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Institut
- Theodor-Boveri-Institut für Biowissenschaften (72)
- Physikalisches Institut (25)
- Medizinische Klinik und Poliklinik II (23)
- Neurologische Klinik und Poliklinik (22)
- Institut für Anorganische Chemie (21)
- Institut für Psychologie (19)
- Institut für Geographie und Geologie (18)
- Institut für Organische Chemie (18)
- Medizinische Klinik und Poliklinik I (17)
- Institut für Hygiene und Mikrobiologie (16)
Sonstige beteiligte Institutionen
- DFG (1)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (1)
- Interdisciplinary Center for Clinical Research (1)
- Johns Hopkins School of Medicine (1)
- University of Bari Medical School, Bari, Italy (1)
Ferreira, Manuel A. ; Gamazon, Eric R. ; Al-Ejeh, Fares ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arason, Adalgeir ; Arndt, Volker ; Aronson, Kristan J. ; Arun, Banu K. ; Asseryanis, Ella ; Azzollini, Jacopo ; Balmaña, Judith ; Barnes, Daniel R. ; Barrowdale, Daniel ; Beckmann, Matthias W. ; Behrens, Sabine ; Benitez, Javier ; Bermisheva, Marina ; Bialkowska, Katarzyna ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Borg, Ake ; Brauch, Hiltrud ; Brenner, Hermann ; Broeks, Annegien ; Burwinkel, Barbara ; Caldés, Trinidad ; Caligo, Maria A. ; Campa, Daniele ; Campbell, Ian ; Canzian, Federico ; Carter, Jonathan ; Carter, Brian D. ; Castelao, Jose E. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Christiansen, Hans ; Chung, Wendy K. ; Claes, Kathleen B. M. ; Clarke, Christine L. ; Couch, Fergus J. ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Daly, Mary B. ; de la Hoya, Miguel ; Dennis, Joe ; Devilee, Peter ; Diez, Orland ; Dörk, Thilo ; Dunning, Alison M. ; Dwek, Miriam ; Eccles, Diana M. ; Ejlertsen, Bent ; Ellberg, Carolina ; Engel, Christoph ; Eriksson, Mikael ; Fasching, Peter A. ; Fletcher, Olivia ; Flyger, Henrik ; Friedman, Eitan ; Frost, Debra ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Ganz, Patricia A. ; Gapstur, Susan M. ; Garber, Judy ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; Giles, Graham G. ; Glendon, Gord ; Godwin, Andrew K. ; Goldberg, Mark S. ; Goldgar, David E. ; González-Neira, Anna ; Greene, Mark H. ; Gronwald, Jacek ; Guenél, Pascal ; Haimann, Christopher A. ; Hall, Per ; Hamann, Ute ; He, Wei ; Heyworth, Jane ; Hogervorst, Frans B. L. ; Hollestelle, Antoinette ; Hoover, Robert N. ; Hopper, John L. ; Hulick, Peter J. ; Humphreys, Keith ; Imyanitov, Evgeny N. ; Isaacs, Claudine ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul A. ; Janavicius, Ramunas ; Jankowitz, Rachel C. ; John, Esther M. ; Johnson, Nichola ; Joseph, Vijai ; Karlan, Beth Y. ; Khusnutdinova, Elza ; Kiiski, Johanna I. ; Ko, Yon-Dschun ; Jones, Michael E. ; Konstantopoulou, Irene ; Kristensen, Vessela N. ; Laitman, Yael ; Lambrechts, Diether ; Lazaro, Conxi ; Leslie, Goska ; Lester, Jenny ; Lesueur, Fabienne ; Lindström, Sara ; Long, Jirong ; Loud, Jennifer T. ; Lubiński, Jan ; Makalic, Enes ; Mannermaa, Arto ; Manoochehri, Mehdi ; Margolin, Sara ; Maurer, Tabea ; Mavroudis, Dimitrios ; McGuffog, Lesley ; Meindl, Alfons ; Menon, Usha ; Michailidou, Kyriaki ; Miller, Austin ; Montagna, Marco ; Moreno, Fernando ; Moserle, Lidia ; Mulligan, Anna Marie ; Nathanson, Katherine L. ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Nevelsteen, Ines ; Nielsen, Finn C. ; Nikitina-Zake, Liene ; Nussbaum, Robert L. ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo I. ; Olsson, Håkan ; Osorio, Ana ; Papp, Janos ; Park-Simon, Tjoung-Won ; Parsons, Michael T. ; Pedersen, Inge Sokilde ; Peixoto, Ana ; Peterlongo, Paolo ; Pharaoh, Paul D. P. ; Plaseska-Karanfilska, Dijana ; Poppe, Bruce ; Presneau, Nadege ; Radice, Paolo ; Rantala, Johanna ; Rennert, Gad ; Risch, Harvey A. ; Saloustros, Emmanouil ; Sanden, Kristin ; Sawyer, Elinor J. ; Schmidt, Marjanka K. ; Schmutzler, Rita K. ; Sharma, Priyanka ; Shu, Xiao-Ou ; Simard, Jaques ; Singer, Christian F. ; Soucy, Penny ; Southey, Melissa C. ; Spinelli, John J. ; Spurdle, Amanda B. ; Stone, Jennifer ; Swerdlow, Anthony J. ; Tapper, William J. ; Taylor, Jack A. ; Teixeira, Manuel R. ; Terry, Mary Beth ; Teulé, Alex ; Thomassen, Mads ; Thöne, Kathrin ; Thull, Darcy L. ; Tischkowitz, Marc ; Toland, Amanda E. ; Torres, Diana ; Truong, Thérèse ; Tung, Nadine ; Vachon, Celine M. ; van Asperen, Christi J. ; van den Ouweland, Ans M. W. ; van Rensburg, Elizabeth J. ; Vega, Ana ; Viel, Alexandra ; Wang, Qin ; Wappenschmidt, Barbara ; Weitzel, Jeffrey N. ; Wendt, Camilla ; Winqvist, Robert ; Yang, Xiaohong R. ; Yannoukakos, Drakoulis ; Ziogas, Argyrios ; Kraft, Peter ; Antoniou, Antonis C. ; Zheng, Wei ; Easton, Douglas F. ; Milne, Roger L. ; Beesley, Jonathan ; Chenevix-Trench, Georgia
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
Fan, Sook-Ha ; Ebner, Patrick ; Reichert, Sebstian ; Hertlein, Tobias ; Zabel, Susanne ; Lankapalli, Aditya Kumar ; Nieselt, Kay ; Ohlsen, Knut ; Götz, Friedrich
The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.
El-Mesery, Mohamed ; Rosenthal, Tina ; Rauert-Wunderlich, Hilka ; Schreder, Martin ; Stühmer, Thorsten ; Leich, Ellen ; Schlosser, Andreas ; Ehrenschwender, Martin ; Wajant, Harald ; Siegmund, Daniela
The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.
Dörk, Thilo ; Peterlongo, Peter ; Mannermaa, Arto ; Bolla, Manjeet K. ; Wang, Qin ; Dennis, Joe ; Ahearn, Thomas ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arndt, Volker ; Aronson, Kristan J. ; Augustinsson, Annelie ; Beane Freeman, Laura E. ; Beckmann, Matthias W. ; Beeghly-Fadiel, Alicia ; Behrens, Sabine ; Bermisheva, Marina ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Brauch, Hiltrud ; Brenner, Hermann ; Burwinkel, Barbara ; Canzian, Federico ; Chan, Tsun L. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Choi, Ji-Yeob ; Christiansen, Hans ; Clarke, Christine L. ; Couch, Fergus J. ; Czene, Kamila ; Daly, Mary B. ; dos-Santos-Silva, Isabel ; Dwek, Miriam ; Eccles, Diana M. ; Ekici, Arif B. ; Eriksson, Mikael ; Evans, D. Gareth ; Fasching, Peter A. ; Figueroa, Jonine ; Flyger, Henrik ; Fritschi, Lin ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Gao, Chi ; Gapstur, Susan M. ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; Giles, Graham G. ; Goldberg, Mark S. ; Goldgar, David E. ; Guenél, Pascal ; Haeberle, Lothar ; Haimann, Christopher A. ; Håkansson, Niclas ; Hall, Per ; Hamann, Ute ; Hartman, Mikael ; Hauke, Jan ; Hein, Alexander ; Hillemanns, Peter ; Hogervorst, Frans B. L. ; Hooning, Maartje J. ; Hopper, John L. ; Howell, Tony ; Huo, Dezheng ; Ito, Hidemi ; Iwasaki, Motoki ; Jakubowska, Anna ; Janni, Wolfgang ; John, Esther M. ; Jung, Audrey ; Kaaks, Rudolf ; Kang, Daehee ; Kapoor, Pooja Middha ; Khusnutdinova, Elza ; Kim, Sung-Won ; Kitahara, Cari M. ; Koutros, Stella ; Kraft, Peter ; Kristensen, Vessela N. ; Kwong, Ava ; Lambrechts, Diether ; Le Marchand, Loic ; Li, Jingmei ; Lindström, Sara ; Linet, Martha ; Lo, Wing-Yee ; Long, Jirong ; Lophatananon, Artitaya ; Lubiński, Jan ; Manoochehri, Mehdi ; Manoukian, Siranoush ; Margolin, Sara ; Martinez, Elena ; Matsuo, Keitaro ; Mavroudis, Dimitris ; Meindl, Alfons ; Menon, Usha ; Milne, Roger L. ; Mohd Taib, Nur Aishah ; Muir, Kenneth ; Mulligan, Anna Marie ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Neven, Patrick ; Newman, William G. ; Offit, Kenneth ; Olopade, Olufunmilayo I. ; Olshan, Andrew F. ; Olson, Janet E. ; Olsson, Håkan ; Park, Sue K. ; Park-Simon, Tjoung-Won ; Peto, Julian ; Plaseska-Karanfilska, Dijana ; Pohl-Rescigno, Esther ; Presneau, Nadege ; Rack, Brigitte ; Radice, Paolo ; Rashid, Muhammad U. ; Rennert, Gad ; Rennert, Hedy S. ; Romero, Atocha ; Ruebner, Matthias ; Saloustros, Emmanouil ; Schmidt, Marjanka K. ; Schmutzler, Rita K. ; Schneider, Michael O. ; Schoemaker, Minouk J. ; Scott, Christopher ; Shen, Chen-Yang ; Shu, Xiao-Ou ; Simard, Jaques ; Slager, Susan ; Smichkoska, Snezhana ; Southey, Melissa C. ; Spinelli, John J. ; Stone, Jennifer ; Surowy, Harald ; Swerdlow, Anthony J. ; Tamimi, Rulla M. ; Tapper, William J. ; Teo, Soo H. ; Terry, Mary Beth ; Toland, Amanda E. ; Tollenaar, Rob A. E. M. ; Torres, Diana ; Torres-Mejía, Gabriela ; Troester, Melissa A. ; Truong, Thérèse ; Tsugane, Shoichiro ; Untch, Michael ; Vachon, Celine M. ; van den Ouweland, Ans M. W. ; van Veen, Elke M. ; Vijai, Joseph ; Wendt, Camilla ; Wolk, Alicja ; Yu, Jyh-Cherng ; Zheng, Wei ; Ziogas, Argyrios ; Ziv, Elad ; Dunnig, Alison ; Pharaoh, Paul D. P. ; Schindler, Detlev ; Devilee, Peter ; Easton, Douglas F.
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Surgical extrusion is a recognised treatment option for teeth that have insufficient coronal tooth structure remaining due to deep caries, resorption or traumatic injury. However, the technique has not been widely adopted, arguably because extraction of a severely compromised tooth may be difficult to achieve in a gentle and predictable way. In this paper, we present our novel approach to surgical extrusion and subsequent management of teeth using a vertical extraction system (Benex), which has become the method of choice in the authors' practice for many teeth that would otherwise be deemed unrestorable. We describe the clinical procedure in detail and discuss the advantages and disadvantages compared to alternative approaches, including surgical crown lengthening and orthodontic extrusion.
Diehl-Schmid, Janine ; Licata, Abigail ; Goldhardt, Oliver ; Förstl, Hans ; Yakushew, Igor ; Otto, Markus ; Anderl-Straub, Sarah ; Beer, Ambros ; Ludolph, Albert Christian ; Landwehrmeyer, Georg Bernhard ; Levin, Johannes ; Danek, Adrian ; Fliessbach, Klaus ; Spottke, Annika ; Fassbender, Klaus ; Lyros, Epameinondas ; Prudlo, Johannes ; Krause, Bernd Joachim ; Volk, Alexander ; Edbauer, Dieter ; Schroeter, Matthias Leopold ; Drzezga, Alexander ; Kornhuber, Johannes ; Lauer, Martin ; Grimmer, Timo
C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, 18F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.
