Max Planck Institute for Medical Research

www.mpimf-heidelberg.mpg.de
Heidelberg, Germany

The Max Planck Institute for Medical Research in Heidelberg, Germany, is a facility of the Max Planck Society for basic medical research. Since its foundation, six Nobel Prize laureates worked at the Institute: Otto Fritz Meyerhof , Richard Kuhn , Walther Bothe , André Michel Lwoff , Rudolf Mößbauer and Bert Sakmann . The Institute has close ties with Heidelberg University. Wikipedia.

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Urban G.,Max Planck Institute for Medical Research
Nature Methods | Year: 2017

Teravoxel volume electron microscopy data sets from neural tissue can now be acquired in weeks, but data analysis requires years of manual labor. We developed the SyConn framework, which uses deep convolutional neural networks and random forest classifiers to infer a richly annotated synaptic connectivity matrix from manual neurite skeleton reconstructions by automatically identifying mitochondria, synapses and their types, axons, dendrites, spines, myelin, somata and cell types. We tested our approach on serial block-face electron microscopy data sets from zebrafish, mouse and zebra finch, and computed the synaptic wiring of songbird basal ganglia. We found that, for example, basal-ganglia cell types with high firing rates in vivo had higher densities of mitochondria and vesicles and that synapse sizes and quantities scaled systematically, depending on the innervated postsynaptic cell types. © 2017 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Helmstaedter M.,Max Planck Institute for Medical Research | Briggman K.L.,Max Planck Institute for Medical Research | Denk W.,Max Planck Institute for Medical Research
Nature Neuroscience | Year: 2011

Neuroanatomic analysis depends on the reconstruction of complete cell shapes. High-throughput reconstruction of neural circuits, or connectomics, using volume electron microscopy requires dense staining of all cells, which leads even experts to make annotation errors. Currently, reconstruction speed rather than acquisition speed limits the determination of neural wiring diagrams. We developed a method for fast and reliable reconstruction of densely labeled data sets. Our approach, based on manually skeletonizing each neurite redundantly (multiple times) with a visualization-annotation software tool called KNOSSOS, is ∼50-fold faster than volume labeling. Errors are detected and eliminated by a redundant-skeleton consensus procedure (RESCOP), which uses a statistical model of how true neurite connectivity is transformed into annotation decisions. RESCOP also estimates the reliability of consensus skeletons. Focused reannotation of difficult locations promises a rather steep increase of reliability as a function of the average skeleton redundancy and thus the nearly error-free analysis of large neuroanatomical datasets. © 2011 Nature America, Inc. All rights reserved.


Lichtman J.W.,Harvard University | Denk W.,Max Planck Institute for Medical Research
Science | Year: 2011

The relation between the structure of the nervous system and its function is more poorly understood than the relation between structure and function in any other organ system. We explore why bridging the structure-function divide is uniquely difficult in the brain. These difficulties also explain the thrust behind the enormous amount of innovation centered on microscopy in neuroscience. We highlight some recent progress and the challenges that remain.


Denk W.,Max Planck Institute for Medical Research | Briggman K.L.,U.S. National Institutes of Health | Helmstaedter M.,Max Planck Institute of Neurobiology
Nature Reviews Neuroscience | Year: 2012

High-resolution, comprehensive structural information is often the final arbiter between competing mechanistic models of biological processes, and can serve as inspiration for new hypotheses. In molecular biology, definitive structural data at atomic resolution are available for many macromolecules; however, information about the structure of the brain is much less complete, both in scope and resolution. Several technical developments over the past decade, such as serial block-face electron microscopy and trans-synaptic viral tracing, have made the structural biology of neural circuits conceivable: we may be able to obtain the structural information needed to reconstruct the network of cellular connections for large parts of, or even an entire, mouse brain within a decade or so. Given that the brain's algorithms are ultimately encoded by this network, knowing where all of these connections are should, at the very least, provide the data needed to distinguish between models of neural computation. © 2012 Macmillan Publishers Limited. All rights reserved.


Rosenthal J.,University of Puerto Rico at San Juan | Seeburg P.,Max Planck Institute for Medical Research
Neuron | Year: 2012

RNA editing by adenosine deamination is a process used to diversify the proteome. The expression of ADARs, the editing enzymes, is ubiquitous among true metazoans, and so adenosine deamination is thought to be universal. By changing codons at the level of mRNA, protein function can be altered, perhaps in response to physiological demand. Although the number of editing sites identified in recent years has been rising exponentially, their effects on protein function, in general, are less well understood. This review assesses the state of the field and highlights particular cases where the biophysical alterations and functional effects caused by RNA editing have been studied in detail. RNA editing is a widespread phenomenon in the nervous system of most animals. In this Perspective, Rosenthal and Seeburg assess the state of the field and highlight particular cases where the biophysical alterations and functional effects caused by RNA editing have been studied in detail. © 2012 Elsevier Inc.


