bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic warping of seismic images
Authors: Hale Dave
Published: February 2013

The problem of estimating relative time (or depth) shifts between two seismic images is ubiquitous in seismic data processing. This problem is especially difficult where shifts are large and vary rapidly with time and space, and where images are contaminated with noise or for other reasons are not shifted versions of one another. A new solution to this problem requires only simple extensions of a classic dynamic time warping algorithm for speech recognition. A key component of that classic algorithm is a nonlinear accumulation of alignment errors. By applying the same nonlinear accumulator repeatedly in all directions along all sampled axes of a multidimensional image, I obtain a new and effective method for dynamic image warping (DIW). In tests where known shifts vary rapidly, this new method is more accurate than methods based on crosscorrelations of windowed images. DIW also aligns seismic reflectors well in examples where shifts are unknown, for images with differences not limited to time shifts.
Knockdown of RyR3 Enhances Adiponectin Expression Through an atf3-Dependent Pathway
Authors: Tsai Shu-Huei , Chang Emily Yun-Chia , Chang Yi-Cheng , Hee Siow-Wey , Tsai Yun-Chih , Chang Tien-Jyun , Chuang Lee-Ming
Published: February 2013

Adiponectin is an important adipose-specific protein, which possesses insulin (INS)-sensitizing, antiinflammatory, and antiatherosclerotic functions. However, its regulation remains largely unknown. In this study, we identified that ryanodine receptor (RyR)3 plays an important role in the regulation of adiponectin expression. RyR3 was expressed in 3T3-L1 preadipocytes, and its level was decreased upon adipogenesis. Silencing of RyR3 expression in 3T3-L1 preadipocytes resulted in up-regulated adiponectin promoter activity, enhanced adiponectin mRNA expression, and more adiponectin protein secreted into the medium. An inverse relation between RyR3 and adiponectin mRNA levels was also observed in adipose tissues of db/db mice. In addition, knockdown of RyR3 with small interfering RNA (siRNA) in db/db mice and high-fat diet-fed obese mice increased serum adiponectin level, improved INS sensitivity, and lowered fasting glucose levels. These effects were in parallel with decreased mitochondrial Ca2+, increased mitochondrial mass, and reduced activating transcription factor 3 (atf3) expression. Overexpression of atf3 in 3T3-L1 preadipocytes blocked the effect of RyR3 silencing on adiponectin expression, indicating that an atf3-dependent pathway mediates the effect downstream of RyR3 silencing. Our data suggest that RyR3 may be a new therapeutic target for improving INS sensitivity and related metabolic disorders.
Vitamin D Receptor in Osteoblasts Is a Negative Regulator of Bone Mass Control
Authors: Yamamoto Yoko , Yoshizawa Tatsuya , Fukuda Toru , Shirode-Fukuda Yuko , Yu Taiyong , Sekine Keisuke , Sato Takashi , Kawano Hirotaka , Aihara Ken-ichi , Nakamichi Yuko , Watanabe Tomoyuki , Shindo Masayo , Inoue Kazuki , Inoue Erina , Tsuji Naoya , Hoshino Maiko , Karsenty Gerard , Metzger Daniel , Chambon Pierre , Kato Shigeaki , Imai Yuuki
Published: February 2013

The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)2D3] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca2+ homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR−/−) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR+/L−) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR+/−) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDRΔOb/ΔOb) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDRΔOb/ΔOb mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDRΔOb/ΔOb osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.
Glucocorticoid Programming of the Fetal Male Hippocampal Epigenome
Authors: Crudo Ariann , Suderman Matthew , Moisiadis Vasilis G. , Petropoulos Sophie , Kostaki Alisa , Hallett Michael , Szyf Moshe , Matthews Stephen G.
Published: February 2013

The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3–4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.
The Roles of Vitamin D in Skeletal Muscle: Form, Function, and Metabolism
Authors: Girgis Christian M. , Clifton-Bligh Roderick J. , Hamrick Mark W. , Holick Michael F. , Gunton Jenny E.
Published: February 2013

Beyond its established role in bone and mineral homeostasis, there is emerging evidence that vitamin D exerts a range of effects in skeletal muscle. Reports of profound muscle weakness and changes in the muscle morphology of adults with vitamin D deficiency have long been described. These reports have been supplemented by numerous trials assessing the impact of vitamin D on muscle strength and mass and falls in predominantly elderly and deficient populations. At a basic level, animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness. To explain these effects, some molecular mechanisms by which vitamin D impacts on muscle cell differentiation, intracellular calcium handling, and genomic activity have been elucidated. There are also suggestions that vitamin D alters muscle metabolism, specifically its sensitivity to insulin, which is a pertinent feature in the pathophysiology of insulin resistance and type 2 diabetes. We will review the range of human clinical, animal, and cell studies that address the impact of vitamin D in skeletal muscle, and discuss the controversial issues. This is a vibrant field of research and one that continues to extend the frontiers of knowledge of vitamin D's broad functional repertoire.
A dynamic model of the hypoxia-inducible factor 1-alpha (HIF-1α) network
Authors: Nguyen Lan K. , Cavadas Miguel A. S. , Scholz Carsten C. , Fitzpatrick Susan F. , Bruning Ulrike , Cummins Eoin P. , Tambuwala Murtaza M. , Manresa Mario C. , Kholodenko Boris N. , Taylor Cormac T. , Cheong Alex
Published: February 2013

