bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of etomidate on complications related to intubation and on mortality in septic shock patients treated with hydrocortisone: a propensity score analysis
Authors: Jung Boris , Clavieras Noemie , Nougaret Stephanie , Molinari Nicolas , Roquilly Antoine , Cisse Moussa , Carr Julie , Chanques Gerald , Asehnoune Karim , Jaber Samir
Published: November 2012

Introduction

Endotracheal intubation in the ICU is associated with a high incidence of complications. Etomidate use is debated in septic shock because it increases the risk of critical illness-related corticosteroid insufficiency, which may impact outcome. We hypothesized that hydrocortisone, administered in all septic shock cases in our ICU, may counteract some negative effects of etomidate.

The aim of our study was to compare septic shock patients who received etomidate versus another induction drug both for short-term safety and for long-term outcomes.

Methods

A single-center observational study was carried out in septic shock patients, treated with hydrocortisone and intubated within the first 48 hours of septic shock. Co-primary end points were life-threatening complications incidence occurring within the first hour after intubation and mortality during the ICU stay. Statistical analyses included unmatched and matched cohorts using a propensity score analysis. P < 0.05 was considered significant.

Results

Sixty patients in the etomidate cohort and 42 patients in the non-etomidate cohort were included. Critical illness-related corticosteroid insufficiency was 79% in the etomidate cohort and 52% in the non-etomidate cohort (P = 0.01). After intubation, life-threatening complications occurred in 36% of the patients whatever the cohort. After adjustment with propensity score analysis, etomidate was a protective factor for death in the ICU both in unmatched (hazard ratio, 0.33 (0.15 to 0.75); P < 0.01)) and matched cohorts (hazard ratio, 0.33 (0.112 to 0.988); P = 0.04).

Conclusion

In septic shock patients treated with hydrocortisone, etomidate did not decrease life-threatening complications following intubation, but when associated with hydrocortisone it also did not impair outcome.
Cost-effectiveness of early intervention in first-episode psychosis: economic evaluation of a randomised controlled trial (the OPUS study)
Authors: Hastrup Lene Halling , Kronborg Christian , Bertelsen Mette , Jeppesen Pia , Jorgensen Per , Petersen Lone , Thorup Anne , Simonsen Erik , Nordentoft Merete
Published: November 2012

Background

Information about the cost-effectiveness of early intervention programmes for first-episode psychosis is limited.

Aims

To evaluate the cost-effectiveness of an intensive early-intervention programme (called OPUS) (trial registration NCT00157313) consisting of enriched assertive community treatment, psychoeducational family treatment and social skills training for individuals with first-episode psychosis compared with standard treatment.

Method

An incremental cost-effectiveness analysis of a randomised controlled trial, adopting a public sector perspective was undertaken.

Results

The mean total costs of OPUS over 5 years (€123683, s.e. = 8970) were not significantly different from that of standard treatment (€148751, s.e. = 13073). At 2-year follow-up the mean Global Assessment of Functioning (GAF) score in the OPUS group (55.16, s.d. = 15.15) was significantly higher than in standard treatment group (51.13, s.d. = 15.92). However, the mean GAF did not differ significantly between the groups at 5-year follow-up (55.35 (s.d. = 18.28) and 54.16 (s.d. = 18.41), respectively). Cost-effectiveness planes based on non-parametric bootstrapping showed that OPUS was less costly and more effective in 70% of the replications. For a willingness-to-pay up to €50000 the probability that OPUS was cost-effective was more than 80%.

Conclusions

The incremental cost-effectiveness analysis showed that there was a high probability of OPUS being cost-effective compared with standard treatment.
Horsepower Hubris
Authors: Slavick Susanne
Published: November 2012

Horsepower Hubris presents hand-painted digital prints that examine vehicles as both weapons and targets of war. Painted motifs and passages borrowed primarily from Persian miniatures combine with contemporary media images of wartime destruction, exposing what has been lost, offering a tentative restitution, and evoking empathic unsettlement. Images of warrior steeds and more contemporary vehicles of violence reflect our aggressive impulses and their consequences, revealing sad continuities between ancient and ongoing armed conflicts.
Non-autonomous crosstalk between the Jak/Stat and Egfr pathways mediates Apc1-driven intestinal stem cell hyperplasia in the Drosophila adult midgut
Authors: Cordero Julia B. , Stefanatos Rhoda K. , Myant Kevin , Vidal Marcos , Sansom Owen J.
Published: November 2012

Inactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia following loss of Apc in the intestine. Our results indicate that the conserved Wnt target Myc and its binding partner Max are required for the initiation and maintenance of intestinal stem cell (ISC) hyperproliferation following Apc1 loss. Importantly, we find that loss of Apc1 leads to the production of the interleukin-like ligands Upd2/3 and the EGF-like Spitz in a Myc-dependent manner. Loss of Apc1 or high Wg in ISCs results in non-cell-autonomous upregulation of upd3 in enterocytes and subsequent activation of Jak/Stat signaling in ISCs. Crucially, knocking down Jak/Stat or Spitz/Egfr signaling suppresses Apc1-dependent ISC hyperproliferation. In summary, our results uncover a novel non-cell-autonomous interplay between Wnt/Myc, Egfr and Jak/Stat signaling in the regulation of intestinal hyperproliferation. Furthermore, we present evidence suggesting potential conservation in mouse models and human CRC. Therefore, the Drosophila adult midgut proves to be a powerful genetic system to identify novel mediators of APC phenotypes in the intestine.
Importance of the pluripotency factor LIN28 in the mammalian nucleolus during early embryonic development
Authors: Vogt Edgar J. , Meglicki Maciej , Hartung Kristina Ilka , Borsuk Ewa , Behr Rüdiger
Published: November 2012

The maternal nucleolus is required for proper activation of the embryonic genome (EGA) and early embryonic development. Nucleologenesis is characterized by the transformation of a nucleolar precursor body (NPB) to a mature nucleolus during preimplantation development. However, the function of NPBs and the involved molecular factors are unknown. We uncover a novel role for the pluripotency factor LIN28, the biological significance of which was previously demonstrated in the reprogramming of human somatic cells to induced pluripotent stem (iPS) cells. Here, we show that LIN28 accumulates at the NPB and the mature nucleolus in mouse preimplantation embryos and embryonic stem cells (ESCs), where it colocalizes with the nucleolar marker B23 (nucleophosmin 1). LIN28 has nucleolar localization in non-human primate (NHP) preimplantation embryos, but is cytoplasmic in NHP ESCs. Lin28 transcripts show a striking decline before mouse EGA, whereas LIN28 protein localizes to NPBs at the time of EGA. Following knockdown with a Lin28 morpholino, the majority of embryos arrest between the 2- and 4-cell stages and never develop to morula or blastocyst. Lin28 morpholino-injected embryos arrested at the 2-cell stage were not enriched with nucleophosmin at presumptive NPB sites, indicating that functional NPBs were not assembled. Based on these results, we propose that LIN28 is an essential factor of nucleologenesis during early embryonic development.
The effort to make mosaic analysis a household tool
Authors: Xu Tian , Rubin Gerald M.
Published: November 2012

The analysis of genetic mosaics, in which an animal carries populations of cells with differing genotypes, is a powerful tool for understanding developmental and cell biology. In 1990, we set out to improve the methods used to make genetic mosaics in Drosophila by taking advantage of recently developed approaches for genome engineering. These efforts led to the work described in our 1993 Development paper.
The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate inDrosophilaphotoreceptors
Authors: Xiong Wenjun , Morillo Santiago A. , Rebay Ilaria
Published: November 2012

The development of a functional organ requires coordinated programs of cell fate specification, terminal differentiation and morphogenesis. Whereas signaling mechanisms that specify individual cell fates are well documented, little is known about the pathways and molecules that maintain these fates stably as normal development proceeds or how their dysregulation may contribute to altered cell states in diseases such as cancer. In Drosophila, the tyrosine kinase Abelson (Abl) interfaces with multiple signaling pathways to direct epithelial and neuronal morphogenesis during embryonic and retinal development. Here we show that Abl is required for photoreceptor cell fate maintenance, as Abl mutant photoreceptors lose neuronal markers during late pupal stages but do not re-enter a proliferative state or undergo apoptosis. Failure to maintain the differentiated state correlates with impaired trafficking of the Notch receptor and ectopic Notch signaling, and can be suppressed by reducing the genetic dose of Notch or of its downstream transcriptional effector Suppressor of Hairless. Together, these data reveal a novel mechanism for maintaining the terminally differentiated state of Drosophila photoreceptors and suggest that neuronal fates in the fly retina retain plasticity late into development. Given the general evolutionary conservation of developmental signaling mechanisms, Abl-mediated regulation of Notch could be broadly relevant to cell fate maintenance and reprogramming during normal development, regeneration and oncogenic transformation.
Acoustic gaze adjustments during active target selection in echolocating porpoises
Authors: Wisniewska Danuta Maria , Johnson Mark , Beedholm Kristian , Wahlberg Magnus , Madsen Peter Teglberg
Published: November 2012

Visually dominant animals use gaze adjustments to organize perceptual inputs for cognitive processing. Thereby they manage the massive sensory load from complex and noisy scenes. Echolocation, as an active sensory system, may provide more opportunities to control such information flow by adjusting the properties of the sound source. However, most studies of toothed whale echolocation have involved stationed animals in static auditory scenes for which dynamic information control is unnecessary. To mimic conditions in the wild, we designed an experiment with captive, free-swimming harbor porpoises tasked with discriminating between two hydrophone-equipped targets and closing in on the selected target; this allowed us to gain insight into how porpoises adjust their acoustic gaze in a multi-target dynamic scene. By means of synchronized cameras, an acoustic tag and on-target hydrophone recordings we demonstrate that porpoises employ both beam direction control and range-dependent changes in output levels and pulse intervals to accommodate their changing spatial relationship with objects of immediate interest. We further show that, when switching attention to another target, porpoises can set their depth of gaze accurately for the new target location. In combination, these observations imply that porpoises exert precise vocal-motor control that is tied to spatial perception akin to visual accommodation. Finally, we demonstrate that at short target ranges porpoises narrow their depth of gaze dramatically by adjusting their output so as to focus on a single target. This suggests that echolocating porpoises switch from a deliberative mode of sensorimotor operation to a reactive mode when they are close to a target.
Strike mechanics of an ambush predator: the spearing mantis shrimp
Authors: deVries M. S. , Murphy E. A. K. , Patek S. N.
Published: November 2012

