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18,402 results on '"Risch, A."'

1. The hadronic vacuum polarization contribution to the muon $g-2$ at long distances

Author

Djukanovic, Dalibor, von Hippel, Georg, Kuberski, Simon, Meyer, Harvey B., Miller, Nolan, Ottnad, Konstantin, Parrino, Julian, Risch, Andreas, and Wittig, Hartmut

Subjects
High Energy Physics - Lattice, High Energy Physics - Phenomenology
Abstract

We present our lattice QCD result for the long-distance part of the hadronic vacuum polarization contribution, $(a_\mu^{\rm hvp})^{\rm LD}$, to the muon $g-2$ in the time-momentum representation. This is the numerically dominant, and at the same time the most challenging part regarding statistical precision. Our calculation is based on ensembles with dynamical up, down and strange quarks, employing the O($a$)-improved Wilson fermion action with lattice spacings ranging from $0.035-0.099$ fm. In order to reduce statistical noise in the long-distance part of the correlator to the per-mille level, we apply low-mode averaging and combine it with an explicit spectral reconstruction. Our result is $(a_\mu^{\rm hvp})^{\rm LD} = 423.2(4.2)_{\rm stat}(3.4)_{\rm syst}\times 10^{-10}$ in isospin-symmetric QCD, where the pion decay constant is used to set the energy scale. When combined with our previous results for the short- and intermediate-distance window observables and after including all sub-dominant contributions as well as isospin-breaking corrections, we obtain the total leading-order hadronic vacuum polarization contribution as $a_\mu^{\rm hvp} = 724.9(5.0)_{\rm stat}(4.9)_{\rm syst}\times 10^{-10}$. Our result displays a tension of 3.9 standard deviations with the data-driven estimate published in the 2020 White Paper, but leads to a SM prediction for the total muon anomalous magnetic moment that agrees with the current experimental average., Comment: 55 pages, 14 figures, 8 tables

Published
2024

2. Gauge field smearing and controlled continuum extrapolations

Author

Risch, Andreas

Subjects
High Energy Physics - Lattice
Abstract

When designing lattice actions, gauge field smearing is often used in the definition of the lattice Dirac operator. Too much smearing can result in uncontrolled continuum extrapolations as the short distance behaviour of the theory is mutilated, which is a situation to be avoided. As a smearing prescription we focus on the gradient flow formalism as it allows to study both smearing and physical flow simultaneously. We investigate the effect of smearing and physical flow on the scaling towards the continuum limit in pure gauge theory. We focus on the example of Creutz ratios, which provide a measure of the physical forces felt by the fermions. For suitable smearing strengths we further investigate the impact of replacing the Wilson gradient flow by stout smearing., Comment: 10 pages, 5 figures, proceedings to talk presented at the European network for Particle physics, Lattice field theory and Extreme computing (EuroPLEx2023), 11-15 September 2023, Berlin, Germany

Published
2024

3. Climate, food and humans predict communities of mammals in the United States

Author

Kays, Roland, Snider, Matthew H., Hess, George, Cove, Michael V., Jensen, Alex, Shamon, Hila, McShea, William J., Rooney, Brigit, Allen, Maximilian L., Pekins, Charles E., Wilmers, Christopher C., Pendergast, Mary E., Green, Austin M., Suraci, Justin, Leslie, Matthew S., Nasrallah, Sophie, Farkas, Dan, Jordan, Mark, Grigione, Melissa, LaScaleia, Michael C., Davis, Miranda L., Hansen, Chris, Millspaugh, Josh, Lewis, Jesse S., Havrda, Michael, Long, Robert, Remine, Kathryn R., Jaspers, Kodi J., Lafferty, Diana J. R., Hubbard, Tru, Studds, Colin E., Barthelmess, Erika L., Andy, Katherine, Romero, Andrea, O'Neill, Brian J., Hawkins, Melissa T. R., Lombardi, Jason V., Sergeyev, Maksim, Fisher-Reid, M. Caitlin, Rentz, Michael S., Nagy, Christopher, Davenport, Jon M., Rega-Brodsky, Christine C., Appel, Cara L., Lesmeister, Damon B., Giery, Sean T., Whittier, Christopher A., Alston, Jesse M., Sutherland, Chris, Rota, Christopher, Murphy, Thomas, Lee, Thomas E., Mortelliti, Alessio, Bergman, Dylan L., Compton, Justin A., Gerber, Brian D., Burr, Jess, Rezendes, Kylie, DeGregorio, Brett A., Wehr, Nathaniel H., Benson, John F., O’Mara, M. Teague, Jachowski, David S., Gray, Morgan, Beyer, Dean E., Belant, Jerrold L., Horan, Robert V., Lonsinger, Robert C., Kuhn, Kellie M., Hasstedt, Steven C. M., Zimova, Marketa, Moore, Sophie M., Herrera, Daniel J., Fritts, Sarah, Edelman, Andrew J., Flaherty, Elizabeth A., Petroelje, Tyler R., Neiswenter, Sean A., Risch, Derek R., Iannarilli, Fabiola, van der Merwe, Marius, Maher, Sean P., Farris, Zach J., Webb, Stephen L., Mason, David S., Lashley, Marcus A., Wilson, Andrew M., Vanek, John P., Wehr, Samuel R., Conner, L. Mike, Beasley, James C., Bontrager, Helen L., Baruzzi, Carolina, Ellis-Felege, Susan N., Proctor, Mike D., Schipper, Jan, Weiss, Katherine C. B., Darracq, Andrea K., Barr, Evan G., Alexander, Peter D., Şekercioğlu, Çağan H., Bogan, Daniel A., Schalk, Christopher M., Fantle-Lepczyk, Jean E., Lepczyk, Christopher A., LaPoint, Scott, Whipple, Laura S., Rowe, Helen Ivy, Mullen, Kayleigh, Bird, Tori, Zorn, Adam, Brandt, LaRoy, Lathrop, Richard G., McCain, Craig, Crupi, Anthony P., Clark, James, and Parsons, Arielle

Published
2024

4. Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium

Author

Meagher, Nicola S, White, Kami K, Wilkens, Lynne R, Bandera, Elisa V, Berchuck, Andrew, Carney, Michael E, Cramer, Daniel W, Cushing-Haugen, Kara L, Jordan, Susan, Kaufmann, Scott H, Le, Nhu D, Pike, Malcolm C, Riggan, Marjorie, Qin, Bo, Rothstein, Joseph H, Titus, Linda, Winham, Stacey J, Anton-Culver, Hoda, Doherty, Jennifer A, Goode, Ellen L, Pearce, Celeste Leigh, Risch, Harvey A, Webb, Penelope M, Cook, Linda S, Goodman, Marc T, Harris, Holly R, Le Marchand, Loic, McGuire, Valerie, Pharoah, Paul DP, Sarink, Danja, Schildkraut, Joellen M, Sieh, Weiva, Terry, Kathryn L, Thompson, Pamela J, Whittemore, Alice S, Wu, Anna H, Peres, Lauren C, and Merritt, Melissa A

Subjects
Epidemiology, Health Sciences, Ovarian Cancer, Rare Diseases, Cancer, Minority Health, Prevention, Women's Health, Humans, Female, Ovarian Neoplasms, Middle Aged, Carcinoma, Ovarian Epithelial, Risk Factors, Adult, Native Hawaiian or Other Pacific Islander, Case-Control Studies, Aged, Sterilization, Tubal, Parity, Asian, White People, Hispanic or Latino, United States, Contraceptives, Oral, Logistic Models, Smoking, Neoplasms, Glandular and Epithelial, Ethnicity, Odds Ratio, ovarian cancer, risk factors, race, ethnicity, Mathematical Sciences, Medical and Health Sciences
Abstract

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

Published
2024

5. Real time detection of C reactive protein in interstitial fluid using electrochemical impedance spectroscopy, towards wearable health monitoring

Author

Grammoustianou, Aristea, Saeidi, Ali, Longo, Johan, Risch, Felix, and Ionescu, Adrian M.