Activation of the hypoxia-inducible factor (HIF) pathway is a critical step in the transcriptional response to hypoxia. While many of the key proteins involved have been characterised, the dynamics of their interactions in generating this response remain unclear. We have generated a comprehensive mathematical model of the HIF-1α pathway based on core validated components and dynamic experimental data, and confirm the previously described connections within the predicted network topology. Our model confirms previous work demonstrating that the steps leading to optimal HIF-1α transcriptional activity require sequential inhibition of both prolyl- and asparaginyl-hydroxylases. We predict from our model (and confirm experimentally) that there is residual activity of the asparaginyl-hydroxylase FIH at low oxygen tension. Furthermore silencing FIH under conditions where prolyl-hydroxylases are inhibited results in increased HIF-1α transcriptional activity but paradoxically decreases HIF-1α stability. Using a core module of the HIF network and mathematical proof supported by experimental data, we propose that asparaginyl hydroxylation confers a degree of resistance upon HIF-1α to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1α transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.
Fast Computations in Cortical Ensembles Require Rapid Initiation of Action Potentials
Authors: Ilin Vladimir , Malyshev Aleksey , Wolf Fred , Volgushev Maxim
Published: February 2013

The abilities of neuronal populations to encode rapidly varying stimuli and respond quickly to abrupt input changes are crucial for basic neuronal computations, such as coincidence detection, grouping by synchrony, and spike-timing-dependent plasticity, as well as for the processing speed of neuronal networks. Theoretical analyses have linked these abilities to the fast-onset dynamics of action potentials (APs). Using a combination of whole-cell recordings from rat neocortical neurons and computer simulations, we provide the first experimental evidence for this conjecture and prove its validity for the case of distal AP initiation in the axon initial segment (AIS), typical for cortical neurons. Neocortical neurons with fast-onset APs in the soma can phase-lock their population firing to signal frequencies up to ∼300–400 Hz and respond within 1–2 ms to subtle changes of input current. The ability to encode high frequencies and response speed were dramatically reduced when AP onset was slowed by experimental manipulations or was intrinsically slow due to immature AP generation mechanisms. Multicompartment conductance-based models reproducing the initiation of spikes in the AIS could encode high frequencies only if AP onset was fast at the initiation site (e.g., attributable to cooperative gating of a fraction of sodium channels) but not when fast onset of somatic AP was produced solely by backpropagation. We conclude that fast-onset dynamics is a genuine property of cortical AP generators. It enables fast computations in cortical circuits that are rich in recurrent connections both within each region and across the hierarchy of areas.
Differential Contribution of Hippocampal Circuits to Appetitive and Consummatory Behaviors during Operant Conditioning of Behaving Mice
Authors: Jurado-Parras M. Teresa , Sánchez-Campusano Raudel , Castellanos Nazareth P. , del-Pozo Francisco , Gruart Agnès , Delgado-García José M.
Published: February 2013

Operant conditioning is a type of associative learning involving different and complex sensorimotor and cognitive processes. Because the hippocampus has been related to some motor and cognitive functions involved in this type of learning (such as object recognition, spatial orientation, and associative learning tasks), we decided to study in behaving mice the putative changes in strength taking place at the hippocampal CA3–CA1 synapses during the acquisition and performance of an operant conditioning task. Mice were chronically implanted with stimulating electrodes in the Schaffer collaterals and with recording electrodes in the hippocampal CA1 area and trained to an operant task using a fixed-ratio (1:1) schedule. We recorded the field EPSPs (fEPSPs) evoked at the CA3–CA1 synapse during the performance of appetitive (going to the lever, lever press) and consummatory (going to the feeder, eating) behaviors. In addition, we recorded the local field potential activity of the CA1 area during similar behavioral displays. fEPSPs evoked at the CA3–CA1 synapse presented larger amplitudes for appetitive than for consummatory behaviors. This differential change in synaptic strength took place in relation to the learning process, depending mainly on the moment in which mice reached the selected criterion. Thus, selective changes in CA3–CA1 synaptic strength were dependent on both the behavior display and the learning stage. In addition, significant changes in theta band power peaks and their corresponding discrete frequencies were noticed during these behaviors across the sequence of events characterizing this type of associative learning but not during the acquisition process.
ATF4 Protects Against Neuronal Death in Cellular Parkinson's Disease Models by Maintaining Levels of Parkin
Authors: Sun Xiaotian , Liu Jin , Crary John F. , Malagelada Cristina , Sulzer David , Greene Lloyd A. , Levy Oren A.
Published: February 2013

