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News Article | February 23, 2017
Site: www.eurekalert.org

ROCHESTER, Minn. -- A Mayo Clinic study has shown evidence linking the biology of aging with idiopathic pulmonary fibrosis, a disease that impairs lung function and causes shortness of breath, fatigue, declining quality of life, and, ultimately, death. Researchers believe that these findings, which appear today in Nature Communications, are the next step toward a possible therapy for individuals suffering from idiopathic pulmonary fibrosis. "Idiopathic pulmonary fibrosis is a poorly understood disease, and its effects are devastating," says Nathan LeBrasseur, Ph.D., director, Healthy Aging and Independent Living program, Mayo Clinic Robert and Arlene Kogod Center on Aging and senior author of this study. "Individuals with idiopathic pulmonary fibrosis express difficulty completing routine activities. There are currently no effective treatment options, and the disease leads to a dramatic decrease in health span and life span, with life expectancy after diagnosis between three to five years." Dr. LeBrasseur and his team, which included experts across several departments at Mayo Clinic, as well as Newcastle University Institute for Ageing and The Scripps Research Institute, studied the lung tissue of healthy individuals and of persons with mild, moderate and severe idiopathic pulmonary fibrosis. The tissue samples were made available from the Lung Tissue Research Consortium, a resource program of the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH). Researchers found that the markers of cellular senescence, a process triggered by damage to cells and linked to aging, were higher in individuals with idiopathic pulmonary fibrosis, and senescent cell burden increased with the progression of the disease. Then, they demonstrated that factors secreted by senescent cells could drive inflammation and aberrant tissue remodeling and fibrosis, which are hallmarks of idiopathic pulmonary fibrosis. "We discovered that senescent cells, which accumulate in the idiopathic pulmonary fibrosis lung, are a viable source of multiple factors that drive fibrotic activation," explains Marissa Schafer, Ph.D., a postdoctoral fellow in Dr. LeBrasseur's lab and lead author of the study. According to Dr. LeBrasseur, the findings represent a conceptual shift in the way they think about idiopathic pulmonary fibrosis. "Up to this point, research efforts have largely focused on understanding the unique elements that contribute to idiopathic pulmonary fibrosis. Here, we are considering whether the biology of aging is accelerated in this aggressive disease. What we've found is that senescent cells are prevalent, secreting toxic molecules that affect healthy cells in that environment and are essentially promoting tissue fibrosis." Equipped with the findings from their studies of human lung tissue, researchers then replicated the process in mice. They found that, much like in humans, mice with clinical features of idiopathic pulmonary fibrosis also demonstrated increased amounts of senescent cells. Researchers used a genetic model programmed to make senescent cells self-destruct and a drug combination of dasatinib and quercetin which, in previous studies conducted by Mayo Clinic, was shown to eliminate senescent cells. Results showed that clearing senescent cells from unhealthy mice improved measures of lung function and physical health, such as exercise capacity on a treadmill. While further research is needed, Drs. LeBrasseur and Schafer hope that targeting senescent cells could be a viable treatment option for individuals who suffer from idiopathic pulmonary fibrosis. "Previous work from the Center on Aging has shown in a number of models how senescent cells contribute to aging and aging-related conditions," says Dr. LeBrasseur. "We are exploring whether senolytic drugs, or drugs that can selectively kill senescent cells, can be used for the treatment of aging-associated conditions, including idiopathic pulmonary fibrosis. More research is needed to validate this, and our goal is to move quickly from discovery to translation to application, and, ultimately, meet the unmet needs of our patients." The research was supported by a Team Science Award from the Mayo Clinic Clinical and Translational Science Award grant from the National Center for Advancing Translational Science, National Institutes of Health, a generous gift from the John E. and Virginia H. Kunkel Family, the Glenn Foundation for Medical Research, the American Federation for Aging Research, the Connor Group, Noaber Foundation, the Mayo Clinic Robert and Arlene Kogod Center on Aging, a David Phillips Fellowship funded by the Biotechnology and Biological Sciences Research Council and a Biotechnology and Biological Sciences Research Council grant. Others on the research team are: Mayo Clinic and Drs. Kirkland, Pirtskhalava, Tchkonia and Zhu have a financial interest related to this research. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit http://www. or http://newsnetwork. .


News Article | November 17, 2016
Site: www.prweb.com

The Human Vaccines Project and Boehringer Ingelheim are pleased to announce a three-year collaboration agreement to support their mutual objective to decode the human immune system with the aim of accelerating understanding and development of immunotherapies overall as well as better vaccines for cancer treatment. Under the terms of the agreement, Boehringer Ingelheim’s contributions to the Project will help catalyze the Project’s expanding programs. “We are tremendously honored that Boehringer Ingelheim has elected to partner with the Project, joining a growing number of leading, global biopharmaceutical companies committed to addressing the key scientific challenges impeding development of next generation vaccines and immunotherapies,” said Wayne C. Koff, Ph.D., President and CEO of the Human Vaccines Project. “Boehringer Ingelheim brings exceptional basic science and clinical research expertise in the areas of oncology and human immunology, and is at the forefront of biopharma innovation in these areas.” A revolution is ongoing in cancer immunotherapy, due to the recent realization of the importance of “checkpoints,” proteins that enable tumors to evade the immune system’s ability to kill the tumor, and novel therapeutics termed “checkpoint inhibitors” that have provided dramatic clinical benefit in managing a subset of cancers in a limited number of patients. “Despite these exciting breakthroughs, our understanding of how the immune system can best be harnessed to attack and eliminate tumors remains limited. A better understanding of the human immune system in healthy individuals as well as patients, and how best to measure and direct the immune system is needed,” said Clive R. Wood, Ph.D., Senior Corporate Vice President, Discovery Research at Boehringer Ingelheim. “We are pleased to become a partner in this groundbreaking project which offers the potential to open a new era in vaccine and immunotherapeutic development. This complements our strong commitment to cancer immunology with a pipeline that includes among others, a therapeutic cancer vaccine and next generation checkpoint inhibitors.” Within the Human Vaccines Project’s scientific network, investigators at leading academic research centers are seeking to determine the central components of the human immune system at the molecular and structural level, as well as the common rules by which the immune system generates specific and durable protective responses against a range of infectious and neoplastic diseases. Successful achievement of these goals should enable accelerated development of new and improved vaccines and therapeutics for major global diseases. “The Human Vaccines Project is one of the more promising projects to help transform the future of vaccine development and cancer immunotherapy. JCVI is pleased to be adding our bioinformatics acumen as part of this effort to help conquer some of the most devastating diseases of the 21st century,” said J. Craig Venter, Founder, Chairman and CEO of the J. Craig Venter Institute which recently joined together with the Scripps Research Institute, La Jolla Institute and UC San Diego to serve as a scientific hub for the Project. About the Human Vaccines Project The Human Vaccines Project is a non-profit public-private partnership with the mission to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers by decoding the human immune system. The Project has a growing list of partners and financial supporters including: Vanderbilt University Medical Center, the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, UC San Diego, Aeras, Crucell/Janssen, GSK, Pfizer, MedImmune, Regeneron, Sanofi Pasteur, the Robert Wood Johnson Foundation and the John D. and Catherine T. MacArthur Foundation. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies, and has been endorsed by 35 of the world’s leading vaccine scientists.


News Article | November 10, 2016
Site: www.eurekalert.org

LA JOLLA, CA - Nov. 9, 2016 - Three groups at The Scripps Research Institute (TSRI) have been awarded grants from the National Institutes of Health (NIH) to develop methods for computational modeling and to apply them to cutting-edge systems in biology and health. "The three projects are highly symbiotic, each addressing a different state-of-the-art challenge in computational biology, but built using a common computational framework that will allow facile collaboration between the groups," said Professor Arthur Olson, founder of the Molecular Graphics Laboratory, which is currently part of the TSRI Department of Integrative Structural and Computational Biology. Stefano Forli, assistant professor of integrative structural and computational biology, was awarded $2.7 million to continue development of AutoDock, the most widely used method for computational docking of drugs and inhibitors to targets of medicinal interest. The proposed work will include improvements to the scoring function, allowing faster and more accurate prediction of how drugs act, new tools for advanced structure-based design of drugs and simplified methods for use by a wide community of non-expert users. David S. Goodsell, associate professor of molecular biology, was awarded $2.3 million to develop new methods for modeling the molecular structure of entire cells. The size and complexity of these structural models is unprecedented, and the project is currently leveraging methods developed by the gaming community. In collaboration with experimental scientists, the methods will be used to study bacterial nucleoid structure, cell division and other cellular processes. Michel F. Sanner, associate professor of molecular biology, initiated a research project addressing a significant challenge: the incorporation of the dynamic nature of proteins into docking simulations. Years six through nine of this project have been funded with an award of $1.6 million. His group will continue development of AutoDockFR, a fast computational docking method with advanced features, to represent local and global receptor motions during binding of flexible drug-like molecules to biomolecular targets. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 23, 2015
Site: www.nature.com

Human bronchial epithelial cells (CFBE41o−) carrying the ∆F508 CFTR mutation, or HBE41o− cells harbouring a WT CFTR allele, and isogenic CFTR null cells (CFBE41o−, null) were provided by J. Clancy. Cells were cultured at 37 °C, 5% CO in Advanced MEM (Gibco) supplemented with 1% penicillin/streptomycin (Gibco), 10% fetal bovine serum (Gibco) and 2 mM l-glutamine (Gibco) and appropriate selective antibiotics. Twenty hours before IP, cells were treated with DMSO (vehicle) or DMSO and 100 nM TSA (Sigma-Aldrich), 5 μM SAHA (Cayman Chemicals), 15 μM N-[2-(5-chloro-2-methoxyphenylamino)-4′-methyl-[4,5′]bithiazolyl-2′-yl]-benzamide (Cmpd 4a, C4, Cystic Fibrosis Foundation, http://www.cftrfolding.org/CFTReagents.htm). For siRNA-mediated knock down of HDAC7, CFBE41o− cells were transfected with Lipofectamine RNAiMAX (Invitrogen) and 50 nM of validated HDAC7-specific siRNA (Ambion) or scrambled control siRNA (Ambion) according to the manufacturers’ protocol. The cell culture medium was changed the next day and cells harvested 72 h after transfection. Primary bronchial epithelial cells were obtained from the Cystic Fibrosis Center at the University of Alabama according to institutional review board regulations or from Lonza, and were cultured in complete BEGM medium (Lonza) at 37 °C, 5% CO for up to three passages, starting with passage 0. Cell lines were tested for mycoplasma contamination with DAPI staining and their identity validated based on presence of the correct CFTR alleles as determined with polymerase chain reaction (PCR) and mass spectrometry. Cell culture experiments as well as subsequent sample processing and mass spectrometric data-taking were randomized. The investigators were not blinded to allocation during experiments and outcome assessment. Lentiviral particles containing shRNA sequences specific for the target proteins were generated in HEK293T cells using the Mission shRNA system with validated shRNA sequences (Sigma-Aldrich) following standard protocols41. CFBE41o− cells were infected with lentiviral particles for 16 h and cultivated for additional 48 h before harvest. Lentivirus production and infection is covered under approval 01-13-10-07 from The Scripps Research Institute and all steps were performed in a biosafety level 2/3-certified laboratory. Rescue of ∆F508 CFTR was monitored by western blotting followed by immunodetection of CFTR using rat monoclonal 3G11 antibody. The RNAi Consortium identification numbers for the shRNAs used are given in Supplementary Table 15. Protein lysates were prepared as described above, denatured in SDS sample buffer42 either for 15 min at 37 °C to detect CFTR or for 5 min at 95 °C, separated by SDS–polyacrylamide gel electrophoresis and transferred onto nitrocellulose (Protran; Schleicher & Schuell). The following primary antibodies were used: rat monoclonal antibody against CFTR (3G11), mouse monoclonal antibodies against CFTR (24.1, ATCC; M3A7, Chemicon) and β-actin (AC-15, Sigma), rabbit polyclonal antibodies against HDAC2 (9928S, Cell Signaling), PABPC1 (ab21060, Abcam), anti-galectin-3BP (AF2226, R&D Systems), anti-PTPLAD1 (WH0051495M1, Sigma), anti-52 kDA Ro/SSA (sc-25351, Santa Cruz) and anti-Na+/K+ATPase α Antibody (H-300, sc28800, Santa Cruz). Horseradish-peroxidase-conjugated secondary antibodies (Jackson ImmunoResearch) were detected with enhanced chemiluminescence reagent (ECL, Pierce). For immunofluorescence, CFBE41o− cells fixed with 4% paraformaldehyde were permeabilized with 0.1% Triton X100, blocked in 10% FBS in 1× PBS for 1 h at room temperature (21 °C) and incubated with the following antibodies for 4 h at room temperature (21 °C): anti-CFTR (3G11), anti-galectin-3BP (R&D Systems, AF2226), anti-PTPLAD1 (Sigma, WH0051495M1), anti-KLHDC10 (Sigma, HPA020119), anti-52 kDa Ro/SSA (Santa Cruz, sc-25351), anti-Rab45 (Santa Cruz, sc-81925), anti-Surfeit4 (Santa Cruz, sc-107304), anti-Erp72 (Abcam, ab82587, Enzo ADI-SPS-720), anti-PABPC1 (Abcam, ab21060) and anti-P4HB (3501S, Cell Signaling). AlexaFluor 488-, DyLight 488- or DyLight 549-conjugated secondary antibodies (Jackson ImmunoResearch) were used for detection of the primary antibodies. Nuclei were counterstained with DAPI (Molecular Probes, Invitrogen). Photographs of cells mounted in ProLong Gold antifade reagent (Molecular Probes, Invitrogen) were taken with a laser scanning confocal microscope LSM 710 (Zeiss) or Radiance 2100 Rainbow (Zeiss). Chloride channel activity of CFTR was determined with a Premo Halide Sensor assay (Invitrogen) measuring quenching of a halide-sensitive YFP variant (Venus YFP). To this end, HBE41o−, CFBE41o− and CFBE41o− cell lines stably transduced with shRNA lentivirus were infected with the Bacman gene delivery system to introduce the halide-sensitive Venus YFP. Subsequently, cells were seeded in glass bottom 96- or 24-well plates and cultivated overnight. Quenching of YFP fluorescence by iodide influx was measured at single-cell level with a Radiance 2100 Rainbow laser scanning confocal microscope (Zeiss) according to the protocol initially established in ref. 43. Briefly, before time-lapse recording, cells were pre-incubated with 50 μM genistein. Cells with sufficient YFP fluorescence were then selected and data acquisition was started with a frame speed of 0.5–1.0 s. After 5 s, sodium iodide was added to a final concentration of 0.1 M and chloride channel activity was further stimulated by addition of forskolin (20 μM). Acquired data were analysed with Matlab (http://www.mathworks.com) and Prism (GraphPad Software), and decay curves were fitted over the time course. At least ten individual cells for each cell line were recorded per experiment. Primary human CF and control (WT) bronchial epithelial cells infected with Mission shRNA lentiviral particles with a multiplicity of infection between 3 and 5 were plated on 12 mm Snapwell membranes (Corning) coated with rat tail collagen I (BD Biosciences) at a density of 1 × 105 cells per square centimetre and cultured in BEGM. Upon confluence, cells were maintained in B-ALI differentiation medium (Lonza) under ALI conditions for at least 21 d. Transepithelial resistance (R ) of the ALI cultures was measured with a Millicell ERS2 Voltohmmeter (Millipore) and was between 200 and 2,700 Ω cm−2. Polarized cultures were mounted in EasyMount Ussing chambers (Physiological Instruments), bathed bilaterally with Krebs–Ringer bicarbonate solution (140 mM Na+, 119.8 mM Cl−, 25 mM HCO −, 2.8 mM K+, 2.4 mM HPO 2−, 0.4 mM PO 3−, 1.2 mM Mg+, 1.2 mM Ca+, 5 mM glucose) and the solution saturated with 95% O , 5% CO . The epithelial sodium channel was blocked with 100 μM amiloride (Sigma-Aldrich). CFTR was stimulated by addition of forskolin (10 μM) and genistein (50 μM) to the apical side of the chamber followed by CFTR Inhibitor 172 (20 μM, EMD Biosciences, apical) to isolate the CFTR-specific, apical Cl− current. Measurements were performed at 37 °C and the short-circuit current (I ) was recorded and analysed with Acquire and Analyze 2.0 (Physiological Instruments). The detailed CoPIT protocol is available on the Nature protocol exchange website44. Rat monoclonal anti-CFTR antibody (3G11) was coupled to Protein G Sepharose 4 Fast Flow beads (GE Healthcare) at 6 mg ml−1 packed beads and covalently crosslinked to the beads with 20 mM dimethylpimelimidate (DMP, Pierce). CFBE41o− or HBE41o− cells from passages 5 to 19 were grown to confluence in Advanced MEM supplemented with 10% FCS, 1% penicillin/streptomycin, 2 mM l-glutamine and additional appropriate antibiotics. Approximately 4 × 107 or ~1 × 108 cells were harvested per IP, rinsed with PBS, lysed, CFTR protein complexes immunoprecipitated and prepared for MS analysis according to the CoPIT protocol. Briefly, cells were lysed on ice in TNI-buffer (0.5% Igepal CA-630 (Sigma-Aldrich), 50 mM Tris pH 7.5, 250 mM NaCl, 1 mM EDTA and 1× Complete EDTA-free Protease Inhibitor mix (Roche)). After water-bath sonication, insoluble material was removed by centrifugation (30 min, 18,000g, 4 °C) and the supernatant pre-cleared by incubation with Sepharose CL-4B (GE Healthcare). The pre-cleared lysate was then incubated overnight at 4 °C with 50 μl (approximately 250 μg) of anti-CFTR 3G11 antibody covalently coupled to Protein G Sepharose. Immunoprecipitates were recovered by centrifugation (500 g, 5 min, 4 °C), washed three times with lysis buffer and twice with lysis buffer containing no detergent. Bound proteins were eluted twice with 0.2 M glycine pH 2.3 and 0.5% Igepal CA-630 (30 min, 37 °C) and precipitated (eluate:methanol:chloroform, 1:4:1, v:v:v). The precipitate was washed with 95% methanol and re-solubilized in 100 mM Tris pH 8.5 and 0.2% Rapigest (Waters). Samples were reduced with 5 mM TCEP (Pierce), alkylated with 10 mM iodoacetamide (Pierce) and proteins digested overnight with 3 μg of sequencing-grade recombinant trypsin (Promega). Formic acid (9% final, v-v) was added to inactivate Rapigest (2 h, 37 °C), any precipitate removed by centrifugation (15 min, 18,000g at room temperature), and samples reduced to near dryness in vacuo. To identify non-specific contaminating proteins, control IPs were performed from (1) isogenic CFTR null cells to identify background that is recognized by the 3G11 antibody and (2) by using mock-IPs, in which no antibody is coupled to the beads, to identify bead- and cell-specific background. Protein lysates from CFBE41o− and HBE41o− cells at the same passage number were prepared in TNI lysis buffer, precipitated (lysate:methanol:chloroform (1:4:1, v:v:v) and 100 μg of protein reduced, alkylated and digested with trypsin as described above. Resulting peptides were labelled with 6-plex Tandem Mass Tag (TMT) labelling reagent (Thermo-Fisher) according to the manufacturer’s recommendations. Subsequently, Rapigest was inactivated by acidification with 10% formic acid, insoluble precipitate removed by centrifugation (15 min, 18,000g) and samples reduced to near dryness in vacuo. Samples were analysed by nano-electrospray ionization (ESI)–LC/LC–MS/MS on an LTQ-Orbitrap XL, LTQ or Orbitrap Elite (Thermo Fisher) by placing the triphasic MudPIT column in-line with an Agilent 1100 quaternary HPLC pump (Agilent) and separating the peptides in multiple dimensions with a modified six-step gradient containing 0%, 20%, 40%, 60%, and 100% of buffer C (500 mM ammonium acetate/5% acetonitrile/0.1% formic acid) over 12 h with the last step (100%) repeated, or a ten-step gradient (0%, 10%, 20%, 30%, 40%, 50%, 70%, 80%, 90%, 100% buffer C) over 20 h as described previously45. Each full-scan mass spectrum (400–2000 m/z) was followed by 6 (LTQ, LTQ-Orbitrap XL,) or 20 (Orbitrap Elite) data-dependent MS/MS scans at 35% normalized collisional energy and an ion count threshold of 1,000 (LTQ-Orbitrap XL, Orbitrap Elite) or 500 counts (LTQ). Dynamic exclusion was used with an exclusion list of 500, repeat time of 60 s and asymmetric exclusion window of −0.51 and +1.5 Da. To avoid cross-contaminations between the different samples, each sample was loaded onto a fresh column. Raw files were extracted with RawExtract (fields.scripps.edu/researchtools.php) and MS/MS spectra searched with ProLuCID46 against the human International Protein Index database version 3.23, using a target–decoy approach in which each protein sequence was reversed and concatenated to the normal database47. Search parameters were set to no enzyme specificity, 50 p.p.m. precursor mass tolerance and carboxyamidomethylation (m = 57.021464 Da) as a static modification. Search results were filtered with DTASelect version 2.1 (ref. 48), allowing for tryptic peptides only and a peptide false discovery rate of less than 0.5%, usually corresponding to a protein false discovery rate of less than 1.0%. To uniformly control the false discovery rate across samples in CoPIT, and to facilitate comparison, sqt files of replicate samples were filtered in a single DTASelect run and split again in corresponding replicate subsets for further analysis. Samples with non-sufficient recovery of the bait (<35 spectral counts) were excluded from further analysis. To remove redundancy due to isoform-specific identifiers, which is problematical for statistical analysis, International Protein Index numbers were first converted to Entrez Gene symbols using the X-REF Converter developed by RIKEN (http://refdic.rcai.riken.jp/tools/xrefconv.cgi) and manual annotation based on the Ensembl release 43 (http://www.regulatorygenomics.org); the highest PSM (peptide-spectrum match) values of all protein variants per gene and experiment were retained. CoPIT assumes that proteins binding non-specifically and non-selectively to carrier or antibody are detected with equal likelihood in experimental conditions (e) and control (c), as shown previously49, 50. Ratios for proteins p were calculated as    , where n is the number of experiments. Data were then plotted in Matlab, and a bimodal model was applied to analyse the frequency distribution of all ratios r and fitted with a Gaussian of two terms with a goodness of fit between 0.90 ≤ R2 ≤ 0.98, where (bg) is background- and (sp) bait-specific interactors. Confidence values were calculated for each protein according to where σ , μ , σ and μ were derived from the respective terms of the Gaussian fit. Proteins that were identified only in background control samples were eliminated from the analysis as obvious background contaminants. For a protein to be considered a potentially true interactor, we required further that it be detected in at least two independent biological replicates of the same condition to minimize random sampling errors and identities. Fold change of a protein p between two different experimental conditions was calculated according to Sample sizes were not pre-determined with statistical methods in this discovery-based proteomic approach. Errors for relative changes were calculated on the basis of random error of measurement in CoPIT. If not indicated otherwise, the following significance definitions were used throughout all figures: *, ; **, ; wherein r is the average relative ratio of the protein and is the random error of measurement. Annotation data were derived from Uniprot Knowledge Base, Entrez Gene information, GO Miner and literature review on PubMed. Interactions between the identified interactors were obtained with the GeneMANIA 2.2 Plugin51 in Cytoscape 2.8.2 using physical interactions reported in BIOGRID-small scale studies, BIOGRID and BIND as well as Pathway information reported in Pathway Commons. Proteins, their connections and according functional annotation were then graphed in Radial Topology Viewer 0.6, which was based on Medusa52, whereby length of individual edges reflects a quantitative relationship with the bait such as enrichment over background. Analysis of additional small networks was performed using Osprey 1.2.0 (ref. 53) and Ingenuity Pathway Analysis (Ingenuity). Analysis of the expression profiling experiments was performed in Census and the Integrated Proteomics pipeline IP2 (Integrated Proteomics Applications) using the TMT option with a tolerance of 10 millidaltons and a minimum intensity threshold of 100,000 relative ion counts54. Statistical significance was determined with an unpaired t-test for differential expression (two-tailed and two-sample t-test on every protein). The volcano plot was generated with the biostatistics package in Matlab (Mathworks). The data set was uploaded to Proteomics INTegrator (PINT; S.M.-B., unpublished observations) for online accession at http://sealion.scripps.edu/pint?project=CFTR (‘CFTR’ data set). It includes all qualitative and quantitative data over all experimental conditions and replicates measured. In addition, PINT provides an advanced query and annotation system, including the retrieval of Uniprot annotations assigned to the proteins in the data set. The CFTR interaction profile of a given condition was represented by log -transformed ratios of core interactome protein abundances (sum of spectral counts across the replicates of that condition) and the abundance value of CFTR in that same condition. Hierarchical clustering of the different conditions was produced using the average linkage algorithm. The distance between two conditions was set to one minus their Pearson correlation. Heat-map representation was produced using gplots version 2.14.1, and bootstrap values were obtained using the R package pvclust 1.2-2 (ref. 55).


