape the underlying policy and organizational structure of managed care itself. Integrating managed care with public health policy will require this type of affirmative effort with both Medicaid agencies as well as other managed care purchasers.

A key role of the prefrontal cortex in the maintenance of chronic tinnitus: An fMRI study using a Stroop task.

PubMed

Araneda, Rodrigo; Renier, Laurent; Dricot, Laurence; Decat, Monique; Ebner-Karestinos, Daniela; Deggouj, Naïma; De Volder, Anne G

2018-01-01

Since we recently showed in behavioural tasks that the top-down cognitive control was specifically altered in tinnitus sufferers, here we wanted to establish the link between this impaired executive function and brain alterations in the frontal cortex in tinnitus patients. Using functional magnetic resonance imaging (fMRI), we monitored the brain activity changes in sixteen tinnitus patients (TP) and their control subjects (CS) while they were performing a spatial Stroop task, both in audition and vision. We observed that TP differed from CS in their functional recruitment of the dorsolateral prefrontal cortex (dlPFC, BA46), the cingulate gyrus and the ventromedial prefrontal cortex (vmPFC, BA10). This recruitment was higher during interference conditions in tinnitus participants than in controls, whatever the sensory modality. Furthermore, the brain activity level in the right dlPFC and vmPFC correlated with the performance in the Stroop task in TP. Due to the direct link between poor executive functions and prefrontal cortex alterations in TP, we postulate that a lack of inhibitory modulation following an impaired top-down cognitive control may maintain tinnitus by hampering habituation mechanisms. This deficit in executive functions caused by prefrontal cortex alterations would be a key-factor in the generation and persistence of tinnitus.

Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention.

PubMed

Rubio-Aliaga, Isabel; Roos, Baukje de; Sailer, Manuela; McLoughlin, Gerard A; Boekschoten, Mark V; van Erk, Marjan; Bachmair, Eva-Maria; van Schothorst, Evert M; Keijer, Jaap; Coort, Susan L; Evelo, Chris; Gibney, Michael J; Daniel, Hannelore; Muller, Michael; Kleemann, Robert; Brennan, Lorraine

2011-04-27

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

PubMed

Vanicek, Thomas; Kutzelnigg, Alexandra; Philippe, Cecile; Sigurdardottir, Helen L; James, Gregory M; Hahn, Andreas; Kranz, Georg S; Höflich, Anna; Kautzky, Alexander; Traub-Weidinger, Tatjana; Hacker, Marcus; Wadsak, Wolfgang; Mitterhauser, Markus; Kasper, Siegfried; Lanzenberger, Rupert

2017-02-01

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP ND ) in patients with ADHD and to assess associations of SERT BP ND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [ 11 C]DASB. SERT BP ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP ND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula (R 2  = 0.284, R 2  = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Astroglial role in the pathophysiology of status epilepticus: an overview

PubMed Central

Vargas-Sánchez, Karina; Mogilevskaya, Maria; Rodríguez-Pérez, John; Rubiano, María G.; Javela, José J.; González-Reyes, Rodrigo E.

2018-01-01

Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

Long-term alterations in neural and endocrine processes induced by motherhood in mammals.

PubMed

Bridges, Robert S

2016-01-01

This article is part of a Special Issue "Parental Care". The reproductive experience of pregnancy, lactation and motherhood can significantly remodel the female's biological state, affecting endocrine, neuroendocrine, neural, and immunological processes. The brain, pituitary gland, liver, thymus, and mammary tissue are among the structures that are modified by reproductive experience. The present review that focuses on rodent research, but also includes pertinent studies in sheep and other species, identifies specific changes in these processes brought about by the biological states of pregnancy, parturition, and lactation and how the components of reproductive experience contribute to the remodeling of the maternal brain and organ systems. Findings indicate that prior parity alters key circulating hormone levels and neural receptor gene expression. Moreover, reproductive experience results in modifications in neural processes and glial support. The possible role of pregnancy-induced neurogenesis is considered in the context of neuroplasticity and behavior, and the effects of reproductive experience on maternal memory, i.e. the retention of maternal behavior, together with anxiety and learning are presented. Together, these sets of findings support the concept that the neural and biological state of the adult female is significantly and dramatically altered on a long-term basis by the experiences of parity and motherhood. Remodeling of the maternal brain and other biological systems is posited to help facilitate adaptations to environmental/ecological challenges as the female raises young and ages. Copyright © 2015 Elsevier Inc. All rights reserved.

Astroglial role in the pathophysiology of status epilepticus: an overview.

PubMed

Vargas-Sánchez, Karina; Mogilevskaya, Maria; Rodríguez-Pérez, John; Rubiano, María G; Javela, José J; González-Reyes, Rodrigo E

2018-06-01

Status epilepticus is a medical emergency with elevated morbidity and mortality rates, and represents a leading cause of epilepsy-related deaths. Though status epilepticus can occur at any age, it manifests more likely in children and elderly people. Despite the common prevalence of epileptic disorders, a complete explanation for the mechanisms leading to development of self-limited or long lasting seizures (as in status epilepticus) are still lacking. Apart from neurons, research evidence suggests the involvement of immune and glial cells in epileptogenesis. Among glial cells, astrocytes represent an ideal target for the study of the pathophysiology of status epilepticus, due to their key role in homeostatic balance of the central nervous system. During status epilepticus, astroglial cells are activated by the presence of cytokines, damage associated molecular patterns and reactive oxygen species. The persistent activation of astrocytes leads to a decrease in glutamate clearance with a corresponding accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Moreover, major alterations in astrocytic gap junction coupling, inflammation and receptor expression, facilitate the generation of seizures. Astrocytes are also involved in dysregulation of inhibitory transmission in the central nervous system and directly participate in ionic homeostatic alterations during status epilepticus. In the present review, we focus on the functional and structural changes in astrocytic activity that participate in the development and maintenance of status epilepticus, with special attention on concurrent inflammatory alterations. We also include potential astrocytic treatment targets for status epilepticus.

Do fossil vertebrate biominerals hold the key to the Palaeozoic climate?

NASA Astrophysics Data System (ADS)

Žigaitė, Ž.

2012-04-01

Fossil vertebrate hard tissues - teeth and dermoskeleton - are considered among the most geochemically stable biominerals, and therefore are widely used for palaeoenvironmental and palaeoclimatic reconstructions. Elemental and isotopic compositions of fossil dental tissues may provide unique palaeoenvironmental information, ranging from the diet and trophic positions on a food chain, to the palaeosalinity and water temperatures of ancient seas. However, the post-mortem alteration and re-crystallisation of fossil hard tissues may hamper these interpretations. Chemical composition and isotopic equilibrium of the biomineral change readily at any time from the earliest diagenesis to the final laboratory acid treatment during the fossil preparation. This is why particular attention shall be given to the preservation of fossil tissues, evaluating carefully the level of possible alteration in the primary geochemical composition. Pre-evaluation of fossil preservation can be made by semi-quantitative spot geochemistry analyses on fine polished teeth and scale thin sections using Energy Dispersive X-ray Spectroscopy (EDS), and help to preview the chemical composition of biomineral. The Electron Backscatter Diffractometry (EBSD) is useful to examine the cristallinity and possible structural alterations. In addition, rare earth element (REE) abundances can be measured in situ within the fine fossil tissues (such as enamel) using Laser Ablation Inductively Coupled Plasma Mass-spectrometry (LA-ICP-MS), giving evidence on the selective geochemical resilience between separate vertebrate hard tissues. Therefore, in order to decipher the geochemical signal correctly, the evaluation of preservation is a necessary starting point to any further studies of fossil biomineral geochemistry.

Anterior Cortical Development During Adolescence in Bipolar Disorder

PubMed Central

Najt, Pablo; Wang, Fei; Spencer, Linda; Johnston, Jennifer A.Y.; Cox Lippard, Elizabeth T.; Pittman, Brian P.; Lacadie, Cheryl; Staib, Lawrence H.; Papademetris, Xenophon; Blumberg, Hilary P.

2015-01-01

Background Increasing evidence supports a neurodevelopmental model for bipolar disorder (BD), with adolescence as a critical period in its development. Developmental abnormalities of anterior paralimbic and heteromodal frontal cortices, key structures in emotional regulation processes and central in BD, are implicated. However, few longitudinal studies have been conducted, limiting understanding of trajectory alterations in BD. In this study, we performed longitudinal neuroimaging of adolescents with and without BD and assessed volume changes over time, including changes in tissue overall and within gray and white matter. Larger decreases over time in anterior cortical volumes in the adolescents with BD were hypothesized. Gray matter decreases and white matter increases are typically observed during adolescence in anterior cortices. It was hypothesized that volume decreases over time in BD would reflect alterations in those processes, showing larger gray matter contraction and decreased white matter expansion. Methods Two high-resolution magnetic resonance imaging scans were obtained approximately two-years apart for 35 adolescents with BDI and 37 healthy adolescents. Differences over time between groups were investigated for volume overall and specifically for gray and white matter. Results Relative to healthy adolescents, adolescents with BDI showed greater volume contraction over time in a region including insula, and orbitofrontal, rostral and dorsolateral prefrontal cortices (P<.05, corrected), including greater gray matter contraction and decreased white matter expansion over time, in the BD compared to the healthy group. Conclusions: The findings support neurodevelopmental abnormalities during adolescence in BDI in anterior cortices, include altered developmental trajectories of anterior gray and white matter. PMID:26033826

Is Traumatic and Non-Traumatic Neck Pain Associated with Brain Alterations? - A Systematic Review.

PubMed

DePauw, Robby; Coppieters, Iris; Meeus, Mira; Caeyenberghs, Karen; Danneels, Lieven; Cagnie, Barbara

2017-05-01

Chronic neck pain affects 50% - 85% of people who have experienced an acute episode. This transition and the persistence of chronic complaints are believed to be mediated by brain alterations among different central mechanisms. This study aimed to systematically review and critically appraise the current existing evidence regarding structural and functional brain alterations in patients with whiplash associated disorders (WAD) and idiopathic neck pain (INP). Additionally, associations between brain alterations and clinical symptoms reported in neck pain patients were evaluated. Systematic review. The present systematic review was performed according to the PRISMA guidelines. PubMed, Web of Science, and Cochrane databases were searched. First, the obtained articles were screened based on title and abstract. Secondly, the screening was based on the full text. Risk of bias in included studies was investigated. Twelve studies met the inclusion criteria. Alterations in brain morphology and function, including perfusion, neurotransmission, and blood oxygenation level dependent-signal, were demonstrated in chronic neck pain patients. There is some to moderate evidence for both structural and functional brain alterations in patients with chronic neck pain. In contrast, no evidence for structural brain alterations in acute neck pain patients was found. Only 12 articles were included, which allows only cautious conclusions to be drawn. Brain alterations were observed in both patients with chronic WAD and chronic INP. Furthermore, more evidence exists for brain alterations in chronic WAD, and different underlying mechanisms might be present in both pathologies. In addition, pain and disability were correlated with the observed brain alterations. Accordingly, morphological and functional brain alterations should be further investigated in patients with chronic WAD and chronic INP with newer and more sensitive techniques, and associative clinical measurements seem indispensable in future research.

Grazers structure the bacterial and algal diversity of aquatic metacommunities.

PubMed

Birtel, Julia; Matthews, Blake

2016-12-01

Consumers can have strong effects on the biotic and abiotic dynamics of spatially-structured ecosystems. In metacommunities, dispersing consumers can alter local assembly dynamics either directly through trophic interactions or indirectly by modifying local environmental conditions. In aquatic systems, very little is known about how key grazers, such as Daphnia, structure the microbial diversity of metacommunities and influence bacterial-mediated ecosystem functions. In an outdoor mesocosm experiment with replicate metacommunities (two 300 L mesocosms), we tested how the presence and absence of Daphnia and the initial density of the microbial community (manipulated via dilution) influenced the diversity and community structure of algae and bacteria, and several ecosystem properties (e.g., pH, dissolved substances) and functions (e.g., enzyme activity, respiration). We found that Daphnia strongly affected the local and regional diversity of both phytoplankton and bacteria, the taxonomic composition of bacterial communities, the biomass of algae, and ecosystem metabolism (i.e., respiration). Diluting the microbial inoculum (0.2-5 μm size fraction) to the metacommunities increased local phytoplankton diversity, decreased bacteria beta-diversity, and changed the relative abundance of bacterial classes. Changes in the rank abundance of different bacterial groups exhibited phylogenetic signal, implying that closely related bacteria species might share similar responses to the presence of Daphnia. © 2016 by the Ecological Society of America.

