bluuebunny/crossref_metadata_2025 huggingface dataset:
Three‐dimensional seismic structure of a Mid‐Atlantic Ridge segment characterized by active detachment faulting (Trans‐Atlantic Geotraverse, 25°55′N‐26°20′N)
Authors: Zhao Minghui , Canales Juan Pablo , Sohn Robert A.
Published: October 2012

We use air gun shots recorded by ocean bottom seismometers (OBSs) to generate a three‐dimensional (3D)P‐wave tomographic velocity model of the Trans‐Atlantic Geotraverse (TAG) segment of the Mid‐Atlantic Ridge, and to search for evidence of reflections from a shallow crustal fault interface. Near‐vertical reflections were observed in some of the seismic records from OBSs deployed within the active seismicity zone defined by microearthquake hypocenters. Forward modeling of synthetic seismograms indicates that these reflections are consistent with a fault interface dipping at a low angle toward the ridge axis. Our observations suggest that the fault zone may extend beneath the volcanic blocks forming the eastern valley wall. Our 3D tomographic results show that the across‐axis structural asymmetry associated with detachment faulting extends at least 15 km to the east of the ridge axis, indicating that detachment faulting and uplifting of deep lithologies has been occurring at the TAG segment for at least the last ∼1.35 Myr. The velocity model contains a 5 km by 8 km velocity anomaly within the detachment footwall. This anomaly, which is present beneath the active TAG hydrothermal mound, is characterized by a velocity inversion at 1.5–2.0 km below seafloor underlain by reducedP‐wave velocities (∼6.2–6.5 km/s compared to surrounding areas ∼7.0–7.2 km/s) extending down to 3.5 km below seafloor. The velocity anomaly likely results from some combination of thermal and/or hydrothermal processes, and in either case our results suggest that hydrothermal fluids circulate within the upper section of the detachment footwall beneath the active mound.
Reliability of decadal predictions
Authors: Corti S. , Weisheimer A. , Palmer T. N. , Doblas‐Reyes F. J. , Magnusson L.
Published: October 2012

The reliability of multi‐year predictions of climate is assessed using probabilistic Attributes Diagrams for near‐surface air temperature and sea surface temperature, based on 54 member ensembles of initialised decadal hindcasts using the ECMWF coupled model. It is shown that the reliability from the ensemble system is good over global land areas, Europe and Africa and for the North Atlantic, Indian Ocean and, to a lesser extent, North Pacific basins for lead times up to 6–9 years. North Atlantic SSTs are reliably predicted even when the climate trend is removed, consistent with the known predictability for this region. By contrast, reliability in the Indian Ocean, where external forcing accounts for most of the variability, deteriorates severely after detrending. More conventional measures of forecast quality, such as the anomaly correlation coefficient (ACC) of the ensemble mean, are also considered, showing that the ensemble has significant skill in predicting multi‐annual temperature averages.
The role of large‐scale atmospheric flow and Rossby wave breaking in the evolution of extreme windstorms over Europe
Authors: Hanley John , Caballero Rodrigo
Published: October 2012

We investigate the relationship between large‐scale atmospheric flow and the evolution of the most extreme windstorms affecting Western Continental Europe. The 25 most destructive Western Continental European wind storms are selected from a 43‐year climatology. 22 of these storms are grouped as having a similar trajectory and evolution. We show that these storms typically occur during particularly strong and persistent positive NAO anomalies which peak approximately 2 days before the storms' peak intensity; the NAO pattern then shifts eastward to a position over the European continent when the storms strike Europe. A temporal composite of potential temperature on the 2‐PVU surface suggests that this NAO shift is the result of simultaneous cyclonic and anticyclonic wave breaking penetrating further to the east than during a typical high‐NAO event. This creates an extremely intense, zonally‐orientated jet over the North Atlantic whose baroclinicity favours explosive intensification of storms while steering them into Western Continental Europe.
Coseismic and postseismic stress rotations due to great subduction zone earthquakes
Authors: Hardebeck Jeanne L.
Published: October 2012

The three largest recent great subduction zone earthquakes (2011 M9.0 Tohoku, Japan; 2010 M8.8 Maule, Chile; and 2004 M9.2 Sumatra‐Andaman) exhibit similar coseismic rotations of the principal stress axes. Prior to each mainshock, the maximum compressive stress axis was shallowly plunging, while immediately after the mainshock, both the maximum and minimum compressive stress axes plunge at ∼45°. Dipping faults can be oriented for either reverse or normal faulting in this post‐mainshock stress field, depending on their dip, explaining the observed normal‐faulting aftershocks without requiring a complete reversal of the stress field. The significant stress rotations imply near‐complete stress drop in the mainshocks, with >80% of the pre‐mainshock stress relieved in the Tohoku and Maule earthquakes and in the northern part of the Sumatra‐Andaman rupture. The southern part of the Sumatra‐Andaman rupture relieved ∼60% of the pre‐mainshock stress. The stress axes rotated back rapidly in the months following the Tohoku and Maule mainshocks, and similarly in the southern part of the Sumatra‐Andaman rupture. A rapid postseismic rotation is possible because the near‐complete stress drop leaves very little “background” stress at the beginning of the postseismic reloading. In contrast, there has been little or no postseismic rotation in the northern part of the Sumatra‐Andaman rupture over the 7 years since the mainshock. All M ≥8.0 subduction earthquakes since 1990 with an adequate number of pre‐ and post‐mainshock events were evaluated, and not all show similar coseismic stress rotations. Deeper earthquakes exhibit smaller coseismic stress rotations, likely due to increasing deviatoric stress with depth.
Seasonal forecasts of Arctic sea ice initialized with observations of ice thickness
Authors: Lindsay R. , Haas C. , Hendricks S. , Hunkeler P. , Kurtz N. , Paden J. , Panzer B. , Sonntag J. , Yungel J. , Zhang J.
Published: October 2012