News Article | November 8, 2016
Site: www.eurekalert.org

JUPITER, FL, November 8, 2016 - The Celia Lipton Farris and Victor W. Farris Foundation has made a $1.135 million gift to The Scripps Research Institute (TSRI) to create the Farris Foundation Endowed Graduate Fellowship on the Jupiter, Florida campus. "I want to thank the Farris Foundation for its generous gift to support our graduate program," said TSRI President Peter Schultz. "Gifts like this will help train the next generation of scientists who are critical to the future of biomedical research--and to build a lasting legacy of scientific excellence." The new Farris Foundation Endowed Graduate Fellowship will provide annual support for doctoral students at Scripps Florida in perpetuity. "Our gift is an investment in the continued strength of biomedical research at Scripps Florida," said Christine Koehn, executive director of the Farris Foundation, "so that young scholars will be able to reach their full potential as world-class scientists." TSRI's graduate program is consistently rated by U.S. News and World Report as in the top 10 of its kind in the nation for chemistry and biology. Scripps Florida established a branch of the graduate program in 2005; the campus has since graduated 28 PhDs, and 49 doctoral students are currently enrolled. The Celia Lipton Farris and Victor W. Farris Foundation, created in 1986 by a merger of the Victor W. Farris Foundation and the Celia Lipton Farris Foundation, seeks to support projects that provide the structure, encouragement and incentive that enable people to help themselves lead more successful, inspired and fulfilling lives. More information on The Celia Lipton Farris and Victor W. Farris Foundation and TSRI's graduate program is available on their respective websites. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 22, 2016
Site: www.eurekalert.org

LA JOLLA, CA - December 21, 2016 - A new study led by scientists at The Scripps Research Institute (TSRI) is the first to show exactly how the drug Arbidol stops influenza infections. The research reveals that Arbidol stops the virus from entering host cells by binding within a recessed pocket on the virus. The researchers believe this new structural insight could guide the development of future broad-spectrum therapeutics that would be even more potent against influenza virus. "This is a very interesting molecule, and now we know where it binds and precisely how it works," said study senior author Ian Wilson, Hanson Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI. The study was published today in the journal Proceedings of the National Academy of Sciences. Arbidol (also called umifenovir) is an anti-flu treatment sold in Russia and China by the Russian pharmaceutical company Pharmstandard. The drug is currently in stage-four clinical trials in the United States. The drug targets many strains of influenza, giving it an advantage over seasonal vaccines that target only a handful of strains. The new study sheds light on exactly how it accomplishes this feat. Scientists had long been curious whether Arbidol bound to the viral proteins used to recognize host cells--or with the viral "fusion machinery" that enters and infects host cells. To answer this question, the researchers used a high-resolution imaging technique called X-ray crystallography to create 3D structures showing how Arbidol binds to two different strains of influenza virus. The structures revealed that Arbidol binds to the virus's fusion machinery, as some had suspected. The small molecule binds to a viral protein called hemagglutinin, stopping the virus from rearranging its conformation in a way that enables the virus to fuse its membrane with a host cell. "We found that the small molecule binds to a hidden pocket in hemagglutinin," said study first author Rameshwar U. Kadam, senior research associate at TSRI. He added that the drug acts as a sort of "glue" to hold the subunits of hemagglutinin together. "Arbidol is the first influenza treatment shown to use a hemagglutinin-binding approach," he said. This vulnerable pocket is "conserved," meaning it is likely important for viral function--and more difficult to mutate as the virus spreads--suggesting why Arbidol has relatively broad use in fighting many strains of the virus, including emerging strains. The new findings also help scientists understand how Arbidol compares to influenza treatments such as Tamiflu. Wilson explained that Tamiflu prevents the virus from getting out of cells, while Arbidol prevents it from getting in. This means Arbidol, or future drugs that take a similar approach, could be given as a preventative treatment before an outbreak hits. "When we had the 2009 H1N1 pandemic, the vaccine came too late," said Wilson. "If we had a front-line therapeutic, that could have worked much better until a vaccine was ready." Wilson said the next step for researchers is to discover and/or design other small molecule therapeutics that can bind even more tightly with the hemagglutinin. This study, "Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol," was supported by the National Institutes of Health (grant R56 AI117675) and an Early Mobility Postdoctoral Fellowship from the Swiss National Science Foundation. This study used resources funded in whole or in part by the National Cancer Institute (grant Y1-CO-1020); the National Institute of General Medical Science (grant Y1-GM-1104); the U.S. Department of Energy, Basic Energy Sciences, Office of Science (contracts DE-AC02-06CH11357 and DE-AC02-76SF00515); the U.S. Department of Energy, Office of Biological and Environmental Research and by the National Institute of General Medical Science (grant P41GM103393). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


JUPITER, FL, Feb. 14, 2017 - A pair of scientists from the Florida campus of The Scripps Research Institute (TSRI) have been awarded up to $3.3 million from the National Cancer Institute of the National Institutes of Health (NIH) to create the next generation of breast cancer treatments for the thousands of patients whose current treatment options are limited. Ben Shen, TSRI professor and co-chair of the Department of Chemistry, and Christoph Rader, TSRI associate professor in the Department of Immunology and Microbiology, will co-lead the new five-year study. The researchers aim to develop a potent type of therapy known as an antibody-drug conjugate (ADC). This new class of anti-cancer drugs combines the specificity of antibodies, which attack only cells they recognize, with a highly toxic payload designed to kill specific cancer cells with far greater efficiency than most currently available treatments. So far, only three of these combination therapies have been approved by the U.S. Food and Drug Administration (FDA). The new ADC approach targets HER2-postive and ROR1-positive breast cancers, which are often aggressive and harder to treat with conventional chemotherapy and hormone drugs. The new grant builds on the work done in both the Shen and Rader labs. Shen and his colleagues recently uncovered a new class of natural products called tiancimycins, (TNMs) which kill selected cancer cells more rapidly and more completely compared with the toxic molecules already used in FDA-approved ADCs. Rader, who has spent most of his scientific career at TSRI and the NIH, has been studying and developing site-specific ADCs to treat cancer. "This grant matches my lab's work on advancing antibody engineering and conjugation technologies with the world-class natural product-based drug discovery in Ben Shen's lab," Rader said. "It's precisely what I came to Scripps Florida for: to build new molecules at the interface of chemistry and biology that can advance medicine. I'm very pleased that the NIH continues to invest in our ideas." Since HER2 and ROR1 expression is highly complementary, the new collaboration could provide new treatment options for at least 50 percent of breast cancer patients, Shen noted. "At Scripps Florida we not only do great science, but we have even greater opportunities to collaborate on projects like this," Shen added. "The combination of Christoph Rader's antibody technology and the tiancimycins, which have been proven to be exquisitely potent, should produce an antibody drug conjugate that we hope to move very quickly into the clinic." The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


LA JOLLA, CA - February 22, 2017 - The MagnaSafe Registry, a new multicenter study led by scientists at The Scripps Research Institute (TSRI), has demonstrated that appropriately screened and monitored patients with standard or non-MRI-conditional pacemakers and defibrillators can undergo MRI at a field strength of 1.5 tesla without harm. These devices are not presently approved by the U.S. Food and Drug Administration (FDA) for MRI scanning. The researchers observed no patient deaths, device or lead failures, losses of pacing function or ventricular arrhythmias in 1,500 patients who underwent MRI using a specific protocol for device interrogation, device programming, patient monitoring and follow-up designed to reduce the risk of patient harm from MRI effects. The research will be published as an Original Article in the February 23, 2017 issue of The New England Journal of Medicine. The use of MRI poses potential safety concerns for patients with an implanted cardiac device. These concerns are a result of the potential for magnetic field-induced cardiac lead heating, which could result in cardiac injury and damage to an implanted device. As a result, it has long been recommended that patients with a pacemaker or defibrillator not undergo MRI scanning, even when MRIs are considered the most appropriate diagnostic imaging method for their care. Despite the development of devices designed to reduce the potential risks associated with MRI, a large number of patients have devices that have not been shown to meet these criteria and are considered "non-MRI-conditional." At least half these patients are predicted to have the need for MRI after a device has been implanted. Researchers established the MagnaSafe Registry to determine the frequency of cardiac device-related events among patients with non-MRI-conditional devices, as well as to define a simplified protocol for screening, monitoring and device programming before MRI. "Given the great clinical demand for MRI for patients with a standard pacemaker or defibrillator, we wanted to determine the risk," said study leader Dr. Robert Russo, an adjunct professor at TSRI and director of The La Jolla Cardiovascular Research Institute. In the MagnaSafe Registry, researchers at 19 U.S. institutions tested 1,000 cases with a non-MRI-conditional pacemaker (one not approved for use in an MRI) and 500 cases of patients with a non-MRI-conditional implantable cardioverter defibrillator (ICD), a device that can shock the heart in response to a potentially fatal cardiac rhythm. They scanned regions other than the chest, such as the brain, spine or extremities--where MRI is traditionally the best option for imaging. The researchers tested the devices at an MRI field strength of 1.5 tesla, a standard strength for MRI scanners and reprogrammed some devices according to a prespecified protocol for the MRI examination. "If the patient was not dependent upon their pacemaker, the device was turned off," explained Russo. "If they could not tolerate having the device turned off, it was set to a pacing mode that did not sense cardiac activity. The reason was that the pacemaker could sense the electrical activity (radiofrequency energy) from the MRI scanner and the function of the device could be inhibited, which could be catastrophic if you depend upon your pacemaker for your heartbeat." Russo and his co-investigators did observe adverse effects in a small group of patients. Six patients had a brief period of atrial fibrillation, and in six additional cases pacemaker partial reset (a loss of stored patient information) was noted. But in no cases did the researchers observe device failure or a failure in the leads that connect the device to the heart when the protocol was followed. "One ICD generator could not be interrogated after MRI and required immediate replacement; the device had not been appropriately programmed per protocol before the MRI," explained Russo. These findings led the researchers to conclude that "device removal and replacement seem unlikely to be safer than proceeding with scanning for patients with a pacemaker or an ICD who require a nonthoracic MRI," provided a protocol similar to the MagnaSafe protocol was followed. "Patients with a standard or non-MRI-conditional pacemaker can undergo clinically indicated MRI without harm if a protocol such as the 'MagnaSafe' protocol used in this study is followed and patients are screened and monitored as described," said Russo. The researchers also noted that their results may not be predictive of findings with all device and lead combinations, higher MRI field strengths, patients younger than 18 years of age and MRI examinations of the chest or cardiac resynchronization devices (those designed to increase the function of a failing heart). The researchers plan to follow up by studying the risk for patients in need of a chest scan at scanner field strength of 1.5 tesla, as well as an MRI of any anatomic area at a higher field strength (3.0 tesla). The study, "Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator," also included authors from the University of California, San Diego; Scripps Memorial Hospital; the University of California, Los Angeles; Providence St. Joseph Medical Center; the University of Arizona; Intermountain Medical Center; Inova Heart and Vascular Institute; Allegheny General Hospital; Abington Memorial Hospital; Yale University School of Medicine; Providence Heart Institute; Oklahoma Heart Institute; the University of Mississippi Medical Center; the Medical College of Wisconsin; Bassett Medical Center; Carnegie Hill Radiology; Methodist DeBakey Heart and Vascular Center and Baptist Health. The study was supported by grants from St. Jude Medical, Biotronik, Boston Scientific and the Hewitt Foundation for Medical Research, and by philanthropic gifts from Mr. and Mrs. Richard H. Deihl, Evelyn F. and Louis S. Grubb, Roscoe E. Hazard, Jr. and the Shultz Steel Company. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


News Article | December 12, 2016
Site: www.businesswire.com

GERMANTOWN, Md.--(BUSINESS WIRE)--Zalgen Labs LLC (Zalgen), a biotechnology and diagnostics company focused on high-impact, neglected infectious diseases, today announced the launch of a new web-based marketplace to further affirm the Company as the global leader in e-commerce for hemorrhagic fever research and clinical testing. At launch, the Zalgen product list includes nine test kits for Ebola and Lassa fevers in rapid diagnostic test (RDT) and ELISA test formats. The intended use of the RDTs is for the presumptive detection of Ebola and Lassa fever viruses in individuals with signs and symptoms of virus infection in conjunction with epidemiological risk factors (including geographic locations with high prevalence of infection). Additionally, the site includes Lassa virus antibodies specifically for use in various testing formats, including Western blot, ELISA, Immunoprecipitation and Immunofluorescence. The hemorrhagic fever products licensed to and marketed by Zalgen have been developed by Tulane University in cooperation with additional members of the Viral Hemorrhagic Fever Consortium (VHFC). The VHFC is a collaboration of academic and industry members headed by Tulane University, including Autoimmune Technologies LLC, The Scripps Research Institute and the University of Texas Medical Branch at Galveston, as well as other collaborators in West Africa. “This expansion of our corporate website to include e-commerce capability will enable researchers and our distribution partners to easily secure these high-performance, critical reagents and materials to address Ebola, Lassa and other hemorrhagic fevers,” said Luis M Branco, Ph.D., Managing Director and Co-Founder of Zalgen Labs. “We will continue to expand the e-commerce site to include additional tropical diseases.” Development of the Zalgen kits and reagents was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) along with additional support provided by The Bill & Melinda Gates Foundation and the Paul G. Allen Family Foundation. Zalgen Labs is a biotechnology and diagnostics company with headquarters in Germantown, Md., and an advanced diagnostic product development center in Aurora, Colo. The company specializes in the design and production of superior biological molecules critical for the development and commercialization of immunotherapeutics, novel vaccines, and reliable, rapid and affordable diagnostic platforms targeting neglected and underrepresented human infectious diseases. For more information, visit www.zalgenlabs.com. The Viral Hemorrhagic Fever Consortium was established in 2010 as a result of several multi-year grants and contracts awarded to Tulane University by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to support Tulane’s ongoing efforts to treat and prevent Lassa fever. For more information, visit www.vhfc.org.


News Article | December 13, 2016
Site: www.eurekalert.org

LA JOLLA, CA - December 13, 2016 - Diet composition around the time of pregnancy may influence whether offspring become obese, according to a new study using animal models at The Scripps Research Institute (TSRI). "Your diet itself matters, not just whether you are gaining excess weight or developing gestational diabetes," said TSRI Associate Professor Eric Zorrilla, who led the study in collaboration with Tim R. Nagy of the University of Alabama at Birmingham and Barry E. Levin of the Veterans Affairs (VA) Medical Center of East Orange, New Jersey, and Rutgers University. In fact, the researchers found that giving females a typical American, or Western, diet appeared to set the next generation up for lifelong obesity issues. This work was published recently in the American Journal of Physiology and featured in APSselect, a collection of the best research papers from all journals published by the American Physiological Society. It's Not Just about Weight The researchers made this discovery by studying two lines of rats, one selectively bred to be obesity-resistant to a high-fat diet and one bred to be unusually vulnerable. Rats from each group were fed either a diet with the same overall fat, saturated fat, carbohydrate and protein levels as a typical Western diet, or a lower-fat, higher-grain control diet. The scientists found that female rats given a Western diet in the weeks leading up to pregnancy, during pregnancy and during nursing had offspring more prone to obesity at birth, during early adolescence and--many months later--through adulthood. This occurred even if the mothers themselves did not overeat and maintained a healthy weight, body fat and insulin status. Zorrilla said the results were surprising because, whereas previous studies had shown that overweight mothers were more likely to have overweight offspring, the new findings suggest that diet alone can make a difference independent of weight gain. The Western diet seemed to set in motion a metabolic "program" that lasted throughout the rat's life. Although these rats slimmed down during puberty and early adulthood, they still showed a lower basal metabolic rate (less energy expended at while rest) and higher food intake during that time, which led to a return of obesity in mid-adulthood. "What we found interesting was that you sometimes see the same thing in humans, when a kid goes through a growth spurt," said study first author Jen Frihauf, who recently completed her PhD through the University of California, San Diego, while working in the Zorrilla lab at TSRI. The researchers also spotted an interesting difference in the effects of the Western diet between the obesity-vulnerable and obesity-resistant lines: in females, the diet impaired the reproduction of the obesity vulnerable lines. Significantly fewer of females were able to reproduce, and those that did reproduce had fewer offspring. "This wasn't the focus of the study, but it supports the idea that a Western diet promotes infertility in mothers vulnerable to diet-induced obesity," said Zorrilla. The researchers also identified elevated levels of several molecules, such as insulin and hormones called leptin and adiponectin, starting at birth in both the Western diet and genetically vulnerable offspring. This hormone profile may serve as an early biomarker for detecting obesity risk. The Takeaway for Moms: Better Nutrition Research is ongoing into which aspects of a Western diet trigger these effects--and the molecular changes in the offspring responsible for them. Zorrilla said the findings should raise awareness of the importance of a healthy pre- and post-natal diet. For example, doctors may want to discuss nutrition with all women who are pregnant or are planning to become pregnant, not just those already overweight. "Doctors often use weight gain as a hallmark of a healthy pregnancy," said Frihauf. "But we realized there was something going on in utero that wasn't detectable in the mother's weight." Frihauf added that few pregnant women, even in the United States, eat a high-fat, high-sugar diet all day, every day. "We're not trying to tell pregnant women not to occasionally splurge on a piece of cake," she said. Studies have also shown that paternal diet, through "epigenetic" mechanisms that control how genes are expressed, can affect obesity risk in offspring, added Zorrilla, so nutritional information may be valuable for potential fathers as well. In addition to Zorrilla, Nagy, Levin and Frihauf, the study, "Maternal Western Diet Increases Adiposity Even in Male Offspring of Obesity-Resistant Rat Dams: Early Endocrine Risk Markers," was authored by Éva M. Fekete, previous of TSRI and now at The University of Wisconsin-Madison. This study was supported by the National Institutes of Health (grants R01DK-070118, R01DK-30066, R01DK-076896, F31DA026708-01A2, R21DK-077616, P30DK-056336 and P30DK-079626) and the Research Service of the VA. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 23, 2016
Site: www.eurekalert.org