Parkinson's disease (PD) is a common neurodegenerative disorder, for which there are no effective disease-modifying therapies. The transcription factor ATF4 (activating transcription factor 4) is induced by multiple PD-relevant stressors, such as endoplasmic reticulum stress and oxidative damage. ATF4 may exert either protective or deleterious effects on cell survival, depending on the paradigm. However, the role of ATF4 in the pathogenesis of PD has not been explored. We find that ATF4 levels are increased in neuromelanin-positive neurons in the substantia nigra of a subset of PD patients relative to controls. ATF4 levels are also upregulated in neuronal PC12 cells treated with the dopaminergic neuronal toxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). To explore the role of ATF4 in cell survival in PD-relevant contexts, we either silenced or overexpressed ATF4 in cellular models of PD. In neuronal PC12 cells, silencing of ATF4 enhanced cell death in response to either 6-OHDA or MPP+. Conversely, overexpression of ATF4 reduced cell death caused by dopaminergic neuronal toxins. ATF4 was also protective against 6-OHDA-induced death of cultured mouse ventral midbrain dopaminergic neurons. We further show thatparkin, a gene associated with autosomal recessive PD, plays a critical role in ATF4-mediated protection. After treatment with 6-OHDA or MPP+, parkin protein levels fall, despite an increase in mRNA levels. ATF4 silencing exacerbates the toxin-induced reduction of parkin, whereas ATF4 overexpression partially preserves parkin levels. Finally, parkin silencing blocked the protective capacity of ATF4. These results indicate that ATF4 plays a protective role in PD through the regulation of parkin.
Increased 20-HETE Synthesis Explains Reduced Cerebral Blood Flow But Not Impaired Neurovascular Coupling after Cortical Spreading Depression in Rat Cerebral Cortex
Authors: Fordsmann Jonas C. , Ko Rebecca W. Y. , Choi Hyun B. , Thomsen Kirsten , Witgen Brent M. , Mathiesen Claus , Lønstrup Micael , Piilgaard Henning , MacVicar Brian A. , Lauritzen Martin
Published: February 2013

Cortical spreading depression (CSD) is associated with release of arachidonic acid, impaired neurovascular coupling, and reduced cerebral blood flow (CBF), caused by cortical vasoconstriction. We tested the hypothesis that the released arachidonic acid is metabolized by the cytochrome P450 enzyme to produce the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), and that this mechanism explains cortical vasoconstriction and vascular dysfunction after CSD. CSD was induced in the frontal cortex of rats and the cortical electrical activity and local field potentials recorded by glass microelectrodes, CBF by laser Doppler flowmetry, and tissue oxygen tension (tpO2) using polarographic microelectrodes. 20-HETE synthesis was measured in parallel experiments in cortical brain slices exposed to CSD. We used the specific inhibitor HET0016 (N-hydroxy-N′-(4-n-butyl-2-methylphenyl)formamidine) to block 20-HETE synthesis. CSD increased 20-HETE synthesis in brain slices for 120 min, and the time course of the increase in 20-HETE paralleled the reduction in CBF after CSDin vivo. HET0016 blocked the CSD-induced increase in 20-HETE synthesis and ameliorated the persistent reduction in CBF, but not the impaired neurovascular coupling after CSD. These findings suggest that CSD-induced increments in 20-HETE cause the reduction in CBF after CSD and that the attenuation of stimulation-induced CBF responses after CSD has a different mechanism. We suggest that blockade of 20-HETE synthesis may be clinically relevant to ameliorate reduced CBF in patients with migraine and acute brain cortex injuries.
Blocking the eIF2α Kinase (PKR) Enhances Positive and Negative Forms of Cortex-Dependent Taste Memory
Authors: Stern Elad , Chinnakkaruppan Adaikkan , David Orit , Sonenberg Nahum , Rosenblum Kobi
Published: February 2013

Age-associated memory deterioration (and the decline in ability to acquire new information) is one of the major diseases of our era. Cognitive enhancement can be achieved by using psycho-stimulants, such as caffeine or nicotine, but very little is known about drugs that can enhance the consolidation phase of memories in the cortex, the brain structure considered to store, at least partially, long-term memories. We used cortex-dependent taste-learning paradigms to test the hypothesis that pharmacological manipulation of the translation initiation eIF2α, which plays a role in hippocampus-dependent memory, can enhance positive or negative forms of taste memories. We found that dephosphorylation (Ser51) of eIF2α, specifically in the cortex, is both correlated with and necessary for normal memory consolidation. To reduce eIF2α phosphorylation and improve memory consolidation, we pharmacologically inhibited one of the eIF2α kinases, PKR, which is known to be involved in brain aging and Alzheimer's disease. Systemic or local microinjection of PKR inhibitor to the gustatory cortex enhanced both positive and negative forms of taste memory in rats and mice. Our results provide clear evidence that PKR plays a major role in cortex-dependent memory consolidation and, therefore, that pharmacological inhibition of PKR is a potential target for drugs to enhance cognition.
A Target Cell-Specific Role for PresynapticFmr1in Regulating Glutamate Release onto Neocortical Fast-Spiking Inhibitory Neurons
Authors: Patel Ankur B. , Hays Seth A. , Bureau Ingrid , Huber Kimberly M. , Gibson Jay R.
Published: February 2013

