bluuebunny/crossref_metadata_2025 huggingface dataset:
American ginseng suppresses Western diet-promoted tumorigenesis in model of inflammation-associated colon cancer: role of EGFR
Authors: Dougherty Urszula , Mustafi Reba , Wang Yunwei , Musch Mark W , Wang Chong-Zhi , Konda Vani J , Kulkarni Anirudh , Hart John , Dawson Glyn , Kim Karen E , Yuan Chun-Su , Chang Eugene B , Bissonnette Marc
Published: December 2011

Background

Western diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth.

Methods

Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA.

Results

Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth.

Conclusions

Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.
Bridging health technology assessment (HTA) with multicriteria decision analyses (MCDA): field testing of the EVIDEM framework for coverage decisions by a public payer in Canada
Authors: Tony Michèle , Wagner Monika , Khoury Hanane , Rindress Donna , Papastavros Tina , Oh Paul , Goetghebeur Mireille M
Published: December 2011

Background

Consistent healthcare decisionmaking requires systematic consideration of decision criteria and evidence available to inform them. This can be tackled by combining multicriteria decision analysis (MCDA) and Health Technology Assessment (HTA). The objective of this study was to field-test a decision support framework (EVIDEM), explore its utility to a drug advisory committee and test its reliability over time.

Methods

Tramadol for chronic non-cancer pain was selected by the health plan as a case study relevant to their context. Based on extensive literature review, a by-criterion HTA report was developed to provide synthesized evidence for each criterion of the framework (14 criteria for the MCDA Core Model and 6 qualitative criteria for the Contextual Tool). During workshop sessions, committee members tested the framework in three steps by assigning: 1) weights to each criterion of the MCDA Core Model representing individual perspective; 2) scores for tramadol for each criterion of the MCDA Core Model using synthesized data; and 3) qualitative impacts of criteria of the Contextual Tool on the appraisal. Utility and reliability of the approach were explored through discussion, survey and test-retest. Agreement between test and retest data was analyzed by calculating intra-rater correlation coefficients (ICCs) for weights, scores and MCDA value estimates.

Results

The framework was found useful by the drug advisory committee in supporting systematic consideration of a broad range of criteria to promote a consistent approach to appraising healthcare interventions. Directly integrated in the framework as a "by-criterion" HTA report, synthesized evidence for each criterion facilitated its consideration, although this was sometimes limited by lack of relevant data. Test-retest analysis showed fair to good consistency of weights, scores and MCDA value estimates at the individual level (ICC ranging from 0.676 to 0.698), thus lending some support for the reliability of the approach. Overall, committee members endorsed the inclusion of most framework criteria and revealed important areas of discussion, clarification and adaptation of the framework to the needs of the committee.

Conclusions

By promoting systematic consideration of all decision criteria and the underlying evidence, the framework allows a consistent approach to appraising healthcare interventions. Further testing and validation are needed to advance MCDA approaches in healthcare decisionmaking.
Direct synthesis and characterization of optically transparent conformal zinc oxide nanocrystalline thin films by rapid thermal plasma CVD
Authors: Pedersen Joachim D , Esposito Heather J , Teh Kwok Siong
Published: December 2011

We report a rapid, self-catalyzed, solid precursor-based thermal plasma chemical vapor deposition process for depositing a conformal, nonporous, and optically transparent nanocrystalline ZnO thin film at 130 Torr (0.17 atm). Pure solid zinc is inductively heated and melted, followed by ionization by thermal induction argon/oxygen plasma to produce conformal, nonporous nanocrystalline ZnO films at a growth rate of up to 50 nm/min on amorphous and crystalline substrates including Si (100), fused quartz, glass, muscovite, c- and a-plane sapphire (Al2O3), gold, titanium, and polyimide. X-ray diffraction indicates the grains of as-deposited ZnO to be highly textured, with the fastest growth occurring along the c-axis. The individual grains are observed to be faceted by (103) planes which are the slowest growth planes. ZnO nanocrystalline films of nominal thicknesses of 200 nm are deposited at substrate temperatures of 330°C and 160°C on metal/ceramic substrates and polymer substrates, respectively. In addition, 20-nm- and 200-nm-thick films are also deposited on quartz substrates for optical characterization. At optical spectra above 375 nm, the measured optical transmittance of a 200-nm-thick ZnO film is greater than 80%, while that of a 20-nm-thick film is close to 100%. For a 200-nm-thick ZnO film with an average grain size of 100 nm, a four-point probe measurement shows electrical conductivity of up to 910 S/m. Annealing of 200-nm-thick ZnO films in 300 sccm pure argon at temperatures ranging from 750°C to 950°C (at homologous temperatures between 0.46 and 0.54) alters the textures and morphologies of the thin film. Based on scanning electron microscope images, higher annealing temperatures appear to restructure the ZnO nanocrystalline films to form nanorods of ZnO due to a combination of grain boundary diffusion and bulk diffusion.