The Biophysical Society has announced the winners of its Education Committee Travel Awards to attend the Biophysical Society's 61st Annual Meeting in New Orleans, Louisiana, February 11-15, 2017. The recipients of this competitive award, all of whom are students and postdoctoral fellows, are selected based on scientific merit. Each awardee will be presenting their research during the meeting, will receive a travel grant, and will be recognized at a reception on Saturday, February 11, at the Ernest N. Morial Convention Center. Mihai Azoitei, University of North Carolina at Chapel Hill, NOVEL BIOSENSOR DESIGN REVEALS THE ROLE AND REGULATION OF GEF-H1 IN CELL MIGRATION. Mouhanad Babi, McMaster University, THE CHARACTERIZATION OF CELLULOSE NANOSTRUCTURE USING SUPER-RESOLUTION FLUORESCENCE MICROSCOPY. Curtis Balusek, Georgia Institute of Technology, CONSTRUCTING AN IN SILICO MODEL OF THE GRAM-NEGATIVE CELLULAR ENVELOPE. Paola Bisignano, University of California, San Francisco, STRUCTURAL INSIGHTS INTO SODIUM-DEPENDENT SUGAR TRANSPORTERS AND THEIR INHIBITION MECHANISM. Breane Budaitis, University of Michigan, THE ROLE OF THE COVER-NECK BUNDLE IN MULTI-MOTOR TRANSPORT AGAINST LOAD IN CELLS. Shirley Chen, University of Michigan, ENGINEERING INHIBITABLE KINESIN-3 MOTORS BY A NOVEL CHEMICAL-GENETIC APPROACH. Saikat Chowdhury, The Scripps Research Institute, USING CRYOEM TO UNDERSTAND HOW PHAGES EVADE BACTERIAL CRISPR DEFENSE SYSTEM. Alexander Chu, California Institute of Technology, TOWARDS A UNIVERSALCHARACTERIZATION OF THE MEMBRANE PROTEIN EXPRESSION LANDSCAPE. Miranda Collier, University of Oxford, EVIDENCE FOR CHAPERONE FUNCTION IN MECHANOSENSATION. Caitlin Cornell, University of Washington, DIRECT IMAGING OF LIQUID DOMAINS BY CRYOTEM IN SUBMICRON VESICLES. Yavuz Dagdas University of California, Berkeley, CONFORMATIONAL DYNAMICS OF CAS9 DURING DNA BINDING. Peter Dahl, University of Michigan, A SUPPORTED TUBULATED BILAYER SYSTEM SHOWS EFFECTS OF SYNAPTOTAGMIN-7 ON MEMBRANE CURVATURE. Russell Davidson, Colorado State University, MOLECULAR ALLOSTERY IN DENGUE NS3 HELICASE ALONG THE ATP HYDROLYSIS CYCLE. Melody Di Bona, Italian Institute of Technology, CHROMATIN ACCESSIBILITY STUDIED BY SLOW SCAN FCS IN THE EUKARYOTIC NUCLEUS. Matthew Dragovich, Lehigh University, INVESTIGATION OF THE RELIABILITY OF AFM NANOINDENTATION-DERIVED MEASUREMENTS OF CELL MECHANICS. Paige Engen, Hamline University, STRUCTURAL ANALYSIS OF TAU PEPTIDE INTERACTIONS WITH LIPID MEMBRANES USING FOURIER TRANSFORM INFRARED SPECTROSCOPY. CristianEscobar, Florida State University, CONFORMATION PLASTICITY ANDPEPTIDOGLYCAN CLEAVAGE BY THE N-TERMINAL INTRINSICALLY DISORDERED DOMAIN OF CHIZ. Gozde Eskici, University of Pennsylvania, MICROSECOND SIMULATIONS OF AMYLOID BETA FIBRIL NUCLEATION IN REVERSE MICELLES. Emmet Francis, University of California at Davis, SINGLE-CELL INVESTIGATION OFTHE ROLE OF CALCIUM BURSTS IN HUMAN IMMUNE CELLS. Wolfgang Gross, University of Bayreuth, MACROPHAGES ARE SENSITIVE TO SUBSTRATE ELASTICITY DURING PHAGOCYTOSIS. Shubhasis Haldar, Columbia University, TRIGGER FACTOR BOOSTS THE WORK DONE BY PROTEIN FOLDING UNDER FORCE. Alice Herneisen, Swarthmore College, SITE-DIRECTED SPIN LABELING EPR SPECTROSCOPY OF THE CYTOPLASMIC TAIL OF INFLUENZA A M2. Naoto Hori, University of Texas, MULTISTEP FOLDING KINETICS OF GROUP I INTRON RNA STUDIED BY Mg2+-CONCENTRATION JUMP SIMULATIONS. Jesse Howe, CSU San Marcos, EXPANDING THE SCOPE OF SINGLE MOLECULE FRET SPECTROSCOPY TOWARDS PRIMARILY UNDERGRADUATE INSTITUTIONS. Abir Kabbani, Wayne State University, NANOSCALE MEMBRANE BUDS INDUCED BY CTXB-GM1 IN ONE COMPONENT BILAYER DETECTED BY POLARIZED LOCALIZATION MICROSCOPY (PLM). Shachi Katira, University of California, Berkeley, PRE-TRANSITION EFFECTS MEDIATE FORCES OF ASSEMBLY BETWEEN TRANSMEMBRANE PROTEINS: RECENT RESULTS ON THE ORDERPHOBIC EFFECT. Hema Chandra, Kotamarthi, Massachusetts Institute of Technology, SINGLE-MOLECULE DISSECTION OF THE ROLE OF DIRECTIONALITY IN PROTEIN DEGRADATION BY Clp PROTEOLYTIC MACHINES. Sudipta Lahiri, Wesleyan University, ELUCIDATION OF THE STRUCTURE-FUNCTION RELATIONSHIP OF S. CEREVISIAE MUTS HOMOLOG MSH4 AND MSH5 WITH THE HOLLIDAY JUNCTION. Ying Lai, Stanford University, MUNC13 AND MUNC18 COOPERATE TO PROPERLY ASSEMBLE SNARES FOR FAST NEUROTRANSMITTER RELEASE. Christopher Lee, University of California, San Diego, INVESTIGATING TRANSPORT PROPERTIES WITH MULTI-SCALE COMPUTABLE MESH MODELS FROM HETEROGENEOUS STRUCTURAL DATASETS. Maureen Leninger, New York University, INVESTIGATING THE STRUCTURE OF THE DRUG TRANSPORTER EMRE. Alyssa Lombardi Temple University School of Medicine, GENETIC ABLATION OFFIBROBLAST MITOCHONDRIAL CALCIUM UPTAKE INCREASES MYOFIBROBLASTTRANSDIFFERENTIATION AND EXACERBATES FIBROSIS IN MYOCARDIAL INFARCTION. Victor Pui-Yan Ma, Emory University, RATIOMETRIC TENSION PROBES FOR MAPPING RECEPTOR FORCES AND CLUSTERING AT INTERMEMBRANE JUNCTIONS. Mohammad Mehdi Maneshi, University at Buffalo, SHEAR STRESS STIMULATED MSC ACTIVITIES: DIRECT CHANGES OF MEMBRANE TENSION OR CYTOSKELETALSTRESS? Dipak Maskey, Institute of Medicine, DEGRADATION OF CALPONIN 2 IS REQUIRED FOR CYTOKINESIS. Isha Mehta, Texas Woman's University, PROTEIN ENERGY NETWORK MODELS TO CLASSIFY AND PREDICT FUNCTIONALLY LINKED INTERFACES OF PROTEINS FROM FUNCTIONALLY UNCORRELATED INTERFACES. Paula Morales, University of North Carolina at Greensboro, CONSTRUCTION OF A GPR3 HOMOLOGY MODEL USING CONFORMATIONAL MEMORIES. Medeea Popescu, Wellesley College, EXAMINING THE ROLE OF PHOSPHORYLATION ON INTERACTIONS BETWEEN THE CARDIAC POTASSIUM CHANNEL ALPHA-SUBUNITS HERG AND KVLQT1. Dana Reinemann, Vanderbilt University, SINGLE MOLECULE CHARACTERIZATION OF MITOTIC KIF15 REVEALS CAPABILITY TO GENERATE FORCE IN ANTI-PARALLEL MICROTUBULES. Talant Ruzmetov, Kent State University, EXPLORING THE ROLE OF FLEXIBILITY IN BINDING KINETICS AND AFFINITY OF PKID-KIX THROUGH COARSE GRAINED SIMULATIONS. Kristin Schimert, University of Michigan, INTRACELLULAR CARGO TRANSPORT BY SINGLE-HEADED KINESIN MONOMERS. Digvijay Singh, Johns Hopkins University School of Medicine, INVESTIGATION OF DNA BINDING, NUCLEOLYSIS AND PRODUCT RELEASE SPECIFICITY OF RNA GUIDED ENDONUCLEASE CRISPR-CPF1 FAMILY REVEALS IMPORTANT DIFFERENCES FROM CAS9-RNA. Kyle Smith, Northwestern University, THE TWO GTPASE DOMAINS OF THE OUTER MITOCHONDRIAL MEMBRANE PROTEIN MIRO HAVE NOVEL ACTIVE SITE CONFORMATIONS AND DISTINCT BIOCHEMICAL PROPERTIES. Kevin Votaw, Colorado State University, INSIGHTS INTO DAMAGED BASE DETECTION BY DNA GLYCOSYLASES: A COMPUTATIONAL STUDY OF ALKD. Sienna Wong, Wayne State University, ENGINEERING OF CHIMERIC PROTEINS TO ENHANCE IMMUNOGENICITY FOR THE PRODUCTION OF HIGH-AFFINITY SPECIFIC MONOCLONAL ANTIBODIES. Riley Workman, Duquesne University, CHARACTERIZATION OF THE CONFORMATIONAL ENSEMBLE OF POLYGLUTAMINE PEPTIDES VIA METADYNAMICS MD SIMULATIONS AND UV RESONANCE RAMAN SPECTROSCOPY. Goli Yamini, The Catholic University of America, IMPACT OF DENDRIMER SURFACE CHEMISTRY ON ANTHRAX TOXIN CHANNEL BLOCKAGE: A SINGLE MOLECULE STUDY. Fan Yang, University of California, Davis, RATIONAL DESIGN AND VALIDATION OF A VANILLOID-SENSITIVE TRPV2 ION CHANNEL. Chen-Ching Yuan, University of Miami, DISTINCT LATTICE STRUCTURE ALTREATIONS IN DCM AND HCM MOUSE MODELS ASSOCIATED WITH MUTATIONS IN MYOSIN REGULATORY LIGHT CHAIN. Rebecca Zaunbrecher, University of Washington, GENETICALLY ENGINEERED HUMAN STEM CELL-DERIVED CARDIOMYOCYTES TO STUDY THE FUNCTIONALITY OF CRONOS TITIN. Zhenfu Zhang, University of Toronto, INTERPLAY AMONG BINDING, PHOSPHORYLATION AND DENATURATION IN DISORDERED 4E-BP2 AS PROBED BY SINGLE MOLECULE FLUORESCENCE. Yue Zhang, Mississippi State University, MODELING THE EARLY STAGES OF AGGREGATION IN DISORDERED ELASTIN-LIKE PROTEINS. Haiqing Zhao, University Of Maryland, PROMISCUOUS HISTONE MIS-ASSEMBLY IS ACTIVELY PREVENTED BY CHAPERONES. Chi Zhao, University of Texas at Austin, PLASMA MEMBRANE VESICLES WITH ENGINEERED TRANSMEMBRANE PROTEIN LIGANDS FOR HIGH-AFFINITY CELL TARGETING. The Biophysical Society, founded in 1958, is a professional, scientific Society established to encourage development and dissemination of knowledge in biophysics. The Society promotes growth in this expanding field through its annual meeting, monthly journal, and committee and outreach activities. Its 9000 members are located throughout the U.S. and the world, where they teach and conduct research in colleges, universities, laboratories, government agencies, and industry. For more information on these awards, the Society, or the 2017 Annual Meeting, visit http://www. .


News Article | November 1, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 1, 2016 - Scientists at The Scripps Research Institute (TSRI) have developed a broadly useful method to unmask new functional features of human proteins. Proteins carry out thousands of essential functions in cells, but their activity typically is controlled--raised or lowered, even switched on or off--by the attachment of other functional groups called modifications. When these modifications are chemically reactive, they often serve as cofactors for enzymes. Knowing how these modifications impart protein function can be essential to understanding important biological processes and diseases. In a study published online on October 31, 2016 by Nature Chemistry, TSRI scientists demonstrated new chemical probes that can be used to discover and characterize previously unknown modifications of proteins. "In our first try using these probes, we found a reactive protein modification that has never been reported before in biology--that's really exciting and suggests that there are many other reactive modifications, likely to be cofactors, awaiting discovery with these new tools," said Megan L. Matthews, first author of the study and a research associate in the laboratory of Benjamin F. Cravatt, professor and chair of the Department of Chemical Physiology at TSRI. The new technique is broadly based on a research method known as "activity-based protein-profiling" (ABPP) that the Cravatt lab pioneered. It involves small-molecule probes that report on the activity states of entire enzyme classes. By capturing catalytic residues that have enhanced reactivity, the probes can also monitor whether an enzyme is in its active or inactive state. "It's a powerful technique--ABPP probes have been used to discover new enzymes, new enzyme inhibitors and new candidate drug therapies," said Matthews. ABPP probes have been used to screen proteins for enzymatic activity by forming covalent bonds with certain reactive groups called "nucleophiles," which are naturally found on the side chains of amino acids, the building blocks of proteins. In the new study, Matthews and colleagues created similar small-molecule probes that instead screen for protein "electrophiles"--which have the opposing reactivity. Strongly electrophilic sites are typically not part of a protein's amino-acid building blocks, but can be installed into proteins by other enzymes to create modified sites that confer function. The new electrophile-finding probes thus can be used to monitor and discover reactive modifications and enzyme cofactors. "There are many functional electrophiles found throughout Nature," said Matthews, "but one reason they haven't been studied until now with probes like ours is because a protein's sequence doesn't generally predict where an electrophile will be found or if one might exist." Matthews and her colleagues turned this uncertainty to their advantage, using the probes in living cells to mark and isolate protein electrophiles in an unbiased, catch-all manner. With the help of advanced techniques for determining the chemical structure of any protein and its modifications, the researchers were also able to study some of these electrophiles in detail and discover new aspects of how enzyme activity is controlled in the cell. In one case, they used a probe to monitor an important enzyme and drug target, AMD1, which uses a known electrophilic cofactor that effectively switches on its activity. The scientists discovered that the presence of this cofactor is, in turn, regulated by surrounding levels of yet another molecule, the amino acid methionine. In another case, they discovered a previously unknown type of protein modification, an attachment by a cluster of atoms called a glyoxylyl group. "This had never been described before in any species, but it occurs at a highly conserved site on the protein so it's probably functional--I suspect that it could represent a new class of cofactors," Matthews said. In all, the study uncovered dozens of proteins with apparent electrophiles that have never been characterized. Among them are unknown modifications to the Alzheimer's-related amyloid precursor protein, and to KEAP1, which plays a role in cancers and has been eyed as a potential drug target. Matthews is now busy following up on those and other leads. Key contributions to the research came from Lin He, who during the study was a research associate in the laboratory of TSRI Professor John R. Yates III. He and Matthews worked together to develop algorithms to predict the structure of the glyoxylyl-modified protein from the probe-based data. Erika J. Olson, a graduate student in the laboratory of Philip E. Dawson, professor in TSRI's Department of Chemistry, also provided crucial assistance in validating the newly discovered structure. Other co-authors of the paper, "Chemoproteomic profiling and discovery of protein electrophiles in human cells," were Benjamin D. Horning and Bruno E. Correia, all of TSRI at the time of the study. Funding for the research was provided by the National Institutes of Health (CA132630, P41 GM103533, U54 GM114833), the National Science Foundation (DGE-1346837) and a Helen Hay Whitney Foundation Postdoctoral Fellowship sponsored by Merck & Co. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 16, 2016
Site: www.eurekalert.org

The interaction between bacteria and worms can be used to understand host-microbiome signals in humans that contribute to diseases such as type 2 diabetes and obesity December 13, 2016/Novato, California: The billions of microorganisms living within the human digestive tract appear to play a significant role in health and disease, notably metabolic syndrome, autoimmune disorders and diabetes - but how these organisms do so is not well understood. Researchers at the Buck Institute have used worms to provide a framework for deciphering how specific bacterial signals from the microbiome influence the host, whether the host is a worm or a human. The work, done in the nematode worm C. elegans and detailed in Scientific Reports, an online open access journal from the publishers of Nature, reveals for the first time how different genes in bacteria - rather than metabolites produced by the bacteria - modify the biology of the worms that eat them. "The dynamic nature of the gut microbial community has proven hard to study in mice and even harder in human subjects," said Buck professor Pankaj Kapahi, PhD, senior scientist on the study. To start to untangle the complicated interactions, his team thought to use worms, which eat bacteria as part of their normal diet. "We have uncovered the effects of bacterial genetics on the physiology of a simple organism, which may serve as a model system to study the gut microbiome in mammals to identify novel therapeutics to treat diseases," he said. "Humans have a gut full of bacteria that are 'talking' with intestinal cells and ultimately affect the whole organism, so there has been a lot of research targeting bacterial metabolites associated with human disease. This study is the first one to explore how the bacteria themselves talk to the host," said Amit Khanna, PhD, a postdoctoral research fellow in Kapahi's lab. The foundations of this study began years ago not as a study of the microbiome, but as a contemplation of why worms that ate less lived longer. Kapahi wondered what in the worms' diet was responsible for this change in lifespan, and he thought the best way to answer that question would be to genetically mutate the bacteria they eat to see what caused any changes. To have an easy yes-or-no answer as to whether different mutations in bacteria affected the worms, the team took advantage of a phenomenon in the worm's life cycle called dauer, in which larvae shut down their functions to survive harsh environmental conditions. It is known that one of the factors causing worms to enter dauer are compounds produced by the bacteria they eat and that one of the pathways that controls this response is the insulin-like signaling pathway. Although humans and nematodes are of course quite different, Kapahi noted, many pathways are very similar, including insulin-like signaling, which plays a role in human diseases, such as type 2 diabetes and obesity. To ask the question about what genes in bacteria normally present at low levels in human gut flora would affect the insulin-like signaling pathway in worms, the team first systematically screened nearly 4,000 stains of E. coli bacteria that each had a single gene deactivated ("knocked out") to see which enhanced dauer formation. They found 56 mutants that did so. Some of these mutants also extended adult lifespan in control worms. The team picked one of the bacterial mutants that increased lifespan by the largest amount - called adenylate cyclase (cyaA) - to further explore. They found cyaA modulates dauer formation and lifespan by influencing TGF-β signaling, and they uncovered the entire molecular mechanism: they could see how the sensory neurons talk to the target cells and what were the molecular pathways involved that caused a worm to enter dauer. "The idea that a single gene mutation - in the bacteria that the worms normally eat - could throw off an entire animal and send it into a dauer state was certainly not a concept that we anticipated when we began this study," said Kapahi. The results demonstrate that the combination of bacterial and worm genetics can be a powerful tool to study the molecular signals by which bacteria modulate nutrient signaling and host physiological processes, such as development and aging. These processes are often very similar in higher organisms, so the significance of the study is not limited to C. elegans. Worms also allow questions to be answered rapidly, on the order of 10 to 15 days. "There a lot of studies showing that the microbiome influences this and that, but we have very little understanding of the mechanisms and how to make sense of the mounds of data," said Khanna. "We think our method might be the way forward: to be able to ask specific questions about what do individual bacterial components contribute and how do they do it." Citation: A genome-wide screen of bacterial mutants that enhance dauer formation in C. elegans [Scientific Reports 6, Article number: 38764 (2016)] DOI: 10.1038/srep38764 Other Buck researchers involved in the study include co-first authors Jitendra Kumar and Misha A. Vargas, LaKisha Barrett, Subhash Katewa, Patrick Li, Tom McCloskey, Amit Sharma, Nicole Naude?, Christopher Nelson and Rachel Brem. Other collaborators include David W. Killilea from Children's Hospital Oakland Research Institute, Sean Mooney from University of Washington and Matthew Gill from The Scripps Research Institute - Florida. Acknowledgements: The work was supported by grants from the American Federation for Aging Research and the NIH : R01AG038688 and RL1 AAG032113. About the Buck Institute for Research on Aging The Buck Institute challenges the way we think about aging by approaching it as if it were a disease. We do not accept aging as an inevitable decline. Our mission is to extend the healthy, vital years of life. Our research is aimed at rendering chronic diseases as preventable, deferrable, curable or, at the least, manageable. Whenever possible, we want to restore function. Buck scientists are pioneers. They work in a dynamic, collaborative environment to understand how normal aging contributes to conditions such as Alzheimer's and Parkinson's diseases, cancer, osteoporosis, arthritis, heart disease, diabetes, macular degeneration, and glaucoma, among others. We are an independent nonprofit organization working in an architectural landmark located in northern Marin County, California. For more information: http://www.


News Article | November 16, 2016
Site: www.sciencedaily.com

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily "circadian" clocks in influencing cancer growth. The research, published recently in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked. "This appears to have big implications for the connection between circadian rhythms and cancer," said TSRI biologist Katja Lamia, senior author of the study. There is growing evidence that shift work and frequent jet lag can raise a person's risk of cancer, suggesting a link between daily rhythms and cell growth. "We know this connection exists, but we haven't known why," said Lamia. The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more. Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells' ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation -- similar to the abnormal growth seen in cancers. Further studies of protein structures suggested that CRY2 is a key player in a process to "mark" cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription -- once the proteins are already produced -- rather than during transcription, as in many other cryptochrome functions. "This is a function of a circadian protein that has never been seen before," said TSRI Research Associate Anne-Laure Huber, who served as first author of the study. The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.


Researchers at the Scripps Translational Science Institute (STSI) and The Scripps Research Institute (TSRI) who looked at the effect of aging on induced pluripotent stem cells (iPSCs) found that genetic mutations increased with the age of the donor who provided the source cells, according to study results published today by the journal Nature Biotechnology. The findings reinforce the importance of screening iPSCs for potentially harmful DNA mutations before using them for therapeutic purposes, said lead investigators Ali Torkamani, Ph.D., director of genome informatics at STSI, and Kristin Baldwin Ph.D., the study's co-lead investigators and associate professor of molecular and cellular neuroscience at the Dorris Neuroscience Center at TSRI. "Any time a cell divides, there is a risk of a mutation occurring. Over time, those risks multiply," Torkamani said. "Our study highlights that increased risk of mutations in iPSCs made from older donors of source cells." Researchers found that iPSCs made from donors in their late 80s had twice as many mutations among protein-encoding genes as stem cells made from donors in their early 20s. That trend followed a predictable linear track paired with age with one exception. Unexpectedly, iPSCs made from blood cells donated by people over 90 years old actually contained fewer mutations than what researchers had expected. In fact, stem cells from those extremely elderly participants had mutation numbers more comparable to iPSCs made from donors one-half to two-thirds younger. Researchers said the reason for this could be tied to the fact that blood stem cells remaining in elderly people have been protected from mutations over their lifetime by dividing less frequently. "Using iPSCs for treatment has already been initiated in Japan in a woman with age-related macular degeneration," said paper co-author and STSI Director Eric Topol, M.D. "Accordingly, it's vital that we fully understand the effects of aging on these cells being cultivated to treat patients in the future." STSI is a National Institutes of Health-sponsored site led by Scripps Health in collaboration with TSRI. This innovative research partnership is leading the effort to translate wireless and genetic medical technologies into high-quality, cost-effective treatments and diagnostics for patients. Of the 336 different mutations that were identified in the iPSCs generated for the study, 24 were in genes that could impair cell function or trigger tumor growth if they malfunctioned. How troublesome these mutations could be depends on how well the stem cells are screened to filter out the defects and how they are used therapeutically, Torkamani said. For example, cells made from iPSCs for a bone marrow transplant would be potentially dangerous if they contained a TET2 gene mutation linked to blood cancer, which surfaced during the study. "We didn't find any overt evidence that these mutations automatically would be harmful or pathogenic," he said. For the study, researchers tapped three sources for 16 participant blood samples: The Wellderly Study, an ongoing STSI research project that is searching for the genetic secrets behind lifelong health by looking at the genes of healthy elderly people ages 80 to 105; the STSI GeneHeart Study, which involves people with coronary artery disease; and TSRI's research blood donor program. The iPSCs were generated by study co-authors Valentina Lo Sardo, Ph.D., and Will Ferguson, M.S., researchers in the TSRI group led by Baldwin. "When we proposed this study, we weren't sure whether it would even be possible to grow iPSCs from the blood of the participants in the Wellderly Study, since others have reported difficulty in making these stem cells from aged patients," Baldwin said. "But through the hard work and careful experiments designed by Valentina and Will, our laboratories became the first to produce iPSCs from the blood of extremely elderly people." Explore further: Research on rare genetic disease reveals new stem cell pathway More information: Influence of donor age on induced pluripotent stem cells, Nature Biotechnology, nature.com/articles/doi:10.1038/nbt.3749