Ambush predation is characterized by an animal scanning the environment from a concealed position and then rapidly executing a surprise attack. Mantis shrimp (Stomatopoda) consist of both ambush predators (‘spearers’) and foragers (‘smashers’). Spearers hide in sandy burrows and capture evasive prey, whereas smashers search for prey away from their burrows and typically hammer hard-shelled, sedentary prey. Here, we examined the kinematics, morphology and field behavior of spearing mantis shrimp and compared them with previously studied smashers. Using two species with dramatically different adult sizes, we found that strikes produced by the diminutive species, Alachosquilla vicina, were faster (mean peak speed 5.72±0.91 m s–1; mean duration 3.26±0.41 ms) than the strikes produced by the large species, Lysiosquillina maculata (mean peak speed 2.30±0.85 m s–1; mean duration 24.98±9.68 ms). Micro-computed tomography and dissections showed that both species have the spring and latch structures that are used in other species for producing a spring-loaded strike; however, kinematic analyses indicated that only A. vicina consistently engages the elastic mechanism. In the field, L. maculata ambushed evasive prey primarily at night while hidden in burrows, striking with both long and short durations compared with laboratory videos. We expected ambush predators to strike with very high speeds, yet instead we found that these spearing mantis shrimp struck more slowly and with longer durations than smashers. Nonetheless, the strikes of spearers occurred at similar speeds and durations to those of other aquatic predators of evasive prey. Although counterintuitive, these findings suggest that ambush predators do not actually need to produce extremely high speeds, and that the very fastest predators are using speed to achieve other mechanical feats, such as producing large impact forces.
In Vivo Imaging of Nano-hydroxyapatite Biodistribution Using Positron Emission Tomography Imaging
Authors: Zheng Jun , Zhou Wei
Published: November 2012

18F-Radiolabeled nano-hydroxyapatite (HAP) was synthesized by a simple wet-chemical method. Then, anesthetized experimental rabbits were injected in the auricular vein with an 18F-radiolabeled nano-HAP suspension dispersed in physiological saline. Through PET/CT scanning, the nano-HAP biodistribution could be observed and analyzed in dynamically acquired PET images. The current work may provide a new approach for the investigation of the biodistribution and pharmacokinetics of nano-HAP and other related nanoparticles in vivo.
Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms
Authors: Erkelenz Steffen , Mueller William F. , Evans Melanie S. , Busch Anke , Schöneweis Katrin , Hertel Klemens J. , Schaal Heiner
Published: November 2012

Alternative splicing is regulated by splicing factors that modulate splice site selection. In some cases, however, splicing factors show antagonistic activities by either activating or repressing splicing. Here, we show that these opposing outcomes are based on their binding location relative to regulated 5′ splice sites. SR proteins enhance splicing only when they are recruited to the exon. However, they interfere with splicing by simply relocating them to the opposite intronic side of the splice site. hnRNP splicing factors display analogous opposing activities, but in a reversed position dependence. Activation by SR or hnRNP proteins increases splice site recognition at the earliest steps of exon definition, whereas splicing repression promotes the assembly of nonproductive complexes that arrest spliceosome assembly prior to splice site pairing. Thus, SR and hnRNP splicing factors exploit similar mechanisms to positively or negatively influence splice site selection.
Safe Dike Heights at Minimal Costs: The Nonhomogeneous Case
Authors: Brekelmans Ruud , Hertog Dick den , Roos Kees , Eijgenraam Carel
Published: November 2012

Dike height optimization is of major importance to the Netherlands because a large part of the country lies below sea level, and high water levels in rivers can cause floods. Recently impovements have been made on the cost-benefit model introduced by van Dantzig after the devastating flood in the Netherlands in 1953. We consider the extension of this model to nonhomogeneous dike rings, which may also be applicable to other deltas in the world. A nonhomogeneous dike ring consists of different segments with different characteristics with respect to flooding and investment costs. The individual segments can be heightened independently at different moments in time and by different amounts, making the problem considerably more complex than the homogeneous case. We show how the problem can be modeled as a mixed-integer nonlinear programming problem, and we present an iterative algorithm that can be used to solve the problem. Moreover, we consider a robust optimization approach to deal with uncertainty in the model parameters. The method has been implemented and integrated in software, which is used by the government to determine how the safety standards in the Dutch Water Act should be changed.
A Hierarchical Framework for Organizing a Software Development Process
Authors: Iravani Foad , Dasu Sriram , Ahmadi Reza
Published: November 2012

