Leibniz Institute for Neurobiology

, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

The widespread popularity of density functional theory has given rise to an extensive range of dedicated codes for predicting molecular and crystalline properties. However, each code implements the formalism in a different way, raising questions about the reproducibility of such predictions. We report the results of a community-wide effort that compared 15 solid-state codes, using 40 different potentials or basis set types, to assess the quality of the Perdew-Burke-Ernzerhof equations of state for 71 elemental crystals. We conclude that predictions from recent codes and pseudopotentials agree very well, with pairwise differences that are comparable to those between different high-precision experiments. Older methods, however, have less precise agreement. Our benchmark provides a framework for users and developers to document the precision of new applications and methodological improvements.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Usually, monolithic bulk metallic glasses undergo inhomogeneous plastic deformation and exhibit poor ductility (< 1%) at room temperature. We present a new class of bulk metallic glass, which exhibits high strength of up to 2265 MPa together with extensive "work hardening" and large ductility of 18%. Significant increase in the flow stress was observed during deformation. The "work-hardening" capability and ductility of this class of metallic glass is attributed to a unique structure correlated with atomic-scale inhomogeneity, leading to an inherent capability of extensive shear band formation, interactions, and multiplication of shear bands.

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 369 nominally genome-wide significant loci ( P &lt; 5 × 10 −8 ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P &lt; 8.3 × 10 −10 ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

The investigation of biological processes by chemical methods, commonly referred to as chemical biology, often requires chemical access to biologically relevant macromolecules such as peptides and proteins. Building upon solid-phase peptide synthesis, investigations have focused on the development of chemoselective ligation and modification strategies to link synthetic peptides or other functional units to larger synthetic and biologically relevant macromolecules. This Review summarizes recent developments in the field of chemoselective ligation and modification strategies and illustrates their application, with examples ranging from the total synthesis of proteins to the semisynthesis of naturally modified proteins.

Insects are favorable subjects for neuroethological studies. Their nervous systems are relatively small and contain many individually identifiable cells. The CNS is highly compartmentalized with clear separations between multisensory higher order neuropiles in the brain and neuropiles serving sensory-motor routines in the ventral cord (Huber, 1974). The rich behavior of insects includes orientation in space and time, visual, chemical, and mechanical communication, and complex motor routines for flying, walking, swimming, nest building, defense, and attack. Learning and memory, though, are not usually considered to be a strong point of insects. Rather, insect behavior is often regarded as highly stereotyped and under tight control of genetically programmed neural circuits. This view, however, does not do justice to the insect order of Hymenoptera (bees, wasps, ants). Most Hymenopteran species care for their brood either as individual females or as a social group of females. Consequently, they regularly return to their nest site to feed, protect, and nurse the larvae, store food, and hide from adverse environmental conditions. Since they search for food (prey; nectar and pollen on flowers) at unpredictable sites, they have to learn the celestial and terrestrial cues that guide their foraging trips over long distances and allow them to find their nest sites (central place foraging; von Frisch, 1967; Seeley, 1985). They learn to relate the sun's position and sky pattern of polarized light to the time of the day (Lindauer, 1959), and landmarks are learned in relationship to the nest site within the framework of the time-compensated sun compass. The honeybee communicates direction and distance of a feeding place to hive mates by performing a ritualized body movement, the waggle dance (von Frisch, 1967). Associative learning is an essential component of the bee's central place foraging behavior and dance communication. Hive mates attending a dance performance learn the odor emanating from the dancing bee and seek it at the indicated food site. The odor, color, and shape of flowers are learned when the bee experiences these stimuli shortly before it finds food (nectar, pollen). This appetitive learning in bees has many characteristics of associative learning well known from mammalian learning studies (Menzel, 1985, 1990; Bitterman, 1988). It follows the rules of classical and operant conditioning, respectively, so that stimuli or behavioral acts are associated with evaluating stimuli. Since associative learning, especially of the classical type, is well described at the phenomenological and operational level (Rescorla, 1988), it provides a favorable approach in the search for the neural substrate underlying learning and memory.(ABSTRACT TRUNCATED AT 400 WORDS)