Regional Genetic Structure and Environmental Variables Influence our Conservation Approach for Feather Heads (Ptilotus macrocephalus)

PubMed Central

2016-01-01

Continued alterations to the Australian environment compromise the long-term viability of many plant species. We investigate the population genetics of Ptilotus macrocephalus, a perennial herb that occurs in 2 nationally endangered communities on the Victorian Volcanic Plain Bioregion (VVP), Australia, to answer key questions regarding regional differentiation and to guide conservation strategies. We evaluate genetic structure and diversity within and among 17 P. macrocephalus populations from 3 regions of southeastern Australia using 17 microsatellite markers developed de novo. Genetic structure was present in P. macrocephalus between the 3 regions but not at the population level. Environmental factors, namely temperature and precipitation, significantly explained differentiation between the North region and the other 2 regions indicating isolation by environment. Within regions, genetic structure currently shows a high level of gene flow and genetic variation. Our results suggest that within-region gene flow does not reflect current habitat fragmentation in southeastern Australia whereas temperature and precipitation are likely to be responsible for the differentiation detected among regions. Climate change may severely impact P. macrocephalus on the VVP and test its evolutionary resilience. We suggest taking a proactive conservation approach to improve long-term viability by sourcing material for restoration to assist gene flow to the VVP region to promote an increased adaptive capacity. PMID:26865733

Structural complexity and land-surface energy exchange along a gradient from arctic tundra to boreal forest

USGS Publications Warehouse

Thompson, C.; Beringer, J.; Chapin, F. S.; McGuire, A.D.

2004-01-01

Question: Current climate changes in the Alaskan Arctic, which are characterized by increases in temperature and length of growing season, could alter vegetation structure, especially through increases in shrub cover or the movement of treeline. These changes in vegetation structure have consequences for the climate system. What is the relationship between structural complexity and partitioning of surface energy along a gradient from tundra through shrub tundra to closed canopy forest? Location: Arctic tundra-boreal forest transition in the Alaskan Arctic. Methods: Along this gradient of increasing canopy complexity, we measured key vegetation characteristics, including community composition, biomass, cover, height, leaf area index and stem area index. We relate these vegetation characteristics to albedo and the partitioning of net radiation into ground, latent, and sensible heating fluxes. Results: Canopy complexity increased along the sequence from tundra to forest due to the addition of new plant functional types. This led to non-linear changes in biomass, cover, and height in the understory. The increased canopy complexity resulted in reduced ground heat fluxes, relatively conserved latent heat fluxes and increased sensible heat fluxes. The localized warming associated with increased sensible heating over more complex canopies may amplify regional warming, causing further vegetation change in the Alaskan Arctic.

Extracellular environment modulates the formation and propagation of particular amyloid structures

PubMed Central

Westergard, Laura; True, Heather L.

2016-01-01

Summary Amyloidogenic proteins, including prions, assemble into multiple forms of structurally distinct fibres. The [PSI+] prion, endogenous to the yeast Saccharomyces cerevisiae, is a dominantly inherited, epigenetic modifier of phenotypes. [PSI+] formation relies on the coexistence of another prion, [RNQ+]. Here, in order to better define the role of amyloid diversity on cellular phenotypes, we investigated how physiological and environmental changes impact the generation and propagation of diverse protein conformations from a single polypeptide. Utilizing the yeast model system, we defined extracellular factors that influence the formation of a spectrum of alternative self-propagating amyloid structures of the Sup35 protein, called [PSI+] variants. Strikingly, exposure to specific stressful environments dramatically altered the variants of [PSI+] that formed de novo. Additionally, we found that stress also influenced the association between the [PSI+] and [RNQ+] prions in a way that it superceded their typical relationship. Furthermore, changing the growth environment modified both the biochemical properties and [PSI+]-inducing capabilities of the [RNQ+] template. These data suggest that the cellular environment contributes to both the generation and the selective propagation of specific amyloid structures, providing insight into a key feature that impacts phenotypic diversity in yeast and the cross-species transmission barriers characteristic of prion diseases. PMID:24628771

Silencing of IFN-stimulated gene transcription is regulated by histone H1 and its chaperone TAF-I

PubMed Central

Kadota, Shinichi; Nagata, Kyosuke

2014-01-01

Chromatin structure and its alteration play critical roles in the regulation of transcription. However, the transcriptional silencing mechanism with regard to the chromatin structure at an unstimulated state of the interferon (IFN)-stimulated gene (ISG) remains unclear. Here we investigated the role of template activating factor-I (TAF-I, also known as SET) in ISG transcription. Knockdown (KD) of TAF-I increased ISG transcript and simultaneously reduced the histone H1 level on the ISG promoters during the early stages of transcription after IFN stimulation from the unstimulated state. The transcription factor levels on the ISG promoters were increased in TAF-I KD cells only during the early stages of transcription. Furthermore, histone H1 KD also increased ISG transcript. TAF-I and histone H1 double KD did not show the additive effect in ISG transcription, suggesting that TAF-I and histone H1 may act on the same regulatory pathway to control ISG transcription. In addition, TAF-I KD and histone H1 KD affected the chromatin structure near the ISG promoters. On the basis of these findings, we propose that TAF-I and its target histone H1 are key regulators of the chromatin structure at the ISG promoter to maintain the silent state of ISG transcription. PMID:24878923

Secure Multicast Tree Structure Generation Method for Directed Diffusion Using A* Algorithms

NASA Astrophysics Data System (ADS)

Kim, Jin Myoung; Lee, Hae Young; Cho, Tae Ho

The application of wireless sensor networks to areas such as combat field surveillance, terrorist tracking, and highway traffic monitoring requires secure communication among the sensor nodes within the networks. Logical key hierarchy (LKH) is a tree based key management model which provides secure group communication. When a sensor node is added or evicted from the communication group, LKH updates the group key in order to ensure the security of the communications. In order to efficiently update the group key in directed diffusion, we propose a method for secure multicast tree structure generation, an extension to LKH that reduces the number of re-keying messages by considering the addition and eviction ratios of the history data. For the generation of the proposed key tree structure the A* algorithm is applied, in which the branching factor at each level can take on different value. The experiment results demonstrate the efficiency of the proposed key tree structure against the existing key tree structures of fixed branching factors.

Brain Imaging and Human Nutrition: Which Measures to Use in Intervention Studies?12

PubMed Central

Sizonenko, Stéphane V.; Babiloni, Claudio; Sijben, John W.; Walhovd, Kristine B.

2013-01-01

Throughout the life span, the brain is a metabolically highly active organ that uses a large proportion of total nutrient and energy intake. Furthermore, the development and repair of neural tissue depend on the proper intake of essential structural nutrients, minerals, and vitamins. Therefore, what we eat, or refrain from eating, may have an important impact on our cognitive ability and mental performance. Two of the key areas in which diet is thought to play an important role are in optimizing neurodevelopment in children and in preventing neurodegeneration and cognitive decline during aging. From early development to aging, brain imaging can detect structural, functional, and metabolic changes in humans and modifications due to altered nutrition or to additional nutritional supplementation. Inclusion of imaging measures in clinical studies can increase understanding with regard to the modification of brain structure, metabolism, and functional endpoints and may provide early sensitive measures of long-term effects. In this symposium, the utility of existing brain imaging technologies to assess the effects of nutritional intervention in humans is described. Examples of current research showing the utility of these markers are reviewed. PMID:24038255

The role of the hippocampus in the pathophysiology of major depression

PubMed Central

Campbell, Stephanie; MacQueen, Glenda

2004-01-01

Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness. PMID:15644983

Defect reduction in MBE-grown AlN by multicycle rapid thermal annealing

NASA Astrophysics Data System (ADS)

Greenlee, Jordan D.; Gunning, Brendan; Feigelson, Boris N.; Anderson, Travis J.; Koehler, Andrew D.; Hobart, Karl D.; Kub, Francis J.; Doolittle, W. Alan

2016-01-01

Multicycle rapid thermal annealing (MRTA) is shown to reduce the defect density of molecular beam epitaxially grown AlN films. No damage to the AlN surface occurred after performing the MRTA process at 1520°C. However, the individual grain structure was altered, with the emergence of step edges. This change in grain structure and diffusion of AlN resulted in an improvement in the crystalline structure. The Raman E2 linewidth decreased, confirming an improvement in crystal quality. The optical band edge of the AlN maintained the expected value of 6.2 eV throughout MRTA annealing, and the band edge sharpened after MRTA annealing at increased temperatures, providing further evidence of crystalline improvement. X-ray diffraction shows a substantial improvement in the (002) and (102) rocking curve FWHM for both the 1400 and 1520°C MRTA annealing conditions compared to the as-grown films, indicating that the screw and edge type dislocation densities decreased. Overall, the MRTA post-growth annealing of AlN lowers defect density, and thus will be a key step to improving optoelectronic and power electronic devices. [Figure not available: see fulltext.

Impurity effects on ionic-liquid-based supercapacitors

NASA Astrophysics Data System (ADS)

Liu, Kun; Lian, Cheng; Henderson, Douglas; Wu, Jianzhong

2017-02-01

Small amounts of an impurity may affect the key properties of an ionic liquid and such effects can be dramatically amplified when the electrolyte is under confinement. Here the classical density functional theory is employed to investigate the impurity effects on the microscopic structure and the performance of ionic-liquid-based electrical double-layer capacitors, also known as supercapacitors. Using a primitive model for ionic species, we study the effects of an impurity on the double layer structure and the integral capacitance of a room temperature ionic liquid in model electrode pores and find that an impurity strongly binding to the surface of a porous electrode can significantly alter the electric double layer structure and dampen the oscillatory dependence of the capacitance with the pore size of the electrode. Meanwhile, a strong affinity of the impurity with the ionic species affects the dependence of the integral capacitance on the pore size. Up to 30% increase in the integral capacitance can be achieved even at a very low impurity bulk concentration. By comparing with an ionic liquid mixture containing modified ionic species, we find that the cooperative effect of the bounded impurities is mainly responsible for the significant enhancement of the supercapacitor performance.

Recent Advances in the Realm of Allosteric Modulators for Opioid Receptors for Future Therapeutics.

PubMed

Remesic, Michael; Hruby, Victor J; Porreca, Frank; Lee, Yeon Sun

2017-06-21

Opioids, and more specifically μ-opioid receptor (MOR) agonists such as morphine, have long been clinically used as therapeutics for severe pain states but often come with serious side effects such as addiction and tolerance. Many studies have focused on bringing about analgesia from the MOR with attenuated side effects, but its underlying mechanism is not fully understood. Recently, focus has been geared toward the design and elucidation of the orthosteric site with ligands of various biological profiles and mixed subtype opioid activities and selectivities, but targeting the allosteric site is an area of increasing interest. It has been shown that allosteric modulators play key roles in influencing receptor function such as its tolerance to a ligand and affect downstream pathways. There has been a high variance of chemical structures that provide allosteric modulation at a given receptor, but recent studies and reviews tend to focus on the altered cellular mechanisms instead of providing a more rigorous description of the allosteric ligand's structure-function relationship. In this review, we aim to explore recent developments in the structural motifs that potentiate orthosteric binding and their influences on cellular pathways in an effort to present novel approaches to opioid therapeutic design.

Structure-activity relationships of 3-O-β-chacotriosyl oleanane-type triterpenoids as potential H5N1 entry inhibitors.

PubMed

Song, Gaopeng; Shen, Xintian; Li, Sumei; Li, Yibin; Si, Hongzong; Fan, Jihong; Li, Junhua; Gao, Erqiang; Liu, Shuwen

2016-08-25

A series of 3-O-β-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on a small molecule inhibitor saponin 1 previously discovered by us. Detailed structure-activity relationships (SARs) studies on the aglycone of compound 1 indicated that the subtle modification of oleanolic acid as an aglycon has key influences on the antiviral activity. These results suggested that either the introduction of a disubstituted amide structure at the 17-COOH of OA or alteration of the C-3 configuration of OA from 3β-to 3α-forms can significantly improve the selective index while maintaining their antiviral activities in vitro. Compound 8 was selected for further mechanistic study because of its distinguished inhibition activity and good selective index. Molecular simulation study and surface plasmon resonance analysis confirmed that compound 8 stabilized HA2 subunit of hemagglutinin (HA) by binding with amino acid residues LYS-26, ASN-53, ASN-27 and ASN-50, therefore may prevent HA from conformational rearranging, which is a critical step for viral entry. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Epigenetics, obesity and early-life cadmium or lead exposure

PubMed Central

Park, Sarah S; Skaar, David A; Jirtle, Randy L; Hoyo, Cathrine

2017-01-01

Obesity is a complex and multifactorial disease, which likely comprises multiple subtypes. Emerging data have linked chemical exposures to obesity. As organismal response to environmental exposures includes altered gene expression, identifying the regulatory epigenetic changes involved would be key to understanding the path from exposure to phenotype and provide new tools for exposure detection and risk assessment. In this report, we summarize published data linking early-life exposure to the heavy metals, cadmium and lead, to obesity. We also discuss potential mechanisms, as well as the need for complete coverage in epigenetic screening to fully identify alterations. The keys to understanding how metal exposure contributes to obesity are improved assessment of exposure and comprehensive establishment of epigenetic profiles that may serve as markers for exposures. PMID:27981852

In utero and postnatal exposure to arsenic alters pulmonary structure and function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lantz, R. Clark; Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ 85721; BIO5 Institute, University of Arizona, Tucson, AZ 85721