Every year, companies that produce commercial tax preparation software struggle with thousands of state and federal changes to tax laws and forms. Three competitors dominate the market with its short selling season, and release delays slash profits. Tax authorities issue updates August–December, and all changes must be processed and incorporated before year end. Systematic resource allocation and process management are crucial yet problematic due to the volume and complexity of changes, brief production time frame, and feedback loops for bug resolution. A leading tax software provider asked us to propose systematic approaches for managing process flow and staffing development stages with the goal of releasing the new version on time at minimum cost. To that end, we developed deterministic models that partitioned tax forms into development groups and determined staffing levels for each group. Partitioning forms into groups simplified workflow management and staffing decisions. To provide a range of resource configurations, we used two modeling approaches. Numerical experiments showed that our models capture the salient features of the process and that our heuristics perform well. Implementing our models reduced company overtime hours by 31% and total workforce cost by 13%.
Saying No!: Profligacy versus austerity, or metaphor against model in justifying the Arts and Humanities in the contemporary university
Authors: Pollock Griselda
Published: November 2012

Demonstrating an analysis of two musicals that both disclose and seek imaginatively to resolve political and economic conflict, an analysis that was the product of the radical interdisciplinary ‘studies’ movements of the culture wars in the late twentieth century university,
this article seeks to examine what modes of defence are available to the critical projects in the Arts and Humanities, developed in that moment, when now faced with the culture of austerity. Under the twin rationalizations of audit culture with the accountable excellence and the new model
that defines the Arts and Humanities as ‘profligate’ expenses in an age of financial rationing based on economic necessity and required technological orientation, there is a temptation to fall back on nostalgia for an imagined period of academic freedom identified, problematically
but not untruthfully, with struggles for democracy through and in education. Based on Hannah Arendt’s defence of thinking via a reading by Judith Butler, and with Gayatri Spivak’s notions of teaching to read as a necessary route to the creation of a planetary community, the article
seeks to go beyond the historically compromised defences of self-determining academic freedom, themselves shown to be founded in nationalist and imperialist agendas of the past.
Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone
Authors: Saha Bhaskar , Ypsilanti Athéna R. , Boutin Camille , Cremer Harold , Chédotal Alain
Published: November 2012

In the postnatal forebrain, the subventricular zone (SVZ) contains a pool of undifferentiated cells, which proliferate and migrate along the rostral migratory stream (RMS) to the olfactory bulb and differentiate into granule cells and periglomerular cells. Plexin-B2 is a semaphorin receptor previously known to act on neuronal proliferation in the embryonic brain and neuronal migration in the cerebellum. We show here that, in the postnatal and adult CNS, Plexin-B2 is expressed in the subventricular zone lining the telencephalic ventricles and in the rostral migratory stream. We analyzedPlxnb2−/−mice and found that there is a marked reduction in the proliferation of SVZ cells in the mutant. Plexin-B2 expression is downregulated in the olfactory bulb as interneurons initiate radial migration. BrdU labeling and GFP electroporation into postnatal SVZ, in addition to time-lapse videomicroscopy, revealed that neuroblasts deficient for Plexin-B2 migrate faster than control ones and leave the RMS more rapidly. Overall, these results show that Plexin-B2 plays a role in postnatal neurogenesis and in the migration of SVZ-derived neuroblasts.
Transmitter Release from Cochlear Hair Cells Is Phase Locked to Cyclic Stimuli of Different Intensities and Frequencies
Authors: Goutman Juan D.
Published: November 2012

The auditory system processes time and intensity through separate brainstem pathways to derive spatial location as well as other salient features of sound. The independent coding of time and intensity begins in the cochlea, where afferent neurons can fire action potentials at constant phase throughout a wide range of stimulus intensities. We have investigated time and intensity coding by simultaneous presynaptic and postsynaptic recording at the hair cell-afferent synapse from rats. Trains of depolarizing steps to the hair cell were used to elicit postsynaptic currents that occurred at constant phase for a range of membrane potentials over which release probability varied significantly. To probe the underlying mechanisms, release was examined using single steps to various command voltages. As expected for vesicular release, first synaptic events occurred earlier as presynaptic calcium influx grew larger. However, synaptic depression produced smaller responses with longer first latencies. Thus, during repetitive hair cell stimulation, as the hair cell is more strongly depolarized, increased calcium channel gating hurries transmitter release, but the resulting vesicular depletion produces a compensatory slowing. Quantitative simulation of ribbon function shows that these two factors varied reciprocally with hair cell depolarization (stimulus intensity) to produce constant synaptic phase. Finally, we propose that the observed rapid vesicle replenishment would help maintain the vesicle pool, which in turn would equilibrate with the stimulus intensity (and therefore the number of open Ca2+channels), so that for trains of different levels the average phase will be conserved.
Contribution of Cholinergic and GABAergic Mechanisms to Direction Tuning, Discriminability, Response Reliability, and Neuronal Rate Correlations in Macaque Middle Temporal Area
Authors: Thiele Alexander , Herrero Jose L. , Distler Claudia , Hoffmann Klaus-Peter
Published: November 2012