Previous studies have identified neurons in the postsubiculum which discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the environment. Anatomical studies have shown that the postsubiculum contains reciprocal connections with the anterior thalamic nuclei (ATN). In order to determine how the head direction (HD) cell signal is processed in the brain, single-unit recordings were monitored in the ATN of freely moving rats in order to characterize their behavioral and spatial correlates. Animals were trained to retrieve food pellets thrown randomly into a cylindrical apparatus containing a single orientation cue. Single unit recordings in the ATN showed that approximately 60% of the recorded cells discharged in relation to the animal's head direction in the horizontal plane. Observation of the animal and quantitative analyses showed that HD cell firing was not dependent on the animal's behavior, trunk position, linear speed, angular head velocity, or location in the environment. Most of these cells were localized to the anterior dorsal thalamic nucleus. Each HD cell contained only one head direction at which the cell discharged maximally and the firing rate decreased linearly away from this preferred direction. The preferred firing directions from all cells recorded were distributed over a 360 degrees range. Quantitative analysis showed that these cells contained similar discharge parameters (peak firing rate, directional firing range) to values reported previously for postsubicular HD cells (Taube et al., 1990a). Experiments involving rotation of the orientation cue showed that the preferred firing direction could be controlled by a salient visual cue. In contrast to postsubicular HD cells, passive rotation of a restrained animal showed that most ATN HD cells ceased discharging when the animal's head was oriented in the preferred direction. These findings demonstrate the presence of HD cells in the ATN and indicate the potential importance of this area for spatial navigation. The origin of the head direction signal is discussed and it is concluded that because of the presence of reciprocal connections between the postsubiculum and the ATN, further studies are required in order to determine the direction in which this head-directional information is flowing. Finally, ATN HD cells differ from postsubicular HD cells by appearing to require volitional motoric input.

Oxygen-isotope ratios of precipitation (delta18OP) inferred from deep-lake ostracods from the Ammersee (southern Germany) provide a climate record with decadal resolution. The record in detail shows many of the rapid climate shifts seen in central Greenland ice cores between 15,000 and 5000 years before the present (B.P.). Negative excursions in the estimated delta18OP from both of these records likely reflect short weakenings of the thermohaline circulation caused by episodic discharges of continental freshwater into the North Atlantic. Deviating millennial-scale trends, however, indicate that climate gradients between Europe and Greenland changed systematically, reflecting a gradual rearrangement of North Atlantic circulation during deglaciation.

A phenomenological theory of chiral symmetry breaking in magnetic nanostructures is developed considering induced, inhomogeneous chiral interactions (Dzyaloshinsky-Moriya-type). Application of the theory to films and multilayers with in-plane and out-of-plane magnetization predicts modulated and two-dimensional localized patterns (vortices). These new classes of magnetic patterns are intrinsically stable and localized on nanometer scale. Various experimental observations agree qualitatively with structures derived from this theory.

Sink strength of growing potato tubers is believed to be limited by sucrose metabolism and/or starch synthesis. Sucrose synthase (Susy) is most likely responsible for the entire sucrose cleavage in sink tubers, rather than invertases. To investigate the unique role of sucrose synthase with respect to sucrose metabolism and sink strength in growing potato tubers, transgenic potato plants were created expressing Susy antisense RNA corresponding to the T-type sucrose synthase isoform. Although the constitutive 35S CaMV promoter was used to drive the expression of the antisense RNA the inhibition of Susy activity was tuber-specific, indicating that independent Susy isoforms are responsible for Susy activity in different potato organs. The inhibition of Susy leads to no change in sucrose content, a strong accumulation of reducing sugars and an inhibition of starch accumulation in developing potato tubers. The increase in hexoses is paralleled by a 40-fold increase in invertase activities but no considerable changes in hexokinase activities. The reduction in starch accumulation is not due to an inhibition of the major starch biosynthetic enzymes. The changes in carbohydrate accumulation are accompanied by a decrease in total tuber dry weight and a reduction of soluble tuber proteins. The reduced protein accumulation is mainly due to a decrease in the major storage proteins patatin, the 22 kDa proteins and the proteinase inhibitors. The lowered accumulation of storage proteins is not a consequence of the availability of the free amino acid pool in potato tubers. Altogether these data are in agreement with the assumption that sucrose synthase is the major determinant of potato tuber sink strength. Contradictory to the hypothesis that the sink strength of growing potato tubers is inversely correlated with the tuber number per plant, no increase in tuber number per plant was found in Susy antisense plants.