Knobloch H.S.,Max Planck Institute for Medical Research | Grinevich V.,Max Planck Institute for Medical Research
Frontiers in Behavioral Neuroscience | Year: 2014

The central oxytocin system transformed tremendously during the evolution, thereby adapting to the expanding properties of species. In more basal vertebrates (paraphyletic taxon Anamnia, which includes agnathans, fish and amphibians), magnocellular neurosecretory neurons producing homologs of oxytocin reside in the wall of the third ventricle of the hypothalamus composing a single hypothalamic structure, the preoptic nucleus. This nucleus further diverged in advanced vertebrates (monophyletic taxon Amniota, which includes reptiles, birds, and mammals) into the paraventricular and supraoptic nuclei with accessory nuclei (AN) between them. The individual magnocellular neurons underwent a process of transformation from primitive uni- or bipolar neurons into highly differentiated neurons. Due to these microanatomical and cytological changes, the ancient release modes of oxytocin into the cerebrospinal fluid were largely replaced by vascular release. However, the most fascinating feature of the progressive transformations of the oxytocin system has been the expansion of oxytocin axonal projections to forebrain regions. In the present review we provide a background on these evolutionary advancements. Furthermore, we draw attention to the non-synaptic axonal release in small and defined brain regions with the aim to clearly distinguish this way of oxytocin action from the classical synaptic transmission on one side and from dendritic release followed by a global diffusion on the other side. Finally, we will summarize the effects of oxytocin and its homologs on pro-social reproductive behaviors in representatives of the phylogenetic tree and will propose anatomically plausible pathways of oxytocin release contributing to these behaviors in basal vertebrates and amniots. © 2014 Knobloch and Grinevich.


Benjdia A.,Max Planck Institute for Medical Research
Current Opinion in Structural Biology | Year: 2012

Light is essential for many critical biological processes including vision, circadian rhythms, photosynthesis and DNA repair. DNA photolyases use light energy and a fully reduced flavin cofactor to repair the major UV-induced DNA damages, the cis-syn cyclobutane pyrimidine dimers (CPDs) and the pyrimidine-pyrimidone (6-4) photoproducts. Catalysis involves two photoreactions, the photoactivation which leads to the conversion of the flavin cofactor to its catalytic active form and the photorepair whose efficiency depends on a light-harvesting antenna chromophore. Very interestingly, an alternative and light-independent direct reversal mechanism to repair a distinct photolesion is found in bacterial spores, catalyzed by spore photoproduct lyase. This radical SAM enzyme uses an iron-sulfur cluster and S-adenosyl- l-methionine (SAM) to split a specific photoproduct, the so-called spore photoproduct (SP), back to two thymidine residues. The recently solved crystal structure of SP lyase provides new insights into this unique DNA repair mechanism and allows a detailed comparison with DNA photolyases. Similarities as well as divergences between DNA photolyases and SP lyase are highlighted in this review. © 2012 Elsevier Ltd.


Dominguez R.,University of Pennsylvania | Holmes K.C.,Max Planck Institute for Medical Research
Annual Review of Biophysics | Year: 2011

Actin is the most abundant protein in most eukaryotic cells. It is highly conserved and participates in more protein-protein interactions than any known protein. These properties, along with its ability to transition between monomeric (G-actin) and filamentous (F-actin) states under the control of nucleotide hydrolysis, ions, and a large number of actin-binding proteins, make actin a critical player in many cellular functions, ranging from cell motility and the maintenance of cell shape and polarity to the regulation of transcription. Moreover, the interaction of filamentous actin with myosin forms the basis of muscle contraction. Owing to its central role in the cell, the actin cytoskeleton is also disrupted or taken over by numerous pathogens. Here we review structures of G-actin and F-actin and discuss some of the interactions that control the polymerization and disassembly of actin. © 2011 by Annual Reviews. All rights reserved.


Benz J.,Max Planck Institute for Medical Research | Meinhart A.,Max Planck Institute for Medical Research
Current Opinion in Microbiology | Year: 2014

Bacteria do not live anchoretic; rather they are constantly in touch with their eukaryotic hosts and with other bacteria sharing their habitat. Therefore, bacteria have evolved sophisticated proteinaceous weapons. To harm other bacteria, they produce antibacterial effector proteins, which they either release into the environment or export via direct intercellular contact. Contact-dependent killing is mediated by two specialized secretion systems, the type V and VI secretion system, whereas contact-independent processes hijack other transport mechanisms. Regardless of the transport system, cells co-express immunity proteins to protect themselves from suicide and fratricide. In general, effector protein activities and secretion mechanisms differ between Gram-positive and Gram-negative bacteria and evidence is emerging that different effector/immunity systems act synergistically and thus extend the bacterial armory. © 2013 The Authors.


Domratcheva T.,Max Planck Institute for Medical Research
Journal of the American Chemical Society | Year: 2011

The two major UV-induced DNA lesions, the cyclobutane pyrimidine dimers (CPD) and (6-4) pyrimidine-pyrimidone photoproducts, can be repaired by the light-activated enzymes CPD and (6-4) photolyases, respectively. It is a long-standing question how the two classes of photolyases with alike molecular structure are capable of reversing the two chemically different DNA photoproducts. In both photolyases the repair reaction is initiated by photoinduced electron transfer from the hydroquinone-anion part of the flavin adenine dinucleotide (FADH -) cofactor to the photoproduct. Here, the state-of-the-art XMCQDPT2-CASSCF approach was employed to compute the excitation spectra of the respective active site models. It is found that protonation of His365 in the presence of the hydroquinone-anion electron donor causes spontaneous, as opposed to photoinduced, coupled proton and electron transfer to the (6-4) photoproduct. The resulting neutralized biradical, containing the neutral semiquinone and the N3′-protonated (6-4) photoproduct neutral radical, corresponds to the lowest energy electronic ground-state minimum. The high electron affinity of the N3′-protonated (6-4) photoproduct underlines this finding. Thus, it is anticipated that the (6-4) photoproduct repair is assisted by His365 in its neutral form, which is in contrast to the repair mechanisms proposed in the literature. The repair via hydroxyl group transfer assisted by neutral His365 is considered. The repair involves the 5′base radical anion of the (6-4) photoproduct which in terms of electronic structure is similar to the CPD radical anion. A unified model of the CPD and (6-4) photoproduct repair is proposed. © 2011 American Chemical Society.

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