Previous studies have investigated the effects of acetylcholine (ACh) on neuronal tuning, coding, and attention in primary visual cortex, but its contribution to coding in extrastriate cortex is unexplored. Here we investigate the effects of ACh on tuning properties of macaque middle temporal area MT neurons and contrast them with effects of gabazine, a GABAAreceptor blocker. ACh increased neuronal activity, it had no effect on tuning width, but it significantly increased the direction discriminability of a neuron. Gabazine equally increased neuronal activity, but it widened tuning curves and decreased the direction discriminability of a neuron. Although gabazine significantly reduced response reliability, ACh application had little effect on response reliability. Finally, gabazine increased noise correlation of simultaneously recorded neurons, whereas ACh reduced it. Thus, both drugs increased firing rates, but only ACh application improved neuronal tuning and coding in line with effects seen in studies in which attention was selectively manipulated.
RIM Controls Homeostatic Plasticity through Modulation of the Readily-Releasable Vesicle Pool
Authors: Müller Martin , Liu Karen Suk Yin , Sigrist Stephan J. , Davis Graeme W.
Published: November 2012

Rab3 interacting molecules (RIMs) are evolutionarily conserved scaffolding proteins that are located at presynaptic active zones. In the mammalian nervous system, RIMs have two major activities that contribute to the fidelity of baseline synaptic transmission: they concentrate calcium channels at the active zone and facilitate synaptic vesicle docking/priming. Here we confirm that RIM has an evolutionarily conserved function at theDrosophilaneuromuscular junction and then define a novel role for RIM during homeostatic synaptic plasticity. We show that loss of RIM disrupts baseline vesicle release, diminishes presynaptic calcium influx, and diminishes the size of the readily-releasable pool (RRP) of synaptic vesicles, consistent with known activities of RIM. However, loss of RIM also completely blocks the homeostatic enhancement of presynaptic neurotransmitter release that normally occurs after inhibition of postsynaptic glutamate receptors, a process termed synaptic homeostasis. It is established that synaptic homeostasis requires enhanced presynaptic calcium influx as a mechanism to potentiate vesicle release. However, despite a defect in baseline calcium influx inrimmutants, the homeostatic modulation of calcium influx proceeds normally. Synaptic homeostasis is also correlated with an increase in the size of the RRP of synaptic vesicles, although the mechanism remains unknown. Here we demonstrate that the homeostatic modulation of the RRP is blocked in therimmutant background. Therefore, RIM-dependent modulation of the RRP is a required step during homeostatic plasticity. By extension, homeostatic plasticity appears to require two genetically separable processes, the enhancement of presynaptic calcium influx and a RIM-dependent modulation of the RRP.
Neurofibromin Mediates FAK Signaling in Confining Synapse Growth atDrosophilaNeuromuscular Junctions
Authors: Tsai Pei-I , Wang Manyu , Kao Hsiu-Hua , Cheng Ying-Ju , Walker James A. , Chen Ruey-Hwa , Chien Cheng-Ting
Published: November 2012

Neurofibromatosis type I (NF1), caused by the mutation in theNF1gene, is characterized by multiple pathological symptoms. Importantly, ∼50% of NF1 patients also suffer learning difficulty. Although downstream pathways are well studied, regulation of theNF1-encoded neurofibromin protein is less clear. Here, we focused on the pathophysiology ofDrosophila NF1mutants in synaptic growth at neuromuscular junctions. Our analysis suggests that theDrosophilaneurofibromin protein NF1 is required to constrain synaptic growth and transmission. NF1 functions downstream of theDrosophilafocal adhesion kinase (FAK) Fak56 and physically interacts with Fak56. The N-terminal region of NF1 mediates the interaction with Fak56 and is required for the signaling activity and presynaptic localization of NF1. In presynapses, NF1 acts via the cAMP pathway, but independent of its GAP activity, to restrain synaptic growth. Thus, presynaptic FAK signaling may be disrupted, causing abnormal synaptic growth and transmission in the NF1 genetic disorder.
KAYAK-α Modulates Circadian Transcriptional Feedback Loops inDrosophilaPacemaker Neurons
Authors: Ling Jinli , Dubruille Raphaëlle , Emery Patrick
Published: November 2012

Circadian rhythms are generated by well-conserved interlocked transcriptional feedback loops in animals. InDrosophila, the dimeric transcription factor CLOCK/CYCLE (CLK/CYC) promotesperiod(per),timeless(tim),vrille(vri), andPAR-domain protein 1(Pdp1) transcription. PER and TIM negatively feed back on CLK/CYC transcriptional activity, whereas VRI and PDP1 negatively and positively regulateClktranscription, respectively. Here, we show that the α isoform of theDrosophilaFOS homolog KAYAK (KAY) is required for normal circadian behavior. KAY-α downregulation in circadian pacemaker neurons increases period length by 1.5 h. This behavioral phenotype is correlated with decreased expression of several circadian proteins. The strongest effects are on CLK and the neuropeptide PIGMENT DISPERSING FACTOR, which are both under VRI and PDP1 control. Consistently, KAY-α can bind to VRI and inhibit its interaction with theClkpromoter. Interestingly, KAY-α can also repress CLK activity. Hence, in flies with low KAY-α levels, CLK derepression would partially compensate for increased VRI repression, thus attenuating the consequences of KAY-α downregulation on CLK targets. We propose that the double role of KAY-α in the two transcriptional loops controllingDrosophilacircadian behavior brings precision and stability to their oscillations.
Cognitive Enhancement with Rosiglitazone Links the Hippocampal PPARγ and ERK MAPK Signaling Pathways
Authors: Denner Larry A. , Rodriguez-Rivera Jennifer , Haidacher Sigmund J. , Jahrling Jordan B. , Carmical J. Russ , Hernandez Caterina M. , Zhao Yingxin , Sadygov Rovshan G. , Starkey Jonathan M. , Spratt Heidi , Luxon Bruce A. , Wood Thomas G. , Dineley Kelly T.
Published: November 2012