In the mouse model of Fragile X syndrome, theFmr1knock-out, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, we performed recordings in acutely prepared slices obtained fromFmr1“mosaic” mice, whereFmr1is deleted in about half of all neurons, and we found that loss of presynaptic, but not postsynaptic,Fmr1fully recapitulates the deficit. The change in connection strength is primarily due to a decrease in release probability indicating that FMRP normally positively regulates these processes. This change in presynaptic neurotransmitter release is observed both in the mosaic mice and in the constitutiveFmr1knock-out mice. Manipulations in release probability enabled both the mimic and rescue of the impaired function in this synaptic pathway. Loss of presynapticFmr1has no effect on excitatory synapses onto excitatory neurons, indicating a target cell-specific function for presynaptic FMRP. Finally, we demonstrate that the excitation decrement onto FS neurons also exists in layer 5 of theFmr1knock-out, suggesting a widespread role for presynapticFmr1in the excitation of inhibitory neurons. In summary, we identify a novel function for presynaptic FMRP in promoting presynaptic neurotransmitter release, and we show that loss of this function accounts for impaired excitation of neocortical FS inhibitory neurons. These changes may contribute to the cognitive dysfunction and circuit hyperexcitability associated with Fragile X syndrome, including patients with complete deletion of FMRP and those with mosaic expression of FMRP.
Symmetrical Serotonin Release during Asymmetrical Slow-Wave Sleep: Implications for the Neurochemistry of Sleep–Waking States
Authors: Lapierre Jennifer L. , Kosenko Peter O. , Kodama Tohru , Peever John H. , Mukhametov Lev M. , Lyamin Oleg I. , Siegel Jerome M.
Published: February 2013

On land, fur seals predominately display bilaterally synchronized electroencephalogram (EEG) activity during slow-wave sleep (SWS), similar to that observed in all terrestrial mammals. In water, however, fur seals exhibit asymmetric slow-wave sleep (ASWS), resembling the unihemispheric slow-wave sleep of odontocetes (toothed whales). The unique sleeping pattern of fur seals allows us to distinguish neuronal mechanisms mediating EEG changes from those mediating behavioral quiescence. In a prior study we found that cortical acetylcholine release is lateralized during ASWS in the northern fur seal, with greater release in the hemisphere displaying low-voltage (waking) EEG activity, linking acetylcholine release to hemispheric EEG activation (Lapierre et al. 2007). In contrast to acetylcholine, we now report that cortical serotonin release is not lateralized during ASWS. Our data demonstrate that bilaterally symmetric levels of serotonin are compatible with interhemispheric EEG asymmetry in the fur seal. We also find greatly elevated levels during eating and hosing the animals with water, suggesting that serotonin is more closely linked to bilateral variables, such as axial motor and autonomic control, than to the lateralized cortical activation manifested in asymmetrical sleep.
Arborization of Dendrites by Developing Neocortical Neurons Is Dependent on Primary Cilia and Type 3 Adenylyl Cyclase
Authors: Guadiana Sarah M. , Semple-Rowland Susan , Daroszewski Daniel , Madorsky Irina , Breunig Joshua J. , Mykytyn Kirk , Sarkisian Matthew R.
Published: February 2013

The formation of primary cilia is a highly choreographed process that can be disrupted in developing neurons by overexpressing neuromodulatory G-protein-coupled receptors GPCRs or by blocking intraflagellar transport. Here, we examined the effects of overexpressing the ciliary GPCRs, 5HT6 and SSTR3, on cilia structure and the differentiation of neocortical neurons. Neuronal overexpression of 5HT6 and SSTR3 was achieved by electroporating mouse embryo cortexin uterowith vectors encoding these receptors. We found that overexpression of ciliary GPCRs in cortical neurons, especially 5HT6, induced the formation of long (>30 μm) and often forked cilia. These changes were associated with increased levels of intraflagellar transport proteins and accelerated ciliogenesis in neonatal neocortex, the induction of which required Kif3a, an anterograde motor critical for cilia protein trafficking and growth. GPCR overexpression also altered the complement of signaling molecules within the cilia. We found that SSTR3 and type III adenylyl cyclase (ACIII), proteins normally enriched in neuronal cilia, were rarely detected in 5HT6-elongated cilia. Intriguingly, the changes in cilia structure were accompanied by changes in neuronal morphology. Specifically, disruption of normal ciliogenesis in developing neocortical neurons, either by overexpressing cilia GPCRs or a dominant-negative form of Kif3a, significantly impaired dendrite outgrowth. Remarkably, coexpression of ACIII with 5HT6 restored ACIII to cilia, normalized cilia structure, and restored dendrite outgrowth, effects that were not observed in neurons coexpressing ACIII and dominant-negative form of Kif3a. Collectively, our data suggest the formation of neuronal dendrites in developing neocortex requires structurally normal cilia enriched with ACIII.
Pain-Specific Modulation of Hippocampal Activity and Functional Connectivity during Visual Encoding
Authors: Forkmann Katarina , Wiech Katja , Ritter Christoph , Sommer Tobias , Rose Michael , Bingel Ulrike
Published: February 2013