PACS: films and coatings, 81.15.-z; nanocrystalline materials, 81.07.Bc; II-VI semiconductors, 81.05.Dz.
Active Learning Not Associated with Student Learning in a Random Sample of College Biology Courses
Authors: Andrews T. M. , Leonard M. J. , Colgrove C. A. , Kalinowski S. T.
Published: December 2011

Previous research has suggested that adding active learning to traditional college science lectures substantially improves student learning. However, this research predominantly studied courses taught by science education researchers, who are likely to have exceptional teaching expertise. The present study investigated introductory biology courses randomly selected from a list of prominent colleges and universities to include instructors representing a broader population. We examined the relationship between active learning and student learning in the subject area of natural selection. We found no association between student learning gains and the use of active-learning instruction. Although active learning has the potential to substantially improve student learning, this research suggests that active learning, as used by typical college biology instructors, is not associated with greater learning gains. We contend that most instructors lack the rich and nuanced understanding of teaching and learning that science education researchers have developed. Therefore, active learning as designed and implemented by typical college biology instructors may superficially resemble active learning used by education researchers, but lacks the constructivist elements necessary for improving learning.
Assessing the ‘true’ effect of active antidepressant therapy v. placebo in major depressive disorder: use of a mixture model
Authors: Thase Michael E. , Larsen Klaus G. , Kennedy Sidney H.
Published: December 2011

Background

There is controversy about the implications of relatively small average drug–placebo differences observed in randomised controlled trials of antidepressant medications.

Aims

To investigate whether efficacy is better understood as a large effect in a subgroup of patients.

Method

The mixture model was used to identify patient subgroups (patients benefiting or not benefiting from treatment) to directly model the skewness of Montgomery–åsberg Depression Rating Scale (MADRS) scores at week 8.

Results

The MADRS scores improved by 15.9 points (95% CI 15.2–16.6) among patients who benefited from treatment. The proportion of patients who benefited from escitalopram and not from placebo treatment was 19.5%, corresponding to a number needed to treat of 5.

Conclusions

This model gave a considerably better fit to the data than the analysis of covariance model in which all patients were assumed to benefit from treatment. The small average antidepressant–placebo difference obscures a much larger effect in a clinically meaningful subgroup of patients.
Limb bud colonization by somite-derived angioblasts is a crucial step for myoblast emigration
Authors: Yvernogeau Laurent , Auda-Boucher Gwenola , Fontaine-Perus Josiane
Published: December 2011

We have combined the use of mouse genetic strains and the mouse-into-chicken chimera system to determine precisely the sequence of forelimb colonization by presomitic mesoderm (PSM)-derived myoblasts and angioblasts, and the possible role of this latter cell type in myoblast guidance. By creating a new Flk1/Pax3 double reporter mouse line, we have established the precise timetable for angioblast and myoblast delamination/migration from the somite to the limb bud. This timetable was conserved when mouse PSM was grafted into a chicken host, which further validates the experimental model. The use of Pax3GFP/GFP knockout mice showed that establishment of vascular endothelial and smooth muscle cells (SMCs) is not compromised by the absence of Pax3. Of note, Pax3GFP/GFP knockout mouse PSM-derived cells can contribute to aortic, but not to limb, SMCs that are derived from the somatopleure. Finally, using the Flk1lacZ/lacZ knockout mouse, we show that, in the absence of angioblast and vascular network formation, myoblasts are prevented from migrating into the limb. Taken together, our study establishes for the first time the time schedule for endothelial and skeletal muscle cell colonization in the mouse limb bud and establishes the absolute requirement of endothelial cells for myoblast delamination and migration to the limb. It also reveals that cells delaminating from the somites display marked differentiation traits, suggesting that if a common progenitor exists, its lifespan is extremely short and restricted to the somite.
When cell cycle meets development
Authors: Kaldis Philipp , Richardson Helena E.
Published: December 2011

The recent Company of Biologists workshop ‘Growth, Division and Differentiation: Understanding Developmental Control’, which was held in September 2011 at Wiston House, West Sussex, UK, brought together researchers aiming to understand cell proliferation and differentiation in various metazoans, ranging from flies to mice. Here, we review the common themes that emerged from the meeting, highlighting novel insights into the interplay between regulators of cell proliferation and differentiation during development.
The second professional and detention renewal: an exploration of a generic statutory role
Authors: Brunskill David , Dorkins Eluned
Published: December 2011