Dekker, Annelot M. ; Diekstra, Frank P. ; Pulit, Sara L. ; Tazelaar, Gijs H. P. ; van der Spek, Rick A. ; van Rheenen, Wouter ; van Eijk, Kristel R. ; Calvo, Andrea ; Brunetti, Maura ; Van Damme, Philip ; Robberecht, Wim ; Hardiman, Orla ; McLaughlin, Russell ; Chiò, Adriano ; Sendtner, Michael ; Ludolph, Albert C. ; Weishaupt, Jochen H. ; Pardina, Jesus S. Mora ; van den Berg, Leonard H. ; Veldink, Jan H.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.
Dammert, Marcel A. ; Brägelmann, Johannes ; Olsen, Rachelle R. ; Böhm, Stefanie ; Monhasery, Niloufar ; Whitney, Christopher P. ; Chalishazar, Milind D. ; Tumbrink, Hannah L. ; Guthrie, Matthew R. ; Klein, Sebastian ; Ireland, Abbie S. ; Ryan, Jeremy ; Schmitt, Anna ; Marx, Annika ; Ozretić, Luka ; Castiglione, Roberta ; Lorenz, Carina ; Jachimowicz, Ron D. ; Wolf, Elmar ; Thomas, Roman K. ; Poirier, John T. ; Büttner, Reinhard ; Sen, Triparna ; Byers, Lauren A. ; Reinhardt, H. Christian ; Letai, Anthony ; Oliver, Trudy G. ; Sos, Martin L.
MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
Steuer Costa, Wagner ; Van der Auwera, Petrus ; Glock, Caspar ; Liewald, Jana F. ; Bach, Maximilian ; Schüler, Christina ; Wabnig, Sebastian ; Oranth, Alexandra ; Masurat, Florentin ; Bringmann, Henrik ; Schoofs, Liliane ; Stelzer, Ernst H. K. ; Fischer, Sabine C. ; Gottschalk, Alexander
Animals must slow or halt locomotion to integrate sensory inputs or to change direction. In Caenorhabditis elegans, the GABAergic and peptidergic neuron RIS mediates developmentally timed quiescence. Here, we show RIS functions additionally as a locomotion stop neuron. RIS optogenetic stimulation caused acute and persistent inhibition of locomotion and pharyngeal pumping, phenotypes requiring FLP-11 neuropeptides and GABA. RIS photoactivation allows the animal to maintain its body posture by sustaining muscle tone, yet inactivating motor neuron oscillatory activity. During locomotion, RIS axonal Ca2+ signals revealed functional compartmentalization: Activity in the nerve ring process correlated with locomotion stop, while activity in a branch correlated with induced reversals. GABA was required to induce, and FLP-11 neuropeptides were required to sustain locomotion stop. RIS attenuates neuronal activity and inhibits movement, possibly enabling sensory integration and decision making, and exemplifies dual use of one cell across development in a compact nervous system.
Annunziata, Ida ; van de Vlekkert, Diantha ; Wolf, Elmar ; Finkelstein, David ; Neale, Geoffrey ; Machado, Eda ; Mosca, Rosario ; Campos, Yvan ; Tillman, Heather ; Roussel, Martine F. ; Weesner, Jason Andrew ; Fremuth, Leigh Ellen ; Qiu, Xiaohui ; Han, Min-Joon ; Grosveld, Gerard C. ; d'Azzo, Alessandra
Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
Al-Zaben, Naim ; Medyukhina, Anna ; Dietrich, Stefanie ; Marolda, Alessandra ; Hünniger, Kerstin ; Kurzai, Oliver ; Figge, Marc Thilo
Migration and interactions of immune cells are routinely studied by time-lapse microscopy of in vitro migration and confrontation assays. To objectively quantify the dynamic behavior of cells, software tools for automated cell tracking can be applied. However, many existing tracking algorithms recognize only rather short fragments of a whole cell track and rely on cell staining to enhance cell segmentation. While our previously developed segmentation approach enables tracking of label-free cells, it still suffers from frequently recognizing only short track fragments. In this study, we identify sources of track fragmentation and provide solutions to obtain longer cell tracks. This is achieved by improving the detection of low-contrast cells and by optimizing the value of the gap size parameter, which defines the number of missing cell positions between track fragments that is accepted for still connecting them into one track. We find that the enhanced track recognition increases the average length of cell tracks up to 2.2-fold. Recognizing cell tracks as a whole will enable studying and quantifying more complex patterns of cell behavior, e.g. switches in migration mode or dependence of the phagocytosis efficiency on the number and type of preceding interactions. Such quantitative analyses will improve our understanding of how immune cells interact and function in health and disease.