Acute and chronic pain automatically attract attention and thus interfere with cognitive functioning. Impaired memory is a prominent complaint of patients with chronic pain that substantially contributes to pain-related disability. In this fMRI study, we investigated the specific influence of pain on neural processes of memory encoding in healthy human volunteers using a visual task. To investigate the specificity of the interruptive effect of pain on the encoding of visual objects, objects were presented (1) alone, (2) with painful heat stimuli, or (3) with auditory stimuli that were matched for unpleasantness to the heat stimuli. The interruptive effect of concomitant aversive stimulation on behavioral measures and neural processing was assessed in a categorization task during encoding and in a subsequent recognition task. Pain interfered with object processing and encoding of visual stimuli. On the behavioral level, this resulted in slower reaction times during the categorization task for pain compared with auditory stimuli and in a lower recognition rate in the pain condition but not in the tone condition. Pain catastrophizing amplified this interruptive effect of pain. On the neural level, this pain-related disruption of encoding was associated with reduced activity in the right anterior hippocampus during encoding. Moreover, the hippocampus exhibited reduced functional connectivity with extrastriate regions during painful stimulation relative to auditory stimulation. In summary, our results show a pain-related disruption of visual encoding over and above the unpleasantness of a stimulus, suggesting a pain-specific interruptive mechanism that interferes with an early stage of memory formation.
Atypical Protein Kinase C and Par3 Are Required for Proteoglycan-Induced Axon Growth Inhibition
Authors: Lee Seong-il , Zhang Weibing , Ravi Mayuri , Weschenfelder Markus , Bastmeyer Martin , Levine Joel M.
Published: February 2013

When the CNS is injured, damaged axons do not regenerate. This failure is due in part to the growth-inhibitory environment that forms at the injury site. Myelin-associated molecules, repulsive axon guidance molecules, and extracellular matrix molecules including chondroitin sulfate proteoglycans (CSPGs) found within the glial scar inhibit axon regeneration but the intracellular signaling mechanisms triggered by these diverse molecules remain largely unknown. Here we provide biochemical and functional evidence that atypical protein kinase C (PKCζ) and polarity (Par) complex proteins mediate axon growth inhibition. Treatment of postnatal rat neuronsin vitrowith the NG2 CSPG, a major component of the glial scar, activates PKCζ, and this activation is both necessary and sufficient to inhibit axonal growth. NG2 treatment also activates Cdc42, increases the association of Par6 with PKCζ, and leads to a Par3-dependent activation of Rac1. Transfection of neurons with kinase-dead forms of PKCζ, dominant-negative forms of Cdc42, or mutant forms of Par6 that do not bind to Cdc42 prevent NG2-induced growth inhibition. Similarly, transfection with either a phosphomutant Par3 (S824A) or dominant-negative Rac1 prevent inhibition, whereas expression of constitutively active Rac1 inhibits axon growth on control surfaces. These results suggest a model in which NG2 binding to neurons activates PKCζ and modifies Par complex function. They also identify the Par complex as a novel therapeutic target for promoting axon regeneration after CNS injury.
Enhanced Proteolytic Clearance of Plasma Aβ by Peripherally Administered Neprilysin Does Not Result in Reduced Levels of Brain Aβ in Mice
Authors: Walker John R. , Pacoma Reynand , Watson James , Ou Weijia , Alves Juliano , Mason Daniel E. , Peters Eric C. , Urbina Hugo D. , Welzel Gus , Althage Alana , Liu Bo , Tuntland Tove , Jacobson Laura H. , Harris Jennifer L. , Schumacher Andrew M.
Published: February 2013

Accumulation of β-amyloid (Aβ) in the brain is believed to contribute to the pathology of Alzheimer's Disease (AD). Aβ levels are controlled by the production of Aβ from amyloid precursor protein, degradation by proteases, and peripheral clearance. In this study we sought to determine whether enhancing clearance of plasma Aβ with a peripherally administered Aβ-degrading protease would reduce brain Aβ levels through a peripheral sink. Neprilysin (NEP) is a zinc-dependent metalloprotease that is one of the key Aβ-degrading enzymes in the brain. We developed a NEP fusion protein within vitrodegradation of Aβ and a 10 day plasma half-life in mouse. Intravenous administration of NEP to wild-type and APP23 transgenic mice resulted in dose-dependent clearance of plasma Aβ. However, this did not correspond to reduced levels of soluble brain Aβ with treatment up to 5 weeks in WT mice or formic acid-extractable brain Aβ with 3 month treatment in aged APP23. In contrast, intracranial injection of NEP resulted in an acute decrease in soluble brain Aβ. We found no change in amyloid precursor protein gene expression in mice treated with intravenous NEP, suggesting that the lack of effects in the brain following this route of administration was not caused by compensatory upregulation of Aβ production. Taken together, these results suggest a lack of a robust peripheral Aβ efflux sink through which brain amyloid burdens can be therapeutically reduced.
Inositol 1,4,5-Triphosphate Drives Glutamatergic and Cholinergic Inhibition Selectively in Spiny Projection Neurons in the Striatum
Authors: Clements Michael A. , Swapna Immani , Morikawa Hitoshi
Published: February 2013