DEERFIELD, Ill.--(BUSINESS WIRE)--Walgreens today announced findings from a collaborative study with the Scripps Translational Science Institute (STSI) suggesting that automated health tracking can significantly improve long-term health engagement. The study examined utilization patterns of participants in Walgreens Balance Rewards for healthy choices® (BRhc), an industry leading, self-monitoring program that allows members to track health activities and receive incentives for continued tracking and healthy behaviors. It explored the impact of manual versus automatic data entries through a supported device or via apps, the study results were recently published in the Journal of Medical Internet Research.1 The researchers examined activity tracking data - including exercise, weight, sleep, blood pressure, blood glucose data recorded, tobacco use and oxygen saturation - from more than 450,000 BRhc members in 2014. After identifying users with sufficient follow-up data, the study explored trends in participation over time. The results demonstrated that 77 percent of users manually recorded their activities and participated in the program for an average of five weeks. However, users who entered activities automatically using the BRhc supported devices or apps remained engaged four times longer and averaged 20 weeks of participation. “This is the first chapter of a remarkable collaboration with Walgreens, enabling us to understand real world connectivity with mobile device health applications, along with behavior and outcome patterns, in an exceptionally large and diverse cohort,” said Eric Topol, MD, director, STSI. “Consumers are increasingly more engaged in their own healthcare and wellness. Digital technology that enables easy data tracking of healthy behaviors, combined with incentives, and trusted professional support, provide additional motivation for our customers to more easily manage their health,” said Harry Leider, M.D., chief medical officer, Walgreens. “We’re especially encouraged by the results of this study. In the two years since it was initiated, we’ve seen a shift from the majority of members in the program tracking their activities manually, to most now tracking them automatically. We’re pleased to continue our relationship with Scripps to advance our work in a way that results in a positive impact on behaviors and outcomes.” The Walgreens Balance Rewards for healthy choices program can be accessed either online or through the Walgreens mobile app. One of the main features of the program is the use of existing consumer incentives to motivate voluntary participation. Through participation in BRhc, members receive loyalty points redeemable for discounts on purchases. For more information about Walgreens Balance Rewards for healthy choices, please visit https://walgreens.com/healthychoices. This research was supported in part by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences through a grant UL1TR001114, and a grant from the Qualcomm Foundation. STSI is a National Institutes of Health-sponsored site in San Diego that merges the considerable biomedical science expertise of The Scripps Research Institute with Scripps Health’s exceptional patient care and clinical research capabilities. This innovative research partnership is leading the effort to translate wireless and genetic medical technologies into high-quality, cost-effective treatments and diagnostics for patients. Walgreens (www.walgreens.com), one of the nation's largest drugstore chains, is included in the Retail Pharmacy USA Division of Walgreens Boots Alliance, Inc. (NASDAQ: WBA), the first global pharmacy-led, health and wellbeing enterprise. More than 10 million customers interact with Walgreens each day in communities across America, using the most convenient, multichannel access to consumer goods and services and trusted, cost-effective pharmacy, health and wellness services and advice. Walgreens operates 8,175 drugstores with a presence in all 50 states, the District of Columbia, Puerto Rico and the U.S. Virgin Islands. Walgreens omnichannel business includes Walgreens.com and VisionDirect.com. Approximately 400 Walgreens stores offer Healthcare Clinic or other provider retail clinic services. 1 Ju Young Kim, Nathan E Wineinger, Michael Taitel, Jennifer M Radin, Osayi Akinbosoye, Jenny Jiang, Nima Nikzad, Gregory Orr, Eric Topol, Steve Steinhubl. Self-Monitoring Utilization Patterns Among Individuals in an Incentivized Program for Healthy Behaviors. J Med Internet Res 2016 (Nov 17); 18(11):e292. http://www.jmir.org/2016/11/e292/


News Article | October 26, 2016
Site: www.eurekalert.org

LA JOLLA, CA -- Oct. 24, 2016 -- Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive. Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body's antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection. "Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go," said co-senior author TSRI Associate Professor Mansun Law. "We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses," said co-senior author Ian A. Wilson, TSRI's Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI. The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs. A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed. The Law and Wilson laboratories have been working together in recent years to study HCV's structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells. Because this receptor-binding site on E2 is crucial to HCV's ability to infect its hosts, it has an amino-acid sequence that is relatively invariant from strain to strain. The receptor-binding site is also relatively accessible to antibodies, and indeed many of the antibodies that have been found to neutralize a broad set of HCV strains do so by targeting this site. For all these reasons, HCV's receptor-binding site has been considered an excellent target for a vaccine. But although candidate HCV vaccines mimicking the E2 protein have elicited high levels of antibodies against the receptor-binding site, these antibody responses--in both animal models and human clinical trials--have not been very effective at preventing HCV infection of liver cells in laboratory assays. To understand why, the Law and Wilson laboratories teamed up with TSRI Associate Professor Andrew Ward and used electron microscopy and several other advanced structural analysis tools to take a closer look at HCV's E2 protein, in particular the dynamics of its receptor binding site. Their investigations focused on the "recombinant" form of the E2 protein, produced in the lab and therefore isolated from the rest of the virus. Recombinant E2 is a prime candidate for HCV vaccine design and is much easier to purify and study than E2 from whole virus particles. One finding was that recombinant E2, probably due to its many strong disulfide bonds, has great structural stability, with an unusually high melting point of 85°C. However, the TSRI scientists also found evidence that, within this highly buttressed construction, the receptor binding site portion is extraordinarily loose and flexible in the recombinant protein. "It adopts a very wide range of conformations," said study first author Leopold Kong, of TSRI at the time of the study, now at the National Institutes of Health. Prior studies have shown that HCV's receptor binding site adopts a narrow range of conformations (shapes) when bound by virus-neutralizing antibodies. A vaccine that elicited high levels of antibodies against only these key conformations would in principle provide effective protection. But this study suggests that the E2 protein used in candidate vaccines displays far too many other binding-site conformations--and thus elicits antibodies that mostly do nothing to stop the actual virus. Law and Wilson and their colleagues plan to follow up by studying E2 and its receptor binding site as they are presented on the surface of the actual virus. They also plan to design a new version of E2 or even an entirely different scaffold protein, on which the receptor binding site is stabilized in conformations that will elicit virus-neutralizing antibodies. In addition to Law, Wilson, Ward and Kong, authors of the study, "Structural flexibility at a major conserved antibody target on hepatitis C virus E2 antigen," included Rameshwar U. Kadam, Erick Giang, Travis Nieusma, Fernando Garces and Netanel Tzarum, all of TSRI; and David E. Lee, Tong Liu, Virgil Woods and Sheng Li, of the University of California, San Diego. Support for the study was provided by the National Institutes of Health (AI079031, AI123861, AI106005, AI123365, GM094586, AI117905, GM020501 and AI101436) and TSRI's Skaggs Institute for Chemical Biology. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 15, 2016
Site: www.eurekalert.org

JUPITER, FL - November 15, 2016 - Autism is an agonizing puzzle, a complex mixture of genetic and environmental factors. One piece of this puzzle that has emerged in recent years is a biochemical cascade called the mTOR pathway that regulates growth in the developing brain. A mutation in one of the genes that controls this pathway, PTEN (also known as phosphatase and tensin homolog), can cause a particular form of autism called macrocephaly/autism syndrome. Using an animal model of this syndrome, scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered that mutations in PTEN affect the assembly of connections between two brain areas important for the processing of social cues: the prefrontal cortex, an area of the brain associated with complex cognitive processes such as moderating social behavior, and the amygdala, which plays a role in emotional processing. "When PTEN is mutated, we find that neurons that project from the prefrontal cortex to the amygdala are overgrown and make more synapses," said TSRI Associate Professor Damon Page. "In this case, more synapses are not necessary a good thing because this contributes to abnormal activity in the amygdala and deficits in social behavior." The study was published on November 15 by the journal Nature Communications. The study also showed that targeting the activity of the mTOR pathway shortly after birth, a time when neurons are forming connections between these brain areas, can block the emergence of abnormal amygdala activity and social behavioral deficits. Likewise, reducing activity neurons that project between these areas in adulthood can also reverse these symptoms. "Given that the functional connectivity between the prefrontal cortex and amygdala is largely conserved between mice and humans," said TSRI Graduate Student Wen-Chin Huang, the first author of the study, "we anticipate the therapeutic strategies suggested here may be relevant for individuals on the autism spectrum." Although caution is warranted in extrapolating findings from animal models to humans, these findings have implications for individualized approaches to treating autism. "Even within individuals exposed to the same risk factor, different strategies may be appropriate to treat the symptoms of autism in early development versus maturity," said Page. In addition to Page and Huang, Youjun Chen of TSRI was an author of the Nature Communications study, "Hyperconnectivity of Prefrontal Cortex to Amygdala Projections in a Mouse Model of Macrocephaly/Autism Syndrome." The research was supported by the National Institutes of Health (grants R01MH105610 and R01MH108519), Ms. Nancy Lurie Marks, The American Honda and Children's Healthcare Charity Inc., Fraternal Order of Eagles, the Simons Foundation (grant 360712) and an anonymous donor. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 11, 2016
Site: www.eurekalert.org

JUPITER, FL - Nov.10, 2016 - While the romantic poets' idea of memories being akin to spirits may have poetic merit, the scientists' perspective is that memories are concrete, physical entities that can be visualized within various regions of the brain. Scientists from the Florida campus of The Scripps Research Institute (TSRI) have now for the first time identified a sub-region in the brain that works to form a particular kind of memory: fear-associated with a specific environmental cue or "contextual fear memory." The study, recently published in the journal Biological Psychiatry Cognitive Neuroscience and Neuroimaging, was led by TSRI Associate Professor Sathyanarayanan V. Puthanveettil. "Much is still unknown about the identities of proteins synthesized to produce long-term memory," Puthanveettil said. "The most striking observation from the new study is that the medial prefrontal cortex is the site of this early protein synthesis. We have also identified what proteins are newly synthesized in the medial prefrontal cortex." In particular, the study showed new protein synthesis in a specific sub-region of the prefrontal cortex known in rodents as the prelimbic. In humans, this area corresponds to the anterior cortex, which has been linked to processing emotional responses. Initially, Puthanveettil and his colleagues ignored the medial prefrontal cortex because no one believed that it had anything to do with early encoding of long term memories. However, when they closely examined the effects on the brain of conditioning rodents with a mild foot shock, the scientists found several messenger RNAs recruited to polyribosomes in the medial prefrontal cortex -- a clear indication of new protein synthesis there. Puthanveettil and his colleagues also discovered that if they inhibited new protein synthesis in the prelimbic region right after fear conditioning took place, those memories did not form. But if the researchers waited just a few hours, inhibiting protein synthesis in prelimbic cortex had no impact and the memories took hold. There is temporal and spatial regulation of new protein synthesis in the medial prefrontal cortex. "It may be that the first wave of protein synthesis is critical for encoding contextual fear memory, while second wave in other sub-regions is important for memory storage," he said. It remains to be determined if other sub-regions of the cortex are also be involved in the synthesis of memory proteins. "The medial prefrontal cortex has many sub-regions," said TSRI Senior Research Associate Bindu L. Raveendra, co-first author of the study with Valerio Rizzo, Khalid Touzani and Supriya Swarnkar, all of TSRI at the time of the study. "But the specific roles of these sub-regions in encoding, expression and retrieval, as well as their underlying molecular mechanisms, remain to be unraveled." Other authors of the study, "Encoding of Contextual Fear Memory Requires De Novo Proteins in The Prelimbic Cortex," include Beena M. Kadakkuzha and Xin-An Liu of TSRI; Joan Lora and Robert W. Stackman of Florida Atlantic University; and Chao Zhang and Doron Betel of Weill Cornell Medical College. The study was supported by the Whitehall Foundation, the National Institutes of Health (grant number 1R21MH096258) and the State of Florida. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 22, 2016
Site: www.eurekalert.org

JUPITER, FL - Nov. 22, 2016 - Anyone who has drifted into a fuzzy-headed stupor after a large holiday meal is familiar with the condition commonly known as a "food coma." Now scientists from the Florida campus of The Scripps Research Institute (TSRI), Florida Atlantic University and Bowling Green State University may have finally found a reason for the phenomenon. Until recently, there has been little more than anecdotal evidence to suggest that "food coma" is an actual physical condition -- and the scientific evidence that does exist is unable to explain why some people fall asleep immediately after eating, some later and some not at all. "Different foods play different roles in mammalian physiology, but there have been very few studies on the immediate effects of eating on sleep," said TSRI's Associate Professor William Ja, who led the study, published today in the online journal eLife. Ja and his colleagues used Drosophila, the common fruit fly, as a model, due to the well-documented sleep-metabolism interaction in which flies suppress sleep or increase locomotion when starved. They created a system called the Activity Recording CAFE (ARC), a small plastic chamber that allowed them to record fly activity before and after feeding. Researchers found that after a meal, flies increased sleep for a short period before returning to a normal state of wakefulness. Their response varied according to food intake -- flies that ate more also slept more. Further investigation of specific food components showed that while protein, salt and the amount eaten promoted sleep, sugar had no effect. "The protein link to post-meal sleep has been mostly anecdotal, too, so to have it turn up in the study was remarkable," Ja said. "In humans, high sugar consumption provides a quick boost to blood glucose followed by a crash, so its effect on sleep might only be observed beyond the 20 to 40 minute food coma window." The fact that larger-sized meals increased sleep in fruit flies may also have parallels in human behavior--it's known that electrical activity increases in the brain with meal size and during certain stages of sleep. Salt consumption also influences sleep in mammals. Unpublished data suggest that the "food coma" condition might be a way to maximize gut absorption of protein and salt, two nutrients that flies might prioritize or find limited in nature, Ja added. "Using an animal model, we've learned there is something to the food coma effect, and we can now start to study the direct relationship between food and sleep in earnest," Ja said. "This behavior seems conserved across species, so it must be valuable to animals for some reason." The study also found some intriguing physiological reasons behind after-meal fly napping. "By turning on and off neurons in the fly brain, we identified several circuits dedicated to controlling postprandial sleep," said TSRI Graduate Student Keith Murphy, the first author of the study. "Some of these circuits responded to protein and others to circadian rhythm, demonstrating that the behavior has a diversity of inputs." In addition to Ja and Murphy, the other authors of the study, "Postprandial Sleep Mechanics in Drosophila," are Sonali A. Deshpande, James P. Quinn, Jennifer L. Weissbach and Seth M. Tomchik of TSRI; Maria E. Yurgel, Alex C. Keene and Ken Dawson-Scully of Florida Atlantic University; and Robert Huber of Bowling Green State University. This work was supported by the National Institutes of Health (grant R21DK092735), an Ellison Medical Foundation New Scholar in Aging Award and a Glenn Foundation for Medical Research Award for Research in Biological Mechanisms of Aging. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 16, 2016
Site: www.eurekalert.org

JUPITER, FL - November 15, 2016 - In new findings that could have an impact the development of therapies for a number of currently untreatable brain disorders such as Parkinson's and Huntington's diseases, scientists from the Florida campus of The Scripps Research Institute (TSRI) have found, for the first time, that a specific signaling circuit in the brain is deeply involved in motor activity. The study, which was led by TSRI's Associate Professor Srinivasa Subramaniam, was published November 15 in the journal Science Signaling. Despite many advances, the precise signaling mechanisms that regulate motor function in the striatum, that part of the brain responsible for motor activity, remain unknown. The new study identified for the first time a protein interaction network that helps control these functions by inhibiting the signaling of dopamine, a neurotransmitter involved in regulating movement. "A pair of proteins operates through a protein-protein interaction network--what we call a 'Rhesactome'--in the striatum," Subramaniam said. "This may have much broader implications in neurological, psychiatric and addictive disorders. Drugs that bind to either of these proteins may have therapeutic benefits for the diseases that affect this part of the brain." The study focused on amphetamine-induced activity affected by what is known as RasGRP1-Rhes signaling circuitry. Drugs like amphetamine, which trigger dopamine release in the striatum, enhance locomotor activity. Rhes acts as a kind of brake on the amphetamine-induced locomotion; in order for normal motor activity to occur, the RasGRP1 and other protein partners in the Rhesactome network induced by amphetamine have to block Rhes. It is the calibrated interaction of Rhes with the protein RasGRP1 that adjusts striatal control of motor functions. In the study, the researchers succeeded in using RasGRP1 to inhibit Rhes-mediated control of striatal motor activity in animal models. Animal models that were Rhes-deficient had a much stronger active behavioral response to amphetamines. But all that changed if RasGRP1 was depleted. "It's a delicate and highly complex relationship," Subramaniam said. "Imagine that you are running. This protein complex carefully controls that motor function by modulating the effect of Rhes. That's why you need to have the double control elements of both RasGRP1 and Rhes to fine-tune those motor functions. Our study captures this dynamic complex, so that now for the first time we can biochemically visualize it at the network level." What remains unknown at this point is how RasGRP1 actually modulates Rhes. "We speculate that both transcriptional and post-transcriptional mechanisms are involved," said TSRI Staff Scientist Neelam Shahani, the first author of the study. "Considering that the Rhes protein is enhanced predominantly at synaptic locations, one intriguing possibility is that RasGRP1 regulates local translation of Rhes messenger RNA at the synapse." In addition to Subramaniam and Shahani, other authors of the study, "RasGRP1- Promotes Amphetamine-Induced Motor Behavior through a Rhes Interaction Network ("Rhesactome") in the Striatum," are Supriya Swarnkar, Vincenzo Giovinazzo, Jenny Morgenweck, Laura M. Bohn, Catherina Scharager-Tapia, Bruce Pascal and Pablo Martinez-Acedo of TSRI; and Kshitij Khare of the University of Florida, Gainesville. The study was supported by the National Institutes of Health (grant R01-NS087019). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | February 15, 2017
Site: www.prweb.com

Catalent Pharma Solutions, the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products, today announced that it will be hosting a two-part workshop on the development and delivery of advanced biologics alongside leading experts from Johns Hopkins University, Scripps Research Institute and University of California/San Francisco, at the upcoming Drug Delivery Partnerships Conference, to be held at the PGA National Resort & Spa, Palm Beach Gardens, Florida, on Feb. 7 – 9, 2017. On Tuesday, Feb. 7, Catalent’s Dr. Gregory Bleck, Global Head of R&D Biologics, will present “Speed to market: production and manufacturing of complex biopharmaceuticals,” in the first part of the workshop, which focuses on the development of biologics, alongside other contributions from Dr. Atul Bedi, Associate Professor, Johns Hopkins University School of Medicine, Dr. Vaughn Smider, Assistant Professor of Molecular Biology, The Scripps Research Institute, and Dr. Charles Craik, Professor of Pharmaceutical Chemistry, Pharmacology, Biochemistry and Biophysics at UCSF. The second workshop session will deal with the delivery of biologics, and Dr. David Rabuka, Catalent’s Global Head of R&D Chemical Biology, will discuss “Latest advances developing antibody drug conjugates and other bioconjugates using SMARTag™ technology,” while Dr. Cornell Stamoran, Vice President of Corporate Strategy will present “Advanced Biologics Delivery: Overview of Non-Invasive Options.” At the end of the workshop sessions, Dr. Stamoran will also chair a panel on the “Future of Biologics Therapeutic Development” with all the day’s presenters. Earlier that day, Dr. Stamoran will be part of the conference’s opening panel session presentation, entitled “Drug Delivery Evolution: 20 Year Outlook – How Far Have We Come, or Have We?” He and senior R&D executives from Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, and Noven, will reflect on key learnings from the last 20 years that can help shape the future of drug delivery, and discuss what steps need to be taken to reach industry goals. For more information on the conference, visit: https://lifesciences.knect365.com/ddp/, and to arrange a meeting with any of the Catalent executives attending the event, contact Richard Kerns at NEPR - richard(at)nepr.eu For more information on Catalent Biologics, visit http://www.catalentbiologics.com About Catalent Catalent is the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products. With over 80 years serving the industry, Catalent has proven expertise in bringing more customer products to market faster, enhancing product performance and ensuring reliable clinical and commercial product supply. Catalent employs approximately 9,500 people, including over 1,400 scientists, at more than 30 facilities across five continents, and in fiscal 2016 generated $1.85 billion in annual revenue. Catalent is headquartered in Somerset, New Jersey. For more information, visit http://www.catalent.com


JUPITER, FL - November 21, 2016 - While there have been advances in the treatment of hormone-driven breast cancer, resistance to these therapies remains a significant problem. Side effects, including an increased risk of uterine cancer among postmenopausal women, also severely curtail their use for prevention. However, a new study by scientists from the Florida campus of The Scripps Research Institute (TSRI) offers a novel structure-based drug design strategy aimed at altering the basic landscape of this type of breast cancer treatment. The findings show that the current approach is not the only, or even the best way, to block the estrogen receptor. "We have created a different approach that gives us a mechanism to produce new types of therapeutic molecules," said TSRI Associate Professor Kendall Nettles. "There are a lot of ways to avoid resistance and other cancer risks, and this gives us a tool box full of alternative approaches that could limit or eliminate those effects." "With the standard method, no one understands the structural basis," he continued. "With our approach we know exactly how we did it. If you can see the shape of the receptor protein and see how the drug works on it, that makes the development process that much faster." The findings were published November 21, 2016, by the journal Nature Chemical Biology. The current method of creating this class of drugs, which includes tamoxifen, involves attaching a bulky cluster of atoms with a chainlike structure (called, appropriately, a side chain) to molecules that disrupt the estrogen receptor binding site. The team's strategy taps a technique called x-ray crystallography to visualize the drug candidate as it binds to the receptor. This image is used to guide the production of estrogen receptor degraders that also lack the side chain, helping to reduce the risk of resistance and the development of other cancers. "Our structure-trapping approach to X-ray crystallography provides a molecular snapshot of how subtle changes to a compound series generate a range of graded activity profiles," said Research Associate Jerome C. Nwachukwu, who was co-first author with Research Associate Sathish Srinivasan. "This structurally distinct mechanism, acting indirectly rather than involvement of the typical side chain, provides a new way to design biologically distinct molecules for breast cancer prevention and treatment." The new method also makes it possible to identify structural rules for how the molecules interact. "This is the first example of a structure-based design strategy targeting the estrogen receptor where there is a clear correlation between the chemistry, crystal structure and activity, which is another big advance that will be of broad interest to the cancer community," Srinivasan said. "We show that indirect antagonism can result in inhibition of proliferation in a predictive fashion." In addition to Nettles, Srinivasan and Nwachukwu, other authors of the study, "Full Antagonism of the Estrogen Receptor without a Prototypical Ligand Side Chain," include Nelson E. Bruno, Venkatasubramanian Dharmarajan, Devrishi Goswami, Scott Novick, Jason Nowak and Patrick R Griffin of TSRI; Irida Kastrati, Nittaya Boonmuen, Yuechao Zhao, Benita S. Katzenellenbogen and John A. Katzenellenbogen, Jian Min and Jonna Frasor of the University of Illinois; Hai-Bing Zhou of Wuhan University (China). The study was supported by the National Institutes of Health (grants PHS 5R37DK015556, 5R33CA132022, 5R01DK077085, 1U01GM102148 and 5R01CA130932); the Breast Cancer Research Foundation, BallenIsles Men's Golf Association, Frenchman's Creek Women for Cancer Research, Susan G. Komen for the Cure® (grant PDF12229484), the National Natural Science Foundation of China (grants 81172935, 81373255 and 81573279) and Hubei Province's Outstanding Medical Academic Leader Program. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 21, 2016
Site: www.eurekalert.org