Subjects
Physics - Medical Physics, Physics - Applied Physics
Abstract

Traditional detection methods of C-reactive protein (CRP) inflammation biomarker, in blood are expensive, time-consuming and labor-intensive. Such existing point-of-care CRP detection devices remain invasive, since they need blood sampling (finger-pricking or venous puncture). Here, we propose an electrochemical impedance spectroscopy (EIS)-based sensor for the real-time, fast, specific, sensitive, and label-free detection of C-reactive protein in the interstitial fluid (ISF) that can be accessed with minimally invasive microneedle arrays. The sensor has the potential to be integrated in a wearable device similar with the continuous glucose monitoring, that will detect CRP in interstitial fluid in a non-invasive, inexpensive and straightforward manner. The affinity based assay was tested in both buffer and ISF-like solution. The limit of detection achieved was 0.7 ug/mL of CRP in buffer, and 0.8 ug/mL of CRP in ISF-like solution and the sensor shows excellent linearity up to 10 ug/mL. It is worth noting that the proposed sensor operates in low sample volume (down to 5 uL), and has a response time of 100 seconds.

Published
2024

6. High precision calculation of the hadronic vacuum polarisation contribution to the muon anomaly

Author

Boccaletti, A., Borsanyi, Sz., Davier, M., Fodor, Z., Frech, F., Gerardin, A., Giusti, D., Kotov, A. Yu., Lellouch, L., Lippert, Th., Lupo, A., Malaescu, B., Mutzel, S., Portelli, A., Risch, A., Sjo, M., Stokes, F., Szabo, K. K., Toth, B. C., Wang, G., and Zhang, Z.

Subjects
High Energy Physics - Lattice, High Energy Physics - Phenomenology, High Energy Physics - Theory
Abstract

We present a new lattice QCD calculation of the leading order hadronic vacuum polarization contribution to the muon anomalous magnetic moment $a_\mu$. We reduce uncertainties compared to our earlier computation by $40\%$, arXiv:2002.12347. We perform simulations on finer lattices allowing for an even more accurate continuum extrapolation. We also include a small, long-distance contribution obtained using input from experiments in a low-energy regime where they all agree. Combined with other standard model contributions our result leads to a prediction that differs from the measurement of $a_\mu$ by only 0.9 standard deviations. This provides a remarkable validation of the standard model to 0.37ppm., Comment: 55 pages, 31 figures

Published
2024

7. Burden of post–acute COVID-19 sequelae in healthcare workers and its course over a 30-month period–results from a prospective multicentre cohort

Author

Dörr, Tamara, Strahm, Carol, Güsewell, Sabine, Ballouz, Tala, Kocan, Emina, Cusini, Alexia, Goppel, Stephan, Grässli, Fabian, Möller, J. Carsten, Puhan, Milo A., Risch, Lorenz, Ruetti, Markus, Schlegel, Matthias, Stocker, Reto, von Kietzell, Matthias, Vuichard-Gysin, Danielle, Kuster, Stefan P., Kahlert, Christian R., and Kohler, Philipp

Published
2024
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8. Widening global variability in grassland biomass since the 1980s

Author

MacDougall, Andrew S., Esch, Ellen, Chen, Qingqing, Carroll, Oliver, Bonner, Colin, Ohlert, Timothy, Siewert, Matthias, Sulik, John, Schweiger, Anna K., Borer, Elizabeth T., Naidu, Dilip, Bagchi, Sumanta, Hautier, Yann, Wilfahrt, Peter, Larson, Keith, Olofsson, Johan, Cleland, Elsa, Muthukrishnan, Ranjan, O’Halloran, Lydia, Alberti, Juan, Anderson, T. Michael, Arnillas, Carlos A., Bakker, Jonathan D., Barrio, Isabel C., Biederman, Lori, Boughton, Elizabeth H., Brudvig, Lars A., Bruschetti, Martin, Buckley, Yvonne, Bugalho, Miguel N., Cadotte, Marc W., Caldeira, Maria C., Catford, Jane A., D’Antonio, Carla, Davies, Kendi, Daleo, Pedro, Dickman, Christopher R., Donohue, Ian, DuPre, Mary Ellyn, Elgersma, Kenneth, Eisenhauer, Nico, Eskelinen, Anu, Estrada, Catalina, Fay, Philip A., Feng, Yanhao, Gruner, Daniel S., Hagenah, Nicole, Haider, Sylvia, Harpole, W. Stanley, Hersch-Green, Erika, Jentsch, Anke, Kirkman, Kevin, Knops, Johannes M. H., Laanisto, Lauri, Lannes, Lucíola S., Laungani, Ramesh, Lkhagva, Ariuntsetseg, Macek, Petr, Martina, Jason P., McCulley, Rebecca L., Melbourne, Brett, Mitchell, Rachel, Moore, Joslin L., Morgan, John W., Muraina, Taofeek O., Niu, Yujie, Pärtel, Meelis, Peri, Pablo L., Power, Sally A., Price, Jodi N., Prober, Suzanne M., Ren, Zhengwei, Risch, Anita C., Smith, Nicholas G., Sonnier, Grégory, Standish, Rachel J., Stevens, Carly J., Tedder, Michelle, Tognetti, Pedro, Veen, G. F. (Ciska), Virtanen, Risto, Wardle, Glenda M., Waring, Elizabeth, Wolf, Amelia A., Yahdjian, Laura, and Seabloom, Eric W.

Published
2024
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11. Hadronic vacuum polarization in the muon $g-2$: The short-distance contribution from lattice QCD

Author

Kuberski, Simon, Cè, Marco, von Hippel, Georg, Meyer, Harvey B., Ottnad, Konstantin, Risch, Andreas, and Wittig, Hartmut

Subjects
High Energy Physics - Lattice, High Energy Physics - Phenomenology
Abstract

We present results for the short-distance window observable of the hadronic vacuum polarization contribution to the muon $g-2$, computed via the time-momentum representation (TMR) in lattice QCD. A key novelty of our calculation is the reduction of discretization effects by a suitable subtraction applied to the TMR kernel function, which cancels the leading $x_0^4$-behaviour at short distances. To compensate for the subtraction, one must substitute a term that can be reliably computed in perturbative QCD. We apply this strategy to our data for the vector current collected on ensembles generated with $2+1$ flavours of O($a$)-improved Wilson quarks at six values of the lattice spacing and pion masses in the range $130-420\,$MeV. Our estimate at the physical point contains a full error budget and reads $(a_\mu^{\rm hvp})^{\rm SD}=68.85(14)_{\rm stat}\,(42)_{\rm syst}\cdot10^{-10}$, which corresponds to a relative precision of 0.7\%. We discuss the implications of our result for the observed tensions between lattice and data-driven evaluations of the hadronic vacuum polarization., Comment: 37 pages, 10 figures, 9 tables