The striatum is critically involved in the selection of appropriate actions in a constantly changing environment. The spiking activity of striatal spiny projection neurons (SPNs), driven by extrinsic glutamatergic inputs, is shaped by local GABAergic and cholinergic networks. For example, it is well established that different types of GABAergic interneurons, activated by extrinsic glutamatergic and local cholinergic inputs, mediate powerful feedforward inhibition of SPN activity. In this study, using mouse striatal slices, we show that glutamatergic and cholinergic inputs exert direct inhibitory regulation of SPN activity via activation of metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors. While pressure ejection of the group I mGluR (mGluR1/5) agonist DHPG [(S)-3,5-dihydroxyphenylglycine] equally engages both mGluR1 and mGluR5 subtypes, the mGluR-dependent component of IPSCs elicited by intrastriatal electrical stimulation is almost exclusively mediated by the mGluR1 subtype. Ca2+release from intracellular stores specifically through inositol 1,4,5-triphospahte receptors (IP3Rs) and not ryanodine receptors (RyRs) mediates this form of inhibition by gating two types of Ca2+-activated K+channels (i.e., small-conductance SK channels and large-conductance BK channels). Conversely, spike-evoked Ca2+influx triggers Ca2+release solely through RyRs to generate SK-dependent slow afterhyperpolarizations, demonstrating functional segregation of IP3Rs and RyRs. Finally, IP3-induced Ca2+release is uniquely observed in SPNs and not in different types of interneurons in the striatum. These results demonstrate that IP3-mediated activation of SK and BK channels provides a robust mechanism for glutamatergic and cholinergic inputs to selectively suppress striatal output neuron activity.
Serum sclerostin levels in men with idiopathic osteoporosis
Authors: Lapauw B , Vandewalle S , Taes Y , Goemaere S , Zmierczak H , Collette J , Kaufman J M
Published: February 2013

Objective

Sclerostin inhibits osteoblast differentiation and bone formation. If aberrant sclerostin action is involved in less efficient bone acquisition in men with idiopathic low bone mass, this might be reflected in higher serum sclerostin levels.

Methods

In 116 men with idiopathic osteoporosis (≤65 years old), 40 of their sons and healthy controls, areal bone parameters were measured using dual-energy X-ray absorptiometry, and volumetric and geometric bone parameters were measured using peripheral quantitative computed tomography. Serum analytes were measured using immunoassays and estradiol (E2) levels using liquid chromatography–tandem mass spectrometry.

Results

Men with idiopathic low bone mass had lower levels of sclerostin than the controls (0.54±0.17 vs 0.66±0.23 ng/ml;P<0.001). In both groups, sclerostin levels were strongly associated with age; when adjusting for age, no associations with anthropometrics were observed (P>0.14). In multivariate analyses, sclerostin levels displayed a positive association with whole-body bone mineral content (BMC) and areal BMD (aBMD), as well as with trabecular and cortical volumetric bone mineral density (vBMD) at the tibia in the probands. No clear associations were observed in the control group, neither were sclerostin levels associated with BMC at the radius or lumbar spine (allP>0.11). Testosterone, but not E2, was inversely related to sclerostin levels in the probands. No difference in sclerostin levels was found in their sons when compared with their controls.

Conclusion

Lower rather than higher serum sclerostin levels in the probands with idiopathic low bone mass suggest that aberrant sclerostin secretion is not involved in the pathogenesis of low bone mass in these subjects.
Inkjet Printing of Electrically Conducting Micron-Wide Lines and Transparent Conducting Films by Edge-Enhanced Twin-Deposition
Authors: Bromberg Vadim , Ma Siyuan , Singler Timothy J.
Published: February 2013

Roll-to-roll manufacturing holds the potential to rapidly and cheaply produce electronic devices in a flexible format as well as to effectively scale up production of emerging nanotechnologies. Developing scalable techniques for the efficient and effective use of solution-processed functional material is a significant factor in realizing the potential of roll-to-roll manufacturing. We present a novel inkjet deposition process developed to rapidly deposit arrays of micron-wide lines of silver nanoparticles for use as an optically transparent and electrically conducting film. The technique involves jetting a controlled number of space-overlapped drops of a dilute nanoparticle silver ink onto a substrate to form a long stable ink rivulet with two parallel and pinned edges. Subsequently, nanoparticles deposit preferentially at the two parallel rivulet edges due to edge-enhanced evaporation of the solvent. The final result is a twin-deposit of parallel continuous nanoparticle lines, each with a characteristic width less than 5μm and height less than 300 nm. The twin lines are separated by a predominantly particle-free region with the spacing between the lines ranging from 100 μm to 600 μm, where the spacing is a function of ink, substrate, and printing conditions. The effect of substrate surface and jetting parameters on nanoparticle line morphology is presented. Arrays of such lines have been printed and evaluated as potential transparent conducting films, showing an effective sheet resistance of ∼5 Ω/□. This edge-enhanced twin-deposition technique has the potential for rapid, material-efficient, and lithography-free patterned deposition of functional material for use in roll-to-roll manufacturing.
Amorphous Silicon Thin Film Transistor Biosensing System
Authors: Ma Hanbin , Miller Ben , Lee Sungsik , Ahnood Arman , Bauza Marius , Milne William I. , Nathan Arokia
Published: February 2013