Seasonal forecasts of the September 2012 Arctic sea ice thickness and extent are conducted starting from 1 June 2012. An ensemble of forecasts is made with a coupled ice‐ocean model. For the first time, observations of the ice thickness are used to correct the initial ice thickness distribution to improve the initial conditions. Data from two airborne campaigns are used: NASA Operation IceBridge and SIZONet. The model was advanced through April and May using reanalysis data from 2012 and for June–September it was forced with reanalysis data from the previous seven summers. The ice extent in the corrected runs averaged lower in the Pacific sector and higher in the Atlantic sector compared to control runs with no corrections. The predicted total ice extent is 4.4 +/− 0.5 M km2, 0.2 M km2 less than that made with the control runs but 0.8 M km2 higher than the observed September extent.
Temperature‐induced marine export production during glacial period
Authors: Chikamoto M. O. , Abe‐Ouchi A. , Oka A. , Smith S. Lan
Published: October 2012

Proxy records indicate that export production was enhanced at the onset of the last glaciation. We examine how glacial cooling affects marine export production through temperature‐dependent phytoplankton productivity and organic carbon remineralization using glacial climate simulation. Compared with the standard assumption of no temperature dependence as applied in existing paleoclimate models, including temperature‐dependence enhances export production globally under glacial climate conditions. The near freezing temperatures of Antarctic seawater significantly reduce organic carbon remineralization. Less remineralization than production results in increasing carbon export to the deep ocean. Nutrients remaining near the surface at high latitudes are advected to lower latitudes via Antarctic Intermediate Water, enhancing primary production, and hence export, in temperate and tropical regions as well. Including temperature‐dependence improves the model's agreement with the glacial proxy records of export production and stable carbon isotopes even under stably stratified conditions with a weakening of North Atlantic Deep Water.
Relationship between the Pacific and Atlantic stepwise climate change during the 1990s
Authors: Chikamoto Y. , Kimoto M. , Watanabe M. , Ishii M. , Mochizuki T.
Published: October 2012

A linkage between climate change in the Atlantic and the Pacific oceans during the 1990s is investigated using three versions of the coupled climate model MIROC and CMIP5 multi‐model ensemble. From the early 1990s to the early 2000s, the observed sea surface temperature (SST) shows warming in the North Atlantic and a La Niña‐like pattern in the Pacific. Associated with the SST pattern, the observations indicate a strengthened Walker circulation in the tropical Pacific and enhanced precipitation in the tropical Atlantic. These SST and precipitation patterns are simulated well by hindcast experiments with external forcing and an initialized ocean anomaly state but are poorly simulated by uninitialized simulation with external forcing only. In particular, the observed La Niña‐like SST pattern becomes prominent in ensemble members with large amplitudes of Atlantic Multidecadal Oscillation (AMO) index during 1996–1998. Our results suggest that ocean initialization in both the Pacific and the Atlantic plays an important role in predicting the Pacific stepwise climate change during the 1990s, which contributes to the accurate estimation of global temperature change in the coming decade. Forecasting typhoon frequency or marine fisheries production in the coming decade may be possible by improving the predictive skill of stepwise climate change.
Seismicity precursors to large earthquakes unified in a stress accumulation framework
Authors: Mignan Arnaud
Published: October 2012

Various seismicity patterns before large earthquakes have been reported in the literature. They include foreshocks (medium‐term acceleration and short‐term activation), quiescence, doughnut patterns and event migration. The existence of these precursory patterns is however debated. Here, we develop an approach based on the concept of stress accumulation to unify and categorize all claimed seismic precursors in a same physical framework. We first extend the Non‐Critical Precursory Accelerating Seismicity Theory (N‐C PAST), which already explains most precursors, to additionally include short‐term activation. Theoretical results are then compared to the time series observed prior to the 2009Mw = 6.3 L'Aquila, Italy, earthquake. We finally show that different precursory paths are possible before large earthquakes, with possible coupling of different patterns or non‐occurrence of any. This is described by a logic tree defined from the combined probabilities of occurrence of the mainshock at a given stress state and of precursory silent slip on the fault. In the case of the L'Aquila earthquake, the observed precursory path is coupling of quiescence and accelerating seismic release, followed by activation. These results provide guidelines for future research on earthquake predictability.
Beyond bulk entrainment and detrainment rates: A new framework for diagnosing mixing in cumulus convection
Authors: Nie Ji , Kuang Zhiming
Published: October 2012