Published
2024

12. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Author

Keaton, Jacob, Kamali, Zoha, Xie, Tian, Vaez, Ahmad, Williams, Ariel, Goleva, Slavina, Ani, Alireza, Evangelou, Evangelos, Hellwege, Jacklyn, Yengo, Loic, Young, William, Traylor, Matthew, Giri, Ayush, Zheng, Zhili, Zeng, Jian, Chasman, Daniel, Morris, Andrew, Caulfield, Mark, Hwang, Shih-Jen, Kooner, Jaspal, Conen, David, Attia, John, Morrison, Alanna, Loos, Ruth, Kristiansson, Kati, Schmidt, Reinhold, Hicks, Andrew, Pramstaller, Peter, Nelson, Christopher, Samani, Nilesh, Risch, Lorenz, Gyllensten, Ulf, Melander, Olle, Riese, Harriette, Wilson, James, Campbell, Harry, Rich, Stephen, Psaty, Bruce, Lu, Yingchang, Guo, Xiuqing, Rice, Kenneth, Vollenweider, Peter, Sundström, Johan, Langenberg, Claudia, Tobin, Martin, Giedraitis, Vilmantas, Luan, Jianan, Tuomilehto, Jaakko, Kutalik, Zoltan, Ripatti, Samuli, Salomaa, Veikko, Girotto, Giorgia, Trompet, Stella, Jukema, J, van der Harst, Pim, Ridker, Paul, Giulianini, Franco, Vitart, Veronique, Goel, Anuj, Watkins, Hugh, Harris, Sarah, Deary, Ian, van der Most, Peter, Oldehinkel, Albertine, Keavney, Bernard, Hayward, Caroline, Campbell, Archie, Boehnke, Michael, Scott, Laura, Boutin, Thibaud, Mamasoula, Chrysovalanto, Järvelin, Marjo-Riitta, Peters, Annette, Gieger, Christian, Lakatta, Edward, Cucca, Francesco, Hui, Jennie, Knekt, Paul, Enroth, Stefan, De Borst, Martin, Polašek, Ozren, Concas, Maria, Catamo, Eulalia, Cocca, Massimiliano, Li-Gao, Ruifang, Hofer, Edith, Schmidt, Helena, Spedicati, Beatrice, Waldenberger, Melanie, Strachan, David, Laan, Maris, Teumer, Alexander, Dörr, Marcus, Gudnason, Vilmundur, Cook, James, Ruggiero, Daniela, Kolcic, Ivana, Boerwinkle, Eric, Traglia, Michela, and Lehtimäki, Terho

Subjects
Female, Humans, Male, Blood Pressure, Genetic Predisposition to Disease, Genetic Risk Score, Genome-Wide Association Study, Hypertension, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors
Abstract

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P

Published
2024

13. Precision Determination of Baryon Masses including Isospin-breaking

Author

Segner, Alexander M., Risch, Andreas, and Wittig, Hartmut

Subjects
High Energy Physics - Lattice
Abstract

We give an update on an ongoing project in which we calculate the masses of octet and decuplet baryons including isospin-breaking effects. To this end, we employ single- and two-state-fits to effective masses up to leading order in the expansion in isospin-breaking parameters. In order to remove subjective bias on asymptotic masses we furthermore compute an AIC-based model-average of our fits, for which we show results on ensembles at lattice spacings of 0.064 fm and 0.076 fm with corresponding pion masses ranging from 220 MeV to 360 MeV.

Published
2023

14. Development of a risk score to identify patients at high risk for a severe course of COVID-19

Author

Jacob, Josephine, Tesch, Falko, Wende, Danny, Batram, Manuel, Loser, Friedrich, Weidinger, Oliver, Roessler, Martin, Seifert, Martin, Risch, Lisa, Nagel, Oliver, König, Christina, Jucknewitz, Roland, Treskova-Schwarzbach, Marina, Hertle, Dagmar, Scholz, Stefan, Stern, Stefan, Ballesteros, Pedro, Baßler, Stefan, Bertele, Barbara, Repschläger, Uwe, Richter, Nico, Riederer, Cordula, Sobik, Franziska, Schramm, Anja, Schulte, Claudia, Walker, Jochen, and Schmitt, Jochen

Published
2024
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15. Gauge field smearing and controlled continuum extrapolations

Author

Risch, Andreas

Subjects
High Energy Physics - Lattice
Abstract

Two popular methods to reduce discretisation effects are Symanzik improvement and gauge field smearing in the Dirac operator. Tree-level $O(a^2)$-improved Wilson fermions can be obtained from $O(a)$-improved Wilson fermions by adding one dimension-6 operator to the action. For gauge field smearing one wants to avoid the situation when too much smearing leads to uncontrolled continuum extrapolations as the short distance behaviour is mutilated. We focus on the gradient flow formalism as it allows to study both smearing and physical flow. We investigate the effect of smearing on the scaling towards the continuum limit in pure gauge theory on the example of Creutz ratios, which provide a measure of the physical forces felt by the fermions. For suitable smearing strengths we also investigate the change when the Wilson gradient flow is replaced by stout smearing., Comment: 7 pages, 6 figures, proceedings to talk presented at the 40th International Symposium on Lattice Field Theory, July 31st - August 4th 2023, Fermi National Accelerator Laboratory, Batavia, Illinois, USA

Published
2023

16. Fabricator: An Open Source Toolkit for Generating Labeled Training Data with Teacher LLMs

Author

Golde, Jonas, Haller, Patrick, Hamborg, Felix, Risch, Julian, and Akbik, Alan

Subjects
Computer Science - Computation and Language, Computer Science - Artificial Intelligence
Abstract

Most NLP tasks are modeled as supervised learning and thus require labeled training data to train effective models. However, manually producing such data at sufficient quality and quantity is known to be costly and time-intensive. Current research addresses this bottleneck by exploring a novel paradigm called zero-shot learning via dataset generation. Here, a powerful LLM is prompted with a task description to generate labeled data that can be used to train a downstream NLP model. For instance, an LLM might be prompted to "generate 500 movie reviews with positive overall sentiment, and another 500 with negative sentiment." The generated data could then be used to train a binary sentiment classifier, effectively leveraging an LLM as a teacher to a smaller student model. With this demo, we introduce Fabricator, an open-source Python toolkit for dataset generation. Fabricator implements common dataset generation workflows, supports a wide range of downstream NLP tasks (such as text classification, question answering, and entity recognition), and is integrated with well-known libraries to facilitate quick experimentation. With Fabricator, we aim to support researchers in conducting reproducible dataset generation experiments using LLMs and help practitioners apply this approach to train models for downstream tasks., Comment: 3 Figures and 2 Tables

Published
2023
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17. Genetic ancestry and diagnostic yield of exome sequencing in a diverse population

Author

Mavura, Yusuph, Sahin-Hodoglugil, Nuriye, Hodoglugil, Ugur, Kvale, Mark, Martin, Pierre-Marie, Van Ziffle, Jessica, Devine, W Patrick, Ackerman, Sara L, Koenig, Barbara A, Kwok, Pui-Yan, Norton, Mary E, Slavotinek, Anne, and Risch, Neil

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Clinical Research, Pediatric, Medical biotechnology
Abstract

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis. Continental/subcontinental genetic ancestry proportions were estimated from the ES data. We compared the distribution of genetic ancestries in positive, negative, and inconclusive cases by Kolmogorov-Smirnov tests and linear associations of ancestry with DY by Cochran-Armitage trend tests. We observed no reduction in overall DY associated with any genetic ancestry (African, Native American, East Asian, European, Middle Eastern, South Asian). However, we observed a relative increase in proportion of autosomal recessive homozygous inheritance versus other inheritance patterns associated with Middle Eastern and South Asian ancestry, due to consanguinity. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations.

Published
2024

18. YgiV promoter mutations cause resistance to cystobactamids and reduced virulence factor expression in Escherichia coli

Author

Timo Risch, Dominik Kolling, Dietrich Mostert, Tim Seedorf, Dominik Heimann, Daniel Kohnhäuser, Felix Deschner, Franziska Fries, Danny Solga, Jil-Sophie Hilgers, Jan Dastbaz, Stefano Mancini, Anna K. H. Hirsch, Mark Brönstrup, Andreas Kirschning, Stephan A. Sieber, Jennifer Herrmann, and Rolf Müller

Subjects
Microbiology, QR1-502
Abstract

Abstract Antimicrobial resistance is one of the major health threats of the modern world. Thus, new structural classes of antimicrobial compounds are needed in order to overcome existing resistance. Cystobactamids represent one such new compound class that inhibit the well-established target bacterial type II topoisomerases while exhibiting superior antibacterial and resistance-breaking properties. Understanding potential mechanisms of emerging resistances is crucial in the development of novel antibiotics as they directly impact the future therapeutic application and market success. Therefore, the frequency and molecular basis of cystobactamid resistance in Escherichia coli was analyzed. High-level resistant E. coli mutants were selected and found to harbor single nucleotide polymorphisms in the promotor region of the ygiV gene, causing an upregulation of the respective protein. These stable mutations are contrary to what was observed as a resistance genotype in the structurally related albicidins, where ygiV gene amplifications were identified as causing resistance. Overexpression of YgiV in the mutants was additionally amplified upon cystobactamid exposition, showing further adaptation to this compound class under treatment. YgiV binds cystobactamids with high binding affinity, thereby preventing their interaction with the antimicrobial targets topoisomerase IV and DNA gyrase. In addition, we observed a substantial impact of YgiV on in vitro gyrase activity by leading to increased DNA cleavage and concurrent reduction in the efficacy of cystobactamids in inhibiting gyrase supercoiling activity. Furthermore, we identified co-upregulation of membrane-modifying proteins, such as EptC, and the transcriptional regulator QseB. This presumably contributes to the observed reduced motility and fimbrial protein expression in resistant mutants, resulting in a reduced expression of virulence factors and potentially pathogenicity, associated with ygiV promotor mutations.