The amended Mental Health Act of 2007 introduced the generic statutory role of the second professional in the renewal of authority for detention, with the purpose of providing an additional safeguard for patients. Completed detention renewals from a National Health Service (NHS) Trust were systematically collected over 12 months ( n = 47). Second professionals identified on Form H5 were requested to return a questionnaire designed to explore the role and the eligibility, knowledge base and attitudes of those fulfilling it, in comparison to the requirements as described in the code of practice and in relation to the stated purpose of the role. Twenty-eight second professionals completed questionnaires, giving a response rate of 60%. Several factors were identified which appeared to conspire against the notion that the aim of the role had been achieved in a meaningful way. The reasons underlying this included tokenistic statutory paperwork and a clear lack of specific training. Training needs identified included increasing legal knowledge and raising awareness of the ethical issues associated with a statutory role with a responsible nature. The findings challenge the assumption of readiness in those being asked to act in the generic statutory role of the second professional and highlight the potential for difficulties in the process of moving towards a cultural change of distributed responsibility in psychiatry, both in terms of the introduction of generic statutory roles in the absence of training and also with relevance to the changing nature of traditionally defined professional roles as suggested by new ways of working.
Adsorption of Fe(NO3)3 onto Activated Nylon-6,6 as a Container and a Possible “Smart” Corrosion Inhibitor-containing System
Authors: Menchaca Elsa C. , Hernández Sara , Tejeda Ana , Sarmiento Estela , Uruchurtu Jorge , García-Sánchez Miguel A.
Published: December 2011

Nylon-6,6 exhibits chemical, thermal and mechanical properties which include resistance to chemical attack, electrical insulating properties and degradation resistance. As a possible container, it can be used to manufacture a new family of active hybrid materials, coatings and corrosion inhibitor-containing systems. The release of encapsulated corrosion inhibitors is triggered by the corrosion process itself, which prevents the spontaneous leakage of such inhibitor and provides a quick response to changes in the service environment. With this in mind, nylon-6,6 pellets were activated using either γ-irradiation or chemical attack in alkaline solution. Better pore formation was achieved employing the latter method, with such pores being filled with adsorbed ferric nitrates. Electrochemical tests were undertaken to demonstrate the performance of the “ smart” nature of the corrosion inhibitor system formed.
Divergence and Flutter Instability of Damped Laminated Beams Subjected to a Triangular Distribution of Nonconservative Forces
Authors: Kim Nam-Il
Published: December 2011

The divergence and flutter instability behavior of the damped laminated beams subjected to a triangular distribution of subtangential forces are investigated based on the finite element model. The formal engineering approach of the mechanics for the laminated beam theory is presented and the extended Hamilton's principle is employed to obtain the mass, damping, elastic stiffness, geometric stiffness matrices, and the load correction stiffness matrix due to the nonconservative forces, respectively. The methods for the evaluation of the divergence and flutter loads of the nonconservative systems are briefly introduced in case of considering and neglecting external and internal damping effects. Throughout numerical examples, the influence of various parameters on the dynamic instability behavior of the laminated beams is newly investigated: 1) the variation of the divergence and flutter loads due to the nonconservativeness with respect to the fiber angle change, 2) the influence the boundary condition of beams on the instability region of the divergence-flutter system, 3) the influence of external and internal damping on the flutter load by analysis of complex natural frequencies.
Event-Related Repetitive Transcranial Magnetic Stimulation of Posterior Superior Temporal Sulcus Improves the Detection of Threatening Postural Changes in Human Bodies
Authors: Candidi Matteo , Stienen Bernard M. C. , Aglioti Salvatore Maria , de Gelder Beatrice
Published: December 2011

Perceiving others' emotions through their body movements and postures is crucial for successful social interaction. While imaging studies indicate that perceiving body emotions relies upon a wide network of subcortico-cortical neural regions, little is known on the causative role of different nodes of this network. We applied event-related repetitive transcranial magnetic stimulation (rTMS) over nonfacial, body- and action-related extrastriate (EBA), temporal (pSTS), and premotor (vPM) cortices to test their active contribution in perceiving changes between two successive images of either threatening or neutral human body or animal postures. While stimulation of EBA and vPM showed no selective effect on threatening stimuli with respect to neutral ones, rTMS over pSTS selectively impaired neutral posture detection and increased the accuracy in detecting changes of threatening human postures with respect to all other experimental conditions. No such effect was found for animal stimuli. These results support the notion that pSTS is crucially devoted to the detection of socially relevant information concerning others' actions, fostering the notion that amygdalo-temporo-cortical modulatory connections mediate perception of emotionally salient body postures.
Congenital CNS Hypomyelination in theFig4Null Mouse Is Rescued by Neuronal Expression of the PI(3,5)P2PhosphataseFig4
Authors: Winters Jesse J. , Ferguson Cole J. , Lenk Guy M. , Giger-Mateeva Vessela I. , Shrager Peter , Meisler Miriam H. , Giger Roman J.
Published: December 2011