A new framework for diagnosing mixing in cumulus convection is proposed, where the vertical evolution of the cloud mass flux distribution as a function of given parcel properties is viewed as a mapping process. Matrices that characterize this mapping process are constructed using a Lagrangian particle dispersion model embedded in a Large Eddy Simulation. Extending previous use of LES‐diagnosed bulk entrainment and detrainment rates to test bulk plume models, the construction of these mapping matrices from LES provides a reference, against which multiple‐parcel models can be compared. The framework is further applied to diagnose the response of shallow cumuli to a small temperature perturbation.
Observation of the multifractal spectrum in the heliosphere and the heliosheath by Voyager 1 and 2
Authors: Macek W. M. , Wawrzaszek A. , Carbone V.
Published: October 2012

We present first results of the multifractal scaling of the fluctuations of the interplanetary magnetic field strength as measured onboard Voyager 2 in the very distant heliosphere and even in the heliosheath. More specifically, the spectra observed by Voyager 2 in a wide range of heliospheric distances from 6 to 90 astronomical units (AU) are compared with those of Voyager 1 already analyzed between 7 and 107 AU. We focus on the singularity multifractal spectrum before and after crossing the termination heliospheric shock by Voyager 1 at 94 AU and Voyager 2 at 84 AU from the Sun. It is worth noting that the spectrum is prevalently right‐skewed inside the whole heliosphere. Moreover, we have observed a change of the asymmetry of the spectrum at the termination shock, where the spectrum changes from (left‐) right‐skewed in the very distant heliosphere to the (right‐) left‐skewed or possibly symmetric spectrum in the heliosheath. We confirm that the degree of multifractality falls steadily with the distance from the Sun. In addition, the multifractal structure is apparently modulated by the solar activity, with a time shift of several years, corresponding to a distance of about 10 AU, resulting from the evolution of the whole heliosphere. Hence this basic result also brings significant additional support to some earlier claims suggesting that the solar wind termination shock is asymmetric.
Observed near‐surface currents under high wind speeds
Authors: Chang Y.‐C. , Chen G.‐Y. , Tseng R.‐S. , Centurioni L. R. , Chu Peter C.
Published: October 2012

From the Surface Velocity Program (SVP) drifter current and QuikSCAT wind data, the relationship between the observed near‐surface current vectors and surface wind vectors for the northwestern Pacific Ocean under high winds (20–50 m s−1) are obtained with quantitative estimations of near‐surface drift ratio (current speed versus wind speed)r(∼2%) and near‐surface drift angleα (∼0°–10° to the right of the winds). These estimations keep unchanged after removing the surface geostrophic component. From the SVP drifter current and daily WindSat wind data, the estimated ris still approximately 2%. Three linear regression equations are obtained between the observed near‐surface current speeds and the surface wind stress for the high wind range.
The effects of deep convection on the concentration and size distribution of aerosol particles within the upper troposphere: A case study
Authors: Yin Yan , Chen Qian , Jin Lianji , Chen Baojun , Zhu Shichao , Zhang Xiaopei
Published: October 2012

A cloud resolving model coupled with a spectral bin microphysical scheme was used to investigate the effects of deep convection on the concentration and size distribution of aerosol particles within the upper troposphere. A deep convective storm that occurred on 1 December, 2005 in Darwin, Australia was simulated, and was compared with available radar observations. The results showed that the radar echo of the storm in the developing stage was well reproduced by the model. Sensitivity tests for aerosol layers at different altitudes were conducted in order to understand how the concentration and size distribution of aerosol particles within the upper troposphere can be influenced by the vertical transport of aerosols as a result of deep convection. The results indicated that aerosols originating from the boundary layer can be more efficiently transported upward, as compared to those from the mid‐troposphere, due to significantly increased vertical velocity through the reinforced homogeneous freezing of droplets. Precipitation increased when aerosol layers were lofted at different altitudes, except for the case where an aerosol layer appeared at 5.4–8.0 km, in which relatively more efficient heterogeneous ice nucleation and subsequent Wegener‐Bergeron‐Findeisen process resulted in more pronounced production of ice crystals, and prohibited the formation of graupel particles via accretion. Sensitivity tests revealed, at least for the cases considered, that the concentration of aerosol particles within the upper troposphere increased by a factor of 7.71, 5.36, and 5.16, respectively, when enhanced aerosol layers existed at 0–2.2 km, 2.2–5.4 km, and 5.4–8.0 km, with Aitken mode and a portion of accumulation mode (0.1–0.2μm) particles being the most susceptible to upward transport.
Space‐based observational constraints for 1‐D fire smoke plume‐rise models
Authors: Val Martin Maria , Kahn Ralph A. , Logan Jennifer A. , Paugam Ronan , Wooster Martin , Ichoku Charles
Published: October 2012