Published
2024
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19. FGFR2-fusions define a clinically actionable molecular subset of pancreatic cancer

Author

Leah Stein, Karthikeyan Murugesan, Julie W. Reeser, Zachary Risch, Michele R. Wing, Anoosha Paruchuri, Eric Samorodnitsky, Emily L. Hoskins, Thuy Dao, Amy Smith, Dat Le, Melissa A. Babcook, Yi Seok Chang, Matthew R. Avenarius, Muhammad Imam, Aharon G. Freud, and Sameek Roychowdhury

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Genomic alterations in fibroblast growth factor receptor (FGFR) genes are present in a small number of metastatic pancreatic ductal adenocarcinomas (PDAC) and may represent an emerging subgroup of patients likely to benefit from FGFR targeted therapies. Here we present four FGFR2 fusion-positive metastatic PDAC patients who exhibited durable responses or disease control to FGFR kinase inhibitors. Utilizing our custom FGFR focused cell-free DNA assay, FGFR-Dx, we serially monitored variant allele fractions of FGFR2 fusions during FGFR inhibitor treatment and observed dynamic changes correlating with clinical responses. Genomic analysis of 30,229 comprehensively profiled pancreatic cancers revealed FGFR1-3 fusions in 245 cases, an incidence of 0.81%. FGFR fusions were generally mutually exclusive from other known oncogenes. Our findings provide clinical evidence for identifying and treating FGFR2 fusion-positive PDAC patients with FGFR targeted therapy.

Published
2024
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20. Manganese Dissolution in alkaline medium with and without concurrent oxygen evolution in LiMn$_2$O$_4$

Author

Bisen, Omeshwari, Baumung, Max, Volkert, Cynthia A., and Risch, Marcel

Subjects
Condensed Matter - Materials Science, Physics - Chemical Physics
Abstract

Manganese dissolution during the oxygen evolution reaction (OER) has been a persistent challenge that impedes the practical implementation of Mn-based electrocatalysts including the LiMn$_x$O$_4$ system in aqueous alkaline electrolyte. The investigated LiMn$_2$O$_4$ particles exhibit two distinct Mn dissolution processes; one independent of OER and the other associated to OER. Combining the bulk sensitive X-ray absorption spectroscopy, surface sensitive X-ray photoelectron spectroscopy and electrochemical detection of Mn dissolution using rotating ring-disk electrode, we explore the less understood Mn dissolution mechanism during OER. We correlate near-surface oxidation with the charge attributed to dissolved Mn, which demonstrates increasing Mn dissolution with the formation of surface Mn4+ species under anodic potential. The observed stronger dissolution during the OER is attributed to the formation of additional Mn$^{4+}$ from Mn$^{3+}$ during OER. We show that control over the amount of Mn4+ in Li$_x$Mn2O$_4$ before the onset of the OER can partially mitigate the OER-triggered dissolution. Overall, our atomistic insights into the Mn dissolution processes are crucial for knowledge-guided mitigation of electrocatalyst degradation, which can be broadly extended to manganese-based oxide systems.

Published
2023

21. Reporting activities for the oxygen evolution reaction: Do we compare apples to apples?

Author

Risch, Marcel

Subjects
Condensed Matter - Materials Science, Physics - Chemical Physics
Abstract

The oxygen evolution reaction (OER) is a key enabler of sustainable chemical energy storage. Here, the author assesses the current status of protocols for benchmarking the OER in materials- and device-centered investigations and makes suggestions for more comparable data.

Published
2023

22. Cooperative Fe sites on transition metal (oxy)hydroxides drive high oxygen evolution activity in base.

Author

Ou, Yingqing, Twight, Liam, Samanta, Bipasa, Liu, Lu, Biswas, Santu, Fehrs, Jessica, Sagui, Nicole, Villalobos, Javier, Morales-Santelices, Joaquín, Antipin, Denis, Risch, Marcel, Toroker, Maytal, and Boettcher, Shannon

Abstract

Fe-containing transition-metal (oxy)hydroxides are highly active oxygen-evolution reaction (OER) electrocatalysts in alkaline media and ubiquitously form across many materials systems. The complexity and dynamics of the Fe sites within the (oxy)hydroxide have slowed understanding of how and where the Fe-based active sites form-information critical for designing catalysts and electrolytes with higher activity and stability. We show that where/how Fe species in the electrolyte incorporate into host Ni or Co (oxy)hydroxides depends on the electrochemical history and structural properties of the host material. Substantially less Fe is incorporated from Fe-spiked electrolyte into Ni (oxy)hydroxide at anodic potentials, past the nominally Ni2+/3+ redox wave, compared to during potential cycling. The Fe adsorbed under constant anodic potentials leads to impressively high per-Fe OER turn-over frequency (TOFFe) of ~40 s-1 at 350 mV overpotential which we attribute to under-coordinated surface Fe. By systematically controlling the concentration of surface Fe, we find TOFFe increases linearly with the Fe concentration. This suggests a changing OER mechanism with increased Fe concentration, consistent with a mechanism involving cooperative Fe sites in FeOx clusters.

Published
2023

23. Integrome signatures of lentiviral gene therapy for SCID-X1 patients.

Author

Yan, Koon-Kiu, Condori, Jose, Ma, Zhijun, Metais, Jean-Yves, Ju, Bensheng, Ding, Liang, Dhungana, Yogesh, Palmer, Lance, Langfitt, Deanna, Ferrara, Francesca, Throm, Robert, Shi, Hao, Risch, Isabel, Bhatara, Sheetal, Shaner, Bridget, Lockey, Timothy, Talleur, Aimee, Easton, John, Meagher, Michael, Puck, Jennifer, Zhou, Sheng, Mamcarz, Ewelina, Gottschalk, Stephen, Yu, Jiyang, and Cowan, Morton

Abstract

Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.

Published
2023

24. Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization.

Author

Canzian, Federico, Du, Mengmeng, Gallinger, Steven, Giles, Graham, Goodman, Phyllis, Haiman, Christopher, Kogevinas, Manolis, Kooperberg, Charles, LeMarchand, Loic, Neale, Rachel, Visvanathan, Kala, White, Emily, Albanes, Demetrius, Andreotti, Gabriella, Babic, Ana, Berndt, Sonja, Brais, Lauren, Brennan, Paul, Buring, Julie, Rabe, Kari, Bamlet, William, Chanock, Stephen, Fuchs, Charles, Gaziano, J, Giovannucci, Edward, Hackert, Thilo, Hassan, Manal, Katzke, Verena, Kurtz, Robert, Lee, I-Min, Malats, Núria, Murphy, Neil, Oberg, Ann, Orlow, Irene, Porta, Miquel, Real, Francisco, Rothman, Nathaniel, Sesso, Howard, Silverman, Debra, Thompson, Ian, Wactawski-Wende, Jean, Wang, Xiaoliang, Wentzensen, Nicolas, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Yu, Kai, Wolpin, Brian, Duell, Eric, Li, Donghui, Hung, Rayjean, Perdomo, Sandra, McCullough, Marjorie, Freedman, Neal, Patel, Alpa, Peters, Ulrike, Riboli, Elio, Sund, Malin, Tjønneland, Anne, Zhong, Jun, Van Den Eeden, Stephen, Kraft, Peter, Risch, Harvey, Amundadottir, Laufey, Klein, Alison, Stolzenberg-Solomon, Rachael, Antwi, Samuel, King, Sontoria, Veliginti, Swathi, Brouwers, Martijn, Ren, Zhewen, Zheng, Wei, Setiawan, Veronica, Wilkens, Lynne, Shu, Xiao-Ou, Arslan, Alan, Beane Freeman, Laura, and Bracci, Paige