JUPITER, FL - December 21, 2016 - In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown how two genes "balance" each other to maintain normal cell function. A disruption in one of the genes, called spns1, can induce degradation and premature "senescence"--or aging--while the other gene, called atp6v0ca, can jump in to suppress that degradation. Their experiments in zebrafish suggest that these combined genetic disruptions can counteract premature aging and extend developmental lifespan. "We found that the dual defects did indeed counteract senescence during development and extended the animal's survival and life span," said TSRI Associate Professor Shuji Kishi. The findings, published recently in the journal Autophagy, could also guide future treatments for diseases that involve the body's inability to degrade unwanted or harmful compounds. Cellular senescence is when cells stop dividing and is a normal part of aging. Interestingly, senescence is not only observed in later aging stages but is also detectable during embryonic development in vertebrates. In the new study, the researchers took a closer look at the gene spns1. In vertebrates, such as zebrafish and humans, the protein encoded by spns1 is important in a cellular process called autophagy, when the cell moves unwanted material to a cellular structure called the lysosome. Previous research had shown that defects in this gene can also cause senescence in the embryonic stage and premature aging symptoms in adulthood. However, Kishi and his colleagues found that a concurrent disruption of another gene-- atp6v0ca, whose sole defect still causes senescence--led to suppression of the process induced by the defective spns1 gene. "Our findings suggest that these two defects actually function at a balance point that is critically involved in the regulation of developmental senescence--and that balance allows for normal cell function," said Kishi. The scientists are now considering ways to influence the balance between these genes as a strategy to treat lysosomal storage diseases such as Pompe disease, where the excessive buildup of a substance called glycogen results in severe muscle weakness. They believe there may also be applications in treating age-associated degenerative diseases linked to late-stage autophagy disruption. "The use of appropriate inhibitors, selective for key steps in the biosynthesis of cellular macromolecules in general, may restore normal dynamics in the autolysosomal compartment and correct the pathological storage that is the ultimate cause of these types of disease," said TSRI Research Associate Shanshan Lian, the co-first author of the study. The findings may also lead to the development of tools to help identify new genes that affect the aging process without the need for performing lengthy adult lifespan analyses. This approach could be applied to the high-throughput identification of pharmacological agents that control aging and lifespan through enhanced resistance to various stressors, including oxygen radicals. In addition to Kishi and Lian, other authors of the study, "Autolysosome Biogenesis and Developmental Senescence Are Regulated by Both Spns1 and V-Atpase," include TSRI's Tomoyuki Sasaki, a co-first author and Alam Khan; Jesse R. Llop, Andrew V. Samuelson of the University of Rochester; Wenbiao Chen of the Vanderbilt University; and Daniel J. Klionsky of the University of Michigan. This study was supported by the National Institutes of Health (grants GM101508 and GM053396). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 1, 2016
Site: www.eurekalert.org

LA JOLLA--(December 1, 2016) Ribosomes--macromolecular machines consisting of RNA and proteins that twist, fold and turn--are responsible for making all of the protein within a cell and could hold the key to deciphering a range of diseases. Despite the intricacies of ribosomes, cells are able to churn out 100,000 of them every hour. But because they assemble so speedily, researchers haven't been able to figure out how they come together. A collaboration led by Salk Institute for Biological Studies and The Scripps Research Institute in La Jolla, California, deployed a cutting-edge imaging method called single-particle cryo-electron microscopy (cryo-EM) and accompanying analysis tools to decipher some of the key steps for how ribosomes are assembled, a first step in understanding their roles in health and disease. The results are published online December 1, 2016, in the journal Cell. "These new structures we captured with cryo-EM show that it is possible to image and interpret diverse molecular machines in action," says the study's co-senior author Dmitry Lyumkis, a Helmsley-Salk Fellow at Salk. "This is a completely different way of seeing and doing structural biology. This paper is a prime example of the fact that we can do far more intricate analyses than have ever been expected." Understanding molecular structures is important not only for basic research into biology but also for the drug development process to better understand how to make safer and more effective medicines. Researchers traditionally turn to X-ray crystallography, a method that requires its users to extensively purify a molecule and then re-make it in crystal form, but this method has limitations. In the past few years, advances in cryo-EM have allowed scientists to image single particles with resolution comparable to that of traditional X-ray methods. But in single-particle cryo-EM, proteins (the "particles") are flash-frozen and imaged using streams of electrons, meaning the molecules don't need to be crystallized and can retain much of their native structure. Although cryo-EM has been around for a while, new cameras are making it easier to capture proteins at high resolution before the electron spray zaps them. Importantly, computational tools for analyzing cryo-EM data have matured such that researchers can now purify molecules in silico by a computer rather than through traditional biochemical approaches. This becomes a much more powerful approach for separating mixtures of species, allowing the researchers to identify and distinguish structurally distinct populations of particles in greater detail than before. In the new study, co-senior author James Williamson, professor of molecular biology and chemistry at The Scripps Research Institute, and his team developed a method to stall one major component of ribosomes, the 50s subunit, from coming together so quickly. The scientists were able to chemically pause a mixture of different molecules in various stages of assembly. Lyumkis's group then used high-end cryo-EM to image and analyze these stalled structures, which had not been attempted for such a mix of diverse forms of a particular molecule. "Others have shown that you can capture a couple of different structural states of a molecule," Lyumkis says. "But, as far as I know, no one has tried to take this crude mixture of stuff, put it onto a cryo-EM grid, and ask what was in there." The team found that there are at least 15 types of complexes in the mixture, 13 of which are actively assembling 50s subunits. They imaged each of these structures at a resolution high enough to decipher the protein and RNA constituents. They were then able to use computer algorithms to order the complexes according to their assembly pathway. The team's analysis suggests that ribosomes can take several different routes for assembly, which is important to ensure that the process is efficient and can withstand a variety of cell stresses, according to Williamson. "If you imagine an assembly line where every step has to happen in sequential order, and there is a problem at one of those steps, everything grinds to a halt," he says. "If there are parallel pathways, then assembly can proceed through other channels until the problem is resolved. It took the scientists over a year to make sense of the structures, employing relatively new image analysis tools. But they have laid the groundwork to study other large, dynamic, and structurally heterogeneous molecular machines, which, Lyumkis says, will lead to new basic science and translational discoveries. Other authors on the study are Joseph H. Davis of The Scripps Research Institute; and Yong Zi Tan, Bridget Carragher and Clinton Potter of Columbia University and the New York Structural Biology Center. The research was supported by the Jane Coffin Child's Foundation; the National Institute of Aging; The Leona M. and Harry B. Helmsley Charitable Trust; the National Institute of General Medical Sciences; the Simons Foundation; and the Agency for Science, Technology and Research Singapore. About the Salk Institute for Biological Studies: Every cure has a starting point. The Salk Institute embodies Jonas Salk's mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer's, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.


News Article | December 20, 2016
Site: www.eurekalert.org

JUPITER, FL - December 20, 2016 - Ron Davis, chair of the Department of Neuroscience on the Florida campus of The Scripps Research Institute (TSRI) has been awarded a $5 million Outstanding Investigator Grant, one of the first of its kind, by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). The new eight-year grant will focus on the biological processes that underlie memory formation, targeting the brain mechanisms that mediate forgetting, how the brain organizes memories, and the role for genes that suppress memory formation. The grant is fully funded for the first five years. At the end of the fifth year, an administrative review of the program's progress will decide on an additional three-year renewal. Davis, who has pioneered the study of memory formation, particularly how the brain actively forgets certain memories, will be the principal investigator for the new grant, which was launched by NINDS earlier this year. "This new type of grant will fund our research program, not just one single project," Davis said. "It's a long-term endorsement of our work. I'm pleased to have the NINDS endorsement and extremely grateful for their support. It will help us build on what we've accomplished over the last ten years." The new funding will cover virtually all the Drosophilia research done in the lab, Davis noted. "We use Drosophilia--the common fruit fly--to better understand the basic principles of active memory formation and as a guide in our drug discovery efforts," he said. "For our drug discovery efforts, our studies with the fly help us filter through genes and brain proteins that might be important targets for developing cognitive enhancers as therapeutics." Davis's research into how the brain actively forgets certain memories represents a breakthrough in what has been a largely unstudied area of memory formation and offers tremendous opportunities for making new discoveries in the molecular biology of the process. "The overall results of our research going forward will offer an unprecedented view of the constraints the brain uses to limit memory formation," Davis said. "There's a rich medical importance to this research, given the well-documented problems of cognition associated with numerous neurological and psychiatric disorders. In fact, the majority of human neurological and psychiatric disorders involve some impairment in learning and memory." According to NINDS, the Outstanding Investigator Grant is designed specifically to give scientists the freedom to "pursue longer range, innovative, high-risk research without feeling pressured to generate results quickly to renew short-term grants." The new grant also had a shorter submission process to reduce the amount of time scientists spend writing and administrating multiple grant awards. The number of the grant is 1R35NS097224-01. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 22, 2016
Site: www.eurekalert.org

LA JOLLA, CA - Dec. 22, 2016 - A protein originally discovered at The Scripps Research Institute (TSRI) appears to be involved in how the body controls breathing, according to a new study led by scientists at TSRI and Harvard Medical School. The study, published in Nature, shows how the Piezo2 protein, previously shown to be the principal sensor of touch and proprioception, also plays a critical role in sensing lung expansion. "The discoveries here could provide important clues on how to treat patients with respiratory disorders" said senior author Ardem Patapoutian, a professor at TSRI and a Howard Hughes Medical Institute (HHMI) investigator. Using genetically modified mouse models, the researchers found that newborn mice lacking the Piezo2 channel show severe respiratory distress that leads to death. The researchers said this study might help shed light on sudden infant death syndrome (SIDS) in human babies, which is thought to be associated with dysfunctional airway sensory neurons. Adult mice lacking the Piezo2 channel in sensory neurons exhibit significantly increased tidal volume (amount of inhaled air in lungs) as well as an impaired Hering-Breuer reflex, an inhibitory respiratory reflex that prevents lung over-expansion. Piezo2 Sends Messages from the Lungs to the Nervous System The Piezo2 ion channel was originally discovered as a novel mechanosensor (sensor of mechanical stimuli such as pressure or stretch) in Patapoutian's lab in 2010. Follow-up studies showed that the Piezo2 channel present in sensory neurons is required for sensing touch sensation and muscle stretch in mice. These studies led researchers to wonder if Piezo2 plays a role as a general stretch sensor in other organs such as lungs. "Previous studies suggested the existence of lung inflation sensors; however, their molecular identity or physiological importance has not been clarified," said Patapoutian. The researchers tackled this question by generating and characterizing Piezo2 "knockout" mice, in which the Piezo2 channel is deleted throughout the animal or only from sensory neurons (more specifically, vagal sensory neurons that are known to control breathing). They found that Piezo2 is essential for establishing proper breathing and lung expansion in newborn mice. Piezo2-deficient newborn mice showed unexpanded lungs and significantly shallow breathing. "The lungs communicate with the brain via sensory neurons. The Piezo2 channel in sensory neurons generates a message about lung volume changes, and Piezo2-containing sensory neurons deliver this message to the brain," said TSRI Research Associate Keiko Nonomura, co-first author of the study with TSRI Research Associate Seung-Hyun Woo. "Piezo2-deficient mice cannot generate an accurate message about their lung volume changes. As a result, these mice cannot receive proper output from the brain." Strikingly, according to recently published papers, Piezo2-deficient human infants also show shallow breathing and require medical attention. "Piezo2-deficient newborn mice develop normally until birth. The problem only arise once the mice are born and try to breathe on their own" added Nonomura. The researchers were surprised to see an unexpected consequence of deleting Piezo2 in sensory neurons of adult mice. When the Piezo2 channel was deleted either in all sensory neurons or only from vagal sensory neurons, adult mice could still breathe, but they inhaled significantly more air than Piezo2-intact mice. Under normal conditions, animals stop breathing when they are forced to breathe in more air, but Piezo2-deficient adult mice lacked the Hering-Breuer reflex and continued breathing when they were forced to breathe in more air. Why this difference between adults and newborns? The researchers found that Piezo2 performs different functions in newborns and adults because establishing autonomous breathing in newborns is more complex. "At birth, newborn respiratory system undergoes drastic structural changes as liquid-filled compressed fetal airways are being cleared and inflated with air," said Patapoutian. "Therefore, newborn airways experience larger mechanical changes, compared to adult airways, which have already established normal breathing." These data, for the first time, define the importance of mechanosensory transduction in adult respiration. This research is also relevant for understanding respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and sleep apnea, which appears to be tied to disruption of the airway sensory feedback system. The team said future studies could also use similar genetic manipulations to better understand the role of Piezo2 in other physiological processes such as heart rate control and bladder function. In addition to Nonomura, Woo and Patapoutian, authors of the study, "Piezo2 senses airway stretch and mediates lung inflation-induced apnoea," were Rui B. Chang and Stephen D. Liberles of Harvard Medical School; Astrid Gillich of HHMI and the Stanford University School of Medicine; Zhaozhu Qiu, previously of TSRI and the Genomics Institute of the Novartis Foundation, now at Johns Hopkins University; Allain G. Francisco of HHMI and TSRI; and Sanjeev S. Ranade, previously of HHMI and TSRI, and now at the Gladstone Institutes. This research was supported by the National Institutes of Health (grants R01DE022358 and R01HL132255), a Giovanni Armenise-Harvard Foundation Grant and the Howard Hughes Medical Institute. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Sciences, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 10, 2015
Site: www.biosciencetechnology.com

Can you touch a finger to the tip of your nose with your eyes closed? Most of us can, thanks to a sense called proprioception, which tells us where our body parts are relative to each other and our environment. Not surprisingly, this sense is essential for normal movement and balance—walking, for instance. For decades, biologists have been trying to find the crucial sensor protein in nerve endings that translates muscle and tendon stretching into proprioceptive nerve signals. Now in a study published in Nature Neuroscience on November 9, 2015, a team led by scientists from The Scripps Research Institute (TSRI) has identified this sensor protein in mice. It turns out to be a protein called Piezo2, which was found recently to mediate the sense of touch. “To the layman it might not seem surprising that touch and proprioception would use the same sensor protein, but within this field there has been a lot of evidence suggesting otherwise—so finding that Piezo2 does both was a surprise,” said lead investigator Ardem Patapoutian, a professor at TSRI and investigator with Howard Hughes Medical Institute. The laboratories of Thomas M. Jessell at Columbia University and Katherine A. Wilkinson at San Jose State University collaborated on the study. Patapoutian and his laboratory specialize in identifying and characterizing sensory transducer proteins and over the past 15 years have identified transducers of cold, heat and pain. In two studies published last year, they identified Piezo2 as the principal sensor for ordinary, non-painful touch in mice. The new findings stem in part from those studies, in which Patapoutian and his team developed transgenic mice that can be made to switch off Piezo2 activity in “touch” neurons and other sensory neurons based in the spine. With Piezo2 silenced, the mice showed profound deficits in responding to touch. But they also showed a different kind of deficit. “Their walking was a bit abnormal, which gave us a hint that some proprioceptive neurons might be affected, too,” said Seung-Hyun Woo, a research associate in the Patapoutian laboratory who was first author of the new study. In an initial set of experiments for the new study, the team managed to isolate mouse sensory neurons involved in proprioception and tested these neurons’ electrical responses to mild mechanical pressure. Such neurons’ nerve ends and cell bodies are known to be studded with mechanically activated ion channel proteins, which essentially spring open—admitting a surge of charged molecules (ions) and triggering an electrical nerve impulse—when the surrounding nerve or cell membrane is distorted sufficiently by a stretching of the local muscle tissue. Prior studies had suggested that the main stretch-sensing protein expressed by proprioceptive neurons is one that specializes in admitting sodium ions. However, the team found evidence from these initial tests that the main ion-channel protein on proprioceptive neurons is not a selective sodium-channel protein, but in fact has properties consistent with Piezo2s. The researchers then confirmed that Piezo2 is expressed in mouse proprioceptive neurons and their muscle-embedded nerve ends. To establish Piezo2’s role with more certainty, they developed two lines of transgenic mice in which Piezo2 production could be switched off in proprioceptive neurons shortly after the mice were born. The resulting animals showed severe abnormalities in walking and limb positioning. “Their limbs were everywhere—they looked like they were trying to do yoga,” said Woo. In a final set of experiments, the team found that leg muscle tissue from these mice lacking Piezo2—tissue with proprioceptive nerves embedded—produced almost no nerve signals in response to muscle stretching, whereas muscle tissue from normal mice produced robust signals. “The data that we have now in support of Piezo2’s role in proprioception are really overwhelming,” said Patapoutian. While the finding is a milestone in sensory neuroscience, it may also lead to a better understanding of some human diseases relating to proprioception. For example, a genetic disorder known as distal arthrogryposis type 5, whose sufferers are born with severely contracted joints, was found in 2013—by Patapoutian and colleagues—to be caused by a mutation to the human version of Piezo2. The Patapoutian lab is continuing to investigate. Funding was provided by the Howard Hughes Medical Institute and the National Institutes of Health.


News Article | December 12, 2016
Site: www.marketwired.com

Scripps researchers say results should be considered when designing iPSC therapies SAN DIEGO, CA--(Marketwired - December 12, 2016) - As it is in much of life, the aging process isn't kind to an important type of stem cell that has great therapeutic promise. Researchers at the Scripps Translational Science Institute (STSI) and The Scripps Research Institute (TSRI) who looked at the effect of aging on induced pluripotent stem cells (iPSCs) found that genetic mutations increased with the age of the donor who provided the source cells, according to study results published today by the journal Nature Biotechnology. The findings reinforce the importance of screening iPSCs for potentially harmful DNA mutations before using them for therapeutic purposes, said lead investigators Ali Torkamani, Ph.D., director of genome informatics at STSI, and Kristin Baldwin Ph.D., associate professor of molecular and cellular neuroscience at the Dorris Neuroscience Center at TSRI. "Any time a cell divides, there is a risk of a mutation occurring. Over time, those risks multiply," Torkamani said. "Our study highlights that increased risk of mutations in iPSCs made from older donors of source cells." Researchers found that iPSCs made from donors in their late 80s had twice as many mutations among protein-encoding genes as stem cells made from donors in their early 20s. That trend followed a predictable linear track paired with age with one exception. Unexpectedly, iPSCs made from blood cells donated by people over 90 years old actually contained fewer mutations than what researchers had expected. In fact, stem cells from those extremely elderly participants had mutation numbers more comparable to iPSCs made from donors one-half to two-thirds younger. Researchers said the reason for this could be tied to the fact that blood stem cells remaining in elderly people have been protected from mutations over their lifetime by dividing less frequently. Understanding effects of aging "Using iPSCs for treatment has already been initiated in Japan in a woman with age-related macular degeneration," said paper co-author and STSI Director Eric Topol, M.D. "Accordingly, it's vital that we fully understand the effects of aging on these cells being cultivated to treat patients in the future." STSI is a National Institutes of Health-sponsored site led by Scripps Health in collaboration with TSRI. This innovative research partnership is leading the effort to translate wireless and genetic medical technologies into high-quality, cost-effective treatments and diagnostics for patients. Of the 336 different mutations that were identified in the iPSCs generated for the study, 24 were in genes that could impair cell function or trigger tumor growth if they malfunctioned. How troublesome these mutations could be depends on how well the stem cells are screened to filter out the defects and how they are used therapeutically, Torkamani said. For example, cells made from iPSCs for a bone marrow transplant would be potentially dangerous if they contained a TET2 gene mutation linked to blood cancer, which surfaced during the study. "We didn't find any overt evidence that these mutations automatically would be harmful or pathogenic," he said. For the study, researchers tapped three sources for 16 participant blood samples: The Wellderly Study, an ongoing STSI research project that is searching for the genetic secrets behind lifelong health by looking at the genes of healthy elderly people ages 80 to 105; the STSI GeneHeart Study, which involves people with coronary artery disease; and TSRI's research blood donor program. The iPSCs were generated by study co-authors Valentina Lo Sardo, Ph.D., and Will Ferguson, M.S., researchers in the TSRI group led by Baldwin. "When we proposed this study, we weren't sure whether it would even be possible to grow iPSCs from the blood of the participants in the Wellderly Study, since others have reported difficulty in making these stem cells from aged patients," Baldwin said. "But through the hard work and careful experiments designed by Valentina and Will, our laboratories became the first to produce iPSCs from the blood of extremely elderly people." Paper co-authors included Lo Sardo, Ferguson and Baldwin with TSRI; and Galina A. Erikson, Dr. Topol and Torkamani with STSI. ABOUT SCRIPPS TRANSLATIONAL SCIENCE INSTITUTE The Scripps Translational Science Institute aims to replace traditional one-size-fits-all medicine with individualized health care by leveraging the power of genomic medicine, wireless health sensors and mobile phone applications, and other digital medicine technologies. In a unique collaboration, STSI merges the considerable biomedical science expertise of The Scripps Research Institute with Scripps Health's exceptional patient care and clinical research capabilities. STSI is supported in part by the National Institutes of Health Clinical and Translational Science Award. For more information, visit www.stsiweb.org.