We use a plume height climatology derived from space‐based Multiangle Imaging Spectroradiometer (MISR) observations to evaluate the performance of a widely used plume‐rise model. We initialize the model with assimilated meteorological fields from the NASA Goddard Earth Observing System and estimated fuel moisture content at the location and time of the MISR measurements. Fire properties that drive the plume‐rise model are difficult to constrain, and we test the model with four estimates each of active fire area and total heat flux, obtained from Moderate Resolution Imaging Spectroradiometer (MODIS) fire radiative power (FRP) thermal anomalies available for each MISR plume and other empirical data. We demonstrate the degree to which the fire dynamical heat flux (related to active fire area and sensible heat flux) and atmospheric stability structure influence plume rise, although entrainment and possibly other less well constrained factors are also likely to be significant. Using atmospheric stability conditions, MODIS FRP, and MISR plume heights, we find that smoke plumes reaching high altitudes are characterized by higher FRP and weaker atmospheric stability conditions than those at low altitude, which tend to remain confined below the boundary layer, consistent with earlier results. However, over the diversity of conditions studied, the model simulations generally underestimate the plume height dynamic range observed by MISR and do not reliably identify plumes injected into the free troposphere, key information needed for atmospheric models to simulate smoke dispersion. We conclude that embedding in large‐scale atmospheric studies an advanced plume‐rise model using currently available fire constraints remains a difficult proposition, and we propose a simplified model that crudely constrains plume injection height based on two main physical factors for which some observational constraints often exist. Field experiments aimed at directly measuring fire and smoke plume properties in detail are likely to produce the next major advances in plume‐rise modeling.
Aluminum abundance on the surface of Mercury: Application of a new background‐reduction technique for the analysis of gamma‐ray spectroscopy data
Authors: Peplowski Patrick N. , Rhodes Edgar A. , Hamara David K. , Lawrence David J. , Evans Larry G. , Nittler Larry R. , Solomon Sean C.
Published: October 2012

A new technique has been developed for characterizing gamma‐ray emission from a planetary surface in the presence of large background signals generated in a spacecraft. This technique is applied to the analysis of Al gamma rays measured by the MESSENGER Gamma‐Ray Spectrometer to determine the abundance of Al on the surface of Mercury. The result (Al/Si = 0.29−0.13+0.05) is consistent with Al/Si ratios derived from the MESSENGER X‐Ray Spectrometer and confirms the finding of low Al abundances. The measured abundance rules out a global, lunar‐like feldspar‐rich crust and is consistent with previously suggested analogs for surface material on Mercury, including terrestrial komatiites, low‐iron basalts, partial melts of CB chondrites, and partial melts of enstatite chondrites. Additional applications of this technique include the measurement of other elements on Mercury's surface as well as the analysis of data from other planetary gamma‐ray spectrometer experiments.
ISKANDARnet IOMOS: Near real‐time equatorial space weather monitoring and alert system in Peninsular Malaysia
Authors: Musa Tajul Ariffin , Leong Shien Kwun , Abdullah Khairul Anuar , Othman Rusli
Published: October 2012

This work proposes ISKANDARnet Ionospheric Outburst MOnitoring and alert System (IOMOS), along with Ionospheric Outburst Index (IOX) to develop an operational near real‐time space weather service for Malaysia. The IOMOS is based on Global Positioning System (GPS) Network‐based Real‐Time Kinematic (NRTK) concept which is by nature for atmospheric (ionosphere and troposphere) modeling within the network coverage. The elegance of this solution lies in the fact that IOMOS utilize differential ionospheric residual from network of GPS baselines which incur no additional cost for operation. Users will be informed about the ionospheric perturbation through Short Message Service (SMS), email or Twitter®. This approach will ultimately beneficial for the navigation and satellite positioning communities, particularly during the coming Solar Cycle 24. In addition, a combination of local and global GPS network has been employed to study the equatorial ionosphere geomorphology and climatology in the Malaysian sector. Equatorial Total Electron Content (TEC) over Malaysia shows semi‐annual, annual, and seasonal variations with maximum values appearing during equinoctial months and minimum during solstices months. The TEC value during vernal equinox is about 21% higher than autumnal equinox, and December solstice exceeds that at the June solstice by around 14%. It is also found that semi‐annual variation is present at all levels of solar activity, whereas June solstice predominates December solstice during high solar activity for annual and seasonal variations. In near future, a near real‐time TEC derivation system will be developed to support equatorial ionosphere modeling to enhance space weather service for Malaysia.
Fellow travellers: emergent properties of collective cell migration
Authors: Rørth Pernille
Published: October 2012

Cells can migrate individually or collectively. Collective movement is common during normal development and is also a characteristic of some cancers. This review discusses recent insights into features that are unique to collective cell migration, as well as properties that emerge from these features. The first feature is that cells of the collective affect each other through adhesion, force‐dependent and signalling interactions. The second feature is that cells of the collective differ from one another: leaders from followers, tip from stalk and front from back. These are dynamic differences that are important for directional movement. Last, an unexpected property is discussed: epithelial cells can rotate persistently in constrained spaces.
Science and rock
Authors: Leão Maria João , Castro Sílvia
Published: October 2012