Subjects
Humans, Non-alcoholic Fatty Liver Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Mendelian Randomization Analysis, Pancreatic Neoplasms, Obesity, Polymorphism, Single Nucleotide
Abstract

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Published
2023

28. Assessing the potential of acoustic telemetry to underpin the regional management of basking sharks (Cetorhinus maximus)

Author

Thorburn, James, Collins, Patrick C., Garbett, Amy, Vance, Heather, Phillips, Natasha, Drumm, Alan, Cooney, Joseph, Waters, Catherine, Ó’Maoiléidigh, Niall, Johnston, Emmett, Dolton, Haley R., Berrow, Simon, Hall, Graham, Hall, Jackie, Delvillar, Diego, McGill, Ross, Whoriskey, Fred, Fangue, Nann A., McInturf, Alexandra G., Rypel, Andrew L., Kennedy, Richard, Lilly, Jessie, Rodger, Jessica R., Adams, Colin E., van Geel, Nienke C. F., Risch, Denise, Wilkie, Lorna, Henderson, Suzanne, Mayo, Paul A., Mensink, Paul J., Witt, Matthew J., Hawkes, Lucy A., Klimley, A. Peter, and Houghton, Jonathan D. R.

Published
2024
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30. Cases of trisomy 21 and trisomy 18 among historic and prehistoric individuals discovered from ancient DNA

Author

Rohrlach, Adam Benjamin, Rivollat, Maïté, de-Miguel-Ibáñez, Patxuka, Moilanen, Ulla, Liira, Anne-Mari, Teixeira, João C., Roca-Rada, Xavier, Armendáriz-Martija, Javier, Boyadzhiev, Kamen, Boyadzhiev, Yavor, Llamas, Bastien, Tiliakou, Anthi, Mötsch, Angela, Tuke, Jonathan, Prevedorou, Eleni-Anna, Polychronakou-Sgouritsa, Naya, Buikstra, Jane, Onkamo, Päivi, Stockhammer, Philipp W., Heyne, Henrike O., Lemke, Johannes R., Risch, Roberto, Schiffels, Stephan, Krause, Johannes, Haak, Wolfgang, and Prüfer, Kay

Published
2024
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31. Advancing forest inventorying and monitoring

Author

Ferretti, Marco, Fischer, Christoph, Gessler, Arthur, Graham, Catherine, Meusburger, Katrin, Abegg, Meinrad, Bebi, Peter, Bergamini, Ariel, Brockerhoff, Eckehard G., Brunner, Ivano, Bühler, Christoph, Conedera, Marco, Cothereau, Pierre, D’Odorico, Petra, Düggelin, Christoph, Ginzler, Christian, Grendelmeier, Alex, Haeni, Matthias, Hagedorn, Frank, Hägeli, Martin, Hegetschweiler, Karin Tessa, Holderegger, Rolf, Krumm, Frank, Gugerli, Felix, Queloz, Valentin, Rigling, Andreas, Risch, Anita C., Rohner, Brigitte, Rosset, Christian, Scherrer, Daniel, Schulz, Tobias, Thürig, Esther, Traub, Berthold, von Arx, Georg, Waldner, Peter, Wohlgemuth, Thomas, Zimmermann, Niklaus E., and Shackleton, Ross T.

Published
2024
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32. Historic methicillin-resistant Staphylococcus aureus: expanding current knowledge using molecular epidemiological characterization of a Swiss legacy collection

Author

Benvenga, Vanni, Cuénod, Aline, Purushothaman, Srinithi, Dasen, Gottfried, Weisser, Maja, Bassetti, Stefano, Roloff, Tim, Siegemund, Martin, Heininger, Ulrich, Bielicki, Julia, Wehrli, Marianne, Friderich, Paul, Frei, Reno, Widmer, Andreas, Herzog, Kathrin, Fankhauser, Hans, Nolte, Oliver, Bodmer, Thomas, Risch, Martin, Dubuis, Olivier, Pranghofer, Sigrid, Calligaris-Maibach, Romana, Graf, Susanne, Perreten, Vincent, Seth-Smith, Helena M. B, and Egli, Adrian

Published
2024
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33. Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Author

Wang, Xinan, Zhang, Ziwei, Ding, Yi, Chen, Tony, Mucci, Lorelei, Albanes, Demetrios, Landi, Maria Teresa, Caporaso, Neil E., Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Johansson, Mattias, Risch, Angela, Bickeböller, Heike, Wichmann, H-Erich, Rennert, Gadi, Arnold, Susanne, Brennan, Paul, McKay, James D., Field, John K., Shete, Sanjay S., Le Marchand, Loic, Liu, Geoffrey, Andrew, Angeline S., Kiemeney, Lambertus A., Zienolddiny-Narui, Shan, Behndig, Annelie, Johansson, Mikael, Cox, Angie, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Hung, Rayjean J., Amos, Christopher I., Lin, Xihong, and Christiani, David C.

Published
2024
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35. Mammal responses to global changes in human activity vary by trophic group and landscape