We previously reported that the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (RSG) improved hippocampus-dependent cognition in the Alzheimer's disease (AD) mouse model, Tg2576. RSG had no effect on wild-type littermate cognitive performance. Since extracellular signal-regulated protein kinase mitogen-activated protein kinase (ERK MAPK) is required for many forms of learning and memory that are affected in AD, and since both PPARγ and ERK MAPK are key mediators of insulin signaling, the current study tested the hypothesis that RSG-mediated cognitive improvement induces a hippocampal PPARγ pattern of gene and protein expression that converges with the ERK MAPK signaling axis in Tg2576 AD mice. In the hippocampal PPARγ transcriptome, we found significant overlap between peroxisome proliferator response element-containing PPARγ target genes and ERK-regulated, cAMP response element-containing target genes. Within the Tg2576 dentate gyrus proteome, RSG induced proteins with structural, energy, biosynthesis and plasticity functions. Several of these proteins are known to be important for cognitive function and are also regulated by ERK MAPK. In addition, we found the RSG-mediated augmentation of PPARγ and ERK2 activity during Tg2576 cognitive enhancement was reversed when hippocampal PPARγ was pharmacologically antagonized, revealing a coordinate relationship between PPARγ transcriptional competency and phosphorylated ERK that is reciprocally affected in response to chronic activation, compared with acute inhibition, of PPARγ. We conclude that the hippocampal transcriptome and proteome induced by cognitive enhancement with RSG harnesses a dysregulated ERK MAPK signal transduction pathway to overcome AD-like cognitive deficits in Tg2576 mice. Thus, PPARγ represents a signaling system that is not crucial for normal cognition yet can intercede to restore neural networks compromised by AD.
A Polymorphic Microsatellite Repeat within the ECE-1c Promoter Is Involved in Transcriptional Start Site Determination, Human Evolution, and Alzheimer's Disease
Authors: Li Yaosi , Seidel Kerstin , Marschall Peter , Klein Michael , Hope Antonia , Schacherl Jens , Schmitz Jennifer , Menk Mario , Schefe Jan H. , Reinemund Jana , Hugel Rebecca , Walden Peter , Schlosser Andreas , Volkmer Rudolf , Schimkus Julia , Kölsch Heike , Maier Wolfgang , Kornhuber Johannes , Frölich Lutz , Klare Sabrina , Kirsch Sebastian , Schmerbach Kristin , Scheele Sylvia , Grittner Ulrike , Zollmann Frank , Goldin-Lang Petra , Peters Oliver , Kintscher Ulrich , Unger Thomas , Funke-Kaiser Heiko
Published: November 2012

Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid β content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG]m–[CA]nECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.
Purging of Memories from Conscious Awareness Tracked in the Human Brain
Authors: Levy Benjamin J. , Anderson Michael C.
Published: November 2012

Understanding the neural basis of conscious experience and its regulation are fundamental goals of science. While recent research has made substantial progress in identifying the neural correlates of conscious experiences, it remains unclear how individuals exert control over the contents of awareness. In particular, can a memory that has entered the aware state be purged from consciousness if it is not currently desired? Here we tracked the correlates of consciousness in humans using functional magnetic resonance imaging and demonstrated the involvement of a downregulation mechanism that purges contents from conscious awareness. When individuals tried to prevent the retrieval of a memory in response to reminders, hippocampal activity was reduced, as previously established. Crucially, using trial-by-trial reports of phenomenal awareness, we found that this reduction of hippocampal activation was specifically associated with moments when a memory involuntarily intruded into conscious awareness and needed to be purged. This downregulation of activity during memory intrusions appears to disrupt momentary awareness of unwanted contents and, importantly, predicts impaired recall of the memory on later tests. These results tie the voluntary control of phenomenal awareness to observable changes in neural activity linked to awareness, and so provide a neurobiological model for guiding inquiry into the physical foundations of control over consciousness.
Suppression of β1-Integrin in Gonadotropin-Releasing Hormone Cells Disrupts Migration and Axonal Extension Resulting in Severe Reproductive Alterations
Authors: Parkash Jyoti , Cimino Irene , Ferraris Nicoletta , Casoni Filippo , Wray Susan , Cappy Hélène , Prevot Vincent , Giacobini Paolo
Published: November 2012