The plt (pale tremor) mouse carries a null mutation in theFig4(Sac3)gene that results in tremor, hypopigmentation, spongiform degeneration of the brain, and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal–lysosomal pathway. In humans, the missense mutationFIG4I41Tcombined with aFIG4null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show thatFig4null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller-caliber axons lack myelin sheaths entirely, whereas many large- and intermediate-caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In theFig4null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution, but the number of myelinating OLs is greatly compromised. The total number of axons in theFig4null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression ofFig4, demonstrating a non-cell-autonomous function ofFig4in OL maturation and myelin development. In transgenic mice with global overexpression of the human pathogenicFIG4variant I41T, there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4I41Tmutant protein.
Noninvasive Associative Plasticity Induction in a Corticocortical Pathway of the Human Brain
Authors: Buch Ethan R. , Johnen Vanessa M. , Nelissen Natalie , O'Shea Jacinta , Rushworth Matthew F. S.
Published: December 2011

Coincident pairing of presynaptic and postsynaptic activity selectively strengthens synaptic connections, a key mechanism underlying cortical plasticity. Using paired associative transcranial magnetic stimulation (TMS), we demonstrate selective potentiation of physiological connectivity between two human brain regions, ventral premotor cortex (PMv) and primary motor cortex (M1) after repeated paired-pulse TMS of PMv and M1. The effect was anatomically specific: paired stimulation of the presupplementary motor area and M1 did not induce changes in PMv–M1 pathway connectivity. The effect was dependent on stimulation order: repeated stimulation of PMv before M1 led to strengthening of the PMv–M1 pathway, while repeated stimulation of M1 before PMv diminished the strength of the PMv–M1 pathway. The expression of the change in the pathway depended on the cognitive state of the subject at the time of testing: when the subject was tested at rest, paired PMv–M1 stimulation led to an increased inhibitory influence of PMv over M1, but when the subject was tested while engaged in a visuomotor task, PMv–M1 stimulation led to an increased facilitatory influence of PMv over M1. Plasticity evolved rapidly, lasted for at least 1 h, and began to reverse 3 h after intervention.
Getting Drowsy? Alert/Nonalert Transitions and Visual Thalamocortical Network Dynamics
Authors: Bereshpolova Yulia , Stoelzel Carl R. , Zhuang Jun , Amitai Yael , Alonso Jose-Manuel , Swadlow Harvey A.
Published: December 2011

The effects of different EEG brain states on spontaneous firing of cortical populations are not well understood. Such state shifts may occur frequently under natural conditions, and baseline firing patterns can impact neural coding (e.g., signal-to-noise ratios, sparseness of coding). Here, we examine the effects of spontaneous transitions from alert to nonalert awake EEG states in the rabbit visual cortex (5 s before and after the state-shifts). In layer 4, we examined putative spiny neurons and fast-spike GABAergic interneurons; in layer 5, we examined corticotectal neurons. We also examined the behavior of retinotopically aligned dorsal lateral geniculate nucleus (LGNd) neurons, usually recorded simultaneously with the above cortical populations. Despite markedly reduced firing and sharply increased bursting in the LGNd neurons following the transition to the nonalert state, little change occurred in the spiny neurons of layer 4. However, fast-spike neurons of layer 4 showed a paradoxical increase in firing rates as thalamic drive decreased in the nonalert state, even though some of these cells received potent monosynaptic input from the same LGNd neurons whose rates were reduced. The firing rates of corticotectal neurons of layer 5, similarly to spiny cells of layer 4, were not state-dependent, but these cells did become more bursty in the nonalert state, as did the fast-spike cells. These results show that spontaneous firing rates of midlayer spiny populations are remarkably conserved following the shift from alert to nonalert states, despite marked reductions in excitatory thalamic drive and increased activity in local fast-spike inhibitory interneurons.
Mechanism of Accelerated Current Decay Caused by an Episodic Ataxia Type-1-Associated Mutant in a Potassium Channel Pore
Authors: Peters Christian J. , Werry Daniel , Gill Hira S. , Accili Eric A. , Fedida David
Published: December 2011

In Kv1.1, single point mutants found below the channel activation gate at residue V408 are associated with human episodic ataxia type-1, and impair channel function by accelerating decay of outward current during periods of membrane depolarization and channel opening. This decay is usually attributed to C-type inactivation, but here we provide evidence that this is not the case. Using voltage-clamp fluorimetry inXenopusoocytes, and single-channel patch clamp in mouseltk− cells, of the homologousShakerchannel (with the equivalent mutation V478A), we have determined that the mutation may cause current decay through a local effect at the activation gate, by destabilizing channel opening. We demonstrate that the effect of the mutant is similar to that of trapped 4-aminopyridine in antagonizing channel opening, as the mutation and 10 mm4-AP had similar, nonadditive effects on fluorescence recorded from the voltage-sensitive S4 helix. We propose a model where the Kv1.1 activation gate fails to enter a stabilized open conformation, from which the channel would normally C-type inactivate. Instead, the lower pore lining helix is able to enter an activated-not-open conformation during depolarization. These results provide an understanding of the molecular etiology underlying episodic ataxia type-1 due to V408A, as well as biophysical insights into the links between the potassium channel activation gate, the voltage sensor and the selectivity filter.
Heterosynaptic Long-Term Potentiation at GABAergic Synapses of Spinal Lamina I Neurons
Authors: Fenselau Henning , Heinke Bernhard , Sandkühler Jürgen
Published: December 2011