Electronic systems are a very good platform for sensing biological signals for fast point-of-care diagnostics or threat detection. One of the solutions is the lab-on-a-chip integrated circuit (IC), which is low cost and high reliability, offering the possibility for label-free detection. In recent years, similar integrated biosensors based on the conventional complementary metal oxide semiconductor (CMOS) technology have been reported. However, post-fabrication processes are essential for all classes of CMOS biochips, requiring biocompatible electrode deposition and circuit encapsulation.

In this work, we present an amorphous silicon (a-Si) thin film transistor (TFT) array based sensing approach, which greatly simplifies the fabrication procedures and even decreases the cost of the biosensor. The device contains several identical sensor pixels with amplifiers to boost the sensitivity. Ring oscillator and logic circuits are also integrated to achieve different measurement methodologies, including electro-analytical methods such as amperometric and cyclic voltammetric modes. The system also supports different operational modes. For example, depending on the required detection arrangement, a sample droplet could be placed on the sensing pads or the device could be immersed into the sample solution for real time in-situ measurement. The entire system is designed and fabricated using a low temperature TFT process that is compatible to plastic substrates. No additional processing is required prior to biological measurement. A Cr/Au double layer is used for the biological-electronic interface. The success of the TFT-based system used in this work will open new avenues for flexible label-free or low-cost disposable biosensors.
Environmentally enhanced crack propagation in a chemically degrading isotropic shale
Authors: HU M.M. , HUECKEL T.
Published: February 2013

Crack propagation is studied in a geomaterial subject to weakening by the presence of water, which dissolves a mineral component. Such weakening is common when tensile microcracks develop, constituting sites of enhanced mineral dissolution. A previous concept is adopted of reactive chemo-plasticity, with the yield limit depending on the mineral mass dissolved, causing chemical softening. The dissolution is described by a rate equation and is a function of variable internal specific surface area, which in turn is assumed to be a function of dilative plastic deformation. The crack vicinity in plane strain is subject to a constant subcritical all-round uniform radial tensile traction. The behaviour of the material is rigid-plastic with chemical softening. The extended Johnson approximation is adopted, meaning that all fields involved are axisymmetric around the crack tip, with a small, unstressed cavity around it. Initial dissolution proportional to the initial porosity activates the plastic yielding. The total dissolved mass diffuses out from the process zone and the exiting mineral mass flux can be correlated with the displacement of the crack tip. A simplified semi-analytical solution for this model is presented.
Effect of chemical treatment used in MICP on engineering properties of cemented soils
Authors: QABANY A.AL , SOGA K.
Published: February 2013

Despite the large number of studies concerned with microbially induced carbonate precipitation (MICP) on soils, little attention has been paid to the effect of the chemical concentration used in the treatment on the precipitation pattern of calcium carbonate and their influence on engineering properties of MICP cemented soils. In this study, unconfined compressive strength tests were conducted on sand samples treated using 0·1, 0·25, 0·5 and 1 M urea–calcium chloride solutions. It was found that, although the strength of tested samples all increased after MICP treatment, the magnitude of this increase depended on the concentration used in the treatment and that the use of a low-chemical-concentration (i.e. urea and calcium chloride) solution resulted in stronger samples. Permeability test results showed that the use of a high-urea–calcium chloride-concentration solution resulted in a rapid drop in permeability at the early stage of calcite precipitation, whereas the use of a low-chemical-concentration solution was found to result in a more gradual and uniform decrease in permeability. This observed effect of chemical concentration on the strength and permeability of MICP cemented soils can have implications for the design of MICP for field applications.
Feedbacks underlie the resilience of salt marshes and rapid reversal of consumer‐driven die‐off
Authors: Altieri Andrew H. , Bertness Mark D. , Coverdale Tyler C. , Axelman Eric E. , Herrmann Nicholas C. , Szathmary P. Lauren
Published: February 2013

Understanding ecosystem resilience to human impacts is critical for conservation and restoration. The large‐scale die‐off of New England salt marshes was triggered by overfishing and resulted from decades of runaway crab grazing. In 2009, however, cordgrass began to recover, decreasing die‐off ∼40% by 2010. We used surveys and experiments to test whether plant–substrate feedbacks underlie marsh resilience. Initially, grazer‐generated die‐off swept through the cordgrass, creating exposed, stressful peat banks that inhibited plant growth. This desertification cycle broke when banks eroded and peat transitioned into mud with fewer herbivores, less grazing, and lower physical stress. Cordgrass reestablished in these areas through a feedback where it engineered a recovery zone by further ameliorating physical stresses and facilitating additional revegetation. Our results reveal that feedbacks can play a critical role in rapid, reversible ecosystem shifts associated with human impacts, and that the interplay of facilitative and consumer interactions should be incorporated into resilience theory.
Potential natural vegetation dynamics driven by future long-term climate change and its hydrological impacts in the Hanjiang River basin, China
Authors: Yuan Fei , Ren Liliang , Yu Zhongbo , Zhu Yonghua , Xu Jing , Fang Xiuqin
Published: February 2013