Reproduction in mammals is dependent on the function of hypothalamic neurons whose axons project to the hypothalamic median eminence (ME) where they release gonadotropin-releasing hormone (GnRH) into a specialized capillary network for delivery to the anterior pituitary. These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. The complex developmental events leading to the correct establishment of the GnRH system are tightly regulated by the specific spatiotemporal expression patterns of guidance cues and extracellular matrix molecules, the functions of which, in part, are mediated by their binding to β1-subunit-containing integrins. To determine the biological role of these cell-surface proteins in reproduction, Cre/LoxP technology was used to generate GnRH neuron-specific β1-integrin conditional KO (GnRH-Itgb1−/−) mice. Loss of β1-integrin signaling impaired migration of GnRH neurons, their axonal extension to the ME, timing of pubertal onset, and fertility in these mice. These results identify β1-integrin as a gene involved in normal development of the GnRH system and demonstrate a fundamental role for this protein in acquisition of normal reproductive competence in female mice.
Neural Correlates of Anticipation Risk Reflect Risk Preferences
Authors: Rudorf Sarah , Preuschoff Kerstin , Weber Bernd
Published: November 2012

Individual risk preferences have a large influence on decisions, such as financial investments, career and health choices, or gambling. Decision making under risk has been studied both behaviorally and on a neural level. It remains unclear, however, how risk attitudes are encoded and integrated with choice. Here, we investigate how risk preferences are reflected in neural regions known to process risk. We collected functional magnetic resonance images of 56 human subjects during a gambling task (Preuschoff et al., 2006). Subjects were grouped into risk averters and risk seekers according to the risk preferences they revealed in a separate lottery task. We found that during the anticipation of high-risk gambles, risk averters show stronger responses in ventral striatum and anterior insula compared to risk seekers. In addition, risk prediction error signals in anterior insula, inferior frontal gyrus, and anterior cingulate indicate that risk averters do not dissociate properly between gambles that are more or less risky than expected. We suggest this may result in a general overestimation of prospective risk and lead to risk avoidance behavior. This is the first study to show that behavioral risk preferences are reflected in the passive evaluation of risky situations. The results have implications on public policies in the financial and health domain.
Two novel mutations of the calcium-sensing receptor gene affecting the same amino acid position lead to opposite phenotypes and reveal the importance of p.N802 on receptor activity
Authors: Lia-Baldini Anne-Sophie , Magdelaine Corinne , Nizou Angélique , Airault Coraline , Salles Jean-Pierre , Moulin Pierre , Delemer Brigitte , Aitouares Mina , Funalot Benoît , Sturtz Franck , Lienhardt-Roussie Anne
Published: November 2012

Objective

Gain-of-function mutations of the calcium-sensing receptor (CASR) gene have been identified in patients with sporadic or familial autosomal dominant hypocalcemia (ADH). Inactivating mutations of the CASR gene cause familial hypocalciuric hypercalcemia (FHH). Here, we report two novel CASR mutations affecting the same amino acid (p.N802); one causes ADH and the other atypical FHH.

Patients and methods

The first patient, an 11-year-old girl suffering from hypocalcemia, developed nephrocalcinosis when she was only 5 years old. The second patient is a 30-year-old woman who presented with mild hypercalcemia. PCR amplification of CASR coding exons and direct sequencing of PCR products were used to identify mutations. Site-directed mutagenesis was used to generate mutated CASR cDNAs in an expression plasmid. Using the MAPK assay system and transient transfection of Cos-7 cells with wild-type (WT) and mutated CASR, we studied the responses of these mutated receptors to extracellular Ca2+ and to the negative allosteric CASR modulator, NPS2143.

Results

Two heterozygous missense mutations (p.N802I and p.N802S) affecting a residue in the sixth transmembrane domain of CASR were identified. In functional tests, the response of the p.N802S mutant to calcium was typical of an inactivating mutation. However, the p.N802I mutant had 70% of the maximally stimulated WT receptor activity even in the absence of extracellular calcium. This constitutive activity was only partially inhibited by the inhibitor, NPS2143.

Conclusions

The asparagine at amino acid position 802 appears to be essential for the activity of the CASR protein and is implicated in the mechanism of CASR signaling.
Effect of short-term GH and testosterone administration on body composition and glucose homoeostasis in men receiving chronic glucocorticoid therapy
Authors: Ragnarsson Oskar , Burt Morton G , Ho Ken K Y , Johannsson Gudmundur
Published: November 2012

Objective

Long-term pharmacological glucocorticoid (GC) therapy leads to skeletal muscle atrophy and weakness. The objective of this study was to investigate whether short-term treatment with GH and testosterone (T) can increase lean mass without major impairment of glucose homoeostasis in patients on GC therapy.

Design, materials and methods

This was a prospective, open-label, randomised, crossover study. Twelve men (age 74±6 years) on chronic GC treatment participated. The effects of 2 weeks' treatment with GH, testosterone and the combination of both on lean body mass (LBM), appendicular skeletal muscle mass (ASMM), extracellular water (ECW), body cell mass (BCM) and plasma glucose concentrations were investigated.