2009-02-15

In addition to cancer endpoints, arsenic exposures can also lead to non-cancerous chronic lung disease. Exposures during sensitive developmental time points can contribute to the adult disease. Using a mouse model, in utero and early postnatal exposures to arsenic (100 ppb or less in drinking water) were found to alter airway reactivity to methacholine challenge in 28 day old pups. Removal of mice from arsenic exposure 28 days after birth did not reverse the alterations in sensitivity to methacholine. In addition, adult mice exposed to similar levels of arsenic in drinking water did not show alterations. Therefore, alterations in airwaymore » reactivity were irreversible and specific to exposures during lung development. These functional changes correlated with protein and gene expression changes as well as morphological structural changes around the airways. Arsenic increased the whole lung levels of smooth muscle actin in a dose dependent manner. The level of smooth muscle mass around airways was increased with arsenic exposure, especially around airways smaller than 100 {mu}m in diameter. This increase in smooth muscle was associated with alterations in extracellular matrix (collagen, elastin) expression. This model system demonstrates that in utero and postnatal exposure to environmentally relevant levels of arsenic can irreversibly alter pulmonary structure and function in the adults.« less

Phytoplasma infection of a tropical root crop triggers bottom-up cascades by favoring generalist over specialist herbivores

PubMed Central

Graziosi, Ignazio; Burra, Dharani Dhar; Walter, Abigail Jan

2017-01-01

Global interest on plant-microbe-insect interactions is rapidly growing, revealing the multiple ways in which microorganisms mediate plant-herbivore interactions. Phytopathogens regularly alter whole repertoires of plant phenotypic traits, and bring about shifts in key chemical or morphological characteristics of plant hosts. Pathogens can also cause cascading effects on higher trophic levels, and eventually shape entire plant-associated arthropod communities. We tested the hypothesis that a Candidatus Phytoplasma causing cassava witches’ broom (CWB) on cassava (Manihot esculenta Grantz) is altering species composition of invasive herbivores and their associated parasitic hymenopterans. We conducted observational studies in cassava fields in eastern Cambodia to assess the effect of CWB infection on abundance of specialist and generalist mealybugs (Homoptera: Pseudococcidae), and associated primary and hyper-parasitoid species. CWB infection positively affects overall mealybug abundance and species richness at a plant- and field-level, and disproportionately favors a generalist mealybug over a specialist feeder. CWB phytoplasma infection led to increased parasitoid richness and diversity, with richness of ‘comparative’ specialist taxa being the most significantly affected. Parasitism rate did not differ among infected and uninfected plants, and mealybug host suppression was not impacted. CWB phytoplasma modifies host plant quality for sap-feeding homopterans, differentially affects success rates of two invasive species, and generates niche opportunities for higher trophic orders. By doing so, a Candidatus phytoplasma affects broader food web structure and functioning, and assumes the role of an ecosystem engineer. Our work unveils key facets of phytoplasma ecology, and sheds light upon complex multi-trophic interactions mediated by an emerging phytopathogen. These findings have further implications for invasion ecology and management. PMID:28813469

Modeling sediment transport in Qatar: Application for coastal development planning.

PubMed

Yousif, Ruqaiya; Warren, Christopher; Ben-Hamadou, Radhouan; Husrevoglu, Sinan

2018-03-01

Hydrodynamics and sediment transport are key physical processes contributing to habitat structure within the marine environment. Coastal development that results in the alteration of these processes (e.g., changing water flushing and/or sedimentation rates) can have detrimental impacts on sensitive systems. This is a current, relevant issue in Qatar as its coastal regions continue to be developed, not only around the capital of Doha, but in many areas around this Arabian Gulf peninsula. The northeastern Qatari coast is comprised of diverse and sensitive flora and fauna such as seagrass and macroalgae meadows, coral reefs and patches, turtles, and dugongs that tolerate harsh environmental conditions. In the near future, this area may see a rise in anthropogenic activity in the form of coastal development projects. These projects will add to existing natural stresses, such as high temperature, high salinity, and low rates of precipitation. Consequently, there is a need to characterize this area and assess the potential impacts that these anthropogenic activities may have on the region. In the present study, a novel sediment transport model is described and used to demonstrate the potential impact of altering hydrodynamics and subsequent sediment transport along the northeastern Qatar nearshore marine environment. The developed models will be tested using potential scenarios of future anthropogenic activities forecasted to take place in the area. The results will show the effects on water and sediment behavior and provide a scientific approach for key stakeholders to make decisions with respect to the management of the considered coastal zone. Furthermore, it provides a tool and framework that can be utilized in environmental impact assessment and associated hydrodynamic studies along other areas of the Qatari coastal zone. Integr Environ Assess Manag 2018;14:240-251. © 2017 SETAC. © 2017 SETAC.

Space Plasma Ion Processing of Ilmenite in the Lunar Soil: Insights from In-Situ TEM Ion Irradiation Experiments

NASA Technical Reports Server (NTRS)

Christoffersen, R.; Keller, L. P.

2007-01-01

Space weathering on the moon and asteroids results largely from the alteration of the outer surfaces of regolith grains by the combined effects of solar ion irradiation and other processes that include deposition of impact or sputter-derived vapors. Although no longer considered the sole driver of space weathering, solar ion irradiation remains a key part of the space weathering puzzle, and quantitative data on its effects on regolith minerals are still in short supply. For the lunar regolith, previous transmission electron microscope (TEM) studies performed by ourselves and others have uncovered altered rims on ilmenite (FeTiO3) grains that point to this phase as a unique "witness plate" for unraveling nanoscale space weathering processes. Most notably, the radiation processed portions of these ilmenite rims consistently have a crystalline structure, in contrast to radiation damaged rims on regolith silicates that are characteristically amorphous. While this has tended to support informal designation of ilmenite as a "radiation resistant" regolith mineral, there are to date no experimental data that directly and quantitatively compare ilmenite s response to ion radiation relative to lunar silicates. Such data are needed because the radiation processed rims on ilmenite grains, although crystalline, are microstructurally and chemically complex, and exhibit changes linked to the formation of nanophase Fe metal, a key space weathering process. We report here the first ion radiation processing study of ilmenite performed by in-situ means using the Intermediate Voltage Electron Microscope- Tandem Irradiation facility (IVEM-Tandem) at Argonne National Laboratory. The capability of this facility for performing real time TEM observations of samples concurrent with ion irradiation makes it uniquely suited for studying the dose-dependence of amorphization and other changes in irradiated samples.

Binding of Amphipathic Cell Penetrating Peptide p28 to Wild Type and Mutated p53 as studied by Raman, Atomic Force and Surface Plasmon Resonance spectroscopies.

PubMed

Signorelli, Sara; Santini, Simona; Yamada, Tohru; Bizzarri, Anna Rita; Beattie, Craig W; Cannistraro, Salvatore

2017-04-01

Mutations within the DNA binding domain (DBD) of the tumor suppressor p53 are found in >50% of human cancers and may significantly modify p53 secondary structure impairing its function. p28, an amphipathic cell-penetrating peptide, binds to the DBD through hydrophobic interaction and induces a posttranslational increase in wildtype and mutant p53 restoring functionality. We use mutation analyses to explore which elements of secondary structure may be critical to p28 binding. Molecular modeling, Raman spectroscopy, Atomic Force Spectroscopy (AFS) and Surface Plasmon Resonance (SPR) were used to identify which secondary structure of site-directed and naturally occurring mutant DBDs are potentially altered by discrete changes in hydrophobicity and the molecular interaction with p28. We show that specific point mutations that alter hydrophobicity within non-mutable and mutable regions of the p53 DBD alter specific secondary structures. The affinity of p28 was positively correlated with the β-sheet content of a mutant DBD, and reduced by an increase in unstructured or random coil that resulted from a loss in hydrophobicity and redistribution of surface charge. These results help refine our knowledge of how mutations within p53-DBD alter secondary structure and provide insight on how potential structural alterations in p28 or similar molecules improve their ability to restore p53 function. Raman spectroscopy, AFS, SPR and computational modeling are useful approaches to characterize how mutations within the p53DBD potentially affect secondary structure and identify those structural elements prone to influence the binding affinity of agents designed to increase the functionality of p53. Copyright © 2017 Elsevier B.V. All rights reserved.

No Child Left Behind in Art Education Policy: A Review of Key Recommendations for Arts Language Revisions

ERIC Educational Resources Information Center

Grey, Anne C.

2010-01-01

From bipartisan origins and a laudable intent, the No Child Left Behind (Act) of 2001 has profoundly altered the condition of art education. A historical vantage point and review of literature reveals the current status of pending arts language revisions to the NCLB Act, as well as a pressing need to examine the key recommendations and to consider…

In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver.

PubMed

Drake, Amanda J; O'Shaughnessy, Peter J; Bhattacharya, Siladitya; Monteiro, Ana; Kerrigan, David; Goetz, Sven; Raab, Andrea; Rhind, Stewart M; Sinclair, Kevin D; Meharg, Andrew A; Feldmann, Jörg; Fowler, Paul A

2015-01-29

Maternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown. In this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses. In addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1). Our unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation.

PubMed

Turkmenoglu, F Pinar; Kasirga, U Baran; Celik, H Hamdi

2015-08-01

Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder involving progressive damage to the central and peripheral nervous systems and cardiomyopathy. FRDA is caused by the silencing of the FXN gene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. Skin disorders including hair abnormalities have previously been reported in patients with mitochondrial disorders. However, to our knowledge, ultra-structural hair alterations in FRDA were not demonstrated. The purpose of this study was to determine ultra-structural alterations in the hairs of FRDA patients as well as carriers. Hair specimen from four patients, who are in different stages of the disease, and two carriers were examined by scanning electron microscope. Thin and weak hair follicles with absence of homogeneities on the cuticular surface, local damages of the cuticular layer, cuticular fractures were detected in both carriers and patients, but these alterations were much more prominent in the hair follicles of patients. In addition, erosions on the surface of the cuticle and local deep cavities just under the cuticular level were observed only in patients. Indistinct cuticular pattern, pores on the cuticular surface, and presence of concavities on the hair follicle were also detected in patients in later stages of the disease. According to our results, progression of the disease increased the alterations on hair structure. We suggest that ultra-structural alterations observed in hair samples might be due to oxidative stress caused by deficient frataxin expression in mitochondria. © 2015 Wiley Periodicals, Inc.

Alteration and geochemical zoning in Bodie Bluff, Bodie mining district, eastern California

USGS Publications Warehouse

Herrera, P.A.; Closs, L.G.; Silberman, M.L.

1993-01-01

Banded, epithermal quartz-adularia veins have produced about 1.5 million ounces of gold and 7 million ounces of silver from the Bodie mining district, eastern California. The veins cut dacitic lava flows, pyroclastic rocks and intrusions. Sinter boulders occur in a graben structure at the top of Bodie Bluff and fragments of sinter and mineralized quartz veins occur in hydrothermal breccias nearby. Explosive venting evidently was part of the evolution of the ore-forming geothermal systems which, at one time, must had reached the paleosurface. Previous reconnaissance studies at Bodie Bluff suggested that the geometry of alteration mineral assemblages and distribution of some of the major and trace elements throughout the system correspond to those predicted by models of hot-spring, volcanic rock hosted precious metal deposits (Silberman, 1982; Silberman and Berger, 1985). The current study was undertaken to evaluate these sugestions further. About 500 samples of quartz veins and altered rocks, including sinter, collected over a vertical extent of 200 meters within Bodie Bluff were petrographically examined and chemically analyzed for trace elements by emission spectrographic and atomic absorption methods. Sixty-five samples were analyzed for major elements by X-ray fluorescence methods. The results of these analyses showed that, in general, alteration mineral assemblage and vertical geochemical zoning patterns follow those predicted for hot-spring deposits, but that geochemical zoning patterns for sinter and quartz veins (siliceous deposits), and altered wall rocks are not always similar. The predicted depth-concentration patterns for some elements, notably Au, Ag, Hg, and Tl in quartz veins, and Hg, As and Ag in wall rocks were not as expected, or were perturbed by the main ore producing zone. For both quartz veins and altered wall rocks, the main ore zone had elevated metal contents. Increased concentration of many of these elements could indicate proximity to this zone. However, irregularities in the distribution of some key elements, such as Au and Ag, relative to the predictive models suggest that a larger suite of elements be considered for exploration for ore zones within the district. ?? 1993.

An Old Story Retold: Loss of G1 Control Defines A Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma.

PubMed

Wang, Qiyan; Bai, Jian; Abliz, Amir; Liu, Ying; Gong, Kenan; Li, Jingjing; Shi, Wenjie; Pan, Yaqi; Liu, Fangfang; Lai, Shujuan; Yang, Haijun; Lu, Changdong; Zhang, Lixin; Chen, Wei; Xu, Ruiping; Cai, Hong; Ke, Yang; Zeng, Changqing

2015-08-01

Esophageal squamous cell carcinoma (ESCC) has a high mortality rate. To determine the molecular basis of ESCC development, this study sought to identify characteristic genome-wide alterations in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic alterations were also analyzed. Exome sequencing and verification were performed for nine pairs of ESCC and the matched blood samples, followed by validation with additional samples using Sanger sequencing. Whole-genome SNP arrays were employed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) in 55 cases, including the nine ESCC samples subjected to exome sequencing. A total of 108 non-synonymous somatic mutations (NSSMs) in 102 genes were verified in nine patients. The chromatin modification process was found to be enriched in our gene ontology (GO) analysis. Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations. In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases. These results suggest that the deregulation of the G1 phase during the cell cycle is a key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC samples and three of them, 9p21.3, 7p11.2, and 3p12.1, were associated with lymph node metastasis. With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes. These findings provide clinical significance that could be useful in future molecular diagnoses and therapeutic targeting. Copyright © 2015 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

Compositionally heterogeneous podiform chromitite in the Shetland Ophiolite Complex (Scotland): Implications for chromitite petrogenesis and late-stage alteration in the upper mantle portion of a supra-subduction zone ophiolite

NASA Astrophysics Data System (ADS)

Derbyshire, E. J.; O'Driscoll, B.; Lenaz, D.; Gertisser, R.; Kronz, A.