Neurons in spinal dorsal horn lamina I play a pivotal role for nociception that critically depends on a proper balance between excitatory and inhibitory inputs. Any modification in synaptic strength may challenge this delicate balance. Long-term potentiation (LTP) at glutamatergic synapses between nociceptive C-fibers and lamina I neurons is an intensively studied cellular model of pain amplification. In contrast, nothing is presently known about long-term changes of synaptic strength at inhibitory synapses in the spinal dorsal horn. Using a spinal cord–dorsal root slice preparation from rats, we show that conditioning stimulation of primary afferent fibers with a stimulating protocol that induces LTP at C-fiber synapses also triggered LTP at GABAergic synapses (LTPGABA). This LTPGABAwas heterosynaptic in nature and was mediated by activation of group I metabotropic glutamate receptors. Opening of ionotropic glutamate receptor channels of the AMPA/KA or NMDA subtype was not required for LTPGABA. Paired-pulse ratio, coefficient of variation, and miniature IPSCs analysis revealed that LTPGABAwas expressed presynaptically. Nitric oxide as a retrograde messenger signal mediated this increase of GABA release at spinal inhibitory synapses. This novel form of synaptic plasticity in spinal nociceptive circuits may be an essential mechanism to maintain the relative balance between excitation and inhibition and to improve the signal-to-noise ratio in nociceptive pathways.
Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy
Authors: DiFrancesco Jacopo C. , Barbuti Andrea , Milanesi Raffaella , Coco Stefania , Bucchi Annalisa , Bottelli Georgia , Ferrarese Carlo , Franceschetti Silvana , Terragni Benedetta , Baruscotti Mirko , DiFrancesco Dario
Published: December 2011

The hyperpolarization-activatedIhcurrent, coded for by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, controls synaptic integration and intrinsic excitability in many brain areas. Because of their role in pacemaker function, defective HCN channels are natural candidates for contributing to epileptogenesis. Indeed,Ihis pathologically altered after experimentally induced seizures, and several independent data indicate a link between dysfunctional HCN channels and different forms of epilepsy. However, direct evidence for functional changes of defective HCN channels correlating with the disease in human patients is still elusive.

By screening families with epilepsy for mutations inHcn1andHcn2genes, we found a recessive loss-of-function point mutation in the gene coding for the HCN2 channel in a patient with sporadic idiopathic generalized epilepsy. Of 17 screened members of the same family, the proband was the only one affected and homozygous for the mutation.

The mutation (E515K) is located in the C-linker, a region known to affect channel gating. Functional analysis revealed that homomeric mutant, but not heteromeric wild-type/mutant channels, have a strongly inhibited function caused by a large negative shift of activation range and slowed activation kinetics, effectively abolishing the HCN2 contribution to activity. After transfection into acutely isolated newborn rat cortical neurons, homomeric mutant, but not heteromeric wild type/mutant channels, lowered the threshold of action potential firing and strongly increased cell excitability and firing frequency when compared with wild-type channels.

This is the first evidence in humans for a single-point, homozygous loss-of-function mutation in HCN2 potentially associated with generalized epilepsy with recessive inheritance.
Syntaxin1A Lateral Diffusion Reveals Transient and Local SNARE Interactions
Authors: Ribrault Claire , Reingruber Jürgen , Petković Maja , Galli Thierry , Ziv Noam E. , Holcman David , Triller Antoine
Published: December 2011

At the synapse, vesicles stably dock at the active zone. However, in cellular membranes, proteins undergo a diffusive motion. It is not known how the motion of membrane proteins involved in vesicle exocytosis is compatible with both vesicle docking and the dynamic remodeling of the plasma membrane imposed by cycles of exocytosis and endocytosis. To address this question, we studied the motion of the presynaptic membrane protein syntaxin1A at both the population and single-molecule levels in primary cultures of rat spinal cord neurons. Syntaxin1A was rapidly exchanged between synaptic and extrasynaptic regions. Changes in syntaxin1A mobility were associated with interactions related to the formation of the exocytotic complex. Finally, we propose a reaction-diffusion model reconciling the observed diffusive properties of syntaxin at the population level and at the molecular level. This work allows us to describe the diffusive behavior and kinetics of interactions between syntaxin1A and its partners that lead to its transient stabilization at the synapse.
Visual Pathway for the Optokinetic Reflex in Infant Macaque Monkeys
Authors: Distler Claudia , Hoffmann Klaus-Peter
Published: December 2011

The horizontal optokinetic nystagmus (hOKN) in primates is immature at birth. To elucidate the early functional state of the visual pathway for hOKN, retinal slip neurons were recorded in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) of 4 anesthetized infant macaques. These neurons were direction selective for ipsiversive stimulus movement shortly after birth [postnatal day 9 (P9)], although at a lower direction selectivity index (DSI). The DSI in the older infants (P12, P14, P60) was not different from adults. A total of 96% of NOT-DTN neurons in P9, P12, and P14 were binocular, however, significantly more often dominated by the contralateral eye than in adults. Already in the youngest animals, NOT-DTN neurons were well tuned to different stimulus velocities; however, tuning was truncated toward lower stimulus velocities when compared with adults.