Results

LBM increased significantly after GH (Δ1.7±1.4 kg;P=0.007) and GH+testosterone (Δ2.4±1.1 kg;P=0.003), but not testosterone alone. ASMM increased after all three treatment periods; by 1.0±0.8 kg after GH (P=0.005), 1.7±0.4 kg after GH+testosterone (P=0.002) and 0.8±1.0 kg after testosterone (P=0.018). The increase in ASMM was larger with combined treatment than either GH or testosterone alone (P<0.05). ECW increased significantly after GH+testosterone by 1.5±2.6 l (P=0.038) but not after GH or testosterone alone. BCM increased slightly after single and combined treatments, but the changes were not significant. Fasting glucose increased significantly after GH (Δ0.4±0.4 mmol/l,P=0.006) while both fasting (Δ0.2±0.3 mmol/l,P=0.045) and post glucose-load (Δ1.8±2.3 mmol/l,P=0.023) plasma glucose concentrations increased after GH+testosterone.

Conclusions

GH and testosterone induce favourable and additive body compositional changes in men on chronic, low-dose GC treatment. In the doses used, combination therapy increases fasting and postprandial glucose concentration.
SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells
Authors: Moore Robert L , Faller Douglas V
Published: November 2012

In prostate and breast cancer, the androgen receptor and estrogen receptor (ER) mediate induction of androgen- and estrogen-responsive genes respectively and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a NAD+-dependent class III histone deacetylase that has been linked to gene silencing, control of the cell cycle, apoptosis, and energy homeostasis. In prostate cancer, SIRT1 is required for androgen antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is ERα dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERα in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase activity. Phosphorylated ERα subsequently accumulates in the nucleus, where ERα binds DNA ER-responsive elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ERα-mediated activation and target gene transcription. Like ligand-dependent activation of ERα, SIRT1 inhibition-mediated ERα activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.
Thermal expansion of corium prepared from UO2 and Zircaloy-2
Authors: Hirooka Shun , Akashi Masatoshi , Uchida Teppei , Morimoto Kyoichi , Kato Masato
Published: November 2012

In this study, sintered pellets were prepared from Zircaloy-2 oxide and UO2 as a parameter of content ratio (Zr contents were 0, 24.3, 49.0, 73.4, and 97.9 at% in metal). The sintered pellets were heated in 5%H2/Ar gas. UO2 pellets underwent simple thermal expansion caused by thermal vibration while Zircaloy-2 oxide pellets underwent thermal expansion and volume change with phase transformation. Finally, the 24.3, 49.0, and 73.5 at%Zr-UO2 pellet specimens showed both phenomena. However, phase transformation temperatures were lower than that of Zircaloy-2 oxide, and volume changes were much smaller. X-ray diffraction patterns obtained after thermal expansion measurements showed that the 24.3 at%Zr-UO2 specimen contained tetragonal and cubic (Zr, U)O2 while the 73.5 at%Zr-UO2 specimen contained mainly monoclinic ZrO2.
Biotechnological Mineral Composites via Vaterite Precursors
Authors: Weber E. , Guth C. , Eder M. , Bauer P. , Arzt E. , Weiss I. M.
Published: November 2012

Vaterite is one of the thermodynamically less stable polymorphs of calcium carbonate. Under ambient conditions it transforms into calcite, the most stable form of calcium carbonate. Organisms are able to stabilize minerals such as vaterite by means of organic molecules. The exact mechanisms how biomineralization proteins interact with metastable mineral phases are, however, less well understood. Many in vitro studies were performed using calcite as a model system. A deeper understanding of the interaction of organic molecules with metastable mineral phases would make them useful as a tool to control mineralization processes in vitro. In this study, we report on the co-precipitation of a natively soluble histidine-tagged GFP (green fluorecent protein) with a metastable vaterite phase and the subsequent insolubility of the fluorescent organic matrix in a 30μl calcium carbonate precipitation assay. The intrinsic fluorescence of GFP is conserved during the interaction with the mineral phase, indicating proper folding even in the insoluble state. This experiment can be extended to obtain deeper insights into some mechanistic models of biomineralization proteins by tracking native and modified GFP proteins microscopically during various stages of mineral precipitation and dissolution.
PROBING FRICTION FORCES USING GECKO MATERIALS
Authors: Puthoff J. B. , Holbrook M. , Wilkinson M. J. , Autumn K.
Published: November 2012

Geckos can cling to almost any surface using dense arrays of microscopic hierarchical hairs called setae. The flat, regular, terminal branches of the setae adhere by the van der Waals dispersion force, and the mechanics of the gecko attachment scheme are a current topic among biologists and researchers in smart materials for adhesion. We studied the friction behavior of natural gecko arrays. Our experiments demonstrate the presence of velocity strengthening dynamic friction over the range of velocities from 5×10–4to 158 mm/s and a range of specimen elastic moduli from 1.1 to 3.6 GPa. From these dynamic experiments, we calculate low-vactivation volumes between 1500 and 3000 nm3. Since these volumes are 3 orders of magnitude larger then are typical for bulk materials, we conclude that there is weak coupling between individual sliding contacts in the gecko system.