2013-03-01

The mantle sequence of the ~ 492 Ma Shetland Ophiolite Complex (SOC; Scotland) contains abundant compositionally heterogeneous podiform chromitite bodies enclosed in elongate dunite lenses in the vicinity of the petrological Moho. Chromitite petrogenesis and late-stage alteration events recorded in these seams are examined here using petrography, mineral chemistry and crystal structural data. The resistant nature of Cr-spinel to serpentinisation and other late-stage alteration means that primary igneous compositions are preserved in unaltered crystal cores. Chromitite mineralogy and texture from five sampled localities at The Viels, Hagdale, Harold's Grave, Nikka Vord and Cliff reveal significant inter-pod chemical heterogeneity. The Cr-spinel mineral chemistry is consistent with supra-subduction zone melt extraction from the SOC peridotites. The occurrence of chromitite seams in the centres of the dunite lenses combined with variable Cr-spinel compositions at different chromitite seam localities supports a model of chromitite formation from spatially (and temporally?) fluctuating amounts of melt-rock interaction through channelised and/or porous melt flow. Pervasive serpentinisation of the SOC has led to the almost complete replacement of the primary (mantle) silicate mineral assemblages with serpentine (lizardite with minor chrysotile and antigorite). Magmatic sulphide (e.g., pentlandite) in dunite and chromitite is locally converted to reduced Ni-sulphide varieties (e.g., heazlewoodite and millerite). A post-serpentinisation (prograde) oxidisation event is recorded in the extensively altered Cliff chromitite seams in the west of the studied area, where chromitite Cr-spinel is extensively altered to ferritchromit. The ferritchromit may comprise > 50% of the volume of the Cliff Cr-spinels and contain appreciable quantities of 1-2 μm inclusions of sperrylite (PtAs2) and Ni-arsenide, signifying the coeval formation of these minerals with ferritchromit at temperatures of up to ~ 500 °C. The SOC chromitite Cr-spinels thus not only preserve key insights into the complex melting processes occurring in the upper mantle wedge but can also be utilised to construct a comprehensive alteration history of the lower mantle portions of such supra-subduction zone ophiolites.

Correcting oral contraceptive pharmacokinetic alterations due to obesity. A randomized controlled trial

PubMed Central

Edelman, Alison B; Cherala, Ganesh; Munar, Myrna Y.; McInnis, Martha; Stanczyk, Frank Z.; Jensen, Jeffrey T

2014-01-01

Objective To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. Study design Obese (BMI ≥ 30 kg/m2), ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to: Continuous Cycling [CC, a dose neutral arm using the same OC with no hormone-free interval] or Increased Dose [ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically]. During Cycle 2, 3, and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞), and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. Results A total of 31 women enrolled and completed the study (CC group n = 16; ID group n = 15). Demographics were similar between groups [mean BMI: CC 38kg/m2 (SD 5.1), ID 41kg/m2 (SD 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady-state was 12 days in both groups; Cmax were CC: 3.82 ± 1.28 ng/mL and ID: 3.13 ± 0.87 ng/mL; and AUC0-∞ were CC: 267 ± 115 hr*ng/mL and ID: 199±75 hr*ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p< 0.001) but again required 12 days to achieve steady-state. However, AUC was not significantly different between CC (412 ± 255 hr*ng/mL) and ID (283 ± 130 hr*ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). Conclusion Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters. PMID:25070547

Learning and Memory Impairments in Patients with Minimal Hepatic Encephalopathy are Associated with Structural and Functional Connectivity Alterations in Hippocampus.

PubMed

García-García, Raquel; Cruz-Gómez, Álvaro Javier; Urios, Amparo; Mangas-Losada, Alba; Forn, Cristina; Escudero-García, Desamparados; Kosenko, Elena; Torregrosa, Isidro; Tosca, Joan; Giner-Durán, Remedios; Serra, Miguel Angel; Avila, César; Belloch, Vicente; Felipo, Vicente; Montoliu, Carmina

2018-06-25

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients.

Experimental alteration of artificial and natural impact melt rock from the Chesapeake Bay impact structure

USGS Publications Warehouse

Declercq, J.; Dypvik, H.; Aagaard, Per; Jahren, J.; Ferrell, R.E.; Horton, J. Wright

2009-01-01

The alteration or transformation of impact melt rock to clay minerals, particularly smectite, has been recognized in several impact structures (e.g., Ries, Chicxulub, Mj??lnir). We studied the experimental alteration of two natural impact melt rocks from suevite clasts that were recovered from drill cores into the Chesapeake Bay impact structure and two synthetic glasses. These experiments were conducted at hydrothermal temperature (265 ??C) in order to reproduce conditions found in meltbearing deposits in the first thousand years after deposition. The experimental results were compared to geochemical modeling (PHREEQC) of the same alteration and to original mineral assemblages in the natural melt rock samples. In the alteration experiments, clay minerals formed on the surfaces of the melt particles and as fine-grained suspended material. Authigenic expanding clay minerals (saponite and Ca-smectite) and vermiculite/chlorite (clinochlore) were identified in addition to analcime. Ferripyrophyllite was formed in three of four experiments. Comparable minerals were predicted in the PHREEQC modeling. A comparison between the phases formed in our experiments and those in the cores suggests that the natural alteration occurred under hydrothermal conditions similar to those reproduced in the experiment. ?? 2009 The Geological Society of America.

Functional and conformational transitions of mevalonate diphosphate decarboxylase from Bacopa monniera.

PubMed

Abbassi, Shakeel; Patel, Krunal; Khan, Bashir; Bhosale, Siddharth; Gaikwad, Sushama

2016-02-01

Functional and conformational transitions of mevalonate diphosphate decarboxylase (MDD), a key enzyme of mevalonate pathway in isoprenoid biosynthesis, from Bacopa monniera (BmMDD), cloned and overexpressed in Escherichia coli were studied under thermal, chemical and pH-mediated denaturation conditions using fluorescence and Circular dichroism spectroscopy. Native BmMDD is a helix dominant structure with 45% helix and 11% sheets and possesses seven tryptophan residues with two residues exposed on surface, three residues partially exposed and two situated in the interior of the protein. Thermal denaturation of BmMDD causes rapid structural transitions at and above 40°C and transient exposure of hydrophobic residues at 50°C, leading to aggregation of the protein. An acid induced molten globule like structure was observed at pH 4, exhibiting altered but compact secondary structure, distorted tertiary structure and exposed hydrophobic residues. The molten globule displayed different response at higher temperature and similar response to chemical denaturation as compared to the native protein. The surface tryptophans have predominantly positively charged amino acids around them, as indicated by higher KSV for KI as compared to that for CsCl. The native enzyme displayed two different lifetimes, τ1 (1.203±0.036 ns) and τ2 (3.473±0.12 ns) indicating two populations of tryptophan. Copyright © 2015 Elsevier B.V. All rights reserved.

Theory of mind and frontal lobe pathology in schizophrenia: a voxel-based morphometry study.

PubMed

Hirao, Kazuyuki; Miyata, Jun; Fujiwara, Hironobu; Yamada, Makiko; Namiki, Chihiro; Shimizu, Mitsuaki; Sawamoto, Nobukatsu; Fukuyama, Hidenao; Hayashi, Takuji; Murai, Toshiya

2008-10-01

Impaired ability to infer the mental states of others (theory of mind; ToM) is considered to be a key contributor to the poor social functioning of patients with schizophrenia. Although neuroimaging and lesion studies have provided empirical evidence for the neural basis of ToM ability, including the involvement of several prefrontal and temporal structures, the association between pathology of these structures and ToM impairment in schizophrenia patients is less well understood. To address this issue, we investigated structural brain abnormalities and ToM impairment in patients with schizophrenia, and examined the relationship between them. Twenty schizophrenia patients and 20 age-, sex- and education-matched healthy participants underwent magnetic resonance imaging (MRI) and were examined for ToM ability based on the revised version of the "Reading the Mind in the Eyes" (or Eyes) test [Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb, I., 2001. The 'Reading the Mind in the Eyes' test revised version: A study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child Psychol. Psychiatry 42, 241-251]. Voxel-based morphometry (VBM) was performed to investigate regional brain alterations. Relative to normal controls, schizophrenia patients exhibited gray matter reductions in the dorsomedial prefrontal cortex (DMPFC), left ventrolateral prefrontal cortex (VLPFC), ventromedial prefrontal cortex (VMPFC), anterior cingulate cortex (ACC), right superior temporal gyrus (STG) and right insula. The patients performed poorly on the Eyes test. Importantly, poor performance on the Eyes test was found to be associated with gray matter reduction in the left VLPFC in the patient group. These results suggest that prefrontal cortical reduction, especially in the left VLPFC, is a key pathology underlying the difficulties faced by schizophrenia patients in inferring the mental states of others.

Amorphous Phases on the Surface of Mars

NASA Technical Reports Server (NTRS)

Rampe, E. B.; Morris, R. V.; Ruff, S. W.; Horgan, B.; Dehouck, E.; Achilles, C. N.; Ming, D. W.; Bish, D. L.; Chipera, S. J.

2014-01-01

Both primary (volcanic/impact glasses) and secondary (opal/silica, allophane, hisingerite, npOx, S-bearing) amorphous phases appear to be major components of martian surface materials based on orbital and in-situ measurements. A key observation is that whereas regional/global scale amorphous components include altered glass and npOx, local scale amorphous phases include hydrated silica/opal. This suggests widespread alteration at low water-to-rock ratios, perhaps due to snow/ice melt with variable pH, and localized alteration at high water-to-rock ratios. Orbital and in-situ measurements of the regional/global amorphous component on Mars suggests that it is made up of at least three phases: npOx, amorphous silicate (likely altered glass), and an amorphous S-bearing phase. Fundamental questions regarding the composition and the formation of the regional/global amorphous component(s) still remain: Do the phases form locally or have they been homogenized through aeolian activity and derived from the global dust? Is the parent glass volcanic, impact, or both? Are the phases separate or intimately mixed (e.g., as in palagonite)? When did the amorphous phases form? To address the question of source (local and/or global), we need to look for variations in the different phases within the amorphous component through continued modeling of the chemical composition of the amorphous phases in samples from Gale using CheMin and APXS data. If we find variations (e.g., a lack of or enrichment in amorphous silicate in some samples), this may imply a local source for some phases. Furthermore, the chemical composition of the weathering products may give insight into the formation mechanisms of the parent glass (e.g., impact glasses contain higher Al and lower Si [30], so we might expect allophane as a weathering product of impact glass). To address the question of whether these phases are separate or intimately mixed, we need to do laboratory studies of naturally altered samples made up of mixed phases (e.g., palagonite) and synthetic single phases to determine their short-range order structures and calculate their XRD patterns to use in models of CheMin data. Finally, to address the timing of the alteration, we need to study rocks on the martian surface of different ages that may contain glass (volcanic or impact) with MSL and future rovers to better understand how glass alters on the martian surface, if that alteration mechanism is universal, and if alteration spans across long periods of time or if there is a time past which unaltered glass remains.

Quantitative impact of hydrothermal alteration on electrical resistivity in geothermal systems from a joint analysis of laboratory measurements and borehole data in Krafla area, N-E Iceland

NASA Astrophysics Data System (ADS)

Lévy, Léa; Páll Hersir, Gylfi; Flóvenz, Ólafur; Gibert, Benoit; Pézard, Philippe; Sigmundsson, Freysteinn; Briole, Pierre

2016-04-01

Rock permeability and fluid temperature are the two most decisive factors for a successful geothermal drilling. While those parameters are only measured from drilling, they might be estimated on the basis of their impact on electrical resistivity that might be imaged from surface soundings, for example through TEM (Transient Electro Magnetic) down to one km depth. The electrical conductivity of reservoir rocks is the sum of a volume term depending on fluid parameters and a surface term related to rock alteration. Understanding the link between electrical resistivity and geothermal key parameters requires the knowledge of hydrothermal alteration and its petrophysical signature with the Cation Exchange Capacity (CEC). Fluid-rock interactions related to hydrothermal circulation trigger the precipitation of alteration minerals, which are both witnesses of the temperature at the time of reaction and new paths for the electrical current. Alteration minerals include zeolites, smectites, chlorites, epidotes and amphiboles among which low temperatures parageneses are often the most conductive. The CEC of these mineral phases contributes to account for surface conductivity occuring at the water-rock interface. In cooling geothermal systems, these minerals constitute in petrophysical terms and from surface electrical conduction a memory of the equilibrium phase revealed from electrical probing at all scales. The qualitative impact of alteration minerals on resistivity structure has been studied over the years in the Icelandic geothermal context. In this work, the CEC impact on pore surfaces electrical conductivity is studied quantitatively at the borehole scale, where several types of volcanic rocks are mixed together, with various degrees of alteration and porosity. Five boreholes located within a few km at the Krafla volcano, Northeast Iceland, constitute the basis for this study. The deepest and reference hole, KJ-18, provides cuttings of rock and logging data down to 2215 m depth; CEC measurements performed on cuttings show. KH-1 and KH-3 have cores and logs in the top 200 m only. Boreholes KH-5 and KH-6 sample cores with higher temperature alteration minerals down to 600 m. Together, these 4 shallow holes cover the diversity of rock types and alterations facies found in KJ-18. The petrophysical calibration obtained from cores will then be upscaled to log data analysis in KJ-18: porosity, formation factor, permeability, acoustic velocity, electrical surface conduction at different temperatures and CEC. This research is supported by the IMAGE FP7 EC project (Integrated Methods for Advanced Geothermal Exploration, grant agreement No. 608553).