News Article | December 12, 2016
Site: www.eurekalert.org

JUPITER, FL - Dec. 12, 2016 - Scientists on the Florida campus of The Scripps Research Institute (TSRI) have developed broad methods to design precision medicines against currently incurable diseases caused by RNA. RNA carries out thousands of essential functions in cells, but many RNAs can act in uncontrolled ways and cause disease. For decades, scientists have tried to develop drug candidates that target human RNAs, but they have been hampered by an inability to achieve sufficient selectivity (to reduce the potential of side effects) and potency (ensuring effectiveness). In a study published today online ahead of press in the journal Nature Chemical Biology, researchers -- led by TSRI Professor Matthew Disney and Research Associate Suzanne Rzuczek, with important contributions from Professor Ryohei Yasuda and Research Associate Lesley Colgan of the Max Planck Florida Institute for Neuroscience--have disclosed several approaches to overcome these hurdles. "This study reads like science fiction," Disney said. "We present for the first time multiple solutions to this long-standing problem. With the precision of a surgeon's scalpel, we have shown that small molecules can be designed to seek out and destroy only disease-causing RNAs. Further, we developed novel chemical approaches to use a disease-causing RNA to help make its own drug by using that RNA as a catalyst for drug synthesis at the needed site. It is like having your physician place a drug at the right place without exposing healthy cells." Although these studies have broad implications for RNA diseases in general, they were demonstrated on myotonic dystrophy type 1, an incurable inherited disorder that involves progressive muscle wasting and weakness. It is caused by an RNA defect known as a "triplet repeat," a series of three nucleotides repeated more times than normal in an individual's genetic code, in this case, a cytosine-uracil-guanine (CUG) triplet. In many genetic diseases, there are two copies of the problem gene--a mutant copy that causes a disease and a normal copy that a cell needs to survive. Selective recognition of the diseased gene product has not been possible before. This new study demonstrates that designer small molecules can selectively recognize larger, disease-associated repeats (alleles) over shorter, normal ones. "We developed several approaches to create allele-selective small molecules that seek out only the disease-causing gene product, including covalent binding, cleavage and imaging," said TSRI Research Associate Suzanne G. Rzuczek, first author of the study. "All approaches show precise recognition of toxic r(CUG) repeats and, more importantly, they showed that the mutant repeat is the sole target." The work also offers an innovative way to track the movement of RNA in a diseased cell via imaging. "We have brought RNAs out of the darkness and into the light by developing a chemical flare that goes off when a drug targets the RNA in a diseased cell and then continues to track the RNA's movement," Disney added. "We probed disease-causing RNA using a technique called fluorescence lifetime imaging--a sensitive technique to measure fluorophore binding," said Max Planck's Ryohei Yasuda. "We were very excited when we observed a huge difference in signal from their probes between disease cells and normal cells under our microscope technique." Max Planck's Lesley Colgan added, "The combination of cutting-edge chemistry and microscopy techniques developed in Florida is a powerful approach to identify new methods to probe and manipulate (and kill) disease-causing RNA in cells." Both Disney and Yasuda were 2015 recipients of the National Institutes of Health (NIH) Director's Pioneer Award, which supports individual scientists of exceptional creativity who propose highly innovative approaches with high-impact potential. In addition to Disney, Rzuczek, Colgan and Yasuda, other authors of the study, "Precise Small Molecule Recognition of a Toxic RNA Repeat Expansion," include Yoshio Nakai and Michael D. Cameron of TSRI and Denis Furling of Sorbonne Universités (Paris). The study was supported by the NIH (grants DP1NS096898 and DP1NS096787), the Muscular Dystrophy Association (grant 380467) and the Myotonic Dystrophy Foundation. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | February 15, 2017
Site: www.eurekalert.org

JUPITER, FL - February 15, 2017 - Scientists are working to understand the mechanisms that make weight loss so complicated. Exercise burns calories, of course, but scientists are also looking at how the body burns more energy to stay warm in cold temperatures. Is there a way to get metabolism to ramp up--even when it's not cold out? TSRI Assistant Professor Anutosh Chakraborty is on a mission to answer this question. His past research revealed a new therapeutic target in this battle--a protein that actually promotes fat accumulation in animal models by slowing stored energy (fat) breakdown and encouraging weight gain. Now, in a study recently published online in the journal Molecular Metabolism, Chakraborty and his colleagues have shown that deleting the gene for this protein, known as IP6K1, protects animal models from both obesity and diabetes. This protective effect is seen regardless of diet, even at what's known as a thermoneutral temperature (around 86?F). This means inhibiting IP6K1 should help animals burn more energy, regardless of outside conditions. "In genetically altered animal models that lack IP6K1, we found that deletion dramatically protects these knock-out mice from diet-induced obesity and insulin resistance regardless of the temperature in the environment," Chakraborty said. "When we inhibited the enzyme with chemical compounds, the results were similar." Temperature is important in the study of obesity because an animal in lower temperatures will rapidly lose weight as it burns more energy to try to maintain core body temperature. Because humans can maintain their body temperatures in a number of ways--clothing, for example--any pathway that reduces body weight at higher temperatures is a highly encouraging target in human obesity. The new study suggests a future pharmaceutical may be able to target IP6K1 to mimic the energy burning seen at relatively lower temperatures. "If we delete IP6K1, the animals gain less body weight because they simply expend more energy--regardless of temperature. That's important because blocking weight gain by enhancing energy expenditure in a thermoneutral environment is harder and thus, targeting IP6K1 is expected to be successful in ameliorating obesity in humans," said Chakraborty. "If you're developing an anti-obesity drug based on inhibiting IP6K1, our new findings shows that there are potentially very few restrictions for its use--a subject would lose weight even on a high-fat diet, and nobody would have to sit in a refrigerator to make it work," he added. The first author of the study, "Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain," is TSRI's Qingzhang Zhu. Other authors are Sarbani Ghoshal, at TSRI at the time of the study, now at the Saint Louis University School of Medicine, and Richa Tyagi of the Johns Hopkins University School of Medicine. This work is supported by the National Institutes of Health (grant R01DK103746) and the state of Florida. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .


News Article | November 23, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 23, 2016 - Scientists at The Scripps Research Institute (TSRI) have developed a vaccine that blocks the pain-numbing effects of the opioid drugs oxycodone (oxy) and hydrocodone (hydro) in animal models. The vaccine also appears to decrease the risk of fatal opioid overdose, a growing cause of death in the United States. "We saw both blunting of the drug's effects and, remarkably, prevention of drug lethality," said Kim D. Janda, the Ely R. Callaway Jr. Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at TSRI. "The protection against overdose death was unforeseen but clearly of enormous potential clinical benefit." The study was published this week online ahead of print in the journal ACS Chemical Biology. The new oxy/hydro vaccine takes advantage of the immune system's ability to recognize, seek out and neutralize invaders. Opioids were designed to reach receptors in the brain, causing pain reduction and feelings of euphoria. For their vaccine, the researchers combined a signature opioid structure with a molecule to trigger an immune response. When injected, the vaccine teaches the immune system to bind to the drug molecule and remove it from circulation. The vaccine-derived antibodies were tailored by TSRI scientists to seek out the prescription drug and block the opioid from reaching the brain, potentially depriving a person of the "reward" of consuming the drug, Janda explained. The scientists believe a vaccine approach could have an advantage over current opioid addiction therapies because it would not alter brain chemistry like many of today's anti-addiction therapies do. "The vaccine approach stops the drug before it even gets to the brain," said study co-author Cody J. Wenthur, a research associate in the Janda laboratory. "It's like a preemptive strike." The researchers found that their vaccine design blocked pain perception of oxy/hydro use in mice. Indeed, those given the vaccine did not display the usual symptoms of a drug high, such as ignoring pain and discomfort. In further tests, the rodents also appeared less susceptible to fatal overdose. Although it was found that some vaccinated mice did succumb to the opioid drug's toxic effects, the researchers noted that it took much longer for the drug to impart its toxicity. If this effect holds true in humans, the vaccine could extend the window of time for clinical assistance if overdose occurs. The scientists also discovered that the vaccine remained effective in mice for the entire 60-day study period, and they believe it has the potential to last even longer. This oxy/hydro vaccine is not the first ever tested, but it is the first to use a faithful representation of the opioid in its design, which prompts the remarkable efficacy seen with the TSRI vaccine. "Our goal was to create a vaccine that mirrored the drug's natural structure. Clearly this tactic provided a broadly useful opioid deterrent," said study first author Atsushi Kimishima, a research associate in the Janda laboratory. The study did raise some new questions. For example, researchers found that once antibodies bound to the drug, the drug stayed in the body--though neutralized--for a long time. The next steps will be to investigate this phenomenon and further study the optimal vaccine dose and injection schedule. The scientists also stated it may be possible to make the vaccine even more effective. The additional author of the study, "An Advance in Prescription Opioid Vaccines: Overdose Mortality Reduction and Extraordinary Alteration of Drug Half-Life," was Bin Zhou of TSRI. This study was supported by the National Institute on Drug Abuse of the National Institutes of Health (grant 1UH2DA041146-02). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 16, 2016
Site: www.chromatographytechniques.com

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily "circadian" clocks in influencing cancer growth. The research, published recently in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked. "This appears to have big implications for the connection between circadian rhythms and cancer," said TSRI biologist Katja Lamia, senior author of the study. There is growing evidence that shift work and frequent jet lag can raise a person's risk of cancer, suggesting a link between daily rhythms and cell growth. "We know this connection exists, but we haven't known why," said Lamia. The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more. Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells' ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation--similar to the abnormal growth seen in cancers. Further studies of protein structures suggested that CRY2 is a key player in a process to "mark" cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription--once the proteins are already produced--rather than during transcription, as in many other cryptochrome functions. "This is a function of a circadian protein that has never been seen before," said TSRI Research Associate Anne-Laure Huber, who served as first author of the study. The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.


News Article | December 9, 2016
Site: www.eurekalert.org

LA JOLLA, CA & JUPITER, FL - Dec. 9, 2016 - New research led by scientists at The Scripps Research Institute (TSRI) reveals that a human enzyme has changed little from its days as a bacterial enzyme. In fact, the enzyme appears to be unique in its ability to change its shape--and its job in cells -- without overhauling its basic architecture. "This work illustrates nature's efficiency -- how it can take one thing and convert it to another, with a tweak here and a tweak there," said Paul Schimmel, professor at TSRI and senior author of the new study. The findings were published recently in the journal Proceedings of the National Academy of Sciences. Schimmel and his colleagues focused on a member of a family of enzymes called aminoacyl tRNA synthetases. These enzymes originated in ancient bacteria, where they decode genetic information to help produce amino acids. Over time, the enzymes have evolved to carry out even more functions in complex lifeforms, such as humans. "Aminoacyl tRNA synthetases are associated with--and we believe needed for -- the building of organismal complexity, such as making tissues and organs in humans," Schimmel explained. These new functions are controlled by "decorations," or additions to the aminoacyl tRNA synthetase architecture, which are generally lacking in bacteria; however, there is one aminoacyl tRNA synthetase, called AlaRS, that lacks any new decorations. AlaRS somehow carries out new roles in humans using a preexisting bacterial domain in its structure. "AlaRS presented an exception to what we thought was a 'rule,' " said Schimmel. The scientists in the new study took a closer look at AlaRS using two imaging techniques: X-ray crystallography and small-angle X-ray scattering. The images, combined with functional analysis, showed that a domain of AlaRS's structure, called C-Ala, had been reshaped to take on a new role in humans. The end result is the same as if AlaRS had gained a new decoration. Schimmel compared it to reshaping an airplane's wing to serve as the airplane's tail instead. "Nature has provided ways for reshaping objects, like C-Ala, and when that happens, new functions occur," he said. Schimmel said the next step is to figure out the function of human C-Ala. This work may shed light on diseases linked to mutations in aminoacyl tRNA synthetases, such as the neurodegenerative disease Charcot-Marie-Tooth. In addition to Schimmel, authors of the study, "Two Crystal Structures Reveal Design for Repurposing the C-Ala Domain of Human AlaRS," are Litao Sun (first author), Youngzee Song, David Blocquel and Xiang-Lei Yang of TSRI. This work was supported by the National Cancer Institute (grant CA92577), the National Foundation for Cancer Research and the National Institutes of Health (grant R01 NS085092). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists -- including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine -- work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | December 12, 2016
Site: www.eurekalert.org

SAN DIEGO - As it is in much of life, the aging process isn't kind to an important type of stem cell that has great therapeutic promise. Researchers at the Scripps Translational Science Institute (STSI) and The Scripps Research Institute (TSRI) who looked at the effect of aging on induced pluripotent stem cells (iPSCs) found that genetic mutations increased with the age of the donor who provided the source cells, according to study results published today by the journal Nature Biotechnology. The findings reinforce the importance of screening iPSCs for potentially harmful DNA mutations before using them for therapeutic purposes, said lead investigators Ali Torkamani, Ph.D., director of genome informatics at STSI, and Kristin Baldwin Ph.D., the study's co-lead investigators and associate professor of molecular and cellular neuroscience at the Dorris Neuroscience Center at TSRI. "Any time a cell divides, there is a risk of a mutation occurring. Over time, those risks multiply," Torkamani said. "Our study highlights that increased risk of mutations in iPSCs made from older donors of source cells." Researchers found that iPSCs made from donors in their late 80s had twice as many mutations among protein-encoding genes as stem cells made from donors in their early 20s. That trend followed a predictable linear track paired with age with one exception. Unexpectedly, iPSCs made from blood cells donated by people over 90 years old actually contained fewer mutations than what researchers had expected. In fact, stem cells from those extremely elderly participants had mutation numbers more comparable to iPSCs made from donors one-half to two-thirds younger. Researchers said the reason for this could be tied to the fact that blood stem cells remaining in elderly people have been protected from mutations over their lifetime by dividing less frequently. "Using iPSCs for treatment has already been initiated in Japan in a woman with age-related macular degeneration," said paper co-author and STSI Director Eric Topol, M.D. "Accordingly, it's vital that we fully understand the effects of aging on these cells being cultivated to treat patients in the future." STSI is a National Institutes of Health-sponsored site led by Scripps Health in collaboration with TSRI. This innovative research partnership is leading the effort to translate wireless and genetic medical technologies into high-quality, cost-effective treatments and diagnostics for patients. Of the 336 different mutations that were identified in the iPSCs generated for the study, 24 were in genes that could impair cell function or trigger tumor growth if they malfunctioned. How troublesome these mutations could be depends on how well the stem cells are screened to filter out the defects and how they are used therapeutically, Torkamani said. For example, cells made from iPSCs for a bone marrow transplant would be potentially dangerous if they contained a TET2 gene mutation linked to blood cancer, which surfaced during the study. "We didn't find any overt evidence that these mutations automatically would be harmful or pathogenic," he said. For the study, researchers tapped three sources for 16 participant blood samples: The Wellderly Study, an ongoing STSI research project that is searching for the genetic secrets behind lifelong health by looking at the genes of healthy elderly people ages 80 to 105; the STSI GeneHeart Study, which involves people with coronary artery disease; and TSRI's research blood donor program. The iPSCs were generated by study co-authors Valentina Lo Sardo, Ph.D., and Will Ferguson, M.S., researchers in the TSRI group led by Baldwin. "When we proposed this study, we weren't sure whether it would even be possible to grow iPSCs from the blood of the participants in the Wellderly Study, since others have reported difficulty in making these stem cells from aged patients," Baldwin said. "But through the hard work and careful experiments designed by Valentina and Will, our laboratories became the first to produce iPSCs from the blood of extremely elderly people." Paper co-authors included Lo Sardo, Ferguson and Baldwin with TSRI; and Galina A. Erikson, Dr. Topol and Torkamani with STSI. The Scripps Translational Science Institute aims to replace traditional one-size-fits-all medicine with individualized health care by leveraging the power of genomic medicine, wireless health sensors and mobile phone applications, and other digital medicine technologies. In a unique collaboration, STSI merges the considerable biomedical science expertise of The Scripps Research Institute with Scripps Health's exceptional patient care and clinical research capabilities. STSI is supported in part by the National Institutes of Health Clinical and Translational Science Award. For more information, visit http://www. .


News Article | October 13, 2016
Site: www.medicalnewstoday.com

Sudden death strikes approximately 11,000 people under age 45 in the U.S. every year, leaving living relatives with troubling questions about their own risk. Unfortunately, with many conditions - such as sudden infant death syndrome (SIDS) and sudden cardiac death (SCD) - the cause of death is not always apparent after a traditional clinical autopsy. Now a new study led by scientists at The Scripps Research Institute (TSRI) and the Scripps Translational Science Institute (STSI) suggests that "molecular autopsies" may be valuable in detecting gene mutations responsible for a sudden death. The research, while preliminary, could help doctors alert living family members to hidden health conditions. The research, led by Ali Torkamani, assistant professor of Molecular and Experimental Medicine at TSRI and assistant professor and director of Genome Informatics at STSI, was published in the Journal of the American Medical Association (JAMA). "The key takeaway is that molecular autopsy, when performed in a prospective and family-based manner, can reveal the genetic cause of sudden death in a variety of conditions and provide useful information regarding risk to living relatives," Torkamani said. For the study, the researchers sequenced samples from 25 sudden death cases. To assess possible inherited mutations, the team also sequenced samples from the deceased patients' parents in nine of the cases. This analysis provided clues that weren't apparent in traditional clinical autopsies. In four cases, the researchers found that a genetic mutation was a "likely" cause of death, and they found six more cases where a mutation was a "plausible" cause of death. In seven cases, a mutation was found to be a "speculative" cause of death. Overall, molecular autopsies uncovered a likely or plausible cause of death in 40 percent of cases. Interestingly, many of the findings were variants of genes inherited from relatives who had not suffered from the syndrome. The researchers believe identifying possible genetic mutations behind sudden death could help doctors and family members plan for clinical follow-ups, preventative measures and active surveillance to watch for symptoms - even in cases where the mutation was just a "speculative" cause of death. The researchers said larger studies are needed to collect enough data to provide living relatives with a better idea of their risk. The study was supported by a National Institutes of Health and National Center for Advancing Translational Sciences clinical and translational science award (5-UL1-RR025774) and Scripps Genomic Medicine (grants U01HG006476 and U54GM114833).


News Article | December 20, 2016
Site: www.eurekalert.org

JUPITER, FL - Dec. 20, 2016 - Scientists from the Florida campus of The Scripps Research Institute (TSRI) have developed an efficient process to rapidly discover new "enediyne natural products" from soil microbes that could be further developed into extremely potent anticancer drugs. The study highlights microbial natural products as abundant sources of new drug leads. The researchers' discovery process involves prioritizing the microbes from the TSRI strain collection and focusing on the ones that are genetically predisposed to produce specific families of natural products. The scientists say this process saves time and resources in comparison to the traditional approaches used to identify these rare molecules. The study, led by TSRI Professor Ben Shen, was published today in the journal mBio. Shen and his colleagues uncovered a new family of enediyne natural products, called tiancimycins, (TNMs) which kill selected cancer cells more rapidly and completely in comparison to toxic molecules used in FDA-approved antibody-drug conjugates (ADCs)-- monoclonal antibodies attached to cytotoxic drugs that target only cancer cells. The scientists also discovered several new producers of C-1027, an antitumor antibiotic currently in clinical development, which can produce C-1027 at much higher levels. It has been more than a decade since Shen first reported on the C-1027 enediyne biosynthetic machinery, and he speculated then that the knowledge obtained from studying biosynthesis of C-1027, and other enediynes, could be used for the discovery of novel enediyne natural products. "The enediynes represent one of the most fascinating families of natural products for their extraordinary biological activities," Shen said. "By surveying 3,400 strains from the TSRI collection, we were able to identify 81 strains that harbor genes encoding enediynes. With what we know, we can predict novel structural insights that can be exploited to radically accelerate enediyne-based drug discovery and development." "The work described by the Shen group is an excellent example of what can be achieved by coupling state of the art genomic analyses of potential biosynthetic clusters and modern physicochemical techniques," said David J. Newman, retired chief of the National Cancer Institute's Natural Products Branch. "As a result of their work, the potential number of enediynes has significantly increased." Shen's method of strain prioritization and genome mining means a far more efficient use of resources involved in the discovery process, targeting only those strains that look to produce the most important natural compounds. "This study shows that the potential to rapidly discover new enediyne natural products from a large strain collection is within our reach," said TSRI Research Associate Xiaohui Yan, one of four first authors of the study. "We also show the feasibility of manipulating tiancimycin biosynthesis in vivo, which means that sufficient quantities of these precious natural products can be reliably produced by microbial fermentation for drug development and eventual commercialization." In addition to Shen and Yan, first authors of the study, "Strain Prioritization and Genome Mining for Enediyne Natural Products," include TSRI's Huiming Ge, Tingting Huang and Hindra. Other authors include Dong Yang, Qihui Teng, Ivana Crnovči?, Xiuling Li, Jeffrey D. Rudolf, Jeremy R. Lohman and Christoph Rader of TSRI; Yannick Gansemans and Filip Van Nieuwerburgh of Ghent University, Belgium; Yanwen Duan, Xiangcheng Zhu and Yong Huang of Xiangya International Academy of Translational Medicine, Central South University, China; Li-Xing Zhao and Yi Jiang of Yunnan University, China. The study was supported in part by the Chinese Ministry of Education (111 Project B08034), National High Technology Joint Research Program of China (grant 2011ZX09401-001), National High Technology Research and Development Program of China (grant 2012AA02A705), the National Institutes of Health (grants CA78747 and GM115575), the German Research Foundation and the Arnold and Mabel Beckman Foundation. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 4, 2016
Site: www.rdmag.com

A pair of studies have suggested that the Ebola virus outbreak that began in 2013 may have gained a genetic mutation that appears to have helped it better target human cells. On Nov. 3, a study from the University of Nottingham and a second study conducted by the co-led by scientists at The Scripps Research Institute (TSRI), the University of Massachusetts Medical School, the Broad Institute of the Massachusetts Institute of Technology and Harvard University was published in Cell that conclude that the Ebola virus actually grew in strength as the outbreak started to spread. “There was this belief that Ebola virus essentially never changes,” said TSRI infectious disease researcher Kristian Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI), in a statement. “But this study tells us that a natural mutation in Ebola virus—which occurred during an outbreak—changed infectivity of human cells.” In the Scripps study Andersen and his team used a sequence catalog of viral genomes previously generated from 1,438 of the mora than 28,000 Ebola cases during the recent outbreak, a much larger sample size than ever studied on Ebola before. During this research they discovered a mutation on a site on Ebola’s outer protein—called glycoprotein—that binds to its receptor on host cells, meaning that mutations in that site can affect a virus’s ability to infect. “This receptor binding domain of the virus has been the same since the first Ebola outbreak in 1976,” said Andersen. “This is the only time we’ve ever seen a mutation in this domain.” The researchers found that the version of Ebola carrying the mutation, being dubbed GP-A82V, caused about 90 percent of the infections in the recent outbreak The scientists then tested the mutation’s reaction to many types of animal cells, which proved the mutation specifically helps the virus infect primate cells. It is believed that Ebola normally lives in bats, but the virus had more opportunities to adapt to humans with more human hosts. However, questions still remain for researchers, including how the mutation actually boost the virus’s ability to enter human cells. One hypothesis is that the mutation shifts nearby amino acids in the Ebola receptor binding domain, helping the glycoprotein better fit with the human host receptor. Scientists in the Nottingham study infected human liver cells grown in a test tube with pseudoviruses containing different mutant surface proteins, which proved that the number of genetic changes that occurred during the outbreak increased infectivity. “I think our study reminds us that if you take a virus and allow it to infect a new host for a considerable amount of time, eventually it may acquire a set of mutations that will benefit it, for example increasing its ability to spread or changing the disease that it causes,” Jonathan Ball, Professor of Molecular Virology at the University of Nottingham, and one of the authors of the study said in a statement. “In order to be prepared we need to know whether similar things are occurring in other outbreaks such as the ongoing Zika and MERS-coronavirus epidemics.” Andersen also said there is a chance the GP-A82V form of Ebola is no longer a threat, but research is important because it answers questions as to whether the Ebola virus can gain mutations during outbreaks that can potentially change the function of viral proteins. “It’s important to understand that once the outbreak is over, this particular virus will likely disappear,” Andersen said. The scientists will now examine other mutations that recently showed up and to see if increased infectivity changes mortality rates and the likelihood of a person transmitting the disease.