As early as at P12, electrical stimulation in V1 elicited orthodromic responses in the NOT-DTN. However, the incidence of activated neurons was much lower in infants (40–60% of the tested NOT-DTN neurons) than in adults (97%). Orthodromic latencies from V1 were significantly longer in P12–P14 (x= 12.2 ± 8.9 ms) than in adults (x= 3.51 ± 0.81 ms). At the same age, electrical stimulation in motion-sensitive area MT was more efficient in activating NOT-DTN neurons (80% of the tested cells) and yielded shorter latencies than in V1 (x= 7.8 ± 3.02 ms; adultx= 2.99 ± 0.85 ms).

The differences in discharge rate between neurons in the NOT-DTN contra- and ipsilateral to the stimulated eye are equivalent to the gain asymmetry between monocularly elicited OKN in temporonasal and nasotemporal direction at the various ages.
Morphologically Distinct Classes of Relay Cells Exhibit Regional Preferences in the Dorsal Lateral Geniculate Nucleus of the Mouse
Authors: Krahe Thomas E. , El-Danaf Rana N. , Dilger Emily K. , Henderson Scott C. , Guido William
Published: December 2011

A fundamental feature of the mammalian visual system is the presence of separate channels that work in parallel to efficiently extract and analyze specific elements of a visual scene. Despite the extensive use of the mouse as a model system, it is not clear whether such parallel organization extends beyond the retina to subcortical structures, such as the dorsal lateral geniculate (dLGN) of thalamus. To begin to address this, we examined the morphology of biocytin-filled relay cells recorded in dLGN of mice. Based on a quantitative assessment of their dendritic architecture, we found that even at early postnatal ages relay cells could be readily classified as X-like (biconical), Y-like (symmetrical), or W-like (hemispheric) and that each cell type was regionally specified in dLGN. X-like cells were confined primarily to the monocular ventral region of dLGN. Y-like cells occupied a central core that also contained ipsilateral eye projections, whereas W-like cells were found along the perimeter of dLGN. Similar to cat, Y-like cells were more prevalent than X- and W-like cells, and X-like cells tended to be smaller than other cell types. However, the dendritic fields of X- and W-like cells did not exhibit an orientation bias with respect to optic tract or boundaries of dLGN. Although we found clear morphological differences among relay cells, an analysis of their electrophysiological properties did not reveal any additional distinguishing characteristics. Overall, these data coupled with recent observations in the retina suggest that the mouse has many of the hallmark features of a system-wide parallel organization.
Real-time Avionics Optimization
Authors: Eisenbrand Friedrich , Niemeier Martin , Skutella Martin , Verschae José , Wiese Andreas
Published: December 2011

We report on the solution of a difficult optimization problem which arises in avionics industry. When constructing the on-board controlling-network of an airplane, the engineers need to solve a computationally highly complex problem. The goal is to assign periodic tasks to the processors on the plane and define a schedule for each processor. Current state-of-the-art approaches to tackle the problem are by far not powerful enough to solve instances of real-world size. With the help of the powerful algorithm engineering paradigm we analyzed the mathematical properties of the scheduling problem and designed sophisticated software based on the structural insights. We were able to design a model that outperformed current state-of-the-art approaches by several orders of magnitude. In particular, we could solve industrial size real-world instances to optimality. Our methods lead, for the first time, to an industrial strength tool to schedule aircraft sized instances.
Shortest Paths in Road Networks: From Practice to Theory and Back
Authors: Delling Daniel , Goldberg Andrew V. , Werneck Renato F.
Published: December 2011

We illustrate the use of the scientific method in algorithmics by surveying recent developments in route planning on road networks. Several speed-up techniques proposed in the past decade are intuitive, elegant, and very efficient in practice, but lacked a theoretical explanation of their observed performance. By introducing a formal definition of road networks, recent theoretical work closed this gap. It also predicted that a previously untested algorithm should be even faster, which was confirmed by a subsequent implementation.
A Bayesian Antedependence Model for Whole Genome Prediction
Authors: Yang Wenzhao , Tempelman Robert J
Published: December 2011

