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Upcoming Seminars

Francesco Papaleo, Ph.D. - "A precision medicine genetic marker for core cognitive deficits in schizophrenia"

Genetics of Cognition Laboratory, Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), Genova, Italy
When Feb 27, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Antipsychotics are the first-line and most widely used medications for the treatment of schizophrenia spectrum disorders. Clinical responses to these drugs are highly variable. However, predictors of individual responses to antipsychotic treatments have been elusive. Here we report a pharmacogenetics interaction related to a core cognitive dysfunction in patients with schizophrenia. In particular, genetic variations reducing dysbindin-1 expression differentiate individuals with better executive functions responses to antipsychotic drugs. Multilevel ex vivo and in vivo analyses in post mortem human brains, genetically modified mice, andDrosophilae melanogaster demonstrated that such antipsychotics-by-dysbindin-1 interaction is mediated by enhanced presynaptic dopamine D2 function within the prefrontal cortex (PFC). These findings provide a genetic indicator for a biological mechanism underlying cognitive disabilities in patients with schizophrenia, thus paving the way for the implementation of a precision medicine approach to treatment.

Lukas A. Huber, M.D. - "Structure-function relationship of LAMTOR signaling on endosomes"

Biozentrum der Medizinischen Universität Innsbruck, Sektion für Zellbiologie, Innsbruck, Austria
When Mar 06, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
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Contact Phone 08119230659
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The LAMTOR [late endosomal and lysosomal adaptor and MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) activator] complex, also known as "Ragulator," controls the activity of mTOR complex 1 (mTORC1) on the lysosome. The crystal structure of LAMTOR consists of two roadblock/LC7 domain-folded heterodimers wrapped and apparently held together by LAMTOR1, which assembles the complex on lysosomes. In addition, the Rag guanosine triphosphatases (GTPases) associated with the pentamer through their carboxyl-terminal domains, predefining the orientation for interaction with mTORC1. In vitro reconstitution and experiments with site-directed mutagenesis defined the physiological importance of LAMTOR1 in assembling the remaining components to ensure fidelity of mTORC1 signaling. Functional data validated the effect of two short LAMTOR1 amino acid regions in recruitment and stabilization of the Rag GTPases.

Massimo D'Agostino, Ph.D. - "Non-expanding fusion pores are a stable intermediate of vacuole membrane fusion in vivo"

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università' Federico II, Napoli
When Mar 13, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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While fusion of secretory vesicles in regulated exocytosis is restrained by accessory proteins, fusion of all other intracellular membranes is believed to be constitutive and rapid. SNAREs drive these membranes through docking, hemifusion, fusion pore formation and final pore expansion. Theory predicts that fusion pore expansion faces a major energy barrier but corresponding states with stable, non-opening pores have remained elusive in vivo. Here, we show that docked yeast vacuoles exchange lipids from both of their membrane leaflets, but they do not mix lumenal content. This suggests the existence of a nanoscopic fusion pore. The pore is located close to the vertex ring of fusion proteins that surrounds the organelle-organelle contact zone. Full vacuole fusion can be induced by osmotic pressure gradients, but only after a nanoscopic pore had been established through vacuolar SNAREs and the SM-protein containing HOPS complex. The nanoscopic, metastable fusion pore may thus allow vacuoles to rapidly adapt organelle volume to increases in content. Such pores are then not only a transient intermediate but can be a long-lived, physiologically relevant and regulated state of SNARE-dependent membrane fusion.

Sarah H. Elsea, Ph.D. - "A multi-omics precision medicine approach to diagnosis of inborn errors of metabolism"

Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX USA
When Mar 20, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 08119230659
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Metabolomics is the study of the distinctive chemical fingerprint produced by specific cellular processes. Untargeted mass spectrometry-based metabolomic profiling for small molecules in body fluids is an emerging technique used to produce and analyze this chemical fingerprint. This technology holds the promise of providing new insights into human disease states and serving as a primary diagnostic tool for novel and previously characterized inborn errors of metabolism (IEM), as well as for the identification of biomarkers of disease and treatment.  Clinical metabolomic profiling allows for parallel screening of hundreds of metabolites in a single biological specimen. On average, ~900 small molecules are detected in a given plasma sample with a core group of ~350 analytes found in all specimens tested to date. The analytes detected encompass numerous classes of small molecule biomarkers including acylcarnitines, amino acids, bile acids, carbohydrates, lipids, and nucleotides. In addition, metabolomic data in many cases affords a much richer view of a patient's metabolic disturbance by identifying: (1) elevated metabolites located far upstream of the genetic defect, (2) treatment related compounds, including commonly tested therapeutic drug monitoring analytes, and (3) spectrally unique analytes that are not yet associated with a biochemical phenotype. In our clinical experience, the integration of whole exome sequencing data with the metabolomics profile has improved the interpretation of genetic variants, including ruling out the diagnosis of IEMs, as well as supporting a specific diagnosis, and for the identification of new disease and/or treatment biomarkers. For undifferentiated clinical phenotypes such as intellectual disability, hypotonia, autism, or seizures, many different tests involving different sample types are often needed for diagnosis. This can lead to prohibitive costs and ongoing diagnostic odysseys. Data will be presented on genomic and metabolomic profiling of previously non-diagnostic cases which pointed to genetic disorders such as aromatic amino acid decarboxylase deficiency, GABA transaminase deficiency, adenylosuccinate lyase deficiency, and peroxisome biogenesis disorders, illustrating the powerful synergy of genomic and metabolomic analysis in determining the pathogenicity of variants of uncertain significance. Ultimately, a clinical systems biology approach to the integration clinical data with genomic, transcriptomic, epigenomic, proteomic, and metabolomics data will provide a comprehensive precision medicine approach to improve understanding of natural biological variation and to improve diagnosis and management of disease. 