Author

Burton, A. Cole, Beirne, Christopher, Gaynor, Kaitlyn M., Sun, Catherine, Granados, Alys, Allen, Maximilian L., Alston, Jesse M., Alvarenga, Guilherme C., Calderón, Francisco Samuel Álvarez, Amir, Zachary, Anhalt-Depies, Christine, Appel, Cara, Arroyo-Arce, Stephanny, Balme, Guy, Bar-Massada, Avi, Barcelos, Daniele, Barr, Evan, Barthelmess, Erika L., Baruzzi, Carolina, Basak, Sayantani M., Beenaerts, Natalie, Belmaker, Jonathan, Belova, Olgirda, Bezarević, Branko, Bird, Tori, Bogan, Daniel A., Bogdanović, Neda, Boyce, Andy, Boyce, Mark, Brandt, LaRoy, Brodie, Jedediah F., Brooke, Jarred, Bubnicki, Jakub W., Cagnacci, Francesca, Carr, Benjamin Scott, Carvalho, João, Casaer, Jim, Černe, Rok, Chen, Ron, Chow, Emily, Churski, Marcin, Cincotta, Connor, Ćirović, Duško, Coates, T. D., Compton, Justin, Coon, Courtney, Cove, Michael V., Crupi, Anthony P., Farra, Simone Dal, Darracq, Andrea K., Davis, Miranda, Dawe, Kimberly, De Waele, Valerie, Descalzo, Esther, Diserens, Tom A., Drimaj, Jakub, Duľa, Martin, Ellis-Felege, Susan, Ellison, Caroline, Ertürk, Alper, Fantle-Lepczyk, Jean, Favreau, Jorie, Fennell, Mitch, Ferreras, Pablo, Ferretti, Francesco, Fiderer, Christian, Finnegan, Laura, Fisher, Jason T., Fisher-Reid, M. Caitlin, Flaherty, Elizabeth A., Fležar, Urša, Flousek, Jiří, Foca, Jennifer M., Ford, Adam, Franzetti, Barbara, Frey, Sandra, Fritts, Sarah, Frýbová, Šárka, Furnas, Brett, Gerber, Brian, Geyle, Hayley M., Giménez, Diego G., Giordano, Anthony J., Gomercic, Tomislav, Gompper, Matthew E., Gräbin, Diogo Maia, Gray, Morgan, Green, Austin, Hagen, Robert, Hagen, Robert (Bob), Hammerich, Steven, Hanekom, Catharine, Hansen, Christopher, Hasstedt, Steven, Hebblewhite, Mark, Heurich, Marco, Hofmeester, Tim R., Hubbard, Tru, Jachowski, David, Jansen, Patrick A., Jaspers, Kodi Jo, Jensen, Alex, Jordan, Mark, Kaizer, Mariane C., Kelly, Marcella J., Kohl, Michel T., Kramer-Schadt, Stephanie, Krofel, Miha, Krug, Andrea, Kuhn, Kellie M., Kuijper, Dries P. J., Kuprewicz, Erin K., Kusak, Josip, Kutal, Miroslav, Lafferty, Diana J. R., LaRose, Summer, Lashley, Marcus, Lathrop, Richard, Lee, Jr, Thomas E., Lepczyk, Christopher, Lesmeister, Damon B., Licoppe, Alain, Linnell, Marco, Loch, Jan, Long, Robert, Lonsinger, Robert C., Louvrier, Julie, Luskin, Matthew Scott, MacKay, Paula, Maher, Sean, Manet, Benoît, Mann, Gareth K. H., Marshall, Andrew J., Mason, David, McDonald, Zara, McKay, Tracy, McShea, William J., Mechler, Matt, Miaud, Claude, Millspaugh, Joshua J., Monteza-Moreno, Claudio M., Moreira-Arce, Dario, Mullen, Kayleigh, Nagy, Christopher, Naidoo, Robin, Namir, Itai, Nelson, Carrie, O’Neill, Brian, O’Mara, M. Teague, Oberosler, Valentina, Osorio, Christian, Ossi, Federico, Palencia, Pablo, Pearson, Kimberly, Pedrotti, Luca, Pekins, Charles E., Pendergast, Mary, Pinho, Fernando F., Plhal, Radim, Pocasangre-Orellana, Xochilt, Price, Melissa, Procko, Michael, Proctor, Mike D., Ramalho, Emiliano Esterci, Ranc, Nathan, Reljic, Slaven, Remine, Katie, Rentz, Michael, Revord, Ronald, Reyna-Hurtado, Rafael, Risch, Derek, Ritchie, Euan G., Romero, Andrea, Rota, Christopher, Rovero, Francesco, Rowe, Helen, Rutz, Christian, Salvatori, Marco, Sandow, Derek, Schalk, Christopher M., Scherger, Jenna, Schipper, Jan, Scognamillo, Daniel G., Şekercioğlu, Çağan H., Semenzato, Paola, Sevin, Jennifer, Shamon, Hila, Shier, Catherine, Silva-Rodríguez, Eduardo A., Sindicic, Magda, Smyth, Lucy K., Soyumert, Anil, Sprague, Tiffany, St. Clair, Colleen Cassady, Stenglein, Jennifer, Stephens, Philip A., Stępniak, Kinga Magdalena, Stevens, Michael, Stevenson, Cassondra, Ternyik, Bálint, Thomson, Ian, Torres, Rita T., Tremblay, Joan, Urrutia, Tomas, Vacher, Jean-Pierre, Visscher, Darcy, Webb, Stephen L., Weber, Julian, Weiss, Katherine C. B., Whipple, Laura S., Whittier, Christopher A., Whittington, Jesse, Wierzbowska, Izabela, Wikelski, Martin, Williamson, Jacque, Wilmers, Christopher C., Windle, Todd, Wittmer, Heiko U., Zharikov, Yuri, Zorn, Adam, and Kays, Roland

Published
2024
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40. Low-carbon Lithium Extraction Makes Deep Geothermal Plants Cost-competitive in Energy Systems

Author

Weinand, Jann Michael, Vandenberg, Ganga, Risch, Stanley, Behrens, Johannes, Pflugradt, Noah, Linßen, Jochen, and Stolten, Detlef

Subjects
Economics - General Economics
Abstract

Lithium is a critical material for the energy transition, but conventional procurement methods have significant environmental impacts. In this study, we utilize regional energy system optimizations to investigate the techno-economic potential of the low-carbon alternative of direct lithium extraction in deep geothermal plants. We show that geothermal plants will become cost-competitive in conjunction with lithium extraction, even under unfavorable conditions and partially displace photovoltaics, wind power, and storage from energy systems. Our analysis indicates that if 10% of municipalities in the Upper Rhine Graben area in Germany constructed deep geothermal plants, they could provide enough lithium to produce about 1.2 million electric vehicle battery packs per year, equivalent to 70% of today`s annual electric vehicle registrations in the European Union. This approach could offer significant environmental benefits and has high potential for mass application also in other countries, such as the United States, United Kingdom, France, and Italy, highlighting the importance of further research and development of this technology.

Published
2023

41. G-quadruplex forming regions in GCK and TM6SF2 are targets for differential DNA methylation in metabolic disease and hepatocellular carcinoma patients

Author

Angelika Lahnsteiner, Victoria Ellmer, Anna Oberlercher, Zita Liutkeviciute, Esther Schönauer, Bernhard Paulweber, Elmar Aigner, and Angela Risch

Subjects
Metabolic disease, Hepatocellular carcinoma, DNA methylation, G-quadruplex, PDAL-Seq, Alternative promoter, Medicine, Science
Abstract

Abstract The alarming increase in global rates of metabolic diseases (MetDs) and their association with cancer risk renders them a considerable burden on our society. The interplay of environmental and genetic factors in causing MetDs may be reflected in DNA methylation patterns, particularly at non-canonical (non-B) DNA structures, such as G-quadruplexes (G4s) or R-loops. To gain insight into the mechanisms of MetD progression, we focused on DNA methylation and functional analyses on intragenic regions of two MetD risk genes, the glucokinase (GCK) exon 7 and the transmembrane 6 superfamily 2 (TM6SF2) intron 2-exon 3 boundary, which harbor non-B DNA motifs for G4s and R-loops. Pyrosequencing of 148 blood samples from a nested cohort study revealed significant differential methylation in GCK and TM6SF2 in MetD patients versus healthy controls. Furthermore, these regions harbor hypervariable and differentially methylated CpGs also in hepatocellular carcinoma versus normal tissue samples from The Cancer Genome Atlas (TCGA). Permanganate/S1 nuclease footprinting with direct adapter ligation (PDAL-Seq), native polyacrylamide DNA gel electrophoresis and circular dichroism (CD) spectroscopy revealed the formation of G4 structures in these regions and demonstrated that their topology and stability is affected by DNA methylation. Detailed analyses including histone marks, chromatin conformation capture data, and luciferase reporter assays, highlighted the cell-type specific regulatory function of the target regions. Based on our analyses, we hypothesize that changes in DNA methylation lead to topological changes, especially in GCK exon 7, and cause the activation of alternative regulatory elements or potentially play a role in alternative splicing. Our analyses provide a new view on the mechanisms underlying the progression of MetDs and their link to hepatocellular carcinomas, unveiling non-B DNA structures as important key players already in early disease stages.

Published
2024
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42. Assessing the potential of acoustic telemetry to underpin the regional management of basking sharks (Cetorhinus maximus)

Author

James Thorburn, Patrick C. Collins, Amy Garbett, Heather Vance, Natasha Phillips, Alan Drumm, Joseph Cooney, Catherine Waters, Niall Ó’Maoiléidigh, Emmett Johnston, Haley R. Dolton, Simon Berrow, Graham Hall, Jackie Hall, Diego Delvillar, Ross McGill, Fred Whoriskey, Nann A. Fangue, Alexandra G. McInturf, Andrew L. Rypel, Richard Kennedy, Jessie Lilly, Jessica R. Rodger, Colin E. Adams, Nienke C. F. van Geel, Denise Risch, Lorna Wilkie, Suzanne Henderson, Paul A. Mayo, Paul J. Mensink, Matthew J. Witt, Lucy A. Hawkes, A. Peter Klimley, and Jonathan D. R. Houghton

Subjects
Spatial ecology, Highly mobile species, Multi-species array, Elasmobranchs, Regional monitoring, Conservation, Ecology, QH540-549.5, Animal biochemistry, QP501-801
Abstract

Abstract Acoustic telemetry can provide valuable space-use data for a range of marine species. Yet the deployment of species-specific arrays over vast areas to gather data on highly migratory vertebrates poses formidable challenges, often rendering it impractical. To address this issue, we pioneered the use of acoustic telemetry on basking sharks (Cetorhinus maximus) to test the feasibility of using broadscale, multi-project acoustic receiver arrays to track the movements of this species of high conservation concern through the coastal waters of Ireland, Northern Ireland, and Scotland. Throughout 2021 and 2022, we tagged 35 basking sharks with acoustic transmitters off the west coast of Ireland; 27 of these were detected by 96 receiver stations throughout the study area (n = 9 arrays) with up to 216 detections of an individual shark (mean = 84, s.d. 65). On average, sharks spent ~ 1 day at each acoustic array, with discrete residency periods of up to nine days. Twenty-one sharks were detected at multiple arrays with evidence of inter-annual site fidelity, with the same individuals returning to the same locations in Ireland and Scotland over 2 years. Eight pairs of sharks were detected within 24 h of each other at consecutive arrays, suggesting some level of social coordination and synchronised movement. These findings demonstrate how multi-project acoustic telemetry can support international, cost-effective monitoring of basking sharks and other highly mobile species. Decision support tools such as these can consolidate cross-border management strategies, but to achieve this goal, collaborative efforts across jurisdictions are necessary to establish the required infrastructure and secure ongoing support.