Hierarchical mixed effects models have been demonstrated to be powerful for predicting genomic merit of livestock and plants, on the basis of high-density single-nucleotide polymorphism (SNP) marker panels, and their use is being increasingly advocated for genomic predictions in human health. Two particularly popular approaches, labeled BayesA and BayesB, are based on specifying all SNP-associated effects to be independent of each other. BayesB extends BayesA by allowing a large proportion of SNP markers to be associated with null effects. We further extend these two models to specify SNP effects as being spatially correlated due to the chromosomally proximal effects of causal variants. These two models, that we respectively dub as ante-BayesA and ante-BayesB, are based on a first-order nonstationary antedependence specification between SNP effects. In a simulation study involving 20 replicate data sets, each analyzed at six different SNP marker densities with average LD levels ranging from r2 = 0.15 to 0.31, the antedependence methods had significantly (P < 0.01) higher accuracies than their corresponding classical counterparts at higher LD levels (r2 > 0. 24) with differences exceeding 3%. A cross-validation study was also conducted on the heterogeneous stock mice data resource (http://mus.well.ox.ac.uk/mouse/HS/) using 6-week body weights as the phenotype. The antedependence methods increased cross-validation prediction accuracies by up to 3.6% compared to their classical counterparts (P < 0.001). Finally, we applied our method to other benchmark data sets and demonstrated that the antedependence methods were more accurate than their classical counterparts for genomic predictions, even for individuals several generations beyond the training data.
The Genetic Basis of Heterosis: Multiparental Quantitative Trait Loci Mapping Reveals Contrasted Levels of Apparent Overdominance Among Traits of Agronomical Interest in Maize (Zea mays L.)
Authors: Larièpe A , Mangin B , Jasson S , Combes V , Dumas F , Jamin P , Lariagon C , Jolivot D , Madur D , Fiévet J , Gallais A , Dubreuil P , Charcosset A , Moreau L
Published: December 2011

Understanding the genetic bases underlying heterosis is a major issue in maize (Zea mays L.). We extended the North Carolina design III (NCIII) by using three populations of recombinant inbred lines derived from three parental lines belonging to different heterotic pools, crossed with each parental line to obtain nine families of hybrids. A total of 1253 hybrids were evaluated for grain moisture, silking date, plant height, and grain yield. Quantitative trait loci (QTL) mapping was carried out on the six families obtained from crosses to parental lines following the “classical” NCIII method and with a multiparental connected model on the global design, adding the three families obtained from crosses to the nonparental line. Results of the QTL detection highlighted that most of the QTL detected for grain yield displayed apparent overdominance effects and limited differences between heterozygous genotypes, whereas for grain moisture predominance of additive effects was observed. For plant height and silking date results were intermediate. Except for grain yield, most of the QTL identified showed significant additive-by-additive epistatic interactions. High correlation observed between heterosis and the heterozygosity of hybrids at markers confirms the complex genetic basis and the role of dominance in heterosis. An important proportion of QTL detected were located close to the centromeres. We hypothesized that the lower recombination in these regions favors the detection of (i) linked QTL in repulsion phase, leading to apparent overdominance for heterotic traits and (ii) linked QTL in coupling phase, reinforcing apparent additive effects of linked QTL for the other traits.
Novel Transcript Truncating Function of Rap1p Revealed by Synthetic Codon-Optimized Ty1 Retrotransposon
Authors: Yarrington Robert M , Richardson Sarah M , Lisa Huang Cheng Ran , Boeke Jef D
Published: December 2011

Extensive mutagenesis via massive recoding of retrotransposon Ty1 produced a synthetic codon-optimized retrotransposon (CO-Ty1). CO-Ty1 is defective for retrotransposition, suggesting a sequence capable of down-regulating retrotransposition. We mapped this sequence to a critical ∼20-bp region within CO-Ty1 reverse transcriptase (RT) and confirmed that it reduced Ty1 transposition, protein, and RNA levels. Repression was not Ty1 specific; when introduced immediately downstream of the green fluorescent protein (GFP) stop codon, GFP expression was similarly reduced. Rap1p mediated this down-regulation, as shown by mutagenesis and chromatin immunoprecipitation. A regular threefold drop is observed in different contexts, suggesting utility for synthetic circuits. A large reduction of RNAP II occupancy on the CO-Ty1 construct was observed 3′ to the identified Rap1p site and a novel 3′ truncated RNA species was observed. We propose a novel mechanism of transcriptional regulation by Rap1p whereby it serves as a transcriptional roadblock when bound to transcription unit sequences.
Pediatric Sports-Related Concussion Produces Cerebral Blood Flow Alterations
Authors: Maugans Todd A. , Farley Chad , Altaye Mekibib , Leach James , Cecil Kim M.
Published: December 2011

Objectives:

The pathophysiology of sports-related concussion (SRC) is incompletely understood. Human adult and experimental animal investigations have revealed structural axonal injuries, decreases in the neuronal metabolite N-acetyl aspartate, and reduced cerebral blood flow (CBF) after SRC and minor traumatic brain injury. The authors of this investigation explore these possibilities after pediatric SRC.

Patients And Methods:

Twelve children, ages 11 to 15 years, who experienced SRC were evaluated by ImPACT neurocognitive testing, T1 and susceptibility weighted MRI, diffusion tensor imaging, proton magnetic resonance spectroscopy, and phase contrast angiography at <72 hours, 14 days, and 30 days or greater after concussion. A similar number of age- and gender-matched controls were evaluated at a single time point.