An innovative partnership between a research institute and a music festival is helping to connect scientists and young people in Portugal. It is also bringing in money to fund research.
Not too much and not too little
Authors: van Helden Paul
Published: October 2012

We tend to think in black and white terms of good versus bad alleles and their meaning for disease. However, in doing so, we ignore the potential importance of heterozygous alleles.
The flies of Icarus: science with wings in Crete
Authors: Miguel‐Aliaga Irene , Oliver Brian , Teleman Aurelio A
Published: October 2012

Around 100 researchers gathered at the eighteenth EMBO Conference on ‘The Molecular and Developmental Biology of Drosophila’, which took place in Crete in June 2012. Whether deconstructing or integrating at the genetic, cellular or organ level, the talks highlighted the synergy of combining methods, approaches and disciplines in this increasingly versatile model system.
Amino acid and peptide bioconjugates
Authors: Mihala Nikolett , Hudecz Ferenc
Published: October 2012

This review aims to highlight the most important advances made in the last 3 years in the area of the synthesis of peptide-bioconjugates. The idea is to provide a perspective regarding the current and developing trends with key findings and directions selected to illustrate the underlying potential, current challenges, and future directions.
Self-assembling peptide materials
Authors: Zhang Shuguang
Published: October 2012

Peptides are time-honored substances, ubiquitous in nature and useful in many fields, from argriculture as pestisides, in medicine as antibacteria and antifugal drugs founded in the innate immune systems, to medicinal chemistry as hornmones http://en.wikipedia.org/wiki/Peptide. However, the concept of peptide materials did not come to mind until 1990 when a self-assembling peptide as a repeating segment in a yeast protein was serendipitously discovered. As it was called, the materials peptide since they have bona fide materials property and are made from simple amino acids with amazing nanostructures under physiological conditions. These structures include well-ordered nanofibers, nanotubes and nanovesicles. These structures have been used for 3D tissue cell cultures of primary cells and stem cells, sustained releases of small molecules, growth factors and monoclonal antibody, for accelerated-wound healing in reparative and regenerative medicine as well as tissue engineering. Recent advances in molecular designs have also led to the development of 3D fine-tuned bioactive tissue culture scaffolds. They are also used to stabilize membrane proteins including difficult G-protein coupled receptors for designing nanobiodevices. One of self-assembling peptides has been used in human clinical trials for accelerated-wound healings. It is likely that these peptide materials will open doors for more and more diverse uses. The field of self-assembling peptide materials is growing in a number of directions in areas of materials, synthetic biology, clinical medicine and beyond.
Metal complexes of amino acids and peptides
Authors: Farkas Etelka , Sóvágó Imre
Published: October 2012

This chapter deals with the most important results and observations published on various aspects of the metal complex formation with amino acids, peptides and related ligands during the past two-three years. The major sources of the references collected here are the Abstracts reported by the Web of Science Databases on the Internet but the title pages of the most common journals of inorganic, bioinorganic and coordination chemistry have also been surveyed.
Model systems for folding and tertiary contacts in peptides: A perspective from the physical sciences
Authors: Crain Jason
Published: October 2012

The notions of hydrophobicity, hydrogen bonding and intramolecular flexibility are essential to a wide range of biological self-assembly phenomena including protein folding. The most familiar self-assembling systems comprise large, structurally complex molecules and, in the case of proteins, assembly of functional structures involves formation of so-called tertairy contacts which are widely separated in the primary sequence. Therefore detailed atomistic models of hydration and association are difficult to develop and are often controversial. Recent coordinated computational and experimental effort has focused not on biological macromolecules but on selected model systems. These (lower alcohols and minimal peptide fragments) have the virtue that they are structurally simple but may retain enough of the basic physics to make conclusions drawn from them potentially useful in wider contexts. Because of their simplicity, they can be examined in considerable detail using both experimental and atomistic simulation methods. In this review, we give an overview and comparison of experimental (neutron diffraction and optical spectroscopy) and computational conclusions leading to revised notions of hydration, hydrophobicity and thermodynamics with a focus on small aqueous amphiphiles and peptide fragments. Model systems for more complex phenomena are also introduced.
The Pathophysiology of Schizophrenia
Authors: Szegedi Armin , Egan Michael
Published: October 2012

Schizophrenia is a clinically and neurobiologically heterogeneous disorder that affects approximately 1% of the population worldwide. In the last century it has undergone and continues to undergo substantial changes in its conceptualization, the earlier concepts being driven mainly by clinical symptom classification, while in more recent years neurobiological findings are increasingly implemented. Many individuals experience a variety of symptoms, often in the symptom domains of positive, negative or affective symptoms as well as cognitive impairment. Affected individuals typically experience initial symptoms in the later teens or early adulthood, leading in a majority of cases to a chronic course of the disorder. Functional impairment is generally substantial, resulting in substantial burden of disease and reduced quality of life for the individual. The discovery of antipsychotic drugs in the mid 1950s fundamentally changed the prognosis for the patients, as mainly positive symptoms for the first time became amenable to treatment. However, though antipsychotic drugs have been developed further, overall efficacy has not been improved substantially, but the available antipsychotics vary mainly in their safety and tolerability profile, as well as individual response rates, which still cannot be predicted reliably.