Biological functions of proline in morphogenesis and osmotolerance revealed in antisense transgenic Arabidopsis thaliana.

PubMed

Nanjo, T; Kobayashi, M; Yoshiba, Y; Sanada, Y; Wada, K; Tsukaya, H; Kakubari, Y; Yamaguchi-Shinozaki, K; Shinozaki, K

1999-04-01

Many organisms, including higher plants, accumulate free proline (Pro) in response to osmotic stress. Although various studies have focused on the ability of Pro as a compatible osmolyte involved in osmotolerance, its specific role throughout plant growth is still unclear. It has been reported that Pro is synthesized from Glu catalyzed by a key enzyme, delta 1-pyrroline-5-carboxylate synthetase (P5CS), in plants. To elucidate essential roles of Pro, we generated antisense transgenic Arabidopsis plants with a P5CS cDNA. Several transgenics accumulated Pro at a significantly lower level than wild-type plants, providing direct evidence for a key role of P5CS in Pro production in Arabidopsis. These antisense transgenics showed morphological alterations in leaves and a defect in elongation of inflorescences. Furthermore, transgenic leaves were hypersensitive to osmotic stress. Microscopic analysis of transgenic leaves, in which the mutated phenotype clearly occurred, showed morphological abnormalities of epidermal and parenchymatous cells and retardation of differentiation of vascular systems. These phenotypes were suppressed by exogenous L-Pro but not by D-Pro or other Pro analogues. In addition, Pro deficiency did not broadly affect all proteins but specifically affected structural proteins of cell walls in the antisense transgenic plants. These results indicate that Pro is not just an osmoregulator in stressed plants but has a unique function involved in osmotolerance as well as in morphogenesis as a major constituent of cell wall structural proteins in plants.

The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function

PubMed Central

Hoeijmakers, Lianne; Lucassen, Paul J.; Korosi, Aniko

2015-01-01

Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity. PMID:25620909

Landscape genetic structure of coastal tailed frogs (Ascaphus truei) in protected vs. managed forests.

PubMed

Spear, Stephen F; Storfer, Andrew

2008-11-01

Habitat loss and fragmentation are the leading causes of species' declines and extinctions. A key component of studying population response to habitat alteration is to understand how fragmentation affects population connectivity in disturbed landscapes. We used landscape genetic analyses to determine how habitat fragmentation due to timber harvest affects genetic population connectivity of the coastal tailed frog (Ascaphus truei), a forest-dwelling, stream-breeding amphibian. We compared rates of gene flow across old-growth (Olympic National Park) and logged landscapes (Olympic National Forest) and used spatial autoregression to estimate the effect of landscape variables on genetic structure. We detected higher overall genetic connectivity across the managed forest, although this was likely a historical signature of continuous forest before timber harvest began. Gene flow also occurred terrestrially, as connectivity was high across unconnected river basins. Autoregressive models demonstrated that closed forest and low solar radiation were correlated with increased gene flow. In addition, there was evidence for a temporal lag in the correlation of decreased gene flow with harvest, suggesting that the full genetic impact may not appear for several generations. Furthermore, we detected genetic evidence of population bottlenecks across the Olympic National Forest, including at sites that were within old-growth forest but surrounded by harvested patches. Collectively, this research suggests that absence of forest (whether due to natural or anthropogenic changes) is a key restrictor of genetic connectivity and that intact forested patches in the surrounding environment are necessary for continued gene flow and population connectivity.

Insights into Brain Glycogen Metabolism: THE STRUCTURE OF HUMAN BRAIN GLYCOGEN PHOSPHORYLASE.

PubMed

Mathieu, Cécile; Li de la Sierra-Gallay, Ines; Duval, Romain; Xu, Ximing; Cocaign, Angélique; Léger, Thibaut; Woffendin, Gary; Camadro, Jean-Michel; Etchebest, Catherine; Haouz, Ahmed; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2016-08-26

Brain glycogen metabolism plays a critical role in major brain functions such as learning or memory consolidation. However, alteration of glycogen metabolism and glycogen accumulation in the brain contributes to neurodegeneration as observed in Lafora disease. Glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, catalyzes the rate-limiting step of glycogen mobilization. Moreover, the allosteric regulation of the three GP isozymes (muscle, liver, and brain) by metabolites and phosphorylation, in response to hormonal signaling, fine-tunes glycogenolysis to fulfill energetic and metabolic requirements. Whereas the structures of muscle and liver GPs have been known for decades, the structure of brain GP (bGP) has remained elusive despite its critical role in brain glycogen metabolism. Here, we report the crystal structure of human bGP in complex with PEG 400 (2.5 Å) and in complex with its allosteric activator AMP (3.4 Å). These structures demonstrate that bGP has a closer structural relationship with muscle GP, which is also activated by AMP, contrary to liver GP, which is not. Importantly, despite the structural similarities between human bGP and the two other mammalian isozymes, the bGP structures reveal molecular features unique to the brain isozyme that provide a deeper understanding of the differences in the activation properties of these allosteric enzymes by the allosteric effector AMP. Overall, our study further supports that the distinct structural and regulatory properties of GP isozymes contribute to the different functions of muscle, liver, and brain glycogen. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Disintegration of cruciform and G-quadruplex structures during the course of helicase-dependent amplification (HDA).

PubMed

Li, Dawei; Lv, Bei; Zhang, Hao; Lee, Jasmine Yiqin; Li, Tianhu

2015-04-15

Unlike chemical damages on DNA, physical alterations of B-form of DNA occur commonly in organisms that serve as signals for specified cellular events. Although the modes of action for repairing of chemically damaged DNA have been well studied nowadays, the repairing mechanisms for physically altered DNA structures have not yet been understood. Our current in vitro studies show that both breakdown of stable non-B DNA structures and resumption of canonical B-conformation of DNA can take place during the courses of isothermal helicase-dependent amplification (HDA). The pathway that makes the non-B DNA structures repairable is presumably the relieving of the accumulated torsional stress that was caused by the positive supercoiling. Our new findings suggest that living organisms might have evolved this distinct and economical pathway for repairing their physically altered DNA structures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Attention-Deficit Hyperactivity Disorder.

ERIC Educational Resources Information Center

Barkley, Russell A.

1998-01-01

Attention deficit hyperactivity disorder (ADHD) may arise when key brain circuits do not develop properly, perhaps due to an altered gene or genes. Describes ADHD in detail and introduces a psychological model of ADHD. (ASK)

Evaluation of Structure, Chaperone-Like Activity and Allergenicity of Reduced Glycated Adduct of Bovine β-casein.

PubMed

Yousefi, Reza; Ferdowsi, Leila; Tavaf, Zohreh; Sadeghian, Tanaz; Tamaddon, Ali M; Moghtaderi, Mozhgan; Pourpak, Zahra

2017-01-01

Milk has a potent reducing environment with an important quantity of sugar levels. In the current study β-casein was glycated in the presence of D-glucose and sodium cyanoborohydride as a reducing agent. Then, the reduced glucitol adduct of β-casein was used for the structural and functional analyses using different spectroscopic techniques. The results of fluorescence and far ultraviolet circular dichroism assessments suggest important structural alteration upon non-enzymatic glycation of β-casein. In addition, the chaperone activity, micellization properties and antioxidant activity of this protein were altered upon glucose modification. Also, as a result of reduced glycation, the allergenicity profile of this protein remained largely unchanged. Additional to its energetic and nutritional values, β-casein has important functional properties. The native structure of this protein is important to perform accurately its biological functions. Non-enzymatic glycation under reducing state was capable to alter both structural and functional aspects of β-casein. Due to effective reducing environment and significant quantity of reducing sugar of human milk, similar structural and functional alterations are most likely to occur upon reducing glycation of β-casein in vivo. Also, these changes might be even intensified during chronic hyperglycemia in diabetic mothers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Long term prevention of disturbance induces the collapse of a dominant species without altering ecosystem function

PubMed Central

Yu, Qiang; Wu, Honghui; Wang, Zhengwen; Flynn, Dan F. B.; Yang, Hao; Lü, Fumei; Smith, Melinda; Han, Xingguo

2015-01-01

Limitation of disturbances, such as grazing and fire, is a key tool for nature reserve management and ecological restoration. While the role of these disturbances in shaping ecosystem structure and functioning has been intensively studied, less is known about the consequences of long-term prevention of grazing and fire. Based on a 31-year study, we show that relative biomass of the dominant grass, Leymus chinensis, of grasslands in northern China declined dramatically, but only after 21 years of exclusion of fire and grazing. However, aboveground net primary productivity (ANPP) did not decline accordingly due to compensatory responses of several subdominant grass species. The decline in dominance of L. chinensis was not related to gradually changing climate during the same period, whereas experimentally imposed litter removal (simulating fire), mowing (simulating grazing), fire and moderate grazing enhanced dominance of L. chinensis significantly. Thus, our findings show that disturbances can be critical to maintain the dominance of key grass species in semiarid grassland, but that the collapse of a dominant species does not necessarily result in significant change in ANPP if there are species in the community capable of compensating for loss of a dominant. PMID:26388168

Long term prevention of disturbance induces the collapse of a dominant species without altering ecosystem function.

PubMed

Yu, Qiang; Wu, Honghui; Wang, Zhengwen; Flynn, Dan F B; Yang, Hao; Lü, Fumei; Smith, Melinda; Han, Xingguo

2015-09-21

Limitation of disturbances, such as grazing and fire, is a key tool for nature reserve management and ecological restoration. While the role of these disturbances in shaping ecosystem structure and functioning has been intensively studied, less is known about the consequences of long-term prevention of grazing and fire. Based on a 31-year study, we show that relative biomass of the dominant grass, Leymus chinensis, of grasslands in northern China declined dramatically, but only after 21 years of exclusion of fire and grazing. However, aboveground net primary productivity (ANPP) did not decline accordingly due to compensatory responses of several subdominant grass species. The decline in dominance of L. chinensis was not related to gradually changing climate during the same period, whereas experimentally imposed litter removal (simulating fire), mowing (simulating grazing), fire and moderate grazing enhanced dominance of L. chinensis significantly. Thus, our findings show that disturbances can be critical to maintain the dominance of key grass species in semiarid grassland, but that the collapse of a dominant species does not necessarily result in significant change in ANPP if there are species in the community capable of compensating for loss of a dominant.

Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy.

PubMed

Bernstein, Hans-Gert; Steiner, Johann; Guest, Paul C; Dobrowolny, Henrik; Bogerts, Bernhard

2015-01-01

The past decade has witnessed an explosion of knowledge on the impact of glia for the neurobiological foundation of schizophrenia. A plethora of studies have shown structural and functional abnormalities in all three types of glial cells. There is convincing evidence of reduced numbers of oligodendrocytes, impaired cell maturation and altered gene expression of myelin/oligodendrocyte-related genes that may in part explain white matter abnormalities and disturbed inter- and intra-hemispheric connectivity, which are characteristic signs of schizophrenia. Earlier reports of astrogliosis could not be confirmed by later studies, although the expression of a variety of astrocyte-related genes is abnormal in psychosis. Since astrocytes play a key role in the synaptic metabolism of glutamate, GABA, monoamines and purines, astrocyte dysfunction may contribute to certain aspects of disturbed neurotransmission in schizophrenia. Finally, increased densities of microglial cells and aberrant expression of microglia-related surface markers in schizophrenia suggest that immunological/inflammatory factors are of considerable relevance for the pathophysiology of psychosis. This review describes current evidence for the multifaceted role of glial cells in schizophrenia and discusses efforts to develop glia-directed therapies for the treatment of the disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Helicity within the vortex filament model.

PubMed

Hänninen, R; Hietala, N; Salman, H

2016-11-24

Kinetic helicity is one of the invariants of the Euler equations that is associated with the topology of vortex lines within the fluid. In superfluids, the vorticity is concentrated along vortex filaments. In this setting, helicity would be expected to acquire its simplest form. However, the lack of a core structure for vortex filaments appears to result in a helicity that does not retain its key attribute as a quadratic invariant. By defining a spanwise vector to the vortex through the use of a Seifert framing, we are able to introduce twist and henceforth recover the key properties of helicity. We present several examples for calculating internal twist to illustrate why the centreline helicity alone will lead to ambiguous results if a twist contribution is not introduced. Our choice of the spanwise vector can be expressed in terms of the tangential component of velocity along the filament. Since the tangential velocity does not alter the configuration of the vortex at later times, we are able to recover a similar equation for the internal twist angle to that of classical vortex tubes. Our results allow us to explain how a quasi-classical limit of helicity emerges from helicity considerations for individual superfluid vortex filaments.