Published
2024
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43. The RNA binding protein IGF2BP2/IMP2 alters the cargo of cancer cell-derived extracellular vesicles supporting tumor-associated macrophages

Author

Vida Mashayekhi, Annika Schomisch, Sari Rasheed, Ernesto Aparicio-Puerta, Timo Risch, Daniela Yildiz, Marcus Koch, Simon Both, Nicole Ludwig, Thierry M. Legroux, Andreas Keller, Rolf Müller, Gregor Fuhrmann, Jessica Hoppstädter, and Alexandra K. Kiemer

Subjects
Flow cytometry, Tangential flow filtration, Ultracentrifugation, MMP9, Colorectal cancer, microRNAs, Medicine, Cytology, QH573-671
Abstract

Abstract Background Tumor cells release extracellular vesicles (EVs) that contribute to the polarization of macrophages towards tumor-associated macrophages (TAMs). High expression levels of the RNA binding protein IGF2BP2/IMP2 are correlated with increased tumor cell proliferation, invasion, and poor prognosis in the clinic. However, there is a lack of understanding of whether IMP2 affects the cargo of cancer cell-derived EVs, thereby modulating macrophage polarization. Methods EVs were isolated from IMP2-expressing HCT116 parental cells (WT) and CRISPR/Cas9 IMP2 knockout (KO) cells. EVs were characterized according to MISEV guidelines, microRNA cargo was assessed by microRNA-Seq, and the protein cargo was analyzed by proteomics. Primary human monocyte-derived macrophages (HMDMs) were polarized by EVs, and the expression of genes and surface markers was assessed using qPCR and flow cytometry, respectively. Morphological changes of macrophages, as well as the migratory potential of cancer cells, were assessed by the Incucyte® system and macrophage matrix degradation potential by zymography. Changes in the metabolic activity of macrophages were quantified using a Seahorse® analyzer. For in vivo studies, EVs were injected into the yolk sac of zebrafish larvae, and macrophages were isolated by fluorescence-activated cell sorting. Results EVs from WT and KO cells had a similar size and concentration and were positive for 25 vesicle markers. The expression of tumor-promoting genes was higher in macrophages polarized with WT EVs than KO EVs, while the expression of TNF and IL6 was reduced. A similar pattern was observed in macrophages from zebrafish larvae treated in vivo. WT EV-polarized macrophages showed a higher abundance of TAM-like surface markers, higher matrix degrading activity, as well as a higher promotion of cancer cell migration. MicroRNA-Seq revealed a significant difference in the microRNA composition of WT and KO EVs, particularly a high abundance of miR-181a-5p in WT EVs, which was absent in KO EVs. Inhibitors of macropinocytosis and phagocytosis antagonized the delivery of miR-181a-5p into macrophages and the downregulation of the miR-181a-5p target DUSP6. Proteomics data showed differences in protein cargo in KO vs. WT EVs, with the differentially abundant proteins mainly involved in metabolic pathways. WT EV-treated macrophages exhibited a higher basal oxygen consumption rate and a lower extracellular acidification rate than KO EV-treated cells. Conclusion Our results show that IMP2 determines the cargo of EVs released by cancer cells, thereby modulating the EVs' actions on macrophages. Expression of IMP2 is linked to the secretion of EVs that polarize macrophages towards a tumor-promoting phenotype.

Published
2024
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44. Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

Author

Lindström, Sara, Wang, Lu, Feng, Helian, Majumdar, Arunabha, Huo, Sijia, Macdonald, James, Harrison, Tabitha, Turman, Constance, Chen, Hongjie, Mancuso, Nicholas, Bammler, Theo, Consortium, Breast Cancer Association, Gallinger, Steve, Gruber, Stephen B, Gunter, Marc J, Le Marchand, Loic, Moreno, Victor, Offit, Kenneth, Study, Genetics And Epidemiology Of Colorectal Cancer Consortium Colorectal Transdisciplinary Study Colon Cancer Family Registry, De Vivo, Immaculata, O’Mara, Tracy A, Spurdle, Amanda B, Tomlinson, Ian, Consortium, Endometrial Cancer Association, Fitzgerald, Rebecca, Gharahkhani, Puya, Gockel, Ines, Jankowski, Janusz, Macgregor, Stuart, Schumacher, Johannes, Barnholtz-Sloan, Jill, Bondy, Melissa L, Houlston, Richard S, Jenkins, Robert B, Melin, Beatrice, Wrensch, Margaret, Brennan, Paul, Christiani, David C, Johansson, Mattias, Mckay, James, Aldrich, Melinda C, Amos, Christopher I, Landi, Maria Teresa, Tardon, Adonina, Consortium, International Lung Cancer, Bishop, D Timothy, Demenais, Florence, Goldstein, Alisa M, Iles, Mark M, Kanetsky, Peter A, Law, Matthew H, Consortium, Ovarian Cancer Association, Amundadottir, Laufey T, Stolzenberg-Solomon, Rachael, Wolpin, Brian M, Consortium, Pancreatic Cancer Cohort, Klein, Alison, Petersen, Gloria, Risch, Harvey, Consortium, The PRACTICAL Consortium Pancreatic Cancer Case-Control, Chanock, Stephen J, Purdue, Mark P, Scelo, Ghislaine, Pharoah, Paul, Kar, Siddhartha, Hung, Rayjean J, Pasaniuc, Bogdan, and Kraft, Peter

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Genetics, Digestive Diseases, Prevention, Clinical Research, Urologic Diseases, Cancer, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Male, Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Neoplasms, Risk Factors, Transcriptome, Polymorphism, Single Nucleotide, Breast Cancer Association Consortium, Colorectal Transdisciplinary Study (CORECT), Colon Cancer Family Registry Study (CCFR), Genetics And Epidemiology Of Colorectal Cancer Consortium, Endometrial Cancer Association Consortium, International Lung Cancer Consortium, Ovarian Cancer Association Consortium, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium (Panc4), The PRACTICAL Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.MethodsWe collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.ResultsWe observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.ConclusionsOverall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