An increasing amount of neurobiological data has been accumulated in the last decades, providing evidence for the involvement of dopamine and glutamate as well as other neurotransmitters in the etiopathology of various symptoms in schizophrenia. Evidence of structural abnormalities (e.g. volumetric reductions) has been found in neuropathological and neuroimaging studies. Cognitive impairment and its association with prefrontal cortical function have been well documented. The contribution of genetic factors is well established in addition to environmental and developmental factors, though the contribution of various candidate genes still remains to be elucidated in detail. The totality of neurobiological data has prompted integrative neurobiological theories, which are likely to have implications for drug discovery and drug development efforts in the future.
Monoaminergic Approaches for Treatment of Schizophrenia
Authors: Rotella David P.
Published: October 2012

Since the discovery of haloperidol in the 1950s, monoaminergic receptors have provided a number of potential targets for treatment of schizophrenia. This chapter will survey the profiles of existing dopaminergic-based antipsychotic drugs and review recent medicinal chemistry approaches that engage other monoaminergic receptors to discover novel agents for treatment of schizophrenia. In addition to single-target approaches, attempts to discover molecules that interact selectively (i.e. designed to bind) with more than a single receptor to provide effective antipsychotic agents will be reviewed. These efforts highlight attempts to address unmet needs with existing therapy, including efficacy in a broader range of patients of this complex and debilitating disease.
Glutamatergic Approaches for the Treatment of Schizophrenia
Authors: Morrow John A. , Gilfillan Robert , Neale Stuart A.
Published: October 2012

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and plays a key role in most aspects of normal brain function including cognition, learning and memory. Dysfunction of glutamatergic neurotransmission has been implicated in a number of neurological and psychiatric disorders with a growing body of evidence suggesting that hypofunction of glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor plays an important role in the pathophysiology of schizophrenia. It thus follows that potentiation of NMDA receptor function via pharmacological manipulation may provide therapeutic utility for the treatment of schizophrenia and a number of different approaches are currently being pursued by the pharmaceutical industry with this aim in mind. These include strategies that target the glycine/d-serine site of the NMDA receptor (glycine transporter GlyT1, d-serine transporter ASC-1 and d-amino acid oxidase (DAAO) inhibitors) together with those aimed at enhancing glutamatergic neurotransmission via modulation of AMPA receptor and metabotropic glutamate receptor function. Such efforts are now beginning to bear fruit with compounds such as the GlyT1 inhibitor RG1678 and mGlu2 agonist LY2140023 proving to have clinical meaningful effects in phase II clinical trials. While more studies are required to confirm long-term efficacy, functional outcome and safety in schizophrenic agents, these agents hold real promise for addressing unmet medical needs, in particular refractory negative and cognitive symptoms, not currently addressed by existing antipsychotic agents.
Treating the Cognitive Deficits of Schizophrenia
Authors: Rogers Bruce N. , Gray David L.
Published: October 2012

The cognitive deficits in schizophrenia (CDS) are recognized as a discrete cluster of impairments that can emerge before the onset of frank psychoses. Untreated CDS results in poor work, social and independent living outcomes. Although existing antipsychotic drugs effectively treat positive symptoms, they provide inadequate improvement in CDS in most schizophrenia patients. To address this medical need, significant efforts have been made to develop agents that treat the cognitive aspects of this disease specifically. This chapter provides a brief biological rationale for treatment and describes the most advanced clinical landscape and medicinal chemistry challenges within the main areas of drug discovery for CDS treatment. The main focus is on the α7 nicotinic acetylcholine receptor and the dopamine D1 receptor, two key research areas identified through the Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative as having the highest probability of yielding effective treatments. This chapter also provides a brief synopsis of targets in other areas such as M1 muscarinic acetylcholine receptor, serotonin subtype 6 receptor (5-HT6), histamine H3 and catechol-O-methyl transferase inhibitors.
The Neurobiology of Depression and Anxiety: How Do We Change from Models of Drug Efficacy to Understanding Mood and Anxiety Disorders?
Authors: Hodes Georgia E. , Russo Scott J.
Published: October 2012

Current treatments for depression and anxiety disorders are only effective in approximately half of the patient population. Effective treatments have negative side-effects including sexual dysfunction, weight gain and gastrointestinal problems. Furthermore, even when patients achieve remission, they often need to increase dosage or change treatment across their lifetime as efficacy weakens. The majority of treatments being used today are based on the monoamine hypothesis of depression, a theory of depression that was based on the effectiveness of drugs discovered by chance to alleviate the symptoms of depression. This chapter provides an overview of the neurobiology of depression and anxiety disorders within the context of drug discovery. The chapter starts with what we currently know about these disorders through the lens of the monoamine hypothesis of depression. We then provide a background into the animal models of depression and anxiety that are being used to understand the underlying biology of these disorders and test new treatments. Work conducted using these animal models has directed human imagining and has provided us with new information about both the molecular and cellular mechanism of depression and anxiety as well as the neural circuitry controlling these disorders. Finally, we will conclude with a discussion of new treatments being developed based on empirical evidence about the neurobiology of depression and anxiety and the need to develop more personalized treatments in the future. It is hoped that these new drugs will be able to provide effective treatment for more people, with fewer negative side-effects.
Beyond SSRIs: Second-generation Reuptake Inhibitors for the Treatment of Depression
Authors: Gallagher Peter T.
Published: October 2012