Helicity within the vortex filament model

PubMed Central

Hänninen, R.; Hietala, N.; Salman, H.

2016-01-01

Kinetic helicity is one of the invariants of the Euler equations that is associated with the topology of vortex lines within the fluid. In superfluids, the vorticity is concentrated along vortex filaments. In this setting, helicity would be expected to acquire its simplest form. However, the lack of a core structure for vortex filaments appears to result in a helicity that does not retain its key attribute as a quadratic invariant. By defining a spanwise vector to the vortex through the use of a Seifert framing, we are able to introduce twist and henceforth recover the key properties of helicity. We present several examples for calculating internal twist to illustrate why the centreline helicity alone will lead to ambiguous results if a twist contribution is not introduced. Our choice of the spanwise vector can be expressed in terms of the tangential component of velocity along the filament. Since the tangential velocity does not alter the configuration of the vortex at later times, we are able to recover a similar equation for the internal twist angle to that of classical vortex tubes. Our results allow us to explain how a quasi-classical limit of helicity emerges from helicity considerations for individual superfluid vortex filaments. PMID:27883029

Bioprinting and Organ-on-Chip Applications Towards Personalized Medicine for Bone Diseases.

PubMed

Arrigoni, Chiara; Gilardi, Mara; Bersini, Simone; Candrian, Christian; Moretti, Matteo

2017-06-01

The skeleton supports and confers structure to the whole body but several pathological and traumatic conditions affect the bone tissue. Most of those pathological conditions are specific and different among different patients, such as bone defects due to traumatic injuries or bone remodeling alterations due to congenital diseases. In this context, the development of personalized therapies would be highly desirable. In recent years the advent of innovative techniques like bioprinting and microfluidic organ-on-chip raised hopes of achieving key tools helping the application of personalized therapies for bone diseases. In this review we will illustrate the latest progresses in the bioprinting of personalized bone grafts and generation of patient-specific bone-on-chip devices, describing current approaches and limitations and possible future improvements for more effective personalized bone grafts and disease models.

Sensory aspects of movement disorders

PubMed Central

Patel, Neepa; Jankovic, Joseph; Hallett, Mark

2016-01-01

Movement disorders, which include disorders such as Parkinson’s disease, dystonia, Tourette’s syndrome, restless legs syndrome, and akathisia, have traditionally been considered to be disorders of impaired motor control resulting predominantly from dysfunction of the basal ganglia. This notion has been revised largely because of increasing recognition of associated behavioural, psychiatric, autonomic, and other non-motor symptoms. The sensory aspects of movement disorders include intrinsic sensory abnormalities and the effects of external sensory input on the underlying motor abnormality. The basal ganglia, cerebellum, thalamus, and their connections, coupled with altered sensory input, seem to play a key part in abnormal sensorimotor integration. However, more investigation into the phenomenology and physiological basis of sensory abnormalities, and about the role of the basal ganglia, cerebellum, and related structures in somatosensory processing, and its effect on motor control, is needed. PMID:24331796

A mechanistic model of tau amyloid aggregation based on direct observation of oligomers

NASA Astrophysics Data System (ADS)

Shammas, Sarah L.; Garcia, Gonzalo A.; Kumar, Satish; Kjaergaard, Magnus; Horrocks, Mathew H.; Shivji, Nadia; Mandelkow, Eva; Knowles, Tuomas P. J.; Mandelkow, Eckhard; Klenerman, David

2015-04-01

Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. The fundamental microscopic reactions taking place during aggregation, and their rate constants, have been difficult to determine due to lack of suitable methods to identify and follow the low concentration of oligomers over time. Here we use single-molecule fluorescence to study the aggregation of the repeat domain of tau (K18), and two mutant forms linked with familial frontotemporal dementia, the deletion mutant ΔK280 and the point mutant P301L. Our kinetic analysis reveals that aggregation proceeds via monomeric assembly into small oligomers, and a subsequent slow structural conversion step before fibril formation. Using this approach, we have been able to quantitatively determine how these mutations alter the aggregation energy landscape.

Updates on Modeling the Water Cycle with the NASA Ames Mars Global Climate Model

NASA Technical Reports Server (NTRS)

Kahre, M. A.; Haberle, R. M.; Hollingsworth, J. L.; Montmessin, F.; Brecht, A. S.; Urata, R.; Klassen, D. R.; Wolff, M. J.

2017-01-01

Global Circulation Models (GCMs) have made steady progress in simulating the current Mars water cycle. It is now widely recognized that clouds are a critical component that can significantly affect the nature of the simulated water cycle. Two processes in particular are key to implementing clouds in a GCM: the microphysical processes of formation and dissipation, and their radiative effects on heating/ cooling rates. Together, these processes alter the thermal structure, change the dynamics, and regulate inter-hemispheric transport. We have made considerable progress representing these processes in the NASA Ames GCM, particularly in the presence of radiatively active water ice clouds. We present the current state of our group's water cycle modeling efforts, show results from selected simulations, highlight some of the issues, and discuss avenues for further investigation.­

Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle

PubMed Central

Kim, Yuho; Triolo, Matthew

2017-01-01

Mitochondria are characterized by its pivotal roles in managing energy production, reactive oxygen species, and calcium, whose aging-related structural and functional deteriorations are observed in aging muscle. Although it is still unclear how aging alters mitochondrial quality and quantity in skeletal muscle, dysregulation of mitochondrial biogenesis and dynamic controls has been suggested as key players for that. In this paper, we summarize current understandings on how aging regulates muscle mitochondrial biogenesis, while focusing on transcriptional regulations including PGC-1α, AMPK, p53, mtDNA, and Tfam. Further, we review current findings on the muscle mitochondrial dynamic systems in aging muscle: fusion/fission, autophagy/mitophagy, and protein import. Next, we also discuss how endurance and resistance exercises impact on the mitochondrial quality controls in aging muscle, suggesting possible effective exercise strategies to improve/maintain mitochondrial health. PMID:28656072

Brain Structural and Vascular Anatomy Is Altered in Offspring of Pre-Eclamptic Pregnancies: A Pilot Study.

PubMed

Rätsep, M T; Paolozza, A; Hickman, A F; Maser, B; Kay, V R; Mohammad, S; Pudwell, J; Smith, G N; Brien, D; Stroman, P W; Adams, M A; Reynolds, J N; Croy, B A; Forkert, N D

2016-05-01

Pre-eclampsia is a serious clinical gestational disorder occurring in 3%-5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls. Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay. Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia. This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies. © 2016 by American Journal of Neuroradiology.

Magnetic resonance imaging relaxation time in Alzheimer's disease.

PubMed

Tang, Xiang; Cai, Feng; Ding, Dong-Xue; Zhang, Lu-Lu; Cai, Xiu-Ying; Fang, Qi

2018-05-05

The magnetic resonance imaging (MRI) relaxation time constants, T1 and T2, are sensitive to changes in brain tissue microstructure integrity. Quantitative T1 and T2 relaxation times have been proposed to serve as non-invasive biomarkers of Alzheimer's disease (AD), in which alterations are believed to not only reflect AD-related neuropathology but also cognitive impairment. In this review, we summarize the applications and key findings of MRI techniques in the context of both AD subjects and AD transgenic mouse models. Furthermore, the possible mechanisms of relaxation time alterations in AD will be discussed. Future studies could focus on relaxation time alterations in the early stage of AD, and longitudinal studies are needed to further explore relaxation time alterations during disease progression. Copyright © 2018 Elsevier Inc. All rights reserved.

The Geonames Processing System Synopsis.

DTIC Science & Technology

1985-09-01

although it adds to costs), the majority of this discussion focuses on technical alter- natives for ideograph processing. Chinese hanzi and Japanese ...grammatical inflections. * ’ Hiragana ," used for exclamations, and "katakana," used for foreign words, each have 48 characters. Some characters may be...entry systems use varied strategies. "Hunt and peck" drives the Japanese typewriter, a two-dimensional array of 2000-plus keys (one character/key

Who owns Australia's water--elements of an effective regulatory model.

PubMed

McKay, J

2003-01-01

This paper identifies and describes a number of global trends in regulatory theory and legal scholarship. It points out the huge level of complexity demanded by globalisation and the unfortunate complication of this is that there is legal indeterminacy. The legal indeterminacy springs from the desire to amend and alter existing models. That has been the thrust of the Council of Australian Governments changes to adapt and add huge amounts of complexity to a flawed system. This paper argues that an effective water regulatory model requires a fundamental re-examination of the concept of water ownership and a capturing by the State of the right to allocate rainfall. This foundation is effective and the way forward to deal with the key issues in this transition phase. The second key element to an effective regulatory model is the concept of performance-based assessment. This requires information and schemes to be set up to work out ways to monitor and evaluate the performance of the utility on selected criteria. For Australia at present there is a dire lack of agreed criteria on these key issues and these have the potential to pull apart the whole process. The key issues are indigenous rights, governance issues, public participation, alteration of pre-existing rights and incorporation of environmental requirements.

Altered Cell Mechanics from the Inside: Dispersed Single Wall Carbon Nanotubes Integrate with and Restructure Actin

PubMed Central

Holt, Brian D.; Shams, Hengameh; Horst, Travis A.; Basu, Saurav; Rape, Andrew D.; Wang, Yu-Li; Rohde, Gustavo K.; Mofrad, Mohammad R. K.; Islam, Mohammad F.; Dahl, Kris Noel

2012-01-01

With a range of desirable mechanical and optical properties, single wall carbon nanotubes (SWCNTs) are a promising material for nanobiotechnologies. SWCNTs also have potential as biomaterials for modulation of cellular structures. Previously, we showed that highly purified, dispersed SWCNTs grossly alter F-actin inside cells. F-actin plays critical roles in the maintenance of cell structure, force transduction, transport and cytokinesis. Thus, quantification of SWCNT-actin interactions ranging from molecular, sub-cellular and cellular levels with both structure and function is critical for developing SWCNT-based biotechnologies. Further, this interaction can be exploited, using SWCNTs as a unique actin-altering material. Here, we utilized molecular dynamics simulations to explore the interactions of SWCNTs with actin filaments. Fluorescence lifetime imaging microscopy confirmed that SWCNTs were located within ~5 nm of F-actin in cells but did not interact with G-actin. SWCNTs did not alter myosin II sub-cellular localization, and SWCNT treatment in cells led to significantly shorter actin filaments. Functionally, cells with internalized SWCNTs had greatly reduced cell traction force. Combined, these results demonstrate direct, specific SWCNT alteration of F-actin structures which can be exploited for SWCNT-based biotechnologies and utilized as a new method to probe fundamental actin-related cellular processes and biophysics. PMID:24955540

CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sterjovski, Jasminka; Churchill, Melissa J.; Roche, Michael

2011-02-20

CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n = 16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained bymore » the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.« less

Effects of littoral habitat complexity and sunfish composition on fish production

USGS Publications Warehouse

Carey, Michael P.; Maloney, K.O.; Chipps, S.R.; Wahl, David H.

2010-01-01

Habitat complexity is a key driver of food web dynamics because physical structure dictates resource availability to a community. Changes in fish diversity can also alter trophic interactions and energy pathways in food webs. Few studies have examined the direct, indirect, and interactive effects of biodiversity and habitat complexity on fish production. We explored the effects of habitat complexity (simulated vegetation), sunfish diversity (intra‐ vs. inter‐specific sunfish), and their interaction using a mesocosm experiment. Total fish production was examined across two levels of habitat complexity (low: 161 strands m−2 and high: 714 strands m−2) and two sunfish diversity treatments: bluegill only (Lepomis macrochirus) and bluegill, redear sunfish (Lepomis microlophus), and green sunfish (Lepomis cyanellus) combination. We also measured changes in total phosphorus, phytoplankton, periphyton, and invertebrates to explain patterns in fish production. Bluegill and total fish production were unaffected by the sunfish treatments. Habitat complexity had a large influence on food web structure by shifting primary productivity from pelagic to a more littoral pathway in the high habitat treatments. Periphyton was higher with dense vegetation, leading to reductions in total phosphorus, phytoplankton, cladoceran abundance and fish biomass. In tanks with low vegetation, bluegill exhibited increased growth. Habitat complexity can alter energy flow through food webs ultimately influencing higher trophic levels. The lack of an effect of sunfish diversity on fish production does not imply that conserving biodiversity is unimportant; rather, we suggest that understanding the context in which biodiversity is important to food web dynamics is critical to conservation planning

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells*

PubMed Central

Galdieri, Luciano; Gatla, Himavanth; Vancurova, Ivana; Vancura, Ales

2016-01-01

AMP-activated protein kinase (AMPK) is an energy sensor and master regulator of metabolism. AMPK functions as a fuel gauge monitoring systemic and cellular energy status. Activation of AMPK occurs when the intracellular AMP/ATP ratio increases and leads to a metabolic switch from anabolism to catabolism. AMPK phosphorylates and inhibits acetyl-CoA carboxylase (ACC), which catalyzes carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting reaction in de novo synthesis of fatty acids. AMPK thus regulates homeostasis of acetyl-CoA, a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Nucleocytosolic concentration of acetyl-CoA affects histone acetylation and links metabolism and chromatin structure. Here we show that activation of AMPK with the widely used antidiabetic drug metformin or with the AMP mimetic 5-aminoimidazole-4-carboxamide ribonucleotide increases the inhibitory phosphorylation of ACC and decreases the conversion of acetyl-CoA to malonyl-CoA, leading to increased protein acetylation and altered gene expression in prostate and ovarian cancer cells. Direct inhibition of ACC with allosteric inhibitor 5-(tetradecyloxy)-2-furoic acid also increases acetylation of histones and non-histone proteins. Because AMPK activation requires liver kinase B1, metformin does not induce protein acetylation in liver kinase B1-deficient cells. Together, our data indicate that AMPK regulates the availability of nucleocytosolic acetyl-CoA for protein acetylation and that AMPK activators, such as metformin, have the capacity to increase protein acetylation and alter patterns of gene expression, further expanding the plethora of metformin's physiological effects. PMID:27733682

Pulmonary vasculature in COPD: The silent component.