Albrecht, Franziska ; Mueller, Karsten ; Ballarini, Tommaso ; Lampe, Leonie ; Diehl-Schmid, Janine ; Fassbender, Klaus ; Fliessbach, Klaus ; Jahn, Holger ; Jech, Robert ; Kassubek, Jan ; Kornhuber, Johannes ; Landwehrmeyer, Bernhard ; Lauer, Martin ; Ludolph, Albert C. ; Lyros, Epameinondas ; Prudlo, Johannes ; Schneider, Anja ; Synofzik, Matthis ; Wiltfang, Jens ; Danek, Adrian ; Otto, Markus ; Schroeter, Matthias L.
Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure function relationship of alien/anarchic limb was investigated in multi centric structural magnetic resonance imaging (MRI) data. Whole-group and single subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture. (C) 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Astrophysical sources of gravitational waves, such as binary neutron star and black hole mergers or core-collapse supernovae, can drive relativistic outflows, giving rise to non-thermal high-energy emission. High-energy neutrinos are signatures of such outflows. The detection of gravitational waves and high-energy neutrinos from common sources could help establish the connection between the dynamics of the progenitor and the properties of the outflow. We searched for associated emission of gravitational waves and high-energy neutrinos from astrophysical transients with minimal assumptions using data from Advanced LIGO from its first observing run O1, and data from the Antares and IceCube neutrino observatories from the same time period. We focused on candidate events whose astrophysical origins could not be determined from a single messenger. We found no significant coincident candidate, which we used to constrain the rate density of astrophysical sources dependent on their gravitational-wave and neutrino emission processes.
Albert, A. ; André, M. ; Anghinolfi, M. ; Anton, G. ; Ardid, M. ; Aubert, J.-J. ; Aublin, J. ; Avgitas, T. ; Baret, B. ; Barrios-Martít, J. ; Basa, S. ; Belhorma, B. ; Bertin, V. ; Biagi, S. ; Bormuth, R. ; Boumaaza, J ; Bourret, S. ; Bouwhuis, M. C. ; Brânzas, H. ; Bruijn, R. ; Brunner, J. ; Busto, J. ; Capone, A. ; Caramete, L. ; Carr, J. ; Celli, S. ; Chabab, M. ; Cherkaoui El Moursli, R. ; Chiarusi, T. ; Circella, M. ; Coelho, J. A. B. ; Coleiro, A. ; Colomer, M ; Coniglione, R. ; Costantini, H. ; Coyle, P. ; Creusot, A. ; Díaz, A. F. ; Deschamps, A. ; Distefano, C. ; Di Palma, I. ; Domi, A. ; Donzaud, C. ; Dornic, D. ; Drouhin, D. ; Eberl, T. ; El Bojaddaini, I. ; El Khayati, N. ; Elsässer, D. ; Enzenhöfer, A. ; Ettahiri, A. ; Fassi, F. ; Felis, I. ; Fermani, P. ; Ferrara, G. ; Fusco, L. A. ; Gay, P. ; Glotin, H. ; Grégoire, T. ; Gracia Ruiz, R. ; Graf, K. ; Hallmann, S. ; van Haren, H. ; Heijboer, A. J. ; Hello, Y. ; Hernández-Rey, J. J. ; Hößl, J. ; Hofestädt, J. ; Illuminati, G. ; de Jong, M. ; Jongen, M. ; Kadler, M. ; Kalekin, O. ; Katz, U. ; Khan-Chowdhury, N. R. ; Kouchner, A. ; Kreter, M. ; Kreykenbohm, I. ; Kulikovskiy, V. ; Lachaud, C. ; Lahmann, R. ; Lefèvre, D. ; Leonora, E. ; Levi, G. ; Lotze, M. ; Loucatos, S. ; Marcelin, M. ; Margiotta, A. ; Marinelli, A. ; Martínez-Mora, J. A. ; Mele, R. ; Melis, K. ; Migliozzi, P. ; Moussa, A. ; Navas, S. ; Nezri, E. ; Nuñez, A. ; Organokov, M. ; Pavalas, G. E. ; Pellegrino, C. ; Piattelli, P. ; Popa, V. ; Pradier, T. ; Quinn, L. ; Racca, C. ; Randazzo, N. ; Riccobene, G. ; Sánchez-Losa, A. ; Saldaña, M. ; Salvadori, I. ; Samtleben, D. F. E. ; Sanguineti, M. ; Sapienza, P. ; Schüssler, F. ; Spurio, M. ; Stolarczyk, Th. ; Taiuti, M. ; Tayalati, Y. ; Trovato, A. ; Vallage, B. ; Van Elewyck, V. ; Versari, F. ; Vivolo, D. ; Wilms, J. ; Zaborov, D. ; Zornoza, J. D. ; Zúñiga, J.