While the selective serotonin reuptake inhibitors (SSRIs) are an improvement over the earlier tricyclic antidepressants, they are limited in their effectiveness and have a unique side-effect profile. In this chapter is an assessment of the serotonin-mediated antidepressant strategies that have been identified from the primary and patent literature. The areas covered include combination serotonin reuptake inhibition and pre- or post-synaptic agonist and antagonist action. New approaches to targeting multiple biogenic amine transporters are discussed, as well as a summary of the stand-alone pre- and post-synaptic agonist and antagonist developments. The chapter focuses on the rationale for the antidepressant targets and the medicinal chemical strategies that have led to the newer molecular platforms.
Therapeutic Approaches to Bipolar Disorder
Authors: Ahmad Moghis U. , Ali Shoukath M. , Sheikh Saifuddin , Ahmad Ateeq , Ahmad Imran
Published: October 2012

Bipolar disorder (BPD) is a severe mental disorder that affects millions of people worldwide. BPD is recognized by abnormal mood swings from elation to depression. The cause of BPD is not entirely known but genetic, neurochemical and environmental factors are known to play a role in the onset and progression of BPD. BPD is considered as a biological disorder that occurs in a specific part of the brain and causes the neurotransmitters to malfunction. All of the anti-manic drugs available are either anticonvulsant or antipsychotic with the exception of lithium. Beginning with the discovery of the therapeutic effects of lithium, there have been encouraging developments in the treatment of BPD. Although there are no cures, significant pharmacological and psychotherapeutic advances have led to the reduction of the frequency, severity and morbidity of episodes. In the past two decades, significant efforts have been made to develop new therapeutic agents for BPD but only a few new treatment options are available. A few new drugs are in clinical trials and in the preclinical stage of development. This chapter will highlight the current treatment options and potential drugs under development for bipolar disorder.
Crossing the Blood-brain Barrier – Methods for Evaluating CNS Exposure
Authors: Baker James A. , Martin Iain J.
Published: October 2012

Assessment of CNS penetration is an integral part of psychiatric drug discovery. Compounds that are freely permeable and are not subject to active efflux from the CNS are likely to have free brain levels comparable to free plasma concentrations. In such cases, improvement of CNS exposure will focus on optimizing plasma pharmacokinetics. Experimental approaches are outlined for confirming whether the free drug equilibrium assumption holds true for a particular compound series. Where low CNS exposure (relative to plasma) is seen, a strategy is outlined for improving CNS exposure using in vitro and in vivo tools. Additionally, output from the rat serial CSF model is explored to demonstrate the care needed in interpreting such data. Also discussed are approaches that have been in common use but may not contribute to successful CNS drug discovery.
The Possibilities and Limitations of Animal Models for Psychiatric Disorders
Authors: Tricklebank Mark D. , Garner Joseph P.
Published: October 2012

In the search for novel treatments for psychiatric disorders, many compounds that have shown promising pharmacological properties in disease models have failed to induce benefit in patients. There is good reason to believe that the preclinical approaches routinely used in drug discovery often provide an overly optimistic picture of clinical potential. Here we discuss some of the factors that we believe lead to erroneous decision-making, including: false interpretations of the behavioural significance of drug effects in the model species; fundamental flaws in aspects of experimental design and analysis; and misconceptions about the criteria that need to be applied before a model can be said to be validated. Only by focusing on well-constructed biological hypotheses of drug action in conjunction with reliable neurochemical, electrophysiological and behavioural assays that can be demonstrated to engage clinically relevant brain circuits will the chances of clinical success be improved. As psychiatric disorders come to be viewed less descriptively and more mechanistically as developmental disorders in brain circuits, incorporating biomarkers – measured biological variables that can indicate a normal or abnormal biological etiological process – will become the essential key to improving model development and validation, and target assessment and refinement.
Future Drug Discovery for Psychiatric Disorders
Authors: Schoepp Darryle D. , Hargreaves Richard J.
Published: October 2012

Despite the successful introduction of treatments for many neuropsychiatric disorders, there remains an important unmet medical need. Successes to date generally represent a few well-established mechanisms of action, and newer drugs are largely incremental improvements. Many have efficacy and/or tolerability issues, and there is an opportunity to differentiate new treatments that are more effective or better tolerated. Here we describe the current challenges to finding new therapies and how evolving new research approaches along with better ways of working are showing promise for the neuroscience field.
Structures of trans-2-enoyl-CoA reductases from Clostridium acetobutylicum and Treponema denticola: insights into the substrate specificity and the catalytic mechanism
Authors: Hu Kuan , Zhao Meng , Zhang Tianlong , Zha Manwu , Zhong Chen , Jiang Yu , Ding Jianping
Published: October 2012