PubMed

Blanco, Isabel; Piccari, Lucilla; Barberà, Joan Albert

2016-08-01

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium-dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment. © 2016 Asian Pacific Society of Respirology.

Aggregatibacter actinomycetemcomitans lipopolysaccharide affects human gingival fibroblast cytoskeletal organization.

PubMed

Gutiérrez-Venegas, Gloria; Contreras-Marmolejo, Luis Arturo; Román-Alvárez, Patricia; Barajas-Torres, Carolina

2008-04-01

The cytoskeleton is a dynamic structure that plays a key role in maintaining cell morphology and function. This study investigates the effect of bacterial wall lipopolysaccharide (LPS), a strong inflammatory agent, on the dynamics and organization of actin, tubulin, vimentin, and vinculin proteins in human gingival fibroblasts (HGF). A time-dependent study showed a noticeable change in actin architecture after 1.5 h of incubation with LPS (1 microg/ml) with the formation of orthogonal fibers and further accumulation of actin filament at the cell periphery by 24 h. When 0.01-10 microg/ml of LPS was added to human gingival fibroblast cultures, cells acquired a round, flat shape and gradually developed cytoplasmic ruffling. Lipopolysaccharides extracted from Aggregatibacter actinomycetemcomitans periodontopathogenic bacteria promoted alterations in F-actin stress fibres of human gingival cells. Normally, human gingival cells have F-actin fibres that are organized in linear distribution throughout the cells, extending along the cell's length. LPS-treated cells exhibited changes in cytoskeletal protein organization, and F-actin was reorganized by the formation of bundles underneath and parallel to the cell membrane. We also found the reorganization of the vimentin network into vimentin bundling after 1.5 h of treatment. HGF cells exhibited diffuse and granular gamma-tubulin stain. There was no change in LPS-treated HGF. However, vinculin plaques distributed in the cell body diminished after LPS treatment. We conclude that the dynamic and structured organization of cytoskeletal filaments and actin assembly in human gingival fibroblasts is altered by LPS treatment and is accompanied by a decrease in F-actin pools.

Neuroprotective role of curcumin on the hippocampus against the structural and serological alterations of streptozotocin-induced diabetes in Sprague Dawely rats.

PubMed

Faheem, Nermeen Mohammed; El Askary, Ahmad

2017-06-01

Diabetes mellitus causes impaired memory and cognitive functions. The hippocampus plays a key role in memory and learning. Curcumin attenuates diabetic nephropathy in vivo . Curcumin has shown a neurogenic effect and cognition-enhancing potential in aged rats. The aim of this study is to evaluate the possible protective role of curcumin on the histological and serological changes of the hippocampus in diabetic rats. Forty albino rats were divided into four groups, ten rats each. Group 1 control rats, group 2 rats received curcumin orally (200 mg/kg/day for six weeks), group 3 rats were injected intraperitoneally with streptozotocin (STZ) (100 mg/kg, single dose), group 4 received a single injection of STZ and received curcumin orally for six weeks. Paraffin sections of hippocampus were prepared and stained with hematoxylin and eosin stain, and immnunohistochemical staining for GFAP and caspase-3. Morphometrical and statistical analyses were performed. Glycemic status and parameters of oxidative stress was measured. Examination of hippocampus of diabetic rats showed disorganization of small pyramidal cells in CA1, many cellular losses in the pyramidal cells of CA3, many degenerated granule cells in the dentate gyrus. GFAP positive astrocyte and caspase-3 positive neuron counts were significantly increased. There were significant serum glucose elevation and significant lowered levels of oxidative stress parameters as compared to control rats. Curcumin administration improved the structural and serological alterations of the hippocampus with significant reduction in serum glucose level. Curcumin ameliorates the deterious effect of diabetes on the hippocampus through its antioxidant, antiapoptotic and anti-inflammatory efficacies.

Abnormal structure and functional connectivity of the anterior insula at pain-free periovulation is associated with perceived pain during menstruation.

PubMed

Dun, Wang-Huan; Yang, Jing; Yang, Ling; Ding, Dun; Ma, Xue-Ying; Liang, Feng-Li; von Deneen, Karen M; Ma, Shao-Hui; Xu, Xiao-Ling; Liu, Jixin; Zhang, Ming

2017-12-01

Neuroimaging studies have demonstrated the critical role of the insula in pain pathways and its close relation with the perceived intensity of nociceptive stimuli. We aimed to identify the structural and functional characteristics of the insula during periovulatory phase in women with primary dysmenorrhea (PDM), and further investigate its association with the intensity of perceived pain during menstruation. Optimized voxel-based morphometry and functional connectivity (FC) analyses were applied by using 3-dimensional T1-weighted and resting functional magnetic resonance imaging (fMRI) in 36 patients at the peri-ovulation phase and 29 age-, education-, and gender-matched healthy controls (HC). A visual analogue scale (VAS) was used to examine the intensity of the abdominal pain at periovulation and menstruation. In our results, PDM patients had significant higher VAS-rating during menstruaion than periovulation. Compared with the HC, PDM patients had lower gray matter density in the left anterior insula (aINS). Taken the left aINS as a seed region, we further found hypoconnectivity between aINS and medial prefrontal cortex (mPFC), which showed negative relation with the VAS during menstruation. As the aINS is a key site of the salience network (SN) and the mPFC is a critical region in the default mode network (DMN), it's implicated a trait-related central-alteration that communications between pain attention and perception networks were disrupted without the ongoing menstrual pain. Moreover, result of correlation analysis, at least in part, suggested a possible role of altered FC (pain-free period) in predicting pain perception (menstruation).

Ultra-structural hair alterations of drug abusers: a scanning electron microscopic investigation

PubMed Central

Turkmenoglu, Fatma Pinar; Kasirga, Ugur Baran; Celik, Hakan Hamdi

2015-01-01

As drug abuse carries a societal stigma, patients do not often report their history of drug abuse to the healthcare providers. However, drug abuse is highly co-morbid with a host of other health problems such as psychiatric disorders and skin diseases, and majority of individuals with drug use disorders seek treatment in the first place for other problems. Therefore, it is very important for physicians to be aware of clinical signs and symptoms of drug use. Recently diagnostic value of dermatologic tissue alterations associated with drug abuse has become a very particular interest because skin changes were reported to be the earliest noticeable consequence of drug abuse prompting earlier intervention and treatment. Although hair is an annex of skin, alterations on hair structure due to drug use have not been demonstrated. This study represents the first report on ultra-structural hair alterations of drug abusers. We have investigated ultra-structure of the hair samples obtained from 6 cocaine, 6 heroin, 7 cannabis and 4 lysergic acid diethylamide (LSD) abusers by scanning electron microscope (SEM). SEM analysis of hair samples gave us drug-specific discriminating alterations. We suggest that results of this study will make a noteworthy contribution to cutaneous alterations associated with drug abuse which are regarded as the earliest clinical manifestations, and this SEM approach is a very specific and effective tool in the detection of abuse of respective drugs, leading early treatment. PMID:26309532

Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review.

PubMed

Hermann, Derik; Schneider, Miriam

2012-01-01

Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures. In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced. Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity. Especially direct THC effects (or via endocannabinoids) may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss in a small pilot study. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors. We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD.

Modified Protein Improves Vitiligo Symptoms in Mice

MedlinePlus

... Vitiligo Symptoms in Mice Spotlight on Research Modified Protein Improves Vitiligo Symptoms in Mice By Colleen Labbe, ... D., Ph.D., Rush University. Altering a key protein involved in the development of vitiligo may protect ...

Genetic modifications of pigs for medicine and agriculture

PubMed Central

Whyte, Jeffrey J.; Prather, Randall S.

2011-01-01

SUMMARY Genetically modified swine hold great promise in the fields of agriculture and medicine. Currently, these swine are being used to optimize production of quality meat, to improve our understanding of the biology of disease resistance, and to reduced waste. In the field of biomedicine, swine are anatomically and physiologically analogous to humans. Alterations of key swine genes in disease pathways provide model animals to improve our understanding of the causes and potential treatments of many human genetic disorders. The completed sequencing of the swine genome will significantly enhance the specificity of genetic modifications, and allow for more accurate representations of human disease based on syntenic genes between the two species. Improvements in both methods of gene alteration and efficiency of model animal production are key to enabling routine use of these swine models in medicine and agriculture. PMID:21671302

Biological assessment of environmental flows for Oklahoma

USGS Publications Warehouse

Fisher, William L.; Seilheimer, Titus S.; Taylor, Jason M.

2012-01-01

Large-scale patterns in fish assemblage structure and functional groups are influenced by alterations in streamflow regime. In this study, we defined an objective threshold for alteration for Oklahoma streams using a combination of the expected range of 27 flow indices and a discriminant analysis to predict flow regime group. We found that fish functional groups in reference flow conditions had species that were more intolerant to flow alterations and preferences for stream habitat and faster flowing water. In contrast, altered sites had more tolerant species that preferred lentic habitat and slower water velocity. Ordination graphs of the presence and functional groups of species revealed an underlying geographical pattern roughly conforming to ecoregions, although there was separation between reference and altered sites within the larger geographical framework. Additionally, we found that reservoir construction and operation significantly altered fish assemblages in two different systems, Bird Creek in central Oklahoma and the Kiamichi River in southeastern Oklahoma. The Bird Creek flow regime shifted from a historically intermittent stream to one with stable perennial flows, and changes in fish assemblage structure covaried with changes in all five components of the flow regime. In contrast, the Kiamichi River flow regime did not change significantly for most flow components despite shifts in fish assemblage structure; however, most of the species associated with shifts in assemblage structure in the Kiamichi River system were characteristic of lentic environments and were likely related more to proximity of reservoirs in the drainage system than changes in flow. The spatial patterns in fish assemblage response to flow alteration, combined with different temporal responses of hydrology and fish assemblage structure at sites downstream of reservoirs, indicate that interactions between flow regime and aquatic biota vary depending on ecological setting. This supports the notion that regional variation in natural flow regimes could affect the development of flow recommendations.

Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress.

PubMed

Garza-Lombó, Carla; Posadas, Yanahi; Quintanar, Liliana; Gonsebatt, María E; Franco, Rodrigo

2018-06-20

Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.

Impact of the structural integrity of the three-way junction of adenovirus VAI RNA on PKR inhibition

PubMed Central

Dzananovic, Edis; Astha; Chojnowski, Grzegorz; Deo, Soumya; Booy, Evan P.; Padilla-Meier, Pauline; McEleney, Kevin; Bujnicki, Janusz M.; McKenna, Sean A.

2017-01-01

Highly structured RNA derived from viral genomes is a key cellular indicator of viral infection. In response, cells produce the interferon inducible RNA-dependent protein kinase (PKR) that, when bound to viral dsRNA, phosphorylates eukaryotic initiation factor 2α and attenuates viral protein translation. Adenovirus can evade this line of defence through transcription of a non-coding RNA, VAI, an inhibitor of PKR. VAI consists of three base-paired regions that meet at a three-way junction; an apical stem responsible for the interaction with PKR, a central stem required for inhibition, and a terminal stem. Recent studies have highlighted the potential importance of the tertiary structure of the three-way junction to PKR inhibition by enabling interaction between regions of the central and terminal stems. To further investigate the role of the three-way junction, we characterized the binding affinity and inhibitory potential of central stem mutants designed to introduce subtle alterations. These results were then correlated with small-angle X-ray scattering solution studies and computational tertiary structural models. Our results demonstrate that while mutations to the central stem have no observable effect on binding affinity to PKR, mutations that appear to disrupt the structure of the three-way junction prevent inhibition of PKR. Therefore, we propose that instead of simply sequestering PKR, a specific structural conformation of the PKR-VAI complex may be required for inhibition. PMID:29053745

Outcrop-scale imaging spectroscopy of the Haughton impact structure, Canada

NASA Astrophysics Data System (ADS)

Greenberger, R. N.; Ehlmann, B. L.; Osinski, G. R.; Tornabene, L. L.; Green, R. O.