One of the main objectives of the ANTARES telescope is the search for point- like neutrino sources. Both the pointing accuracy and the angular resolution of the detector are important in this context and a reliableway to evaluate this performance is needed. In order to measure the pointing accuracy of the detector, one possibility is to study the shadow of the Moon, i. e. the deficit of the atmospheric muon flux from the direction of the Moon induced by the absorption of cosmic rays. Analysing the data taken between 2007 and 2016, theMoon shadow is observed with 3.5s statistical significance. The detector angular resolution for downwardgoing muons is 0.73. +/- 0.14.. The resulting pointing performance is consistent with the expectations. An independent check of the telescope pointing accuracy is realised with the data collected by a shower array detector onboard of a ship temporarily moving around the ANTARES location.
The ANTARES neutrino telescope has an energy threshold of a few tens of GeV. This allows to study the phenomenon of atmospheric muon neutrino disappearance due to neutrino oscillations. In a similar way, constraints on the 3+1 neutrino model, which foresees the existence of one sterile neutrino, can be inferred. Using data collected by the ANTARES neutrino telescope from 2007 to 2016, a new measurement of m 2 and (23) has been performed which is consistent with world best-fit values and constraints on the 3+1 neutrino model have been derived.
Alacevich, Massimo ; Carloni Calame, Carlo M. ; Chiesa, Mauro ; Montagna, Guido ; Nicrosini, Oreste ; Piccinini, Fulvio
We consider the process of muon-electron elastic scattering, which has been proposed as an ideal framework to measure the running of the electromagnetic coupling constant at space-like momenta and determine the leading-order hadronic contribution to the muon g-2 (MUonE experiment). We compute the next-to-leading (NLO) contributions due to QED and purely weak corrections and implement them into a fully differential Monte Carlo event generator, which is available for first experimental studies. We show representative phenomenological results of interest for the MUonE experiment and examine in detail the impact of the various sources of radiative corrections under different selection criteria, in order to study the dependence of the NLO contributions on the applied cuts. The study represents the first step towards the realisation of a high-precision Monte Carlo code necessary for data analysis.
The Best for the Most Important: Maintaining a Pristine Proteome in Stem and Progenitor Cells
(2019)
Pluripotent stem cells give rise to reproductively enabled offsprings by generating progressively lineage-restricted multipotent stem cells that would differentiate into lineage-committed stem and progenitor cells. These lineage-committed stem and progenitor cells give rise to all adult tissues and organs. Adult stem and progenitor cells are generated as part of the developmental program and play critical roles in tissue and organ maintenance and/or regeneration. The ability of pluripotent stem cells to self-renew, maintain pluripotency, and differentiate into a multicellular organism is highly dependent on sensing and integrating extracellular and extraorganismal cues. Proteins perform and integrate almost all cellular functions including signal transduction, regulation of gene expression, metabolism, and cell division and death. Therefore, maintenance of an appropriate mix of correctly folded proteins, a pristine proteome, is essential for proper stem cell function. The stem cells' proteome must be pristine because unfolded, misfolded, or otherwise damaged proteins would interfere with unlimited self-renewal, maintenance of pluripotency, differentiation into downstream lineages, and consequently with the development of properly functioning tissue and organs. Understanding how various stem cells generate and maintain a pristine proteome is therefore essential for exploiting their potential in regenerative medicine and possibly for the discovery of novel approaches for maintaining, propagating, and differentiating pluripotent, multipotent, and adult stem cells as well as induced pluripotent stem cells. In this review, we will summarize cellular networks used by various stem cells for generation and maintenance of a pristine proteome. We will also explore the coordination of these networks with one another and their integration with the gene regulatory and signaling networks.