News Article | November 17, 2015
Site: www.biosciencetechnology.com

Scientists at The Scripps Research Institute (TSRI) have new weapons in the fight against HIV. Their new study, published today as the cover article of the November issue of Immunity, describes four prototype antibodies that target a specific weak spot on the virus. Guided by these antibodies, the researchers then mimicked the molecular structure of a protein on HIV when designing their own potential HIV vaccine candidate. “This study is an example of how we can learn from natural infection and translate that information into vaccine development,” said TSRI Research Associate Raiees Andrabi. “This is an important advance in the field of antibody-based HIV vaccine development.” Andrabi served as first author of the study, working in the lab of senior author TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI. The findings build on the success of several recent TSRI studies showing that, with prompting, the immune system can develop antibodies to neutralize many strains of HIV. In the new study, the researchers carried out a series of experiments involving virus modifications, protein and antibody engineering. They found that four antibodies targeted a single spot on HIV’s surface called the V2 apex. This was significant because the V2 apex could be recognized by these antibodies on about 90 percent of known HIV strains—and even related strains that infect other species. A vaccine targeting this region could protect against many forms of the virus. “This region helps stabilize the virus, so it’s an important area to target if you want to neutralize HIV,” said Andrabi. Investigating further, the researchers noticed that two of the four antibodies had an unusual feature that could prove important in vaccine design. The immune system usually begins its fight against infection by activating immune B cells that express “germline” forms of antibodies, on their surface, to bind invading pathogens. Germline antibodies rarely bind viruses very effectively themselves; instead, they are precursors for more developed antibodies, which mutate and hone their response to the invader. Yet in the new study, two of the antibodies did not need to mutate to bind with the V2 apex; instead, these antibodies used part of their basic germline structure, encoded by non-mutated genes. This means any patient with HIV should, in theory, have the ability to kick-start the right immune response. Unfortunately, the immune system seems to naturally produce only a small number of these HIV-neutralizing germline antibodies. To generate an immune response that would favor these antibodies, it was critical for the scientists to find the right proteins in HIV that the antibodies could recognize and bind to. In the new study, the researchers succeeded in mimicking a structure on HIV called the native HIV coat protein. This let them design proteins that do indeed bind well to the germline antibodies and hopefully start a useful immune response. The next step will be to test the vaccine candidates in animal models. HAVI-ID; Pascal Poignard of TSRI and IAVI; and Chung-Yi Wu and Chi-Huey Wong of the Genomics Research Center, Academia Sinica and TSRI. This study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD), the International AIDS Vaccine Initiative (IAVI) and the United States Agency for International Development (USAID).


News Article | December 15, 2016
Site: www.biosciencetechnology.com

Scientists on the Florida campus of The Scripps Research Institute (TSRI) have developed broad methods to design precision medicines against currently incurable diseases caused by RNA. RNA carries out thousands of essential functions in cells, but many RNAs can act in uncontrolled ways and cause disease. For decades, scientists have tried to develop drug candidates that target human RNAs, but they have been hampered by an inability to achieve sufficient selectivity (to reduce the potential of side effects) and potency (ensuring effectiveness). In a study published today online ahead of press in the journal Nature Chemical Biology, researchers—led by TSRI Professor Matthew Disney and Research Associate Suzanne Rzuczek, with important contributions from Professor Ryohei Yasuda and Research Associate Lesley Colgan of the Max Planck Florida Institute for Neuroscience—have disclosed several approaches to overcome these hurdles. “This study reads like science fiction,” Disney said. “We present for the first time multiple solutions to this long-standing problem. With the precision of a surgeon’s scalpel, we have shown that small molecules can be designed to seek out and destroy only disease-causing RNAs. Further, we developed novel chemical approaches to use a disease-causing RNA to help make its own drug by using that RNA as a catalyst for drug synthesis at the needed site. It is like having your physician place a drug at the right place without exposing healthy cells.” Although these studies have broad implications for RNA diseases in general, they were demonstrated on myotonic dystrophy type 1, an incurable inherited disorder that involves progressive muscle wasting and weakness. It is caused by an RNA defect known as a “triplet repeat,” a series of three nucleotides repeated more times than normal in an individual’s genetic code, in this case, a cytosine-uracil-guanine (CUG) triplet. In many genetic diseases, there are two copies of the problem gene—a mutant copy that causes a disease and a normal copy that a cell needs to survive. Selective recognition of the diseased gene product has not been possible before. This new study demonstrates that designer small molecules can selectively recognize larger, disease-associated repeats (alleles) over shorter, normal ones. “We developed several approaches to create allele-selective small molecules that seek out only the disease-causing gene product, including covalent binding, cleavage and imaging,” said TSRI Research Associate Suzanne G. Rzuczek, first author of the study. “All approaches show precise recognition of toxic r(CUG) repeats and, more importantly, they showed that the mutant repeat is the sole target.” The work also offers an innovative way to track the movement of RNA in a diseased cell via imaging. “We have brought RNAs out of the darkness and into the light by developing a chemical flare that goes off when a drug targets the RNA in a diseased cell and then continues to track the RNA’s movement,” Disney added. "We probed disease-causing RNA using a technique called fluorescence lifetime imaging—a sensitive technique to measure fluorophore binding,” said Max Planck’s Ryohei Yasuda. “We were very excited when we observed a huge difference in signal from their probes between disease cells and normal cells under our microscope technique." Max Planck’s Lesley Colgan added, "The combination of cutting-edge chemistry and microscopy techniques developed in Florida is a powerful approach to identify new methods to probe and manipulate (and kill) disease-causing RNA in cells." Both Disney and Yasuda were 2015 recipients of the National Institutes of Health (NIH) Director’s Pioneer Award, which supports individual scientists of exceptional creativity who propose highly innovative approaches with high-impact potential.


News Article | December 1, 2016
Site: www.eurekalert.org

JUPITER, FL- December 1, 2016 - In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a possible drug candidate that suppresses pain and itch in animal models. Their new approach also reduces the potential for drug abuse and avoids the most common side effects--sedation and anxiety--of drugs designed to target the nervous system's kappa opioid receptors (KORs). "The most significant aspect of the study is that we can preserve itch and pain treatment qualities in a KOR agonist that we developed--triazole 1.1--while avoiding the euphoria associated with narcotic opioids and the dysphoria associated with some other selective KOR agonists," said TSRI Professor Laura Bohn, senior author of the new study. The research was published this week online ahead of print in the journal Science Signaling. KORs help regulate the release of the neurotransmitter dopamine. Drugs that target KORs have shown promise as therapeutic candidates because of their efficacy for treating chronic itch and relieving pain. Unlike opioid narcotics that target other opioid receptors, these compounds do not produce a "high" or increased risk of overdose; however, they can deplete the body's supply of dopamine and produce dysphoria and sedation, side effects that have limited their clinical development. Bohn's laboratory has pioneered the concept that KOR signaling can be fine-tuned to preferentially activate certain pathways over others so that the receptor signals through G proteins rather than through a protein called β-arrestin2. In the new study, the researchers used rodent models to compare this kind of "biased" KOR agonist, called triazole 1.1, and a conventional KOR agonist. They found that triazole 1.1 could indeed circumvent the two side effects of previously developed KOR compounds without decreasing dopamine levels, a property associated with dysphoria and sedation. "This adds to the mounting evidence that shows analgesic effects can be separated from the sedative and dysphoric effects by altering how the agonist engages the receptor," said TSRI Research Associate Tarsis Brust, first author of the study. Bohn said the new findings clearly demonstrate that the strategy of developing biased KOR agonists offers a promising new way to treat pain and intractable itch without the potential for abuse. In addition to Bohn, other authors of the study, "Biased Agonists of the Kappa Opioid Receptor Suppress Pain and Itch without Causing Sedation and Dysphoria," include TSRI's Tarsis Brust, Jenny Morgenweck, Lei Zhou, Edward L. Stahl, Cullen L. Schmid and Michael D. Cameron; Susy A. Kim, Jamie H. Rose, Jason Locke, Sara L. Jones, and Thomas J. Martin of Wake Forrest University; and Sarah M. Scarry and Jeffrey Aubé of the University of North Carolina at Chapel Hill. This research was supported by the National Institutes of Health (grants P01GM113852, P50DA006634, R01DA014030, U01AA014091 and R01DA031297). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 17, 2016
Site: www.biosciencetechnology.com

A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily "circadian" clocks in influencing cancer growth. The research, published recently in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked. "This appears to have big implications for the connection between circadian rhythms and cancer," said TSRI biologist Katja Lamia, senior author of the study. There is growing evidence that shift work and frequent jet lag can raise a person's risk of cancer, suggesting a link between daily rhythms and cell growth. "We know this connection exists, but we haven't known why," said Lamia. The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more. Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells' ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation--similar to the abnormal growth seen in cancers. Further studies of protein structures suggested that CRY2 is a key player in a process to "mark" cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription--once the proteins are already produced--rather than during transcription, as in many other cryptochrome functions. "This is a function of a circadian protein that has never been seen before," said TSRI Research Associate Anne-Laure Huber, who served as first author of the study. The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues.


News Article | October 27, 2016
Site: www.eurekalert.org

JUPITER, FL - October 26, 2016 - In a remarkable "two for one" discovery, scientists from the Florida campus of The Scripps Research Institute (TSRI) have illuminated a key molecular player in the addictive effects of morphine in animal models. Interestingly, the protein--known as neurofibromin 1 (NF1)--is also known to be disrupted in an inherited disorder called neurofibromatosis type 1 (also called von Recklinghausen's disease), in which patients suffer from the growth of benign tumors beneath the skin, chronic pain, mild learning disabilities and an elevated risk of developing cancers. "We were searching for proteins that influence the long-term effects of opioids," said TSRI Professor Kirill Martemyanov. "In the short-term, opioids kill pain, but we were curious about mechanisms that lead to long-term adaptations that ultimately result in addiction. We screened for proteins that might possibly be involved in this process and what emerged was NF1." The study, recently published online ahead of print in the journal Current Biology, describes how NF1 influences opioid response through its impact on a signaling protein known as Ras in a part of the brain called the striatum, which is involved in decision making and reward. When the researchers deleted NF1 in striatal neurons of animal models, opioids failed to engage Ras and its downstream signaling reactions, dramatically diminishing the addictive effects of morphine. "One of the peculiar symptoms of neurofibromatosis type 1 is that patients often suffer from chronic, unexplained pain," said Martemyanov. "Given that the endogenous opioid system is involved in controlling pain sensitivity and the role of NF1 protein in mediating signaling of opioid receptors, it makes sense that if the mechanism is broken pain, might become an issue." He also noted the results suggest potential therapies for both conditions: "If you came up with a strategy to inhibit NF1 activity, perhaps the opioids won't be as addictive; but for those suffering from the neurofibromatosis, bypassing NF1 to activate Ras by receptors may be interesting to explore." The first author of the study, "NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum," is Keqiang Xie. Other authors include Maria T. Dao, Brian S. Muntean, Laurie P. Sutton, Cesare Orlandi, Chien-Cheng Shih, Baoji Xu and Roy G. Smith of TSRI; Lesley A. Colgan and Ryohei Yasuda the Max Planck Florida Institute for Neuroscience; and Sanford L. Boye, Shannon E. Boye and Yuqing Li of the University of Florida. The study was supported by the National Institutes of Health (grants DA036082, MH080047, MH101954, NS82244, NS073930 and EY024280); and the Department of Defense (CDMRP grant W81XWH-14-1-0074). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 9, 2015
Site: www.chromatographytechniques.com

A new study led by scientists at The Scripps Research Institute (TSRI) shows that a technology used in thousands of laboratories, called gas chromatography mass spectrometry (GC-MS), fundamentally alters the samples it analyzes. “We found that even relatively low temperatures used in GC-MS can have a detrimental effect on small molecule analysis,” said study senior author Gary Siuzdak, senior director of TSRI’s Scripps Center for Metabolomics and professor of chemistry, molecular and computational biology. Using new capabilities within XCMS, a data analysis platform developed in the Siuzdak lab, the researchers observed small molecules transforming—and even disappearing—during an experiment meant to mimic the GC-MS process, throwing into question the nature of the data being generated by GC-MS. The study was published online ahead of print on October 4 in the journalAnalytical Chemistry. For more than 50 years, chemists and biologists have used GC-MS to identify and measure concentrations of small molecules. When a sample is injected in a GC-MS system, it is heated and vaporized. The vapor travels through a gas chromatography column and the molecules separate, allowing the mass spectrometer to measure the individual molecules in the sample. Today, GC-MS is widely used in thousands of laboratories for tasks such as chemical analysis, disease diagnosis, environmental monitoring and even forensic investigations. The new experiments were initiated when Siuzdak was preparing a short course for students at the American Society for Mass Spectrometry annual meeting. The question arose of how heat from the GC-MS vaporization process could affect results, so Siuzdak and TSRI Research Associate Mingliang Fang ran a set of experiments to compare how small molecules responded to thermal stress. To their surprise, the molecular profiles of as many as 40 percent of the molecules were altered, suggesting that heat from the GC-MS process could dramatically change the chemical composition of the samples. “The results were quite astounding—as this is a technology that has been used for decades,” said Siuzdak. The finding led the researchers to take a closer look at how molecules degrade and transform during GC-MS. The scientists analyzed small molecule metabolites heated at 60, 100 and 250 degrees Celsius to mimic sample preparation and analysis conditions. The team used XCMS combined with a low-temperature liquid chromatography mass spectrometry technology which has been previously shown not to degrade molecules thermally, to determine the extent of the thermal effects. The researchers observed significant degradation even at the lower temperatures. At the higher temperatures, almost half of the molecules were degraded or completely transformed. “In retrospect, there was very little to be surprised about: heat degrades molecules,” said Siuzdak. “However we’ve simply taken for granted the extent of thermal degradation. While this is a negative result and scientists rarely publish them, I felt compelled especially for the students just getting started in their careers to report the limitation of such a ubiquitous technology.” The researchers noted that even molecules not typically observed in GC-MS can also be transformed; for example, the energy metabolite adenosine triphosphate (ATP) was readily converted into adenosine monophosphate (AMP). This transformation is relevant for medical research because scientists often use a heating process to look at the ratio of ATP to AMP in cells to estimate the function of cellular components in aging and disease. “People use this ratio to detect disease, but if the ratio can be changed by the heating process, the results will not be accurate,” said Fang. “It is known that ATP is thermally sensitive, but not how it changed under these conditions.” Thermal degradation could also explain why many scientists have detected many unknown molecular “peaks” in the past. Based on the new study, the researchers now believe these metabolites may be byproducts of the heating process—the result of reactions between metabolites as they degrade. So why hadn’t scientists figured out the effect of heating until now? Siuzdak explained that while some scientists had noticed changes in specific metabolites, it was difficult to see changes in overall molecular profiles that contain thousands of molecules. This omic-based study was made possible by new capabilities within the XCMS program developed at the TSRI Scripps Center for Metabolomics. XCMS is a free, cloud-based data analysis technology used to analyze mass spectrometry data all over the globe. “With XCMS, we could expand our study to obtain a global profile of how the metabolites were altered—not just a few compounds,” said Fang. “Fortunately these problems can be overcome with the use of standards in GC-MS as well as using newer, ambient temperature mass spectrometry technologies, and this report will likely stimulate more scientists to move to these less destructive alternatives,” said Siuzdak. In addition to Siuzdak and Fang, authors of the study, “Thermal Degradation of Small Molecules: A Global Metabolomic Investigation,” were Julijana Ivanisevic of the University of Lausanne, Michael E. Kurczy of Astrazeneca and TSRI, Gary J. Patti of Washington University in St. Louis; and Caroline H. Johnson, Linh T. Hoang, Winnie Uritboonthai and H. Paul Benton of TSRI. Seehttp://pubs.acs.org/doi/abs/10.1021/acs.analchem.5b03003


News Article | November 16, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 16, 2016 - A new study led by scientists at The Scripps Research Institute (TSRI) describes an unexpected role for proteins involved with our daily "circadian" clocks in influencing cancer growth. The research, published recently in the journal Molecular Cell, suggests that disruptions in circadian rhythms might leave levels of an important cancer-linked protein, called cMYC, unchecked. "This appears to have big implications for the connection between circadian rhythms and cancer," said TSRI biologist Katja Lamia, senior author of the study. There is growing evidence that shift work and frequent jet lag can raise a person's risk of cancer, suggesting a link between daily rhythms and cell growth. "We know this connection exists, but we haven't known why," said Lamia. The researchers focused on proteins called cryptochromes, which evolved from bacterial proteins that sense light and repair DNA damage caused by sunlight. In humans, these proteins, called CRY1 and CRY2, regulate our circadian clocks, which influence what times of day we become tired, hungry and much more. Using cells from mouse models, the researchers demonstrated that deleting the gene that expresses CRY2 reduced the cells' ability to degrade a protein called cMYC. Without CRY2 keeping cMYC at normal levels, the researchers saw increased cell proliferation--similar to the abnormal growth seen in cancers. Further studies of protein structures suggested that CRY2 is a key player in a process to "mark" cMYC for degradation. The researchers said it is significant that this process occurs after gene transcription--once the proteins are already produced--rather than during transcription, as in many other cryptochrome functions. "This is a function of a circadian protein that has never been seen before," said TSRI Research Associate Anne-Laure Huber, who served as first author of the study. The researchers say more studies are needed to confirm this connection between circadian clocks and cancer in human tissues. In addition to Lamia and Huber, authors of the study, "CRY2 and FBXL3 Cooperatively Degrade c-MYC," were Stephanie J. Papp, Alanna B. Chan, Sabine D. Jordan, Anna Kriebs and Madelena Nguyen of TSRI; Emma Henriksson of TSRI and Lund University; Martina Wallace and Christian M. Metallo of the University of California, San Diego; and Zhizhong Li of the Genomics Institute of the Novartis Research Foundation and Novartis Institutes for Biomedical Research. This study was supported by the National Institutes of Health (grants DK090188, DK097164, CA188652 and NIGMS P41-GM103311), the Searle Scholars Program through the Kinship Foundation, the Sidney Kimmel Foundation, the Lung Cancer Research Foundation, the Swedish Research Council, the Deutsche Forschungsgemeinschaft and the American Heart Association (grant 15POST22510020). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


LA JOLLA, Calif., Feb. 22, 2017 (GLOBE NEWSWIRE) -- ActivX Biosciences, Inc.®, a wholly owned subsidiary of Kyorin Pharmaceutical Co., Ltd. (Tokyo), announces the appointment of Professor Hugh Rosen of The Scripps Research Institute to the position of Chairman & President of ActivX®, effective April 1, 2017. He will succeed John W. Kozarich who has been at ActivX since 2001, serving as Chairman & President since its acquisition by Kyorin in 2004. John will stay on at ActivX as a Board Director and assume the new position of Distinguished Scientist and Executive Advisor. Professor Rosen’s 30+ year career in the pharmaceutical, biotechnology and academic sectors has been one of significant achievements. Following training in medicine in Cape Town, he received his D.Phil. as a Royal Commission for the Exhibition of 1851 Scholar at the University of Oxford.  He spent 11 years at Merck Research Laboratories before becoming a Professor at TSRI (The Scripps Research Institute) in 2002. There he co-invented ozanimod and was a scientific founder of Receptos, acquired by Celgene in 2015 for $7.3 Billion, as well as BlackThorn Therapeutics, which recently closed a $40M Series A. He serves as an independent Board member at Regulus Therapeutics and will remain on the faculty of TSRI. “Hugh Rosen is a world-class translational physician/scientist and biotechnology entrepreneur,” explained Dr. Kozarich. “We are delighted that he will assume the leadership of ActivX, building on our R&D contributions to Kyorin and adding new dimensions to our cutting-edge KiNativ technology. Hugh has been a friend and colleague to me and to Kyorin for 25 years. I am honored to have him as my successor and look forward to working with him in my new role. Hugh’s appointment clearly signals Kyorin’s ongoing commitment to ActivX as a key component to their future success. This is an ideal outcome for all involved.” Dr. Rosen added that: “The opportunity to lead ActivX Biosciences is especially attractive to a physician-scientist with a record of success in drug discovery and development because the ActivX technologies have unlocked exciting and potentially transforming drug discovery opportunities. This is a tribute to the outstanding work of John Kozarich and colleagues at both ActivX and Kyorin.  I look forward to continuing to work with John, his management team and Kyorin to bring significant new products forward to benefit patient outcomes, caregivers and providers. Through discovery and development, we strive to improve the public health.” Mr. Minoru Hogawa, Representative Director, President and Chief Executive Officer of Kyorin Holdings Inc., commented that: “Kyorin has been and will be creating first-in-class medicines. ActivX Biosciences is the core member for our research group activities. We believe Dr. Rosen will accelerate our research programs and accomplish our goals effectively with his wide experience.” ActivX Biosciences, Inc.® (www.activx.com ) located in La Jolla, California, is a wholly-owned subsidiary of Tokyo-based Kyorin Pharmaceutical Co., Ltd., and has drug discovery and proteomics technology capabilities. The company applies proprietary chemical technologies and high-throughput protein analysis to the drug discovery and development process. By focusing on functional proteins, ActivX® addresses disease mechanisms directly, in contrast to approaches such as expression profiling, in which the measured analyte is several steps removed from the site of drug action. ActivX and its partners utilize ActivX’s proprietary technology and profiling platform (KiNativ® - www.kinativ.com ) to address critical challenges in kinase drug discovery, including selectivity profiling of candidate drug molecules in biological samples to guide their medicinal chemistry efforts. The KiNativ platform aids in the identification of novel drug targets and biomarkers, the determination of target engagement in vivo and the characterization of off-target activities of candidate and established drugs to understand the basis of their efficacy and/or toxicity. About Kyorin Pharmaceutical Co., Ltd. Trusted among patients and professionals in the medical industry, Kyorin Pharmaceutical Co., Ltd. (http://www.kyorin-pharm.co.jp/en/), which is a core company of Kyorin Holdings Inc. (http://www.kyorin-gr.co.jp/en/), strives to be a company that contributes to the public health and is recognized as a one with social significance by improving its presence in specified therapeutic areas and through global discovery of novel drugs. Kyorin Pharmaceutical Co., Ltd. uses its franchise customer strategy in the developing and marketing ethical drugs on the core areas of respiratory, otolaryngology and urology.