Claudio De Virgilio, Ph.D. - "Regulation of TORC1 by Amino Acids: a Central Role for Rag GTPases Within the EGO Complex"

Department of Biology, University of Fribourg, Switzerland
When Apr 03, 2018
from 12:00 PM to 01:00 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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The eukaryotic target of rapamycin complex 1 (TORC1) couples nutrient, energy, and hormonal signals with cell growth, division, and metabolism, and aberrant TORC1 signaling contributes to the progression of human diseases such as cancer and diabetes. Amino acids are important and primeval cues that stimulate TORC1 to promote anabolic processes (such as ribosome biogenesis and protein translation initiation) and inhibit catabolic processes (such as macroautophagy) via the conserved Rag family GTPases. The latter assemble into heterodimeric complexes consisting of Gtr1 and Gtr2 in yeast, or RagA or RagB and RagC or RagD in mammalian cells. These heterodimers are integral to larger complexes coined EGO (exit from rapamycin-induced growth arrest) complex (EGOC) in yeast or Rag-Ragulator complex in mammalian cells, which are predominantly tethered to vacuolar/lysosomal membranes. Because Rag GTPase heterodimers stimulate TORC1 when they contain GTP-loaded RagA/B/Gtr1 and GDP-loaded RagC/D/Gtr2, GTPase activating proteins (GAPs) acting on Gtr1/RagA/B, such as the orthologous yeast SEACIT or mammalian GATOR1 complexes inhibit, while the ones acting on Gtr2/RagC/D, such as the yeast Lst4-Lst7 or the orthologous mammalian FNIP1/2-Folliculin (FLCN) complexes, activate TORC1. The amino-acid sensitive events upstream of GATOR1 that inhibit TORC1 signaling include the cytosolic leucine and arginine sensors Sestrin2 and CASTOR1, respectively. Both sensors stimulate GATOR1 under amino acid deprivation via a poorly understood mechanism involving their binding to the conserved GATOR1-interacting GATOR2 complex coined SEACAT in yeast. How amino acids activate TORC1 through the Lst4-Lst7/FNIP1/2-FLCN GAP complexes is currently not known. In this context, our current research is focused on deciphering the amino-acid sensitive events upstream of the Rag GTPase regulators in yeast, which likely involve both vacuolar and cytoplasmic amino acid sensors. Due to the evolutionary conservation of the EGOC and its regulators, our studies in yeast are expected to contribute to the understanding of the molecular mechanisms leading to diseases that are associated with hyperactive mammalian TORC1.

James H. Hurley, Ph.D. - "Atomistic Autophagy: The Molecular Choreography of Cellular Self-Digestion"

Professor of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, University of California, Berkeley (USA)
When Apr 10, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230569
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Autophagy is a conserved mechanism that is essential for cell survival in starvation and for cellular homeostasis. The autophagosome and the proteasome comprise the two main pathways for the degradation of proteins. Autophagy proceeds by the engulfment of bulk cytosol and organelles by a cup-shaped double membrane sheet known as the phagophore, which matures into the autophagosome. Two protein complexes control the initiation of the phagophore: the Atg1/ULK1 kinase complex and the class III phosphatidylinositol 3-kinase.  ULK1 is in turn regulated downstream of the lysosomal protein kinase complex mTORC1 and its activator, the Ragulator-RagA/B-RagC/C complex. Our laboratory has been applying crystallography, electron microscopy, mass spectrometry, and allied biophysical techniques, in conjunction with cell biology approaches, to understand how these complexes are organized in three dimensional space and time, and how their architectures underpin their regulation and activity.

Adriano Aguzzi, MD, Ph.D. - "The Biology of Mammalian Prions"

Institute of Neuropathology, University Hospital of Zürich, Switzerland
When Jun 12, 2018
from 12:00 PM to 01:00 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species caused by prions. The main constituent of prions is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Prions were found to encipher many phenotypic, genetically stable TSE variants. The latter is very surprising, since PrPC is encoded by the host genome and all prion strains share the same amino acid sequence. Here I will review what is known about the infectivity, the neurotoxicity, and the neuroinvasiveness of prions. Also, I will explain why I regard the prion strain question as a fascinating challenge – with implications that go well beyond prion science. Finally, I will report some recent results obtained in my laboratory, which is attempting to address the strain question and some other basic issues of prion biology with a “systems” approach that utilizes organic chemistry, photophysics, proteomics, and mouse transgenesis.