TERs (trans-2-enoyl-CoA reductases; EC 1.3.1.44), which specifically catalyse the reduction of crotonyl-CoA to butyryl-CoA using NADH as cofactor, have recently been applied in the design of robust synthetic pathways to produce butan-1-ol as a biofuel. We report in the present paper the characterization of a CaTER (a TER homologue in Clostridium acetobutylicum), the structures of CaTER in apo form and in complexes with NADH and NAD+, and the structure of TdTER (Treponema denticola TER) in complex with NAD+. Structural and sequence comparisons show that CaTER and TdTER share approximately 45% overall sequence identity and high structural similarities with the FabV class enoyl-acyl carrier protein reductases in the bacterial fatty acid synthesis pathway, suggesting that both types of enzymes belong to the same family. CaTER and TdTER function as monomers and consist of a cofactor-binding domain and a substrate-binding domain with the catalytic active site located at the interface of the two domains. Structural analyses of CaTER together with mutagenesis and biochemical data indicate that the conserved Glu75 determines the cofactor specificity, and the conserved Tyr225, Tyr235 and Lys244 play critical roles in catalysis. Upon cofactor binding, the substrate-binding loop changes from an open conformation to a closed conformation, narrowing a hydrophobic channel to the catalytic site. A modelling study shows that the hydrophobic channel is optimal in both width and length for the binding of crotonyl-CoA. These results provide molecular bases for the high substrate specificity and the catalytic mechanism of TERs.
Sorafenib treatment improves hepatopulmonary syndrome in rats with biliary cirrhosis
Authors: Chang Ching-Chih , Chuang Chiao-Lin , Lee Fa-Yauh , Wang Sun-Sang , Lin Han-Chieh , Huang Hui-Chun , Teng Tzu-Hua , Hsu Shao-Jung , Hsieh Hsian-Guey , Lee Shou-Dong
Published: October 2012

HPS (hepatopulmonary syndrome) is characterized by oxygen desaturation in patients with chronic liver disease. The initiation of HPS comes from abnormal pulmonary vasodilatation and/or angiogenesis. In the present study, we evaluated anti-angiogenesis therapy using sorafenib in experimental HPS animals. HPS was induced by CBDL (common bile duct ligation) in rats. A 2-week 10 mg·(kg of body weight)−1·day−1 treatment regimen of sorafenib or distilled water (control) was initiated 2 weeks after the surgical procedure. Haemodynamics, liver biochemistry, plasma VEGF (vascular endothelial growth factor) measurements and blood gas analysis of the CBDL rats were performed. The livers of the CBDL rats were dissected for histopathology examination, and the lungs were examined by immunohistochemical staining, real-time PCR and Western blot analysis. In another two parallel groups, intrapulmonary shunts were determined. The AaPO2 (alveolar–arterial O2 gradient) and plasma VEGF levels were reduced after sorafenib treatment [AaPO2, 7.2±3.4 mmHg in sorafenib-treated rats compared with 15.3±4.2 mmHg in controls (P=0.004); VEGF, 45.3±2.7 pg/ml in sorafenib-treated rats compared with 54.4±7.7 pg/ml in controls (P=0.021)]. Sorafenib attenuated pulmonary VEGF mRNA and VEGF, VEGFR-2 (VEGF receptor 2), phospho-VEGFR-2 and Akt protein expression. In addition, sorafenib significantly attenuated intrapulmonary angiogenesis and decreased the degree of intrapulmonary shunting by 33.7% (11.2±5.7% in sorafenib-treated rats compared with 16.9±5.9% in controls; P=0.003). Our findings suggest that sorafenib attenuates intrapulmonary shunting and decreases the AaPO2 in CBDL rats, implicating the improvement of HPS in this experimental animal model. The beneficial effect may be attributed to the reduction in intrapulmonary angiogenesis through inhibition of the VEGF/VEGFR-2/Akt pathway.
Non-Markovian reduced dynamics based upon a hierarchical effective-mode representation
Authors: Burghardt Irene , Martinazzo Rocco , Hughes Keith H.
Published: October 2012

A reduced dynamics representation is introduced which is tailored to a hierarchical, Mori-chain type representation of a bath of harmonic oscillators which are linearly coupled to a subsystem. We consider a spin-boson system where a single effective mode is constructed so as to absorb all system-environment interactions, while the residual bath modes are coupled bilinearly to the primary mode and among each other. Using a cumulant expansion of the memory kernel, correlation functions for the primary mode are obtained, which can be suitably approximated by truncated chains representing the primary-residual mode interactions. A series of reduced-dimensional bath correlation functions is thus obtained, which can be expressed as Fourier-Laplace transforms of spectral densities that are given in truncated continued-fraction form. For a master equation which is second order in the system-bath coupling, the memory kernel is re-expressed in terms of local-in-time equations involving auxiliary densities and auxiliary operators.
Vortex stretching and criticality for the three-dimensional Navier-Stokes equations
Authors: Dascaliuc R. , Grujić Z.
Published: October 2012

A mathematical evidence—in a statistically significant sense—of a geometric scenario leading to criticality of the Navier-Stokes problem is presented.