News Article | November 3, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 3, 2016 - A new study co-led by scientists at The Scripps Research Institute (TSRI) suggests that Ebola virus gained a genetic mutation during the 2013-16 epidemic that appears to have helped it better target human cells. "There was this belief that Ebola virus essentially never changes," said TSRI infectious disease researcher Kristian G. Andersen, who also serves as director of infectious disease genomics at the Scripps Translational Science Institute (STSI). "But this study tells us that a natural mutation in Ebola virus--which occurred during an outbreak--changed infectivity of human cells." The research, published November 3, 2016 in the journal Cell, was co-led by Andersen, Jeremy Luban of the University of Massachusetts Medical School and Pardis Sabeti of the Broad Institute of the Massachusetts Institute of Technology and Harvard University. The new study accompanies a second paper in Cell led by an independent group of scientists at The University of Nottingham. For the new study, Andersen and his colleagues used a sequence catalog of viral genomes previously generated from 1,438 of the more than 28,000 known Ebola cases during the recent outbreak. The new study in Cell is therefore an unprecedented approach to studying Ebola virus. Every previous outbreak had been relatively small, so researchers had never before been able to examine the genomes from this many Ebola cases. As they sorted through these sequences, a mutation on a site on Ebola's outer protein, called its glycoprotein, caught the scientists' attention. Because the glycoprotein of Ebola virus binds to its receptor on host cells, mutations in that site can affect a virus's ability to infect. "This receptor binding domain of the virus has been the same since the first Ebola outbreak in 1976," said Andersen. "This is the only time we've ever seen a mutation in this domain." The researchers found that the version of Ebola virus carrying the mutation, called GP-A82V, emerged early in the epidemic before Ebola virus cases began increasing exponentially. Overall, they estimate that the GP-A82V version of Ebola virus caused about 90 percent of infections in the recent outbreak. Next, the scientists tested GP-A82V's reaction to many types of animal cells and found that the mutation specifically helps the virus infect primate cells. The researchers believe the size of the outbreak made detecting this kind of mutation more likely. Scientists suspect that Ebola normally lives in bats--but with more human hosts, the virus had more opportunities to adapt to humans. "We think this shows that when you have large outbreaks, of Ebola or other viruses, you could have these events where they may evolve to become more successful in a new host," explained TSRI Research Associate Nathan Grubaugh, who served as first author of the study with William E. Diehl of the University of Massachusetts Medical School, Aaron E. Lin of the Broad Institute and Luiz Max Carvalho of the University of Edinburgh. The researchers are not sure exactly how this mutation boosts the virus's ability to enter human cells. One hypothesis is that the mutation shifts nearby amino acids in the Ebola virus receptor binding domain, helping the glycoprotein better fit with the human host receptor--like a key in a lock. Andersen emphasized that the GP-A82V form of Ebola virus is most likely no longer a threat. "It's important to understand that once the outbreak is over, this particular virus will likely disappear," Andersen said. Instead, the findings are important because they answer the question of whether Ebola virus can gain mutations during outbreaks that can potentially change the function of viral proteins. Andersen and Grubaugh also see this study as an example of how genome sequencing can help researchers respond more quickly to epidemics and tailor therapies to the specific strain of a virus active in an outbreak. "This sort of work can affect decision making," said Andersen. The researchers credited their collaboration with other laboratories for making this study possible. "Because of this collaboration, and how other groups quickly made their research data publically available, we were able to track how the virus changed," said Grubaugh. The next steps will be to examine other mutations that showed up during the recent outbreak. The researchers would also like to see if increased infectivity changes mortality rates and the likelihood of a person transmitting the disease. "Along with the accompanying study in Cell, this research shows how mutations in Ebola virus can change infectivity of cells in experimental systems, but we don't know how these findings translate to Ebola virus infection of complicated organisms, including humans," Grubaugh said. "For future studies, that will be critically important to find out." Additional authors of the study, "Ebola Virus Glycoprotein with Increased Infectivity Dominated the 2013-2016 Epidemic," were Kyusik Kim, Sean M. McCauley, Pyae Phyo Kyawe, Elisa Donnard, Alper Kucukural, Patrick McDonel and Manuel Garber of the University of Massachusetts Medical School; Stephen F. Schaffner of the Broad Institute; and Andrew Rambaut of the University of Edinburgh. The study was supported by the National Institutes of Health (NIH) National Institute National Institute on Drug Abuse (NIDA, grant DP1DA034990), the NIH National Institute of Allergy and Infectious Diseases (NIAID, grants R01AI111809, U19AI110818 and HHSN272201400048C), the NIH National Human Genome Research Institute (NHGRI, grants 1U01HG007910 and 5T32AI007244-33), the NIH National Center for Advancing Translational Sciences (NCATS, grant UL1TR001114), a Howard Hughes Medical Investigator award, the European Union Seventh Framework Programme (FP7/2007-2013, grant 278433-PREDEMICS), the National Science Foundation (grant DGE 1144152) and the NIH (grant U19AI110818).


Home > Press > Kymouse success in steps to developing HIV vaccine: Kymab, the Scripps Research Institute and International AIDS Vaccine Initiative collaboration improves discovery and testing of promising HIV vaccine strategies Abstract: A new approach to developing a human vaccine against HIV has been developed by researchers at Kymab, a UK therapeutic antibody platform Company, The Scripps Research Institute (TSRI) of San Diego, California, and the International AIDS Vaccine Initiative (IAVI). HIV is one of the most intransigent targets for vaccine development, and no effective vaccine has been developed in thirty years of global research. The research, which tested the first step in an approach to develop effective vaccines against the range of HIV variants existing worldwide, is published in Science on Thursday 8 September, 2016, and was supported by funding from the International AIDS Vaccine Initiative and the US National Institutes of Health. The results show that Kymouse, which is a mouse that has been modified to mimic human antibody responses, is an effective platform for discovering and testing possible vaccines and suggest ways in which testing of vaccine candidates can be improved. "We increasingly recognize that traditional vaccine strategies will not be successful against all viruses, especially not HIV," says Dennis Burton, chair of the TSRI Department of Immunology and Microbial Science and scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center (NAC) at TSRI and the National Institutes of Health (NIH) Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). "Together with the Kymab team, we have taken a novel approach in which have induced human antibodies in Kymouse that are at the beginning of the pathway to protective antibodies and which is a huge boost to our mission to develop an HIV vaccine." The work is based on the observation that a fraction of people who become infected by HIV develop broadly neutralizing antibodies against diverse HIV strains. Such antibodies would be ideal to protect against or possibly treat HIV infection - if a vaccine could be made to elicit them. However, these antibodies originate from a limited number of precursor antibody-producing cells in the body and acquire their unusual and protective properties only during a long course of infection. Moreover, although these cells have been activated when immunizing certain biased animal models, this is the first time it has been achieved through immunization of an immune system, as in the Kymouse, that resembles the human. The researchers injected Kymouse strains with a nanoparticle formed of 60 copies of a small protein that mimics HIV and was designed to bind and stimulate the specific precursor cells for one class of broadly neutralizing antibody. They expected to find just one such precursor cell (among tens of millions of such cells) in each immunized mouse. The research team then looked to see whether or not the mice had mounted an antibody response to this injection. Given the combined challenges of a complex immunogen structure and the rarity of the right antibodies, an effective response against the HIV immunogen was elicited remarkably efficiently. "Our phenomenal results with the teams at TSRI and IAVI came from work at the boundaries of protein engineering, immunology and vaccine technology," explains Professor Allan Bradley, Chief Technical Officer at Kymab and Director Emeritus of the Wellcome Trust Sanger Institute, who developed the Kymouse platform. "Using Kymouse, we show how an advanced vaccine candidate can search out the one cell among tens of million antibody-producing cells and make it proliferate. "Kymouse can deliver antibody responses that we need to build effective HIV vaccines." The team validated their antibody response by sequencing genes from more than 10,000 cell samples, and showed that genes from responding mice had the expected sequence for precursors to broadly neutralizing antibodies against the HIV target. "It is a big step forward in this branch of HIV vaccine development," says William Schief, TSRI Professor and Director of Vaccine Design for the IAVI Neutralizing Antibody Center at TSRI, in whose lab the vaccine nanoparticle was developed. "We have the first proof of principle that this HIV vaccine strategy and our vaccine candidate can work in a human immune system and trigger the first step in the pathway to developing broadly neutralizing and protective antibodies against the virus. "It is the very sort of response we'd want to see as we test components of a future vaccine." HIV has proved an extremely difficult challenge in vaccine development. The new research shows that Kymouse can produce antibodies of the type that could evolve to confer protection, suggests ways in which the immunization regime can be improved and indicates that Kymab's technologies will support and accelerate the search for other, rarer and perhaps even more effective antibodies. "About 35 million people have died of HIV/AIDS and 36 million are currently infected. Although a vaccine is the most likely way to stem this loss, no successful vaccine has been found in more than thirty years of HIV research," says Professor Paul Kellam, Vice President of Infectious Diseases and Vaccines at Kymab. "This is a pressing need and these results show that our Kymouse technologies can serve a vital part in the search for effective vaccines that help to protect against this most challenging disease." "This dramatic proof of concept gives us hope we can find better broadly effective vaccines for HIV and, indeed, for other infections, using the human immune system to help guide us along the best path." Participating Centers Kymab Ltd, Babraham Research Campus, Cambridge, UK Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA About Don Powell Associates LTD About Kymab Kymab is a leading biopharmaceutical company focused on the discovery and development of fully human monoclonal antibody drugs using its proprietary Kymouse™ antibody platform. Kymouse™ has been designed to maximize the diversity of human antibodies produced in response to immunization with antigens. Selecting from a broad diversity of fully human antibodies assures the highest probability of finding that rare drug candidate with best-in-class characteristics. The Kymouse™ naturally matures these molecules to highly potent drugs obviating the need for further time-consuming modifications. Kymab is using the platform for its internal drug discovery programs and in partnership with pharmaceutical companies. Kymab commenced operations in 2010 and has raised over US$120m of equity financing which includes $90m Series B financing. It has an experienced management team with a successful track record in drug discovery and development and has numerous therapeutic antibody programs in immune-oncology, auto-immunity; hematology, infectious disease and other areas. www.kymab.com About The Scripps Research Institute The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu. About International Aids Vaccine Initiative (IAVI) The International AIDS Vaccine Initiative (IAVI) is a global not-for-profit organization whose mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. Founded in 1996 and operational in 25 countries, IAVI and its network of collaborators research and develop vaccine candidates. IAVI was founded with the generous support of the Alfred P. Sloan Foundation, The Rockefeller Foundation, The Starr Foundation, and Until There's A Cure Foundation. Other major supporters include the Bill & Melinda Gates Foundation, the Foundation for the National Institutes of Health, The John D. Evans Foundation, The New York Community Trust, the James B. Pendleton Charitable Trust; the Governments of Canada, Denmark, India, Ireland, Japan, The Netherlands, Norway, Spain, Sweden, the United Kingdom, and the United States, the Basque Autonomous Government (Spain), the European Union as well as the National Institute of Allergy and Infectious Diseases and The City of New York, Economic Development Corporation; multilateral organizations such as The World Bank and The OPEC Fund for International Development; corporate donors including BD (Becton, Dickinson & Co.), Bristol-Myers Squibb, Continental Airlines, Google Inc., Pfizer Inc, and Thermo Fisher Scientific Inc.; leading AIDS charities such as Broadway Cares/Equity Fights AIDS; and many generous individuals from around the world. For more information, see www.iavi.org. Contacts: For Kymab Don Powell Don Powell Associates Ltd +44 (0)778 6858220 +44 (0)1223 515436 Mary Clark, Supriya Mathur and Hollie Vile Hume Brophy +44 (0)207 862 6390 For TSRI Madeline McCurry-Schmidt Science Writer The Scripps Research Institute Tel: 858-784-9254 Office of Communications The Scripps Research Institute Tel: +1 858-784-2666 Fax: +1 858-784-8118 For IAVI Arne Näveke Executive Director Advocacy, Policy, Communications International AIDS Vaccine Initiative (IAVI) +1.212.847.1055 (office) +1.646.623.47.85 (mobile) If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.


News Article | November 14, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 14, 2016 - A new study led by scientists at The Scripps Research Institute (TSRI) reveals that a protein first discovered at TSRI in 2010 is directly responsible for sensing touch. Knowledge about this protein, called Piezo 1, could be relevant for designing better pain medications and exploring future therapies for blood disorders, hypertension and more. "This latest work provides definitive proof that Piezos are, by themselves, 'mechanosensitive,'" said senior author Ardem Patapoutian, a professor at TSRI and a Howard Hughes Medical Institute (HHMI) Investigator. The study was published recently in the journal Cell Reports. Piezo 1 is an "ion channel," or gateway through the cell membrane. When it senses mechanical force, it opens to allow ions to pass into the cell, starting a chain of events that send a signal to the brain--in other words, Piezo proteins control the sensation of touch. "Out of all our senses, the sense of touch is the least understood, so significant efforts are being made to acquire a more complete understanding," said Ruhma Syeda, a professional scientific collaborator at TSRI and first author of the new study. "We are only now unraveling the physiological roles of Piezo proteins." The new study addressed a lingering question about Piezo 1: Does it sense touch directly, or is it influenced by nearby proteins and other cellular components? To study this, the researchers used a "reductionist" approach, which Syeda helped develop during her postdoctoral research. In this system, scientists extract a protein from its native environment in the cell and study it in a simpler membrane environment. This enables the scientists to see how the protein behaves on its own, without influence from other cellular players. The researchers found that Piezo 1 does appear to directly sense force by detecting tension in the cell membrane. "It seems like it has a built-in sensor," said Syeda. The next step in this research is to better understand the molecular structure of Piezo 1--which could lead to a "map" of the protein and further insights into its function. "I'm also very excited that this reductionist approach can be applied to other channels," said Syeda. "We'll be able to understand more channels and proteins and their physiological roles." In addition to Patapoutian and Syeda, authors of the study, "Piezo1 Channels Are Inherently Mechanosensitive," were Maria N. Florendo and Jennifer M. Kefauver of HHMI and TSRI; Charles D. Cox of the Victor Chang Cardiac Research Institute; Jose S. Santos, previously at the University of California, San Diego, now at Dart NeuroScience; and Boris Martinac of the Victor Chang Cardiac Research Institute and the University of New South Wales. The study was supported by the National Institutes of Health (grant R01NS083174), the National Health and Medical Research Council of Australia and the Howard Hughes Medical Institute. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .


News Article | November 17, 2016
Site: www.medicalnewstoday.com

A new study led by scientists at The Scripps Research Institute (TSRI) reveals that a protein first discovered at TSRI in 2010 is directly responsible for sensing touch. Knowledge about this protein, called Piezo 1, could be relevant for designing better pain medications and exploring future therapies for blood disorders, hypertension and more. "This latest work provides definitive proof that Piezos are, by themselves, 'mechanosensitive,'" said senior author Ardem Patapoutian, a professor at TSRI and a Howard Hughes Medical Institute (HHMI) Investigator. The study was published recently in the journal Cell Reports. Piezo 1 is an "ion channel," or gateway through the cell membrane. When it senses mechanical force, it opens to allow ions to pass into the cell, starting a chain of events that send a signal to the brain - in other words, Piezo proteins control the sensation of touch. "Out of all our senses, the sense of touch is the least understood, so significant efforts are being made to acquire a more complete understanding," said Ruhma Syeda, a professional scientific collaborator at TSRI and first author of the new study. "We are only now unraveling the physiological roles of Piezo proteins." The new study addressed a lingering question about Piezo 1: Does it sense touch directly, or is it influenced by nearby proteins and other cellular components? To study this, the researchers used a "reductionist" approach, which Syeda helped develop during her postdoctoral research. In this system, scientists extract a protein from its native environment in the cell and study it in a simpler membrane environment. This enables the scientists to see how the protein behaves on its own, without influence from other cellular players. The researchers found that Piezo 1 does appear to directly sense force by detecting tension in the cell membrane. "It seems like it has a built-in sensor," said Syeda. The next step in this research is to better understand the molecular structure of Piezo 1 - which could lead to a "map" of the protein and further insights into its function. "I'm also very excited that this reductionist approach can be applied to other channels," said Syeda. "We'll be able to understand more channels and proteins and their physiological roles." The study was supported by the National Institutes of Health (grant R01NS083174), the National Health and Medical Research Council of Australia and the Howard Hughes Medical Institute.


News Article | November 12, 2016
Site: www.sciencedaily.com

A new study led by scientists at The Scripps Research Institute (TSRI) suggests there may be a way to limit tumor growth by targeting immune system cells called macrophages. The research reveals that macrophages can "drill" through tumors to create new vessel-like structures for delivering oxygen and nutrients as tumors grow. "This may represent a whole new therapeutic target for treating tumors," said TSRI Professor Martin Friedlander, senior author of the new study, which was published November 11 in the journal Scientific Reports. Blood vessels are normally built by endothelial cells. In cancer, tumor cells can induce endothelial cells to build new vessels to bring in blood rich with oxygen and nutrients, a process called angiogenesis. Recent research has revealed that not all vessels are lined by endothelial cells. In cancer, vessel-like structures can be created by a non-endothelial cell type. This phenomenon, called "vascular mimicry," has been observed in several types of solid tumors, including glioblastoma, breast cancer and melanoma, and has been attributed to a sub-population of cells within the tumor called cancer stem cells. Yet the scientists in this study found that macrophages can form vascular mimicry channels in tumors, as well as in other low-oxygen environments. Although macrophages are key cells of the immune system that recognize and attack foreign invaders and cancer cells, macrophages can be re-programmed within the tumor environment to promote tumor growth. The scientists in the new study presented a new and unrecognized structural role for macrophages in the formation of a vascular mimicry network connected to the systemic circulation. "These conduits have an architecture distinct from that of traditional blood vessels," said Faith H. Barnett, a cancer researcher and neurosurgeon at Scripps Clinic who served as co-first author of the study with Mauricio Rosenfeld. Using an intravenously injected dye to delineate the established vasculature as well as the newly formed vascular mimicry conduits, the researchers found that macrophages quickly migrate to oxygen-deprived environments and form these vessel-like channels. Experiments spearheaded by Barnett and Rosenfeld showed that these tubular structures are lined with cells that express macrophage cell surface markers. "Macrophages are capable of forming a three-dimensional network," said Rosenfeld. These vessel-like channels appeared too small to carry red blood cells, but the researchers believe that the low oxygen concentrations within tumors drive macrophages to form this network of channels to transport dissolved oxygen and glucose. The findings could explain why current drugs to slow angiogenesis do not slow tumor growth in some patients. Friedlander said future cancer therapies could starve tumors by combining current vessel-targeting drugs with drugs to influence macrophage activity. "There may be an opportunity to intervene therapeutically," Friedlander said. In addition to providing a new approach to cancer, Friedlander added that future studies could focus on better understanding how macrophages influence retinal angiogenesis and blood flow in the eye -- a key concern for people with diseases like age-related wet macular degeneration, where leaky vessels can cause vision loss. The researchers added that this study would not have been possible without TSRI's core facilities scientists, who aided with electron microscopy, confocal imaging, in vivo mouse efforts and quantitative analysis. In addition to Friedlander, Barnett and Rosenfeld, authors of the study, "Macrophages form functional vascular mimicry channels in vivo," were Malcolm Wood, William Kiosses, Yoshihiko Usui, Valentina Marchetti and Edith Aguilar, all of TSRI at the time of the study. The study was supported by the National Institutes of Health (grant R01EY011254).


News Article | November 11, 2016
Site: www.eurekalert.org

LA JOLLA, CA - November 11, 2016 - A new study led by scientists at The Scripps Research Institute (TSRI) suggests there may be a way to limit tumor growth by targeting immune system cells called macrophages. The research reveals that macrophages can "drill" through tumors to create new vessel-like structures for delivering oxygen and nutrients as tumors grow. "This may represent a whole new therapeutic target for treating tumors," said TSRI Professor Martin Friedlander, senior author of the new study, which was published November 11 in the journal Scientific Reports. Blood vessels are normally built by endothelial cells. In cancer, tumor cells can induce endothelial cells to build new vessels to bring in blood rich with oxygen and nutrients, a process called angiogenesis. Recent research has revealed that not all vessels are lined by endothelial cells. In cancer, vessel-like structures can be created by a non-endothelial cell type. This phenomenon, called "vascular mimicry," has been observed in several types of solid tumors, including glioblastoma, breast cancer and melanoma, and has been attributed to a sub-population of cells within the tumor called cancer stem cells. Yet the scientists in this study found that macrophages can form vascular mimicry channels in tumors, as well as in other low-oxygen environments. Although macrophages are key cells of the immune system that recognize and attack foreign invaders and cancer cells, macrophages can be re-programmed within the tumor environment to promote tumor growth. The scientists in the new study presented a new and unrecognized structural role for macrophages in the formation of a vascular mimicry network connected to the systemic circulation. "These conduits have an architecture distinct from that of traditional blood vessels," said Faith H. Barnett, a cancer researcher and neurosurgeon at Scripps Clinic who served as co-first author of the study with Mauricio Rosenfeld. Using an intravenously injected dye to delineate the established vasculature as well as the newly formed vascular mimicry conduits, the researchers found that macrophages quickly migrate to oxygen-deprived environments and form these vessel-like channels. Experiments spearheaded by Barnett and Rosenfeld showed that these tubular structures are lined with cells that express macrophage cell surface markers. "Macrophages are capable of forming a three-dimensional network," said Rosenfeld. These vessel-like channels appeared too small to carry red blood cells, but the researchers believe that the low oxygen concentrations within tumors drive macrophages to form this network of channels to transport dissolved oxygen and glucose. The findings could explain why current drugs to slow angiogenesis do not slow tumor growth in some patients. Friedlander said future cancer therapies could starve tumors by combining current vessel-targeting drugs with drugs to influence macrophage activity. "There may be an opportunity to intervene therapeutically," Friedlander said. In addition to providing a new approach to cancer, Friedlander added that future studies could focus on better understanding how macrophages influence retinal angiogenesis and blood flow in the eye--a key concern for people with diseases like age-related wet macular degeneration, where leaky vessels can cause vision loss. The researchers added that this study would not have been possible without TSRI's core facilities scientists, who aided with electron microscopy, confocal imaging, in vivo mouse efforts and quantitative analysis. In addition to Friedlander, Barnett and Rosenfeld, authors of the study, "Macrophages form functional vascular mimicry channels in vivo," were Malcolm Wood, William Kiosses, Yoshihiko Usui, Valentina Marchetti and Edith Aguilar, all of TSRI at the time of the study. The study was supported by the National Institutes of Health (grant R01EY011254). The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see http://www. .

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