2016-12-01

Field-portable imaging spectrometers are a novel tool to study heterogeneous deposits such as those found at impact structures. Laboratory imaging spectroscopy of samples from the Haughton impact structure, Devon Island, Nunavut, Canada, detects and maps a variety of minerals within hand samples including calcite, dolomite, hydrated silica, gypsum, garnet, and iron oxides and sulfates. Many of these minerals originate from the target rock lithologies (e.g., limestone, dolostone, sandstone, gneiss) that have been shocked, altered, and displaced. An intimate mixture of quenched melts of calcite and hydrated silica is indicative of the melt rock matrix and is a byproduct of the impact process. Based on these preliminary results, we conducted a field campaign in Summer 2016 at the Haughton structure using imaging spectroscopy on the ground to study and quantify outcrops of impact-disrupted materials around the structure. Key questions addressed include (1) to what extent are the different impact-disrupted/exposed target lithologies from discrete stratigraphic units homogenized during impact processes, (2) what single or mixed lithologies are we able to detect, and (3) is variability within the target lithologies observable within the impactites? The Haughton impact structure is an ideal location to address these questions due to its excellent preservation and the nearly flat-lying, undeformed target rocks. We will present results from the field campaign along with supporting laboratory analyses. The results have implications for our understanding of impact processes and interpretation of planetary remote sensing datasets.

Methylphenidate administration determines enduring changes in neuroglial network in rats.

PubMed

Cavaliere, Carlo; Cirillo, Giovanni; Bianco, Maria Rosaria; Adriani, Walter; De Simone, Antonietta; Leo, Damiana; Perrone-Capano, Carla; Papa, Michele

2012-01-01

Repeated exposure to psychostimulant drugs induces complex molecular and structural modifications in discrete brain regions of the meso-cortico-limbic system. This structural remodeling is thought to underlie neurobehavioral adaptive responses. Administration to adolescent rats of methylphenidate (MPH), commonly used in attention deficit and hyperactivity disorder (ADHD), triggers alterations of reward-based behavior paralleled by persistent and plastic synaptic changes of neuronal and glial markers within key areas of the reward circuits. By immunohistochemistry, we observe a marked increase of glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) expression and a down-regulation of glial glutamate transporter GLAST in dorso-lateral and ventro-medial striatum. Using electron microscopy, we find in the prefrontal cortex a significant reduction of the synaptic active zone length, paralleled by an increase of dendritic spines. We demonstrate that in limbic areas the MPH-induced reactive astrocytosis affects the glial glutamatergic uptake system that in turn could determine glutamate receptor sensitization. These processes could be sustained by NO production and synaptic rearrangement and contribute to MPH neuroglial induced rewiring. Copyright © 2011. Published by Elsevier B.V.

Variation in the electrical properties of ion beam irradiated cadmium selenate nanowires

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chauhan, R. P., E-mail: chauhanrpc@gmail.com; Narula, Chetna; Panchal, Suresh

The key feature of nanowires consists in the pronounced change in properties induced by the low dimensionality and high surface to volume ratio. The study of electrical transport properties of nanowires is important for electronic device applications. Energetic ions create changes, which may be structural or chemical, in a material along their track and these changes might alter the material’s properties. The demand of the modern technology is to understand the effect of radiation on the different properties of the material for its further applications. The present study is on the high-energy Nickel ion beam (160 MeV Ni{sup +12}) induced modificationsmore » in the electrical and structural properties of the cadmium selenate nanowires. An enhancement in the electrical conductivity of irradiated wires was observed as the ion fluence was increased especially in the forward I–V characteristics. The creation of defects by ion irradiation and the synergy of the ions during their passage in the sample with the intrinsic charge carriers may be responsible for the variation in the transport properties of the irradiated nanowires.« less

Functional neuroanatomy of tics.

PubMed

Neuner, Irene; Schneider, Frank; Shah, N Jon

2013-01-01

The therapeutic success of haloperidol in the treatment of Tourette syndrome (TS) put an end to the discussion about a "hysteric" or "neurotic" origin of TS. The cortico-striato-thalamo-cortical circuit has been identified as an underlying neurobiological correlate of TS. In this review we explore the main findings of structural alterations in TS including cortical areas, basal ganglia, hippocampus, amygdala, midbrain, and cerebellum. Based on the structural changes we examine the functional pattern described by the findings of fMRI and (15)O-PET/(18)FDG PET investigations. From the neuroimaging findings a cortical origin of the generation of tics is indicated. Future research on the neuronal footprint of TS should be directed towards addressing the question of which patterns of connectivity distinguish individuals in whom tics disappear during early adulthood from those in whom the tics persist. The understanding of this pathomechanism could provide a key on how to influence dysconnectivity in TS, for example, by more specific pharmaceutical intervention or by individually adopted EEG and/or fMRI neurofeedback. © 2013 Elsevier Inc. All rights reserved.

Alternative Conformations of Cytochrome c: Structure, Function, and Detection.

PubMed

Hannibal, Luciana; Tomasina, Florencia; Capdevila, Daiana A; Demicheli, Verónica; Tórtora, Verónica; Alvarez-Paggi, Damián; Jemmerson, Ronald; Murgida, Daniel H; Radi, Rafael

2016-01-26

Cytochrome c (cyt c) is a cationic hemoprotein of ∼100 amino acid residues that exhibits exceptional functional versatility. While its primary function is electron transfer in the respiratory chain, cyt c is also recognized as a key component of the intrinsic apoptotic pathway, the mitochondrial oxidative protein folding machinery, and presumably as a redox sensor in the cytosol, along with other reported functions. Transition to alternative conformations and gain-of-peroxidase activity are thought to further enable the multiple functions of cyt c and its translocation across cellular compartments. In vitro, direct interactions of cyt c with cardiolipin, post-translational modifications such as tyrosine nitration, phosphorylation, methionine sulfoxidation, mutations, and even fine changes in electrical fields lead to a variety of conformational states that may be of biological relevance. The identification of these alternative conformations and the elucidation of their functions in vivo continue to be a major challenge. Here, we unify the knowledge of the structural flexibility of cyt c that supports functional moonlighting and review biochemical and immunochemical evidence confirming that cyt c undergoes conformational changes during normal and altered cellular homeostasis.

Uncovering the role of the insula in non-motor symptoms of Parkinson’s disease

PubMed Central

Christopher, Leigh; Koshimori, Yuko; Lang, Anthony E.; Criaud, Marion

2014-01-01

Patients with Parkinson’s disease experience a range of non-motor symptoms, including cognitive impairment, behavioural changes, somatosensory and autonomic disturbances. The insula, which was once thought to be primarily a limbic cortical structure, is now known to be highly involved in integrating somatosensory, autonomic and cognitive-affective information to guide behaviour. Thus, it acts as a central hub for processing relevant information related to the state of the body as well as cognitive and mood states. Despite these crucial functions, the insula has been largely overlooked as a potential key region in contributing to non-motor symptoms of Parkinson’s disease. The insula is affected in Parkinson’s disease by alpha-synuclein deposition, disruptions in normal neurotransmitter function, alterations in connectivity as well as metabolic and structural changes. Although research focusing on the role of the insula in Parkinson’s disease is scarce, there is evidence from neuroimaging studies linking the insula to cognitive decline, behavioural abnormalities and somatosensory disturbances. Here, we review imaging studies that provide insight into the potential role of the insula in Parkinson’s disease non-motor symptoms. PMID:24736308

USDA Biochar Research: Land Application Advances to Reap Its Multifunctional Abilities

NASA Astrophysics Data System (ADS)

Ippolito, J.; Spokas, K.; Novak, J.; Lentz, R. D.; Stromberger, M.; Ducey, T.; Johnson, M.

2014-12-01

Biochar is the solid byproduct from the pyrolysis of agricultural crop residues, manures, green wastes and wood-based materials. Pyrolyzing biomass causes inorganic and organic compounds to be concentrated within the carbonized remains of the original lignin and cellulose structure. It is through this complex mixture of organic aromatic structures and inorganic elements that potentially imparts biochars with special multi-functional capabilities. Our current research has focused on developing biochar to simultaneously sequester soil carbon and remediate degraded soils. This is accomplished by directly improving soil nutrient and moisture contents, sorbing pollutants, as well as altering microbial signaling. Maintaining these improvements needs to account for biochar physical degradation, which may be overcome by biochar-mineral associations. Additional research is focused on biochar use that minimizes soil microorganism population shifts in order to maintain current ecosystem services. Future USDA research involves more evaluations to understand the multifunctional role of biochar in the agricultural and environmental sectors (e.g., USEPA superfund locations). This presentation will provide highlights of current and future coordinated biochar research efforts from several key laboratory locations across the US.

Matrix Gelatinases in Atherosclerosis and Diabetic Nephropathy: Progress and Challenges.

PubMed

Dimas, Grigorios G; Didangelos, Triantafyllos P; Grekas, Dimitrios M

2017-01-01

Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade components of the extracellular matrix (ECM). In glomerular disease, MMPs are major regulators of ECM degradation as well as structural and functional integrity in the glomerulus. In altered matrix composition diseases, glomerular damage is due to increased degradation of kidney and vessel basement membranes (BMs) by MMPs. MMP -2 and -9 are both considered as the main enzymes that degrade collagen type-IV (coll-IV), which represents the key collagenous component of ECM and constitutes the architectural structure of vessels and glomerular BM. There is growing evidence implicating MMPs in atherosclerosis as well as in cardiovascular disease (CVD) and chronic kidney disease (CKD). Specific endogenous tissue inhibitors of MMPs (TIMPs) are also implicated in CKD, CVD and diabetic nephropathy (DN). The present review discusses the role of MMPs -2 and -9 in DN, as a leading cause of endstage renal disease and as a model of the link between progressive glomerulosclerosis and MMP expression. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Molecular structures guide the engineering of chromatin.

PubMed

Tekel, Stefan J; Haynes, Karmella A

2017-07-27

Chromatin is a system of proteins, RNA, and DNA that interact with each other to organize and regulate genetic information within eukaryotic nuclei. Chromatin proteins carry out essential functions: packing DNA during cell division, partitioning DNA into sub-regions within the nucleus, and controlling levels of gene expression. There is a growing interest in manipulating chromatin dynamics for applications in medicine and agriculture. Progress in this area requires the identification of design rules for the chromatin system. Here, we focus on the relationship between the physical structure and function of chromatin proteins. We discuss key research that has elucidated the intrinsic properties of chromatin proteins and how this information informs design rules for synthetic systems. Recent work demonstrates that chromatin-derived peptide motifs are portable and in some cases can be customized to alter their function. Finally, we present a workflow for fusion protein design and discuss best practices for engineering chromatin to assist scientists in advancing the field of synthetic epigenetics. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Phytoplankton Biogeography and Community Stability in the Ocean

PubMed Central

Cermeño, Pedro; de Vargas, Colomban; Abrantes, Fátima; Falkowski, Paul G.

2010-01-01

Background Despite enormous environmental variability linked to glacial/interglacial climates of the Pleistocene, we have recently shown that marine diatom communities evolved slowly through gradual changes over the past 1.5 million years. Identifying the causes of this ecological stability is key for understanding the mechanisms that control the tempo and mode of community evolution. Methodology/Principal Findings If community assembly were controlled by local environmental selection rather than dispersal, environmental perturbations would change community composition, yet, this could revert once environmental conditions returned to previous-like states. We analyzed phytoplankton community composition across >104 km latitudinal transects in the Atlantic Ocean and show that local environmental selection of broadly dispersed species primarily controls community structure. Consistent with these results, three independent fossil records of marine diatoms over the past 250,000 years show cycles of community departure and recovery tightly synchronized with the temporal variations in Earth's climate. Conclusions/Significance Changes in habitat conditions dramatically alter community structure, yet, we conclude that the high dispersal of marine planktonic microbes erases the legacy of past environmental conditions, thereby decreasing the tempo of community evolution. PMID:20368810

High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure

PubMed Central

Rosa-Garrido, Manuel; Chapski, Douglas J.; Schmitt, Anthony D.; Kimball, Todd H.; Karbassi, Elaheh; Monte, Emma; Balderas, Enrique; Pellegrini, Matteo; Shih, Tsai-Ting; Soehalim, Elizabeth; Liem, David; Ping, Peipei; Galjart, Niels J.; Ren, Shuxun; Wang, Yibin; Ren, Bing

2017-01-01

Background: Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. Methods: To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload–induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. Results: Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. Conclusions: These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy. PMID:28802249

High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure.

PubMed

Rosa-Garrido, Manuel; Chapski, Douglas J; Schmitt, Anthony D; Kimball, Todd H; Karbassi, Elaheh; Monte, Emma; Balderas, Enrique; Pellegrini, Matteo; Shih, Tsai-Ting; Soehalim, Elizabeth; Liem, David; Ping, Peipei; Galjart, Niels J; Ren, Shuxun; Wang, Yibin; Ren, Bing; Vondriska, Thomas M

2017-10-24

Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy. © 2017 The Authors.

Method for producing capsular polysaccharides

NASA Technical Reports Server (NTRS)

Richards, Gil F. (Inventor); Kern, Roger G. (Inventor); Petersen, Gene R. (Inventor)

1994-01-01

Structurally altered capsular polysaccharides are produced by mutant bacteria. These polysaccharides are isolated by selecting a wild type bacterial strain and a phage producing degradative enzymes that have substrate specificity for the capsular polysaccharides produced by the wild type bacteria. Phage-resistant mutants producing capsular polysaccharides are selected and the structurally altered capsular polysaccharide is isolated therefrom.