Magnetic resonance imaging and spectroscopic techniques are widely used in humans both for clinical diagnostic applications and in basic research areas such as cognitive neuroimaging. In recent years, new human MR systems have become available operating at static magnetic fields of 7 T or higher (≥300 MHz proton frequency). Imaging human-sized objects at such high frequencies presents several challenges including non-uniform radiofrequency fields, enhanced susceptibility artifacts, and higher radiofrequency energy deposition in the tissue. On the other side of the scale are gains in signal-to-noise or contrast-to-noise ratio that allow finer structures to be visualized and smaller physiological effects to be detected. This review presents an overview of some of the latest methodological developments in human ultra-high field MRI/MRS as well as associated clinical and scientific applications. Emphasis is given to techniques that particularly benefit from the changing physical characteristics at high magnetic fields, including susceptibility-weighted imaging and phase-contrast techniques, imaging with X-nuclei, MR spectroscopy, CEST imaging, as well as functional MRI. In addition, more general methodological developments such as parallel transmission and motion correction will be discussed that are required to leverage the full potential of higher magnetic fields, and an overview of relevant physiological considerations of human high magnetic field exposure is provided.

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [(11)C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [(11)C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

AMPA glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission. Upon fast consecutive synaptic stimulation, transmission can be depressed. Recuperation from fast synaptic depression has been attributed solely to recovery of transmitter release and/or AMPAR desensitization. We show that AMPAR lateral diffusion, observed in both intact hippocampi and cultured neurons, allows fast exchange of desensitized receptors with naïve functional ones within or near the postsynaptic density. Recovery from depression in the tens of millisecond time range can be explained in part by this fast receptor exchange. Preventing AMPAR surface movements through cross-linking, endogenous clustering, or calcium rise all slow recovery from depression. Physiological regulation of postsynaptic receptor mobility affects the fidelity of synaptic transmission by shaping the frequency dependence of synaptic responses.

During the SAMUM 2006 field campaign in southern Morocco, physical and chemical properties of desert aerosols were measured. Mass concentrations ranging from 30μgm−3 for PM2.5 under desert background conditions up to 300 000μgm−3 for total suspended particles (TSP) during moderate dust storms were measured. TSP dust concentrations are correlated with the local wind speed, whereasPM10 andPM2.5 concentrations are determined by advection from distant sources. Size distributions were measured for particles with diameter between 20 nm and 500μm (parametrizations are given). Two major regimes of the size spectrum can be distinguished. For particles smaller than 500 nm diameter, the distributions show maxima around 80 nm, widely unaffected of varying meteorological and dust emission conditions. For particles larger than 500 nm, the range of variation may be up to one order of magnitude and up to three orders of magnitude for particles larger than 10μm. The mineralogical composition of aerosol bulk samples was measured by X-ray powder diffraction. Major constituents of the aerosol are quartz, potassium feldspar, plagioclase, calcite, hematite and the clay minerals illite, kaolinite and chlorite. A small temporal variability of the bulk mineralogical composition was encountered. The chemical composition of approximately 74 000 particles was determined by electron microscopic single particle analysis. Three size regimes are identified: for smaller than 500 nm in diameter, the aerosol consists of sulphates and mineral dust. For larger than 500 nm up to 50μm, mineral dust dominates, consisting mainly of silicates, and—to a lesser extent—carbonates and quartz. For diameters larger than 50μm, approximately half of the particles consist of quartz. Time series of the elemental composition show a moderate temporal variability of the major compounds. Calcium-dominated particles are enhanced during advection from a prominent dust source in Northern Africa (Chott El Djerid and surroundings). The particle aspect ratio was measured for all analysed particles. Its size dependence reflects that of the chemical composition. For larger than 500 nm particle diameter, a median aspect ratio of 1.6 is measured. Towards smaller particles, it decreases to about 1.3 (parametrizations are given). From the chemical/mineralogical composition, the aerosol complex refractive index was determined for several wavelengths from ultraviolet to near-infrared. Both real and imaginary parts show lower values for particles smaller than 500 nm in diameter (1.55–2.8 × 10−3i at 530 nm) and slightly higher values for larger particles (1.57–3.7 × 10−3i at 530 nm).

The molecular architecture of the cytomatrix of presynaptic nerve terminals is poorly understood. Here we show that Bassoon, a novel protein of >400,000 Mr, is a new component of the presynaptic cytoskeleton. The murine bassoon gene maps to chromosome 9F. A comparison with the corresponding rat cDNA identified 10 exons within its protein-coding region. The Bassoon protein is predicted to contain two double-zinc fingers, several coiled-coil domains, and a stretch of polyglutamines (24 and 11 residues in rat and mouse, respectively). In some human proteins, e.g., Huntingtin, abnormal amplification of such poly-glutamine regions causes late-onset neurodegeneration. Bassoon is highly enriched in synaptic protein preparations. In cultured hippocampal neurons, Bassoon colocalizes with the synaptic vesicle protein synaptophysin and Piccolo, a presynaptic cytomatrix component. At the ultrastructural level, Bassoon is detected in axon terminals of hippocampal neurons where it is highly concentrated in the vicinity of the active zone. Immunogold labeling of synaptosomes revealed that Bassoon is associated with material interspersed between clear synaptic vesicles, and biochemical studies suggest a tight association with cytoskeletal structures. These data indicate that Bassoon is a strong candidate to be involved in cytomatrix organization at the site of neurotransmitter release.