KM3NeT will be a network of deep-sea neutrino telescopes in the Mediterranean Sea. The KM3NeT/ARCA detector, to be installed at the Capo Passero site (Italy), is optimised for the detection of high-energy neutrinos of cosmic origin. Thanks to its geographical location on the Northern hemisphere, KM3NeT/ARCA can observe upgoing neutrinos from most of the Galactic Plane, including the Galactic Centre. Given its effective area and excellent pointing resolution, KM3NeT/ARCA will measure or significantly constrain the neutrino flux from potential astrophysical neutrino sources. At the same time, it will test flux predictions based on gamma-ray measurements and the assumption that the gamma-ray flux is of hadronic origin. Assuming this scenario, discovery potentials and sensitivities for a selected list of Galactic sources and to generic point sources with an E-2 spectrum are presented. These spectra are assumed to be time independent. The results indicate that an observation with 3 sigma significance is possible in about six years of operation for the most intense sources, such as Supernovae Remnants RX J1713.7-3946 and Vela Jr. If no signal will be found during this time, the fraction of the gamma-ray flux coming from hadronic processes can be constrained to be below 50% for these two objects. (C) 2019 The Authors. Published by Elsevier B.V.
Abt, Raimond ; Erdmenger, Johanna ; Gerbershagen, Marius ; Melby-Thompson, Charles M. ; Northe, Christian
We consider the computation of volumes contained in a spatial slice of AdS(3) in terms of observables in a dual CFT. Our main tool is kinematic space, defined either from the bulk perspective as the space of oriented bulk geodesics, or from the CFT perspective as the space of entangling intervals. We give an explicit formula for the volume of a general region in a spatial slice of AdS(3) as an integral over kinematic space. For the region lying below a geodesic, we show how to write this volume purely in terms of entangling entropies in the dual CFT. This expression is perhaps most interesting in light of the complexity = volume proposal, which posits that complexity of holographic quantum states is computed by bulk volumes. An extension of this idea proposes that the holographic subregion complexity of an interval, defined as the volume under its Ryu-Takayanagi surface, is a measure of the complexity of the corresponding reduced density matrix. If this is true, our results give an explicit relationship between entanglement and subregion complexity in CFT, at least in the vacuum. We further extend many of our results to conical defect and BTZ black hole geometries.
Background and Objective: Staphylococcus aureus is one of the major pathogens of nosocomial infections as wells as community-acquired (CA) infections worldwide. So far, large-scale comprehensive molecular and epidemiological characterisation of S. aureus from very diverse settings has not been carried out in India. The objective of this study is to evaluate the molecular, epidemiological and virulence characteristics of S. aureus in both community and hospital settings in Chennai, southern India. Methods: S. aureus isolates were obtained from four different groups (a) healthy individuals from closed community settings, (b) inpatients from hospitals, (c) outpatients from hospitals, representing isolates of hospital-community interface and (d) HIV-infected patients to define isolates associated with the immunocompromised. Antibiotic susceptibility testing, multiplex polymerase chain reactions for detection of virulence and resistance determinants, molecular typing including Staphylococcal cassette chromosome mec (SCCmec) and agr typing, were carried out. Sequencing-based typing was done using spa and multilocus sequence typing (MLST) methods. Clonal complexes (CC) of hospital and CA methicillin-resistant S. aureus (MRSA) were identified and compared for virulence and resistance.
Results and Conclusion: A total of 769 isolates of S. aureus isolates were studied. The prevalence of MRSA was found to be 7.17%, 81.67%, 58.33% and 22.85% for groups a, b, c and d, respectively. Of the four SCCmec types (I, III, IV and V) detected, SCCmec V was found to be predominant. Panton-Valentine leucocidin toxin genes were detected among MRSA isolates harbouring SCCmec IV and V. A total of 78 spa types were detected, t657 being the most prevalent. 13 MLST types belonging to 9 CC were detected. CC1 (ST-772, ST-1) and CC8 (ST238, ST368 and ST1208) were found to be predominant among MRSA. CA-MRSA isolates with SCCmec IV and V were isolated from all study groups including hospitalised patients and were found to be similar by molecular tools. This shows that CA MRSA has probably infiltrated into the hospital settings.