Vegetation and land-surface hydrology are intrinsically linked under long-term climate change. This paper aims to evaluate the dynamics of potential natural vegetation arising from 21st century climate change and its possible impact on the water budget of the Hanjiang River basin in China. Based on predictions of the Intergovernmental Panel on Climate Change Special Report on Emissions Scenarios (IPCC-SRES) A1 scenario from the PRECIS (Providing Regional Climates for Impact Studies) regional climate model, changes in plant functional types (PFTs) and leaf area index (LAI) were simulated via the Lund-Potsdam-Jena dynamic global vegetation model. Subsequently, predicted PFTs and LAIs were employed in the Xinanjiang vegetation-hydrology model for rainfall–runoff simulations. Results reveal that future long-term changes in precipitation, air temperature and atmospheric CO2 concentration would remarkably affect the spatiotemporal distribution of PFTs and LAIs. These climate-driven vegetation changes would further influence regional water balance. With the decrease in forest cover in the 21st century, plant transpiration and evaporative loss of intercepted canopy water will tend to fall while soil evaporation may rise considerably. As a result, total evapotranspiration may increase moderately with a slight increase in annual runoff depth. This indicates that, for long-term hydrological prediction, climate-induced changes in terrestrial vegetation cannot be neglected as the terrestrial biosphere plays an important role in land-surface hydrological responses.
One-dimensional hydrodynamic model accounting for tidal effect
Authors: Zhang Xiaoqin , Bao Weimin , Qu Simin , Yu Zhongbo
Published: February 2013

Tidal effect has a significant impact on flood routing in tidal rivers, conceptually taking on a resistant effect during flood tide and a dynamic effect during ebb tide. Two expressions were developed to reflect the tidal effect in this study, which consisted of the tidal wave velocity, the change rate of tidal level and the change in channel width. By incorporating the expressions into the momentum equation of the one-dimensional (1D) Saint-Venant equations, we propose that there are two types of momentum equations accounting for tidal effect. Based on the continuity equation and proposed momentum equations, two types of 1D hydrodynamic model for tidal rivers (namely the SVN-1 and -2 models) were constructed. In the case study, these models were applied to the tidal reach of the Qiantang River in China. The simulation results show that the SVN-1 and -2 models can obtain better accuracy than the SVN model based on the standard Saint-Venant equations, and that the SVN-1 model performs better than the SVN-2 model. Furthermore, the SVN-1 model can effectively capture water-level fluctuation, indicating that the expression employed is capable of accounting for tidal effect.
Impact of the Three Gorges reservoir operation on downstream ecological water requirements
Authors: Li Qiongfang , Yu Meixiu , Zhao Jianhua , Cai Tao , Lu Guobin , Xie Wei , Bai Xue
Published: February 2013

With population increase and economic growth, the flow regime of the Yangtze River has been altered to some extent by human activities, particularly dam construction. Dam-induced alterations in the flow regime of the Yangtze River will unavoidably influence water allocation among different water users and instream ecological water requirements may not be guaranteed during some months, particularly during phases of reservoir storing water. To assess the impacts of the Three Gorges reservoir operation on the downstream minimum instream ecological water requirements, this paper selected the Three Gorges reservoir and Yichang hydrological station below the reservoir as case study sites. On the basis of long-term time series of daily discharge data, the reservoir outflow was simulated under two water storing schemes and the degree to which the downstream minimum ecological flow was satisfied was computed. The results of this paper could provide references for the integrated management of the Yangtze River water resources and the assessment of dam-induced impacts on the Yangtze River ecosystem health.
The solution to DEM resolution effects and parameter inconsistency by using scale-invariant TOPMODEL
Authors: Xu Jing , Ren Liliang , Yuan Fei , Liu Xiaofan
Published: February 2013

The parameter calibration of TOPMODEL is influenced by digital elevation model (DEM) resolution because of the utilization of scale-dependent topographic index representing hydrologic similarity. The downscaled DEM from the coarse-resolution DEM and the resolution factor are applied to remove the DEM scale effects on the upslope area. Meanwhile, a fractal method is introduced as an approach to account for the effect of DEM resolution on slope. A significant improvement on the estimation of slope directly from the coarse-resolution data is made by applying fractal parameters that are computed from the standard deviation of elevation and the topographic complexity index in a 3 × 3 window of the DEM to account for local variability in the surface. The method to downscale the topographic index distribution is then coupled with the TOPMODEL to develop the scale-invariant TOPMODEL and is applied to perform streamflow simulation in the context of different DEM resolutions in the Zishui catchment. Results show that the calculated hydrograph based on the DEM data at 900 and 1,800 m resolution is consistent with that based on the DEM data at 100 m resolution when the same parameter set is used.