A detailed reconstruction of West African monsoon hydrology over the past 155,000 years suggests a close linkage to northern high-latitude climate oscillations. Ba/Ca ratio and oxygen isotope composition of planktonic foraminifera in a marine sediment core from the Gulf of Guinea, in the eastern equatorial Atlantic (EEA), reveal centennial-scale variations of riverine freshwater input that are synchronous with northern high-latitude stadials and interstadials of the penultimate interglacial and the last deglaciation. EEA Mg/Ca-based sea surface temperatures (SSTs) were decoupled from northern high-latitude millennial-scale fluctuation and primarily responded to changes in atmospheric greenhouse gases and low-latitude solar insolation. The onset of enhanced monsoon precipitation lags behind the changes in EEA SSTs by up to 7000 years during glacial-interglacial transitions. This study demonstrates that the stadial-interstadial and deglacial climate instability of the northern high latitudes exerts dominant control on the West African monsoon dynamics through an atmospheric linkage.

Four sets of near-isogenic lines carrying different combinations of the alleles Rht-B1b , Rht-D1b and Rht-B1c for gibberellin-insensitive dwarfism in hexaploid wheat ( Triticum aestivum L. ) were compared with tall controls in a series of yield trials in eastern England and central Germany. In all four varietal backgrounds the effects of Rht-B1b and Rht-D1b were similar (plant height ≈ 86 and 83% of tall controls respectively) and in combination reduced plant height to c. 58%. The Rht-B1c allele caused more severe dwarfism ( c. 50%) and, when combined with Rht-D1b , reduced plant height still further to c. 41%. Data from the trials were consistent with a model for height/yield relationships in which the pleiotropic effects of the Rht alleles on yield can be inferred from their primary function: insensitivity to gibberellin limits stem extension growth, decreasing assimilate demand for this organ and diverting it to the developing ear (which is not itself dwarfed). The net balance between the resulting increase in harvest index and the curvilinear relationship observed between plant height and total shoot yield results in optimum grain yields at intermediate plant heights. Yield advantages of shorter plants over tall controls were evident over several trials with mean grain yields ranging from 200 to 760 g m −2 . The optimum plant height for yield improvement in different genetic backgrounds was achieved by different Rht alleles according to the background varietal height, such that intrinsically taller genotypes required more potent Rht alleles to achieve maximum potential grain yield. Ear yield components showed increases in grain number due to Rht pleiotropy, from which it is inferred that the number of grains per ear is limited by supply of assimilates pre-anthesis. Increases in grain number were associated with decreases in mean weight per grain which varied according to severity of dwarfism and varietal background, so that the net effect on grain yield per ear was sometimes positive, sometimes negative, and sometimes neutral in different Rht /variety combinations.

PURPOSE: Relaxation times, transmit homogeneity, signal-to-noise ratio (SNR) and parallel imaging g-factor were determined in the human brain at 3T, 7T, and 9.4T, using standard, tight-fitting coil arrays. METHODS: The same human subjects were scanned at all three field strengths, using identical sequence parameters and similar 31- or 32-channel receive coil arrays. The SNR of three-dimensional (3D) gradient echo images was determined using a multiple replica approach and corrected with measured flip angle and T2 (*) distributions and the T1 of white matter to obtain the intrinsic SNR. The g-factor maps were derived from 3D gradient echo images with several GRAPPA accelerations. RESULTS: As expected, T1 values increased, T2 (*) decreased and the B1 -homogeneity deteriorated with increasing field. The SNR showed a distinctly supralinear increase with field strength by a factor of 3.10 ± 0.20 from 3T to 7T, and 1.76 ± 0.13 from 7T to 9.4T over the entire cerebrum. The g-factors did not show the expected decrease, indicating a dominating role of coil design. CONCLUSION: In standard experimental conditions, SNR increased supralinearly with field strength (SNR ∼ B0 (1.65) ). To take full advantage of this gain, the deteriorating B1 -homogeneity and the decreasing T2 (*) have to be overcome.

The endocytosis process is of critical importance for a variety of cellular life functions. Vesicle formation during receptor-mediated endocytosis involves a complex protein machinery and additional proteins to control it. Although our understanding of this endocytic machinery has grown rapidly