Published
2023

45. Author Correction: Widening global variability in grassland biomass since the 1980s

Author

MacDougall, Andrew S., Esch, Ellen, Chen, Qingqing, Carroll, Oliver, Bonner, Colin, Ohlert, Timothy, Siewert, Matthias, Sulik, John, Schweiger, Anna K., Borer, Elizabeth T., Naidu, Dilip, Bagchi, Sumanta, Hautier, Yann, Wilfahrt, Peter, Larson, Keith, Olofsson, Johan, Cleland, Elsa, Muthukrishnan, Ranjan, O’Halloran, Lydia, Alberti, Juan, Anderson, T. Michael, Arnillas, Carlos A., Bakker, Jonathan D., Barrio, Isabel C., Biederman, Lori, Boughton, Elizabeth H., Brudvig, Lars A., Bruschetti, Martin, Buckley, Yvonne, Bugalho, Miguel N., Cadotte, Marc W., Caldeira, Maria C., Catford, Jane A., D’Antonio, Carla, Davies, Kendi, Daleo, Pedro, Dickman, Christopher R., Donohue, Ian, DuPre, Mary Ellyn, Elgersma, Kenneth, Eisenhauer, Nico, Eskelinen, Anu, Estrada, Catalina, Fay, Philip A., Feng, Yanhao, Gruner, Daniel S., Hagenah, Nicole, Haider, Sylvia, Harpole, W. Stanley, Hersch-Green, Erika, Jentsch, Anke, Kirkman, Kevin, Knops, Johannes M. H., Laanisto, Lauri, Lannes, Lucíola S., Laungani, Ramesh, Lkhagva, Ariuntsetseg, Macek, Petr, Martina, Jason P., McCulley, Rebecca L., Melbourne, Brett, Mitchell, Rachel, Moore, Joslin L., Morgan, John W., Muraina, Taofeek O., Niu, Yujie, Pärtel, Meelis, Peri, Pablo L., Power, Sally A., Price, Jodi N., Prober, Suzanne M., Ren, Zhengwei, Risch, Anita C., Smith, Nicholas G., Sonnier, Grégory, Standish, Rachel J., Stevens, Carly J., Tedder, Michelle, Tognetti, Pedro, Veen, G. F. (Ciska), Virtanen, Risto, Wardle, Glenda M., Waring, Elizabeth, Wolf, Amelia A., Yahdjian, Laura, and Seabloom, Eric W.

Published
2024
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46. Setting the Scale Using Baryon Masses with Isospin-Breaking Corrections

Author

Segner, Alexander M., Hanlon, Andrew D., Risch, Andreas, and Wittig, Hartmut

Subjects
High Energy Physics - Lattice
Abstract

We present the status of an ongoing project aimed at the inclusion of isospin-breaking corrections arising from the non-degeneracy of the light quark masses and electromagnetic interactions in calculations of the low-lying octet and decuplet baryon masses. Our ultimate goal is to perform a precision determination of the lattice scale including isospin-breaking effects. We apply the perturbative formalism to isospin-symmetric $N_f=2+1$ CLS ensembles. We show results on baryon masses up to leading order in isospin-breaking corrections on two ensembles with $m_\pi\approx290\,\text{MeV}$ and $m_\pi\approx215\,\text{MeV}$ at a lattice spacing of $a\approx0.076\,\text{fm}$.

Published
2022

47. The influence of gauge field smearing on discretisation effects

Author

Risch, Andreas, Schaefer, Stefan, and Sommer, Rainer

Subjects
High Energy Physics - Lattice
Abstract

When designing lattice actions, gauge field smearing is frequently used to define the lattice Dirac operator. Since the smearing procedure removes effects of ultraviolet fluctuations, the fermions effectively see a larger lattice spacing than the gauge fields. Creutz ratios, formed from ratios of rectangular Wilson loops, based on smeared gauge fields are adequate observables to investigate the effect of smearing since they do not need renormalisation and provide a measure of the physical forces felt by the fermions. We study their behaviour at various smearing radii (fixed in lattice units) and in particular how the smearing influences the scaling towards the continuum limit. Since we employ the Wilson gradient flow as smearing, the same Creutz ratios have another, well defined continuum limit, when the flow time is fixed in physical units. That continuum limit is reached with smaller corrections at finite $a$., Comment: 10 pages, 5 figures, proceedings to talk presented at the 39th International Symposium on Lattice Field Theory, 8th-13th August, 2022, Rheinische Friedrich-Wilhelms-Universit\"at Bonn, Bonn, Germany

Published
2022

48. The hadronic running of the electromagnetic coupling and electroweak mixing angle

Author

José, Teseo San, Wittig, Hartmut, Cè, Marco, Gérardin, Antoine, von Hippel, Georg, Meyer, Harvey B., Miura, Kohtaroh, Ottnad, Konstantin, Risch, Andreas, and Wilhelm, Jonas

Subjects
High Energy Physics - Lattice, High Energy Physics - Phenomenology
Abstract

We present results for the hadronic running of the electromagnetic coupling and the weak mixing angle from simulations of lattice QCD with $N_f=2+1$ flavours of $O(a)$-improved Wilson fermions. Using two different discretisations of the vector current, we compute the quark-connected and -disconnected contributions to the hadronic vacuum polarisation (HVP) functions $\bar{\Pi}^{\gamma\gamma}$ and $\bar{\Pi}^{Z\gamma}$ for spacelike squared momenta $Q^2\leq 7$ $\mathrm{GeV}^2$. Our results are extrapolated to the physical point using ensembles at four lattice spacings, with pion masses ranging from 130 to 420 MeV. We observe a tension of up to 3.5 standard deviations between our lattice results for $\Delta\alpha_{\rm had}^{(5)}(-Q^2)$ and estimates based on the $\textit{R}$-ratio for space-like momenta in the range $Q^2=3-7\,\rm GeV^2$. To obtain an estimate for $\Delta\alpha_\mathrm{had}^{(5)}(M_Z^2)$, we employ the Euclidean split technique. The implications for comparison with global electroweak fits are assessed., Comment: 16 pages, 7 figures, proceedings of the 39th International Symposium on Lattice Field Theory, 8th-13th August 2022, Bonn, Germany

Published
2022

49. The relationship between life satisfaction and risk preferences of couch potatoes, recreational and elite athletes: the impact of mental dispositions and attitudes

Author

Alice Aguiar-Noury, Bernd Frick, and Nikolaus Risch

Subjects
life satisfaction, risk preferences, elite athletes, mental attitudes, personality differences, Economic theory. Demography, HB1-3840
Abstract

IntroductionThis study examines the relationship between physical activity and mental wellbeing among students not playing any sport (“couch potatoes”), recreational athletes and “dual career students”, i.e., students who are at the same time elite athletes. It addresses three closely related, yet different questions: (i) Do couch potatoes, recreational and elite athletes differ in their level of affective well-being or happiness? (ii) Are there any differences in cognitive wellbeing or life satisfaction between these groups? and (iii) Are there any differences in risk preferences and attitudes?MethodsIn our empirical analysis, we use a large cross-section dataset with detailed information on nearly 4,700 students enrolled at 24 different universities and universities of applied sciences all over Germany to identify the relationship between the individuals' personalities and their life satisfaction and risk preferences using standard regression models.ResultsOur findings indicate that, first, elite athletes report higher levels of happiness and life satisfaction than recreational athletes and couch potatoes. Second, both groups of athletes display higher levels of risk tolerance than couch potatoes. Third, and most important, we find significant personality differences between elite athletes and the other two groups of students that drive most, yet not all of our results.DiscussionSince dual career students are often role models for other students, universities should consider investing in their sports facilities and offering sports classes on campus to increase the athletic involvement of the general student body.

Published
2024
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50. How artificial intelligence can enable data classification for market sizing - Insights from applications in practice

Author

L. Stallings, P. Bhat, J. Jacobs, K. Lynch, and Q. Risch

Subjects
Competitive intelligence, Market intelligence, Information classification, Market sizing, Machine learning, Information technology, T58.5-58.64
Abstract

Determining the size of the addressable market is a key aspect of market intelligence and requires identifying and delineating projected budget data from potential customers. The market intelligence arena is characterized by a wide range of disparate sources, many of which are unstructured, ranging across competitive, market, financial, and technology sources, and typically necessitating significant manual work to analyze, reconcile, and integrate. The authors present an approach for classification of data from one of these sources, facilitating aggregation and analysis of intelligence information. We describe a concept proof using machine learning that extends a model for automatic mapping of publicly available budget data to segments and subsegments of a market segmentation taxonomy. This approach automates the tagging of market and market segment for each program and cost element by training classification models on the manually labeled historical data. We describe the evaluation and use of multiple natural language processing (NLP) and classification modeling methods. This work's contribution is demonstrating how NLP and machine learning techniques can provide useful data classification and automatic classification even when source data diverges from its specified taxonomic description.

Published
2024
Full Text
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