Results:

ImPACT results confirmed statistically significant differences in initial total symptom score and reaction time between the SRC and control groups, resolving by 14 days for total symptom score and 30 days for reaction time. No evidence of structural injury was found on qualitative review of MRI. No decreases in neuronal metabolite N-acetyl aspartate or elevation of lactic acid were detected by proton magnetic resonance spectroscopy. Statistically significant alterations in CBF were documented in the SRC group, with reduction in CBF predominating (38 vs 48 mL/100 g per minute; P = .027). Improvement toward control values occurred in only 27% of the participants at 14 days and 64% at >30 days after SRC.

Conclusions:

Pediatric SRC is primarily a physiologic injury, affecting CBF significantly without evidence of measurable structural, metabolic neuronal or axonal injury. Further study of CBF mechanisms is needed to explain patterns of recovery.
Physical modelling analysis of the New Orleans levee breaches
Authors: Steedman R. Scott , Sharp Michael K.
Published: December 2011

As part of the Interagency Performance Evaluation Task Force (IPET) investigation into levee breaches in New Orleans following Hurricane Katrina, centrifuge modelling was undertaken of representative levee cross-sections on the 17th Street, Orleans and London Avenue Canals. Two mechanisms were observed leading to breaching of the levee in the models, both of which stemmed from a water-filled crack that formed in front of the flood wall. Depending on the foundation conditions and geometry of the levee and flood wall, the crack led either to a rotation of the flood wall landwards, with uplift and sliding on the top of the sand towards the landward toe of the levee, or to a translational (sliding) failure in the clay layer commencing from the bottom or toe of the flood wall. In the Orleans models no breach ensued, although it was clear these sections were close to failure. The centrifuge model tests identified, at an early stage in the IPET investigation, the importance of the ‘gap' mechanism affecting the stability of the flood walls, and confirmed that levee geometry and flood wall depth of penetration, together with the underlying soil profile, were critical to the performance of the system under flood loading.
TRAINING PRESCHOOL CHILDREN TO USE VISUAL IMAGINING AS A PROBLEM‐SOLVING STRATEGY FOR COMPLEX CATEGORIZATION TASKS
Authors: Kisamore April N. , Carr James E. , LeBlanc Linda A.
Published: December 2011

It has been suggested that verbally sophisticated individuals engage in a series of precurrent behaviors (e.g., covert intraverbal behavior, grouping stimuli, visual imagining) to solve problems such as answering questions (Palmer, 1991; Skinner, 1953). We examined the effects of one problem solving strategy—visual imagining—on increasing responses to intraverbal categorization questions. Participants were 4 typically developing preschoolers between the ages of 4 and 5 years. Visual imagining training was insufficient to produce a substantial increase in target responses. It was not until the children were prompted to use the visual imagining strategy that a large and immediate increase in the number of target responses was observed. The number of prompts did not decrease until the children were given a rule describing the use of the visual imagining strategy. Within‐session response patterns indicated that none of the children used visual imagining prior to being prompted to do so and that use of the strategy continued after introduction of the rule. These results were consistent for 3 of 4 children. Within‐session response patterns suggested that the 4th child occasionally imagined when prompted to do so, but the gains were not maintained. The results are discussed in terms of Skinner's analysis of problem solving and the development of visual imagining.
INFANT SIGN TRAINING AND FUNCTIONAL ANALYSIS
Authors: Normand Matthew P. , Machado Mychal A. , Hustyi Kristin M. , Morley Allison J.
Published: December 2011

We taught manual signs to typically developing infants using a reversal design and caregiver‐nominated stimuli. We delivered the stimuli on a time‐based schedule during baseline. During the intervention, we used progressive prompting and reinforcement, described by Thompson et al. (2004, 2007), to establish mands. Following sign training, we conducted functional analyses and verified that the signs functioned as mands. These results provide preliminary validation for the verbal behavior functional analysis methodology and further evidence of the functional independence of verbal operants.
INCREASING RESPONSE VARIABILITY OF MAND FRAMES WITH SCRIPT TRAINING AND EXTINCTION
Authors: Betz Alison M. , Higbee Thomas S. , Kelley Kristen N. , Sellers Tyra P. , Pollard Joy S.
Published: December 2011

We examined the effects of script training and extinction on response variability of mand frames used by children with autism. Results demonstrated that extinction following script training was effective for increasing variability for 2 of the 3 participants.
RESISTANCE TO DISRUPTION IN A CLASSROOM SETTING
Authors: Parry‐Cruwys Diana E. , Neal Carrie M. , Ahearn William H. , Wheeler Emily E. , Premchander Raseeka , Loeb Melissa B. , Dube William V.
Published: December 2011

Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable‐interval (VI) 7‐s VI 30‐s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within‐session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants.