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1. Predicting compound activity from phenotypic profiles and chemical structures

Author: Nikita Moshkov, Tim Becker, Kevin Yang, Peter Horvath, Vlado Dancik, Bridget K. Wagner, Paul A. Clemons, Shantanu Singh, Anne E. Carpenter, and Juan C. Caicedo
Subjects: Science
Abstract: Experimental assays are used to determine if compounds cause a desired activity in cells. Here the authors demonstrate that computational methods can predict compound bioactivity given their chemical structure, imaging and gene expression data from historic screening libraries.
Published: 2023
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2. Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations

Author: Tim Becker, Jan Heitkötter, Anna K. Krome, Andrea Schiefer, Kenneth Pfarr, Alexandra Ehrens, Miriam Grosse, Birthe Sandargo, Ingo Stammberger, Marc Stadler, Marc P. Hübner, Stefan Kehraus, Achim Hoerauf, and Karl G. Wagner
Subjects: toxicology, mesoporous silica, poorly soluble drugs, corallopyronin A, preclinical studies, vehicle, Pharmacy and materia medica, RS1-441
Abstract: Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.
Published: 2024
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3. A comparison of open or laparoscopic colectomy outcomes for the management of ischemic colitis using the ACS-NSQIP database

Author: Ben S. Duggan, Tim Becker, Genaro A. DeLeon, Varun Rao, and Kevin Y. Pei
Subjects: Ischemic colitis, Colectomy, Laparoscopy, NSQIP, Colorectal, Surgery, RD1-811
Abstract: Introduction: Ischemic colitis is a common manifestation of intestinal ischemia and is potentially a surgical emergency. Although such surgical emergencies were historically approached via open exploration, it is uncertain if there is a role for minimally invasive techniques. This study compares open vs laparoscopic colectomy techniques in the management of ischemic colitis. Methods: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, patients with ischemic colitis undergoing colectomy from 2005 to 2019 were compared. The primary outcome of interest was 30-day mortality. Additional outcomes of interest were procedure related readmission, procedure related reoperation, length of stay, surgical site infections (SSI), septic shock, and other complications. Outcomes of interest were compared using multivariate logistic regression. Results: 7,928 patients had ischemic colitis with 7,209 undergoing open colectomy and 719 undergoing laparoscopic colectomy. The mortality rate was significantly lower using a laparoscopic approach compared to open (6.4% vs 26%, p=
Published: 2023
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4. Experimental Scattering Matrices of Martian Dust Aerosols with Narrow Particle-size Distributions

Author: Julia Martikainen, Olga Muñoz, Juan Carlos Gómez Martín, Teresa Jardiel, Marco Peiteado, Amador C. Caballero, Santiago Pérez-Hoyos, Agustin Sánchez Lavega, Tim Becker, Gerhard Wurm, Yannick Willame, and Ann Carine Vandaele
Subjects: Mars, Experimental data, Polarimetry, Astrophysics, QB460-466
Abstract: We present experimental scattering matrices of the JSC Mars-1, MMS-2, and MGS-1 simulants at 488 and 640 nm. The analogs were processed so that narrow size distributions representative of Martian dust aerosols during different dust cycles were obtained. We find that the forward peak of the phase function depends on particle size as it becomes narrower with increasing size, whereas the side- and backscattering directions depend on both composition and size so that increasing size and decreasing absorption produce a flatter curve. The position and maximum of the degree of linear polarization varies based on particle size and composition, and the negative polarization branch is more prominent for wavelength-scale particles diminishing with increasing size. The linear depolarization is strongly affected by size and composition. Finally, we compare sky-brightness curves measured by the Navcam and Hazcam engineering cameras on board the Mars Science Laboratory rover to the measured phase functions. The observations show a narrower peak at the forward direction and a flatter curve toward the side- and backscattering directions with an increasing dust load in the atmosphere, similar to what can be seen for the measured phase functions of the analogs with increasing particle size. In the case of the analogs, the flattening of the curve can be caused by an increase in multiple scattering within a particle by wavelength-scale surface roughness and/or internal inclusions. For the observed sky brightnesses, particle aggregation and multiple scattering among particles in denser dust conditions play a major role.
Published: 2024
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5. Identification of de novo variants in nonsyndromic cleft lip with/without cleft palate patients with low polygenic risk scores

Author: Nina Ishorst, Leonie Henschel, Frederic Thieme, Dmitriy Drichel, Sugirthan Sivalingam, Sarah L. Mehrem, Ariane C. Fechtner, Julia Fazaal, Julia Welzenbach, André Heimbach, Carlo Maj, Oleg Borisov, Jonas Hausen, Ruth Raff, Alexander Hoischen, Michael Dixon, Alvaro Rada‐Iglesias, Michaela Bartusel, Augusto Rojas‐Martinez, Khalid Aldhorae, Bert Braumann, Teresa Kruse, Christian Kirschneck, Gerrit Spanier, Heiko Reutter, Stefanie Nowak, Lina Gölz, Michael Knapp, Andreas Buness, Peter Krawitz, Markus M. Nöthen, Michael Nothnagel, Tim Becker, Kerstin U. Ludwig, and Elisabeth Mangold
Subjects: candidate genes, de novo variants, exome sequencing, nonsyndromic cleft lip with/without cleft palate, polygenic risk, single‐molecule molecular inversion probes, Genetics, QH426-470
Abstract: Abstract Background Nonsyndromic cleft lip with/without cleft palate (nsCL/P) is a congenital malformation of multifactorial etiology. Research has identified >40 genome‐wide significant risk loci, which explain less than 40% of nsCL/P heritability. Studies show that some of the hidden heritability is explained by rare penetrant variants. Methods To identify new candidate genes, we searched for highly penetrant de novo variants (DNVs) in 50 nsCL/P patient/parent‐trios with a low polygenic risk for the phenotype (discovery). We prioritized DNV‐carrying candidate genes from the discovery for resequencing in independent cohorts of 1010 nsCL/P patients of diverse ethnicities and 1574 population‐matched controls (replication). Segregation analyses and rare variant association in the replication cohort, in combination with additional data (genome‐wide association data, expression, protein–protein‐interactions), were used for final prioritization. Conclusion In the discovery step, 60 DNVs were identified in 60 genes, including a variant in the established nsCL/P risk gene CDH1. Re‐sequencing of 32 prioritized genes led to the identification of 373 rare, likely pathogenic variants. Finally, MDN1 and PAXIP1 were prioritized as top candidates. Our findings demonstrate that DNV detection, including polygenic risk score analysis, is a powerful tool for identifying nsCL/P candidate genes, which can also be applied to other multifactorial congenital malformations.
Published: 2023
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6. Risky behavior during stair descent for young adults: Differences in men versus women.

Author: HyeYoung Cho, Amanda J Arnold, Chuyi Cui, Zihan Yang, Tim Becker, Ashwini Kulkarni, Anvesh Naik, and Shirley Rietdyk
Subjects: Medicine, Science
Abstract: Injuries commonly occur on stairs, with high injury rates in young adults, especially young women. High injury rates could result from physiological and/or behavioral differences; this study focuses on behaviors. The purposes of this observational study were (1) to quantify young adult behaviors during stair descent and (2) to identify differences in stair descent behavior for young adult men versus women. Young adult pedestrians (N = 2,400, 1,470 men and 930 women) were videotaped during descent of two indoor campus staircases, a short staircase (2 steps) and a long staircase (17 steps). Behaviors during stair descent were coded by experimenters. Risky behaviors observed on the short staircase included: No one used the handrail, 16.1% used an electronic device, and 16.4% had in-person conversations. On the long staircase: 64.8% of pedestrians did not use the handrail, 11.9% used an electronic device, and 14.5% had in-person conversations. Risky behaviors observed more in women included: less likely to use the handrail (long staircase), more likely to carry an item in their hands (both staircases), more likely to engage in conversation (both staircases), and more likely to wear sandals or heels (both staircases) (p≤0.05). Protective behaviors observed more in women included: less likely to skip steps (both staircases), and more likely to look at treads during transition steps (long staircase) (p≤0.05). The number of co-occurring risky behaviors was higher in women: 1.9 vs 2.3, for men vs women, respectively (p
Published: 2023
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7. Prior fluid and electrolyte imbalance is associated with COVID-19 mortality

Author: Satu Nahkuri, Tim Becker, Vitalia Schueller, Steffen Massberg, and Anna Bauer-Mehren
Subjects: Medicine
Abstract: Plain language summary The clinical course of patients with COVID-19 is highly variable, with some patients barely affected and others dying. We wanted to better understand why this is the case and identify markers of COVID-19-associated mortality. To this end, we looked into the entire available medical history of more than 100,000 COVID-19 patients from the United States. We found that patients who had experienced a disturbance of electrolyte or fluid levels in the year before they contracted SARS-CoV-2 were more likely to die than patients without such a history. This observation suggests that careful monitoring and balancing of the hydration and electrolyte status during and even before a SARS-CoV-2 infection may be beneficial and possibly reduce the risk of death with COVID-19.
Published: 2021
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8. Discovery of novel eGFR-associated multiple independent signals using a quasi-adaptive method

Author: Sahar Ghasemi, Tim Becker, Hans J. Grabe, and Alexander Teumer
Subjects: estimated glomerular filtration rate (eGFR), genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), conditional association analysis, SNP-specific alpha-level, colocalization, Genetics, QH426-470
Abstract: A decreased estimated glomerular filtration rate (eGFR) leading to chronic kidney disease is a significant public health problem. Kidney function is a heritable trait, and recent application of genome-wide association studies (GWAS) successfully identified multiple eGFR-associated genetic loci. To increase statistical power for detecting independent associations in GWAS loci, we improved our recently developed quasi-adaptive method estimating SNP-specific alpha levels for the conditional analysis, and applied it to the GWAS meta-analysis results of eGFR among 783,978 European-ancestry individuals. Among known eGFR loci, we revealed 19 new independent association signals that were subsequently replicated in the United Kingdom Biobank (n = 408,608). These associations have remained undetected by conditional analysis using the established conservative genome-wide significance level of 5 × 10–8. Functional characterization of known index SNPs and novel independent signals using colocalization of conditional eGFR association results and gene expression in cis across 51 human tissues identified two potentially causal genes across kidney tissues: TSPAN33 and TFDP2, and three candidate genes across other tissues: SLC22A2, LRP2, and CDKN1C. These colocalizations were not identified in the original GWAS. By applying our improved quasi-adaptive method, we successfully identified additional genetic variants associated with eGFR. Considering these signals in colocalization analyses can increase the precision of revealing potentially functional genes of GWAS loci.
Published: 2022
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9. In vitro neutrophil migration is associated with inhaled corticosteroid treatment and serum cytokines in pediatric asthma

Author: Solveig Lemmel, Markus Weckmann, Anna Wohlers, Adan Chari Jirmo, Ruth Grychtol, Isabell Ricklefs, Gyde Nissen, Anna Bachmann, Shantanu Singh, Juan Caicedo, Thomas Bahmer, Gesine Hansen, Erika Von Mutius, Klaus F. Rabe, Oliver Fuchs, Anna-Maria Dittrich, Bianca Schaub, Christine Happle, Anne E. Carpenter, Matthias Volkmar Kopp, Tim Becker, the ALLIANCE Study Group as part of the German Centre for Lung Research (DZL), Mustafa Abdo, Miguel Alcazar, Mira Berbig, Heike Biller, Xenia Bovermann, Folke Brinkmann, Mifflin-Rae Calveron, David S. DeLuca, Gesa Diekmann, Christian Dopfer, Markus Ege, Svenja Foth, Svenja Gaedcke, Karoline I. Gaede, Anika Habener, Christian Herzmann, Alexander Hose, Sabina Illi, Anne-Marie Kirsten, Naschla Kohistani-Greif, Inke R. König, Silke Van Koningsbruggen-Rietschel, Matthias V. Kopp, Johanna Kurz, Katja Landgraf-Rauf, Kristina Laubhahn, Lena Liboschik, Claudia Liebl, Berrit Liselotte Husstedt, Bin Liu, Nicole Maison, Aydin Malik, Carola Marzi, Meike Meyer, Catharina Nitsche, Frauke Pedersen, Mareike Price, Harald Renz, Ernst Rietschel, Barbara Roesler, Christina Schauberger, Tom Schildberg, Carsten Schmidt-Weber, Nicolaus Schwerk, Chrysanthi Skevaki, Alena Steinmetz, Laila Sultansei, Marlen Szewczyk, Dominik Thiele, Vera Veith, Gesche Voigt, Benjamin Waschki, Henrik Watz, Stefanie Weber, Nils Welchering, Esther Zeitlmann, and Ulrich Zissler
Subjects: neutrophil granulocytes, migration, LTB4, fMLP, high-content image analysis, single-cell analysis, Therapeutics. Pharmacology, RM1-950
Abstract: Background: Different asthma phenotypes are driven by molecular endotypes. A Th1-high phenotype is linked to severe, therapy-refractory asthma, subclinical infections and neutrophil inflammation. Previously, we found neutrophil granulocytes (NGs) from asthmatics exhibit decreased chemotaxis towards leukotriene B4 (LTB4), a chemoattractant involved in inflammation response. We hypothesized that this pattern is driven by asthma in general and aggravated in a Th1-high phenotype.Methods: NGs from asthmatic nd healthy children were stimulated with 10 nM LTB4/100 nM N-formylmethionine-leucyl-phenylalanine and neutrophil migration was documented following our prior SiMA (simplified migration assay) workflow, capturing morphologic and dynamic parameters from single-cell tracking in the images. Demographic, clinical and serum cytokine data were determined in the ALLIANCE cohort.Results: A reduced chemotactic response towards LTB4 was confirmed in asthmatic donors regardless of inhaled corticosteroid (ICS) treatment. By contrast, only NGs from ICS-treated asthmatic children migrate similarly to controls with the exception of Th1-high donors, whose NGs presented a reduced and less directed migration towards the chemokines. ICS-treated and Th1-high asthmatic donors present an altered surface receptor profile, which partly correlates with migration.Conclusions: Neutrophil migration in vitro may be affected by ICS-therapy or a Th1-high phenotype. This may be explained by alteration of receptor expression and could be used as a tool to monitor asthma treatment.
Published: 2022
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10. Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models

Author: Alexander Denninger, Tim Becker, Ulrich Westedt, and Karl G. Wagner
Subjects: PBPK modeling, biphasic dissolution, drug product, prediction, poorly soluble drugs, enabling formulations, Pharmacy and materia medica, RS1-441
Abstract: Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present study was to assess the predictability of human pharmacokinetics by using biphasic dissolution results obtained with the previously established BiPHa+ assay and PBPK tools. For six commercial drug products, formulated by different enabling technologies, the respective organic partitioning profiles were processed with two PBPK in silico modeling tools, namely PK-Sim and GastroPlus®, similar to extended-release dissolution profiles. Thus, a mechanistic dissolution/precipitation model of the assessed drug products was not required. The developed elimination/distribution models were used to simulate the pharmacokinetics of the evaluated drug products and compared with available human data. In essence, an in vitro to in vivo extrapolation (IVIVE) was successfully developed. Organic partitioning profiles obtained from the BiPHa+ dissolution analysis enabled highly accurate predictions of the pharmacokinetic behavior of the investigated drug products. In addition, PBPK models of (pro-)drugs with pronounced first-pass metabolism enabled adjustment of the solely passive diffusion predicting organic partitioning profiles, and increased prediction accuracy further.
Published: 2023
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11. Charged Atmospheric Aerosols from Charged Saltating Dust Aggregates

Author: F. Chioma Onyeagusi, Christian Meyer, Jens Teiser, Tim Becker, and Gerhard Wurm
Subjects: aeolian transport, saltation, fragmentation, dust physics, charged aerosols, charge transfer, Meteorology. Climatology, QC851-999
Abstract: Grain collisions in aeolian events, e.g., due to saltation, result in atmospheric aerosols. They may regularly be electrically charged, but individual charge balances in collisions including small grains are not easily obtained on the ground. We therefore approach this problem in terms of microgravity, which allows for the observation of collisions and the determination of small charges. In a drop tower experiment, ∼1 mm dust aggregates are traced before and after a collision within the electric field of a plate capacitor. The sum of the electric charge of two particles (total charge) before and after the collision often strongly deviates from charge conservation. Due to the average low collision velocities of 0.2 m/s, there is no large scale fragmentation. However, we do observe small charged particles emerging from collisions. The smallest of these particles are as small as the current resolution limit of the optical system, i.e., they are at least as small as tens of µm. In the given setting, these small fragments may carry 1 nC/m2–1 µC/m2 which is between 1% and ten times the surface charge density of the large aggregates. These first experiments indicate that collisions of charged aggregates regularly shed charged grains into the atmosphere, likely down to the suspendable aerosol size.
Published: 2023
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12. Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B

Author: Tim Becker, Andreas Pich, Stephanie Tamm, Silke Hedtfeld, Mohammed Ibrahim, Janine Altmüller, Nina Dalibor, Mohammad Reza Toliat, Sabina Janciauskiene, Burkhard Tümmler, and Frauke Stanke
Subjects: Medicine, Science
Abstract: Abstract SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are responsible for intrapair discordance. Concordant and discordant pairs differed at six SCNN1B markers (Praw = 0.0075, Pcorr = 0.0397 corrected for multiple testing). To identify the factors binding to these six SCNN1B SNPs, we performed an electrophoretic mobility shift assay and captured the DNA–protein complexes. Based on protein mass spectrometry data, the epithelial splicing regulatory protein ESRP2 was identified when using SCNN1B-derived probes and the ESRP2-SCNN1B interaction was independently confirmed by coimmunoprecipitation assays. We observed an alternative SCNN1B transcript and demonstrated in 16HBE14o− cells that levels of this transcript are decreased upon ESRP2 silencing by siRNA. Furthermore, we confirmed that mildly and severely affected siblings have different ESPR2 genetic backgrounds and that ESRP2 markers are linked to the response of CF patients’ nasal epithelium to amiloride, indicating ENaC involvement (Pbest = 0.0131, Pcorr = 0.068 for multiple testing). Our findings demonstrate that sibling pairs clinically discordant for CF can be used to identify meaningful DNA regulatory elements and interacting factors.
Published: 2020
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13. Use of digital teaching resources and predictors of medical student performance during the pandemic: A prospective study

Author: Michelle Seer, Charlotte Kampsen, Tim Becker, Sebastian Hobert, Sven Anders, and Tobias Raupach
Subjects: Medicine, Science
Abstract: Background The coronavirus pandemic has led to increased use of digital teaching formats in medical education. A number of studies have assessed student satisfaction with these resources. However, there is a lack of studies investigating changes in student performance following the switch from contact to virtual teaching. Specifically, there are no studies linking student use of digital resources to learning outcome and examining predictors of failure. Methods Student performance before (winter term 2019/20: contact teaching) and during (summer term 2020: no contact teaching) the pandemic was compared prospectively in a cohort of 162 medical students enrolled in the clinical phase of a five-year undergraduate curriculum. Use of and performance in various digital resources (case-based teaching in a modified flipped classroom approach; formative key feature examinations of clinical reasoning; daily multiple choice quizzes) was recorded in summer 2020. Student scores in summative examinations were compared to examination scores in the previous term. Associations between student characteristics, resource use and summative examination results were used to identify predictors of performance. Results Not all students made complete use of the digital learning resources provided. Timely completion of tasks was associated with superior performance compared to delayed completion. Female students scored significantly fewer points in formative key feature examinations and digital quizzes. Overall, higher rankings within the student cohort (according to summative exams) in winter term 2019/20 as well as male gender predicted summative exam performance in summer 2020. Scores achieved in the first formative key feature examination predicted summative end-of-module exam scores. Conclusions The association between timely completion of tasks as well as early performance in a module and summative exams might help to identify students at risk and offering help early on. The unexpected gender difference requires further study to determine whether the shift to a digital-only curriculum disadvantages female students.
Published: 2022

14. Optical Constants of Martian Dust Analogs at UV–Visible–Near-infrared Wavelengths

Author: Julia Martikainen, Olga Muñoz, Teresa Jardiel, Juan Carlos Gómez Martín, Marco Peiteado, Yannick Willame, Antti Penttilä, Karri Muinonen, Gerhard Wurm, and Tim Becker
Subjects: Mars, Computational methods, Planetary surfaces, Astrophysics, QB460-466
Abstract: We present an advanced light-scattering model to retrieve the optical constants of three Martian dust analogs: Johnson Space Center regolith simulant, Enhanced Mojave Mars Simulant, and Mars Global Simulant. The samples are prepared to have narrow particle-size distributions within the geometric-optics domain. We carry out laboratory measurements to obtain the particle-size distributions, shapes, and diffuse reflectance spectra of the Martian analogs deposited on a surface. Our model framework includes a ray-optics code to compute scattering properties for individual particles, and a radiative-transfer treatment to simulate the surface. The irregular shapes of the dust particles are taken into account in the model. We compare our derived imaginary parts of the refractive indices with those in the literature and find that they are much smaller than the ones that are commonly used for Martian dust. A sensitivity study shows that the retrieved optical constants are sensitive to the particle shape, which needs to be accounted for in applications that use different shapes. Finally, the derived values are validated by using them to reproduce the reflectance spectrum of the Martian surface regolith as observed by the Nadir and Occultation for Mars Discovery instrument on board the ExoMars mission.
Published: 2023
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15. Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

Author: Katharina Rox, Tim Becker, Andrea Schiefer, Miriam Grosse, Alexandra Ehrens, Rolf Jansen, Tilman Aden, Stefan Kehraus, Gabriele M. König, Anna K. Krome, Marc P. Hübner, Karl G. Wagner, Marc Stadler, Kenneth Pfarr, and Achim Hoerauf
Subjects: natural product, pharmacokinetics, pharmacodynamics, Staphylococcus aureus, PK/PD, Pharmacy and materia medica, RS1-441
Abstract: Methicillin-resistant Staphylococcus aureus (MRSA) is a World Health Organization’s high priority pathogen organism, with an estimated > 100,000 deaths worldwide in 2019. Thus, there is an unmet medical need for novel and resistance-breaking anti-infectives. The natural product Co-rallopyronin A (CorA), currently in preclinical development for filariasis, is efficacious against MRSA in vitro. In this study, we evaluated the pharmacokinetics of CorA after dosing in mice. Furthermore, we determined compound concentrations in target compartments, such as lung, kidney and thigh tissue, using LC-MS/MS. Based on the pharmacokinetic results, we evaluated the pharmacodynamic profile of CorA using the standard neutropenic thigh and lung infection models. We demonstrate that CorA is effective in both standard pharmacodynamic models. In addition to reaching effective levels in the lung and muscle, CorA was detected at high levels in the thigh bone. The data presented herein encourage the further exploration of the additional CorA indications treatment of MRSA- and methicillin-sensitive S. aureus- (MSSA) related infections.
Published: 2022
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16. Characterization and prediction of positional 4-hydroxyproline and sulfotyrosine, two post-translational modifications that can occur at substantial levels in CHO cells-expressed biotherapeutics

Author: Oksana Tyshchuk, Christoph Gstöttner, Dennis Funk, Simone Nicolardi, Stefan Frost, Stefan Klostermann, Tim Becker, Elena Jolkver, Felix Schumacher, Claudia Ferrara Koller, Hans Rainer Völger, Manfred Wuhrer, Patrick Bulau, and Michael Mølhøj
Subjects: Biotherapeutics, fab purification, MALDI-ISD FT-ICR, hydroxyproline, mass spectrometry, PTM, Therapeutics. Pharmacology, RM1-950, Immunologic diseases. Allergy, RC581-607
Abstract: Biotherapeutics may contain a multitude of different post-translational modifications (PTMs) that need to be assessed and possibly monitored and controlled to ensure reproducible product quality. During early development of biotherapeutics, unexpected PTMs might be prevented by in silico identification and characterization together with further molecular engineering. Mass determinations of a human IgG1 (mAb1) and a bispecific IgG-ligand fusion protein (BsAbA) demonstrated the presence of unusual PTMs resulting in major +80 Da, and +16/+32 Da chain variants, respectively. For mAb1, analytical cation exchange chromatography demonstrated the presence of an acidic peak accounting for 20%. A + 79.957 Da modification was localized within the light chain complementarity-determining region-2 and identified as a sulfation based on accurate mass, isotopic distribution, and a complete neutral loss reaction upon collision-induced dissociation. Top-down ultrahigh resolution MALDI-ISD FT-ICR MS of modified and unmodified Fabs allowed the allocation of the sulfation to a specific Tyr residue. An aspartate in amino-terminal position-3 relative to the affected Tyr was found to play a key role in determining the sulfation. For BsAbA, a + 15.995 Da modification was observed and localized to three specific Pro residues explaining the +16 Da chain A, and +16 Da and +32 Da chain B variants. The BsAbA modifications were verified as 4-hydroxyproline and not 3-hydroxyproline in a tryptic peptide map via co-chromatography with synthetic peptides containing the two isomeric forms. Finally, our approach for an alert system based on in-house in silico predictors is presented. This system is designed to prevent these PTMs by molecular design and engineering during early biotherapeutic development.
Published: 2019
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17. In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A

Author: Tim Becker, Anna K. Krome, Sahel Vahdati, Andrea Schiefer, Kenneth Pfarr, Alexandra Ehrens, Tilman Aden, Miriam Grosse, Rolf Jansen, Silke Alt, Thomas Hesterkamp, Marc Stadler, Marc P. Hübner, Stefan Kehraus, Gabriele M. König, Achim Hoerauf, and Karl G. Wagner
Subjects: absorption, amorphous solid dispersion, anti-infective, bioavailability, corallopyronin A, dissolution, Pharmacy and materia medica, RS1-441
Abstract: In vivo studies in mice provide a valuable model to test novel active pharmaceutical ingredients due to their low material need and the fact that mice are frequently used as a species for early efficacy models. However, preclinical in vitro evaluations of formulation principles in mice are still lacking. The development of novel in vitro and in silico models supported the preclinical formulation evaluation for the anti-infective corallopyronin A (CorA). To this end, CorA and solubility-enhanced amorphous solid dispersion formulations, comprising povidone or copovidone, were evaluated regarding biorelevant solubilities and dissolution in mouse-specific media. As an acidic compound, CorA and CorA-ASD formulations showed decreased solubilities in mice when compared with human-specific media. In biorelevant biphasic dissolution experiments CorA-povidone showed a three-fold higher fraction partitioned into the organic phase of the biphasic dissolution, when compared with CorA-copovidone. Bioavailabilities determined by pharmacokinetic studies in BALB/c mice correlated with the biphasic dissolution prediction and resulted in a Level C in vitro–in vivo correlation. In vitro cell experiments excluded intestinal efflux by P-glycoprotein or breast cancer resistance protein. By incorporating in vitro results into a physiologically based pharmacokinetic model, the plasma concentrations of CorA-ASD formulations were predicted and identified dissolution as the limiting factor for bioavailability.
Published: 2022
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18. Artificial Intelligence for Prognostic Scores in Oncology: a Benchmarking Study

Author: Hugo Loureiro, Tim Becker, Anna Bauer-Mehren, Narges Ahmidi, and Janick Weberpals
Subjects: electronic health records, machine learning, prognostic scores, real world data, survival analyisis, Electronic computers. Computer science, QA75.5-76.95
Abstract: Introduction: Prognostic scores are important tools in oncology to facilitate clinical decision-making based on patient characteristics. To date, classic survival analysis using Cox proportional hazards regression has been employed in the development of these prognostic scores. With the advance of analytical models, this study aimed to determine if more complex machine-learning algorithms could outperform classical survival analysis methods.Methods: In this benchmarking study, two datasets were used to develop and compare different prognostic models for overall survival in pan-cancer populations: a nationwide EHR-derived de-identified database for training and in-sample testing and the OAK (phase III clinical trial) dataset for out-of-sample testing. A real-world database comprised 136K first-line treated cancer patients across multiple cancer types and was split into a 90% training and 10% testing dataset, respectively. The OAK dataset comprised 1,187 patients diagnosed with non-small cell lung cancer. To assess the effect of the covariate number on prognostic performance, we formed three feature sets with 27, 44 and 88 covariates. In terms of methods, we benchmarked ROPRO, a prognostic score based on the Cox model, against eight complex machine-learning models: regularized Cox, Random Survival Forests (RSF), Gradient Boosting (GB), DeepSurv (DS), Autoencoder (AE) and Super Learner (SL). The C-index was used as the performance metric to compare different models.Results: For in-sample testing on the real-world database the resulting C-index [95% CI] values for RSF 0.720 [0.716, 0.725], GB 0.722 [0.718, 0.727], DS 0.721 [0.717, 0.726] and lastly, SL 0.723 [0.718, 0.728] showed significantly better performance as compared to ROPRO 0.701 [0.696, 0.706]. Similar results were derived across all feature sets. However, for the out-of-sample validation on OAK, the stronger performance of the more complex models was not apparent anymore. Consistently, the increase in the number of prognostic covariates did not lead to an increase in model performance.Discussion: The stronger performance of the more complex models did not generalize when applied to an out-of-sample dataset. We hypothesize that future research may benefit by adding multimodal data to exploit advantages of more complex models.
Published: 2021
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19. Single nucleotide polymorphisms in the angiogenic and lymphangiogenic pathways are associated with lymphedema caused by Wuchereria bancrofti

Author: Linda Batsa Debrah, Anna Albers, Alexander Yaw Debrah, Felix F. Brockschmidt, Tim Becker, Christine Herold, Andrea Hofmann, Jubin Osei-Mensah, Yusif Mubarik, Holger Fröhlich, Achim Hoerauf, and Kenneth Pfarr
Subjects: Lymphatic filariasis, Angiogenesis, Lymphangiogenesis, Single nucleotide polymorphisms, Genotypes, Medicine, Genetics, QH426-470
Abstract: Abstract Background Lymphedema (LE) is a chronic clinical manifestation of filarial nematode infections characterized by lymphatic dysfunction and subsequent accumulation of protein-rich fluid in the interstitial space—lymphatic filariasis. A number of studies have identified single nucleotide polymorphisms (SNPs) associated with primary and secondary LE. To assess SNPs associated with LE caused by lymphatic filariasis, a cross-sectional study of unrelated Ghanaian volunteers was designed to genotype SNPs in 285 LE patients as cases and 682 infected patients without pathology as controls. One hundred thirty-one SNPs in 64 genes were genotyped. The genes were selected based on their roles in inflammatory processes, angiogenesis/lymphangiogenesis, and cell differentiation during tumorigenesis. Results Genetic associations with nominal significance were identified for five SNPs in three genes: vascular endothelial growth factor receptor-3 (VEGFR-3) rs75614493, two SNPs in matrix metalloprotease-2 (MMP-2) rs1030868 and rs2241145, and two SNPs in carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) rs8110904 and rs8111171. Pathway analysis revealed an interplay of genes in the angiogenic/lymphangiogenic pathways. Plasma levels of both MMP-2 and CEACAM-1 were significantly higher in LE cases compared to controls. Functional characterization of the associated SNPs identified genotype GG of CEACAM-1 as the variant influencing the expression of plasma concentration, a novel finding observed in this study. Conclusion The SNP associations found in the MMP-2, CEACAM-1, and VEGFR-3 genes indicate that angiogenic/lymphangiogenic pathways are important in LE clinical development.
Published: 2017
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20. Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness

Author: Stefanie Heilmann-Heimbach, Christine Herold, Lara M. Hochfeld, Axel M. Hillmer, Dale R. Nyholt, Julian Hecker, Asif Javed, Elaine G. Y. Chew, Sonali Pechlivanis, Dmitriy Drichel, Xiu Ting Heng, Ricardo C. -H. del Rosario, Heide L. Fier, Ralf Paus, Rico Rueedi, Tessel E. Galesloot, Susanne Moebus, Thomas Anhalt, Shyam Prabhakar, Rui Li, Stavroula Kanoni, George Papanikolaou, Zoltán Kutalik, Panos Deloukas, Michael P. Philpott, Gérard Waeber, Tim D. Spector, Peter Vollenweider, Lambertus A. L. M. Kiemeney, George Dedoussis, J. Brent Richards, Michael Nothnagel, Nicholas G. Martin, Tim Becker, David A. Hinds, and Markus M. Nöthen
Subjects: Science
Abstract: Male-pattern baldness is a common condition in which hair is progressively lost from the scalp. Here, the authors find 23 new genetic variants associated with this condition and suggest that it is not an isolated trait but may share an underlying biological basis with various diseases.
Published: 2017
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21. Solubility and Stability Enhanced Oral Formulations for the Anti-Infective Corallopyronin A

Author: Anna K. Krome, Tim Becker, Stefan Kehraus, Andrea Schiefer, Christian Steinebach, Tilman Aden, Stefan J. Frohberger, Álvaro López Mármol, Dnyaneshwar Kapote, Rolf Jansen, Lillibeth Chaverra-Muñoz, Marc P. Hübner, Kenneth Pfarr, Thomas Hesterkamp, Marc Stadler, Michael Gütschow, Gabriele M. König, Achim Hoerauf, and Karl G. Wagner
Subjects: corallopyronin A (CorA), antibiotic, anthelmintic, povidone (PVP), copovidone (PVP/VA), solubility enhanced formulation, Pharmacy and materia medica, RS1-441
Abstract: Novel-antibiotics are urgently needed to combat an increase in morbidity and mortality due to resistant bacteria. The preclinical candidate corallopyronin A (CorA) is a potent antibiotic against Gram-positive and some Gram-negative pathogens for which a solid oral formulation was needed for further preclinical testing of the active pharmaceutical ingredient (API). The neat API CorA is poorly water-soluble and instable at room temperature, both crucial characteristics to be addressed and overcome for use as an oral antibiotic. Therefore, amorphous solid dispersion (ASD) was chosen as formulation principle. The formulations were prepared by spray-drying, comprising the water-soluble polymers povidone and copovidone. Stability (high-performance liquid chromatography, Fourier-transform-infrared spectroscopy, differential scanning calorimetry), dissolution (biphasic dissolution), and solubility (biphasic dissolution, Pion’s T3 apparatus) properties were analyzed. Pharmacokinetic evaluations after intravenous and oral administration were conducted in BALB/c mice. The results demonstrated that the ASD formulation principle is a suitable stability- and solubility-enhancing oral formulation strategy for the API CorA to be used in preclinical and clinical trials and as a potential market product.
Published: 2020
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22. CellProfiler 3.0: Next-generation image processing for biology.

Author: Claire McQuin, Allen Goodman, Vasiliy Chernyshev, Lee Kamentsky, Beth A Cimini, Kyle W Karhohs, Minh Doan, Liya Ding, Susanne M Rafelski, Derek Thirstrup, Winfried Wiegraebe, Shantanu Singh, Tim Becker, Juan C Caicedo, and Anne E Carpenter
Subjects: Biology (General), QH301-705.5
Abstract: CellProfiler has enabled the scientific research community to create flexible, modular image analysis pipelines since its release in 2005. Here, we describe CellProfiler 3.0, a new version of the software supporting both whole-volume and plane-wise analysis of three-dimensional (3D) image stacks, increasingly common in biomedical research. CellProfiler's infrastructure is greatly improved, and we provide a protocol for cloud-based, large-scale image processing. New plugins enable running pretrained deep learning models on images. Designed by and for biologists, CellProfiler equips researchers with powerful computational tools via a well-documented user interface, empowering biologists in all fields to create quantitative, reproducible image analysis workflows.
Published: 2018
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23. Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.

Author: Andreas J Forstner, Julian Hecker, Andrea Hofmann, Anna Maaser, Céline S Reinbold, Thomas W Mühleisen, Markus Leber, Jana Strohmaier, Franziska Degenhardt, Jens Treutlein, Manuel Mattheisen, Johannes Schumacher, Fabian Streit, Sandra Meier, Stefan Herms, Per Hoffmann, André Lacour, Stephanie H Witt, Andreas Reif, Bertram Müller-Myhsok, Susanne Lucae, Wolfgang Maier, Markus Schwarz, Helmut Vedder, Jutta Kammerer-Ciernioch, Andrea Pfennig, Michael Bauer, Martin Hautzinger, Susanne Moebus, Lorena M Schenk, Sascha B Fischer, Sugirthan Sivalingam, Piotr M Czerski, Joanna Hauser, Jolanta Lissowska, Neonila Szeszenia-Dabrowska, Paul Brennan, James D McKay, Adam Wright, Philip B Mitchell, Janice M Fullerton, Peter R Schofield, Grant W Montgomery, Sarah E Medland, Scott D Gordon, Nicholas G Martin, Valery Krasnov, Alexander Chuchalin, Gulja Babadjanova, Galina Pantelejeva, Lilia I Abramova, Alexander S Tiganov, Alexey Polonikov, Elza Khusnutdinova, Martin Alda, Cristiana Cruceanu, Guy A Rouleau, Gustavo Turecki, Catherine Laprise, Fabio Rivas, Fermin Mayoral, Manolis Kogevinas, Maria Grigoroiu-Serbanescu, Tim Becker, Thomas G Schulze, Marcella Rietschel, Sven Cichon, Heide Fier, and Markus M Nöthen
Subjects: Medicine, Science
Abstract: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Published: 2017
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24. The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect

Author: Suzana Gispert, Alexander Kurz, Stefan Waibel, Peter Bauer, Inga Liepelt, Christof Geisen, Aaron D. Gitler, Tim Becker, Markus Weber, Daniela Berg, Peter M. Andersen, Rejko Krüger, Olaf Riess, Albert C. Ludolph, and Georg Auburger
Subjects: Ataxin-2, Ataxin-3, Spinocerebellar Ataxia type 2, Motor neuron disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Full expansions of the polyglutamine domain (polyQ≥34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27≤polyQ≤33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30≤polyQ≤35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor.
Published: 2012
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25. Parent-of-origin Effect in Alopecia Areata: A Large-scale Pedigree Study

Author: Silke Redler, F. Buket Basmanav, Bettina Blaumeiser, Natalie Garcia Bartels, Gerhard Lutz, Aylar Tafazzoli, Roland Kruse, Hans Wolff, Markus Böhm, Ulrike Blume-Peytavi, Tim Becker, Markus M. Nöthen, and Regina C. Betz
Subjects: Dermatology, RL1-803
Published: 2017
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26. Low-Voltage DC Training Lab for Electric Drives - Optimizing the Balancing Act Between High Student Throughput and Individual Learning Speed.

Author: Tim Becker and Michael Bragard
Published: 2024
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27. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author: Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)
Subjects: Medicine, Science
Abstract: BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Published: 2014
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28. A one-degree-of-freedom test for supra-multiplicativity of SNP effects.

Author: Christine Herold, Alfredo Ramirez, Dmitriy Drichel, André Lacour, Tatsiana Vaitsiakhovich, Markus M Nöthen, Frank Jessen, Wolfgang Maier, and Tim Becker
Subjects: Medicine, Science
Abstract: Deviation from multiplicativity of genetic risk factors is biologically plausible and might explain why Genome-wide association studies (GWAS) so far could unravel only a portion of disease heritability. Still, evidence for SNP-SNP epistasis has rarely been reported, suggesting that 2-SNP models are overly simplistic. In this context, it was recently proposed that the genetic architecture of complex diseases could follow limiting pathway models. These models are defined by a critical risk allele load and imply multiple high-dimensional interactions. Here, we present a computationally efficient one-degree-of-freedom "supra-multiplicativity-test" (SMT) for SNP sets of size 2 to 500 that is designed to detect risk alleles whose joint effect is fortified when they occur together in the same individual. Via a simulation study we show that the SMT is powerful in the presence of threshold models, even when only about 30-45% of the model SNPs are available. In addition, we demonstrate that the SMT outperforms standard interaction analysis under recessive models involving just a few SNPs. We apply our test to 10 consensus Alzheimer's disease (AD) susceptibility SNPs that were previously identified by GWAS and obtain evidence for supra-multiplicativity ([Formula: see text]) that is not attributable to either two-way or three-way interaction.
Published: 2013
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29. High-throughput miRNA and mRNA sequencing of paired colorectal normal, tumor and metastasis tissues and bioinformatic modeling of miRNA-1 therapeutic applications.

Author: Christina Röhr, Martin Kerick, Axel Fischer, Alexander Kühn, Karl Kashofer, Bernd Timmermann, Andriani Daskalaki, Thomas Meinel, Dmitriy Drichel, Stefan T Börno, Anja Nowka, Sylvia Krobitsch, Alice C McHardy, Christina Kratsch, Tim Becker, Andrea Wunderlich, Christian Barmeyer, Christian Viertler, Kurt Zatloukal, Christoph Wierling, Hans Lehrach, and Michal R Schweiger
Subjects: Medicine, Science
Abstract: MiRNAs are discussed as diagnostic and therapeutic molecules. However, effective miRNA drug treatments with miRNAs are, so far, hampered by the complexity of the miRNA networks. To identify potential miRNA drugs in colorectal cancer, we profiled miRNA and mRNA expression in matching normal, tumor and metastasis tissues of eight patients by Illumina sequencing. We validated six miRNAs in a large tissue screen containing 16 additional tumor entities and identified miRNA-1, miRNA-129, miRNA-497 and miRNA-215 as constantly de-regulated within the majority of cancers. Of these, we investigated miRNA-1 as representative in a systems-biology simulation of cellular cancer models implemented in PyBioS and assessed the effects of depletion as well as overexpression in terms of miRNA-1 as a potential treatment option. In this system, miRNA-1 treatment reverted the disease phenotype with different effectiveness among the patients. Scoring the gene expression changes obtained through mRNA-Seq from the same patients we show that the combination of deep sequencing and systems biological modeling can help to identify patient-specific responses to miRNA treatments. We present this data as guideline for future pre-clinical assessments of new and personalized therapeutic options.
Published: 2013
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30. Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

Author: Rui Li, Felix F Brockschmidt, Amy K Kiefer, Hreinn Stefansson, Dale R Nyholt, Kijoung Song, Sita H Vermeulen, Stavroula Kanoni, Daniel Glass, Sarah E Medland, Maria Dimitriou, Dawn Waterworth, Joyce Y Tung, Frank Geller, Stefanie Heilmann, Axel M Hillmer, Veronique Bataille, Sibylle Eigelshoven, Sandra Hanneken, Susanne Moebus, Christine Herold, Martin den Heijer, Grant W Montgomery, Panos Deloukas, Nicholas Eriksson, Andrew C Heath, Tim Becker, Patrick Sulem, Massimo Mangino, Peter Vollenweider, Tim D Spector, George Dedoussis, Nicholas G Martin, Lambertus A Kiemeney, Vincent Mooser, Kari Stefansson, David A Hinds, Markus M Nöthen, and J Brent Richards
Subjects: Genetics, QH426-470
Abstract: Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻⁹-1.01×10⁻¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻⁸⁸]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.
Published: 2012
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31. A novel validation algorithm allows for automated cell tracking and the extraction of biologically meaningful parameters.

Author: Daniel H Rapoport, Tim Becker, Amir Madany Mamlouk, Simone Schicktanz, and Charli Kruse
Subjects: Medicine, Science
Abstract: Automated microscopy is currently the only method to non-invasively and label-free observe complex multi-cellular processes, such as cell migration, cell cycle, and cell differentiation. Extracting biological information from a time-series of micrographs requires each cell to be recognized and followed through sequential microscopic snapshots. Although recent attempts to automatize this process resulted in ever improving cell detection rates, manual identification of identical cells is still the most reliable technique. However, its tedious and subjective nature prevented tracking from becoming a standardized tool for the investigation of cell cultures. Here, we present a novel method to accomplish automated cell tracking with a reliability comparable to manual tracking. Previously, automated cell tracking could not rival the reliability of manual tracking because, in contrast to the human way of solving this task, none of the algorithms had an independent quality control mechanism; they missed validation. Thus, instead of trying to improve the cell detection or tracking rates, we proceeded from the idea to automatically inspect the tracking results and accept only those of high trustworthiness, while rejecting all other results. This validation algorithm works independently of the quality of cell detection and tracking through a systematic search for tracking errors. It is based only on very general assumptions about the spatiotemporal contiguity of cell paths. While traditional tracking often aims to yield genealogic information about single cells, the natural outcome of a validated cell tracking algorithm turns out to be a set of complete, but often unconnected cell paths, i.e. records of cells from mitosis to mitosis. This is a consequence of the fact that the validation algorithm takes complete paths as the unit of rejection/acceptance. The resulting set of complete paths can be used to automatically extract important biological parameters with high reliability and statistical significance. These include the distribution of life/cycle times and cell areas, as well as of the symmetry of cell divisions and motion analyses. The new algorithm thus allows for the quantification and parameterization of cell culture with unprecedented accuracy. To evaluate our validation algorithm, two large reference data sets were manually created. These data sets comprise more than 320,000 unstained adult pancreatic stem cells from rat, including 2592 mitotic events. The reference data sets specify every cell position and shape, and assign each cell to the correct branch of its genealogic tree. We provide these reference data sets for free use by others as a benchmark for the future improvement of automated tracking methods.
Published: 2011
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32. CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD.

Author: Hendrik P N Scholl, Monika Fleckenstein, Lars G Fritsche, Steffen Schmitz-Valckenberg, Arno Göbel, Christine Adrion, Christine Herold, Claudia N Keilhauer, Friederike Mackensen, Andreas Mössner, Daniel Pauleikhoff, Andreas W A Weinberger, Ulrich Mansmann, Frank G Holz, Tim Becker, and Bernhard H F Weber
Subjects: Medicine, Science
Abstract: Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown.Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6x10(-9), 3.2x10(-3), and P = 2.6x10(-12), respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm(2)/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13).This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.
Published: 2009
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33. Multivariate Time Series Retrieval with Symbolic Aggregate Approximation, Regular Expression, and Query Expansion.

Author: Yuncong Yu 0001, Tim Becker, and Michael Behrisch 0001
Published: 2022
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34. PSEUDo: Interactive Pattern Search in Multivariate Time Series with Locality-Sensitive Hashing and Relevance Feedback.

Author: Yuncong Yu 0001, Dylan Kruyff, Jiao Jiao, Tim Becker, and Michael Behrisch 0001
Published: 2022
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35. Orbits of Abelian Automaton Groups.

Author: Tim Becker and Klaus Sutner
Published: 2019
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36. Combining morphological and migration profiles of in vitro time-lapse data.

Author: Tim Becker, Juan C. Caicedo, Shantanu Singh, Markus Weckmann, and Anne E. Carpenter
Published: 2018
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37. Using item response theory to appraise key feature examinations for clinical reasoning

Author: Simon Zegota, Tim Becker, York Hagmayer, and Tobias Raupach
Subjects: Psychometrics, Humans, Educational Measurement, General Medicine, Clinical Reasoning, behavioral disciplines and activities, Education
Abstract: Validation of examinations is usually based on classical test theory. In this study, we analysed a key feature examination according to item response theory and compared the results with those of a classical test theory approach. Over the course of five years, 805 fourth-year undergraduate students took a key feature examination on general medicine consisting of 30 items. Analyses were run according to a classical test theory approach as well as using item response theory. Classical test theory analyses are reported as item difficulty, discriminatory power, and Cronbach’s alpha while item response theory analyses are presented as item characteristics curves, item information curves and a test information function. According to classical test theory findings, the examination was labelled as easy. Analyses according to item response theory more specifically indicated that the examination was most suited to identify struggling students. Furthermore, the analysis allowed for adapting the examination to specific ability ranges by removing items, as well as comparing multiple samples with varying ability ranges. Item response theory analyses revealed results not yielded by classical test theory. Thus, both approaches should be routinely combined to increase the information yield of examination data.
Published: 2022

38. Ejected Particles after Impact Splash on Mars: Aggregates and Aerodynamics

Author: 0000-0002-5138-3932, 0000-0003-2211-4001, 0000-0002-7962-4961, Tim Becker, Jens Teiser, Teresa Jardiel, Marco Peiteado, Olga Muñoz, Julia Martikainen, Juan Carlos Gomez Martin, Jonathan Merrison, Gerhard Wurm, 0000-0002-5138-3932, 0000-0003-2211-4001, 0000-0002-7962-4961, Tim Becker, Jens Teiser, Teresa Jardiel, Marco Peiteado, Olga Muñoz, Julia Martikainen, Juan Carlos Gomez Martin, Jonathan Merrison, and Gerhard Wurm
Abstract: Our earlier laboratory measurements showed that low-velocity sand impacts release fine <5 {\mu}m dust from a Martian simulant soil. This dust will become airborne in the Martian atmosphere. Here, we extend this study by measuring aerodynamic properties of ejecta and characterizing deviations from the behavior of spherical, monolithic grains. We observe the settling of particles emitted as part of an impact splash. The sizes (20 to 280 {\mu}m) and sedimentation velocities (0.1 to 0.8 ms^{-1} ) of the particles are deduced from high-speed videos while the particles sediment under low ambient pressure of about 1 mbar. The particles regularly settle slower than expected, down to a factor of about 0.3. Using optical microscopy, the shape of the captured particles is characterized by simple axis ratios (longest/smallest), which show that the vast majority of particles are irregular but typically not too elongated, with axis ratios below 2 on average. Electron microscopy further reveals that the particles are typically porous aggregates, which is the most likely reason for the reduction of the sedimentation velocity. Due to the reduced bulk density, aggregates up to 10 {\mu}m in diameter should regularly be a part of the dust in the Martian atmosphere.
Published: 2023

39. The benchmark data SET CeTReS.B-MI for in vitro mitosis detection.

Author: Tim Becker, W. Kanje, Daniel H. Rapoport, Konstantin Thierbach, Nico Scherf, Ingo Roeder, and Amir Madany Mamlouk
Published: 2014
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40. New insights into the genetic etiology of Alzheimer's disease and related dementias

Author: Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., Yaqub, A., Prokic, I., Chapuis, J., Ahmad, S., Giedraitis, V., Aarsland, D., Garcia-Gonzalez, P., Abdelnour, C., Alarcón-Martín, E., Alcolea, D., Alegret, M., Alvarez, I., Álvarez, V., Armstrong, N. J., Tsolaki, A., Antúnez, C., Appollonio, I., Arcaro, M., Archetti, S., Pastor, A. A., Arosio, B., Athanasiu, L., Bailly, H., Banaj, N., Baquero, M., Barral, S., Beiser, A., Pastor, A. B., Below, J. E., Benchek, P., Benussi, L., Berr, C., Besse, C., Bessi, V., Binetti, G., Bizarro, A., Blesa, R., Boada, M., Boerwinkle, E., Borroni, B., Boschi, S., Bossù, P., Bråthen, G., Bressler, J., Bresner, C., Brodaty, H., Brookes, K. J., Brusco, L. I., Buiza-Rueda, D., Bûrger, K., Burholt, V., Bush, W. S., Calero, M., Cantwell, L. B., Chene, G., Chung, J., Cuccaro, M. L., Carracedo, Á., Cecchetti, R., Cervera-Carles, L., Charbonnier, C., Chen, H. -H., Chillotti, C., Ciccone, S., Claassen, J. A. H. R., Clark, C., Conti, E., Corma-Gómez, A., Costantini, E., Custodero, C., Daian, D., Dalmasso, M. C., Daniele, A., Dardiotis, E., Dartigues, J. -F., de Deyn, P. P., de Paiva Lopes, K., de Witte, L. D., Debette, S., Deckert, J., del Ser, T., Denning, N., Destefano, A., Dichgans, M., Diehl-Schmid, J., Diez-Fairen, M., Rossi, P. D., Djurovic, S., Duron, E., Düzel, E., Dufouil, C., Eiriksdottir, G., Engelborghs, S., Escott-Price, V., Espinosa, A., Ewers, M., Faber, K. M., Fabrizio, T., Nielsen, S. F., Fardo, D. W., Farotti, L., Fenoglio, C., Fernández-Fuertes, M., Ferrari, R., Ferreira, C. B., Ferri, E., Fin, B., Fischer, P., Fladby, T., Fließbach, K., Fongang, B., Fornage, M., Fortea, J., Foroud, T. M., Fostinelli, S., Fox, N. C., Franco-Macías, E., Bullido, M. J., Frank-García, A., Froelich, L., Fulton-Howard, B., Galimberti, D., García-Alberca, J. M., García-González, P., Garcia-Madrona, S., Garcia-Ribas, G., Ghidoni, R., Giegling, I., Giorgio, G., Goate, A. M., Goldhardt, O., Gomez-Fonseca, D., González-Pérez, A., Graff, C., Grande, G., Green, E., Grimmer, T., Grünblatt, E., Grunin, M., Gudnason, V., Guetta-Baranes, T., Haapasalo, A., Hadjigeorgiou, G., Haines, J. L., Hamilton-Nelson, K. L., Hampel, H., Hanon, O., Hardy, J., Hartmann, A. M., Hausner, L., Harwood, J., Heilmann-Heimbach, S., Helisalmi, S., Heneka, M. T., Hernández, I., Herrmann, M. J., Hoffmann, P., Holmes, C., Holstege, H., Vilas, R. H., Hulsman, M., Humphrey, J., Biessels, G. J., Jian, X., Johansson, C., Jun, G. R., Kastumata, Y., Kauwe, J., Kehoe, P. G., Kilander, L., Ståhlbom, A. K., Kivipelto, M., Koivisto, A., Kornhuber, J., Kosmidis, M. H., Kukull, W. A., Kuksa, P. P., Kunkle, B. W., Kuzma, A. B., Lage, C., Laukka, E. J., Launer, L., Lauria, A., Lee, C. -Y., Lehtisalo, J., Lerch, O., Lleó, A., Longstreth, W., Lopez, O., de Munain, A. L., Love, S., Löwemark, M., Luckcuck, L., Lunetta, K. L., Ma, Y., Macías, J., Macleod, C. A., Maier, W., Mangialasche, F., Spallazzi, M., Marquié, M., Marshall, R., Martin, E. R., Montes, A. M., Rodríguez, C. M., Masullo, C., Mayeux, R., Mead, S., Mecocci, P., Medina, M., Meggy, A., Mehrabian, S., Mendoza, S., Menéndez-González, M., Mir, P., Moebus, S., Mol, M., Molina-Porcel, L., Montrreal, L., Morelli, L., Moreno, F., Morgan, K., Mosley, T., Nöthen, M. M., Muchnik, C., Mukherjee, S., Nacmias, B., Ngandu, T., Nicolas, G., Nordestgaard, B. G., Olaso, R., Orellana, A., Orsini, M., Ortega, G., Padovani, A., Paolo, C., Papenberg, G., Parnetti, L., Pasquier, F., Pastor, P., Peloso, G., Pérez-Cordón, A., Pérez-Tur, J., Pericard, P., Peters, O., Pijnenburg, Y. A. L., Pineda, J. 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M, Humphrey, J, Biessels, G, Jian, X, Johansson, C, Jun, G, Kastumata, Y, Kauwe, J, Kehoe, P, Kilander, L, Ståhlbom, A, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, M, Kukull, W, Kuksa, P, Kunkle, B, Kuzma, A, Lage, C, Laukka, E, Launer, L, Lauria, A, Lee, C, Lehtisalo, J, Lerch, O, Lleó, A, Longstreth, W, Lopez, O, de Munain, A, Love, S, Löwemark, M, Luckcuck, L, Lunetta, K, Ma, Y, Macías, J, Macleod, C, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, E, Montes, A, Rodríguez, C, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, M, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, B, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, Y, Pineda, J, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, J, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, L, Reinders, M, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, I, Rosende-Roca, M, Royo, J, Rubino, E, Rujescu, D, Sáez, M, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, M, Sanchez-Garcia, F, Juan, P, Sánchez-Valle, R, Sando, S, Sarnowski, C, Satizabal, C, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, J, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, A, Skrobot, O, Slifer, S, Snijders, G, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, J, Tárraga, L, Tesí, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Broeckhoven, C, Vance, J, Vardarajan, B, van der Lugt, A, Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, Wang, L, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Andreoni, S, Ferrarese, C, Sala, G, Zoia, C, Farrer, L, Psaty, B, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, Ikram, M, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, M, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J, Rossi, G, Seshadri, S, Andreassen, O, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, G, van Duijn, C, Sims, R, van der Flier, W, Ruiz, A, Ramirez, A, Lambert, J, VU University medical center, Amsterdam Neuroscience - Neurodegeneration, Neurology, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, APH - Personalized Medicine, APH - Methodology, Bellenguez, Céline [0000-0002-1240-7874], Küçükali, Fahri [0000-0002-3835-9639], Amin, Najaf [0000-0002-8944-1771], Holmans, Peter A [0000-0003-0870-9412], van der Lee, Sven J [0000-0003-1606-8643], Costa, Marcos R [0000-0002-4928-2163], Kuulasmaa, Teemu [0000-0002-1795-7314], Yang, Qiong [0000-0002-3658-1375], de Rojas, Itziar [0000-0002-2148-381X], Bis, Joshua C [0000-0002-3409-1110], Yaqub, Amber [0000-0002-3579-8054], Prokic, Ivana [0000-0002-0370-1473], Chapuis, Julien [0000-0002-5802-2857], Ahmad, Shahzad [0000-0002-8658-3790], Giedraitis, Vilmantas [0000-0003-3423-2021], Garcia-Gonzalez, Pablo [0000-0003-0125-5403], Alcolea, Daniel [0000-0002-3819-3245], Alvarez, Ignacio [0000-0002-8537-3935], Tsolaki, Anthoula [0000-0002-5563-7776], Baquero, Miquel [0000-0002-6861-1831], Pastor, Ana Belén [0000-0001-9637-4688], Berr, Claudine [0000-0001-5254-7655], Bessi, Valentina [0000-0002-6176-3584], Boada, Mercè [0000-0003-2617-3009], Bossù, Paola [0000-0002-1432-0078], Bråthen, Geir [0000-0003-3224-7983], Bressler, Jan [0000-0001-6578-4772], Bresner, Catherine [0000-0003-2673-9762], Brodaty, Henry [0000-0001-9487-6617], Brookes, Keeley J [0000-0003-2427-2513], Burholt, Vanessa [0000-0002-6789-127X], Bush, William S [0000-0002-9729-6519], Calero, Miguel [0000-0001-5366-3324], Chung, Jaeyoon [0000-0002-6431-9454], Cervera-Carles, Laura [0000-0003-2286-200X], Costantini, Emanuele [0000-0002-1096-8221], Dalmasso, Maria Carolina [0000-0002-4901-9955], de Paiva Lopes, Katia [0000-0002-0240-0126], de Witte, Lot D [0000-0002-7235-9958], Debette, Stéphanie [0000-0001-8675-7968], Del Ser, Teodoro [0000-0001-9806-7083], Dichgans, Martin [0000-0002-0654-387X], Diehl-Schmid, Janine [0000-0002-7745-1382], Diez-Fairen, Mónica [0000-0003-1882-0309], Djurovic, Srdjan [0000-0002-8140-8061], Dufouil, Carole [0000-0003-2442-4476], Escott-Price, Valentina [0000-0003-1784-5483], Ewers, Michael [0000-0001-5231-1714], Fabrizio, Tagliavini [0000-0003-1039-7315], Fladby, Tormod [0000-0002-9984-9797], Fornage, Myriam [0000-0003-0677-8158], Fox, Nick C [0000-0002-6660-657X], Bullido, María J [0000-0002-6477-1117], Froelich, Lutz [0000-0003-1494-0813], Galimberti, Daniela [0000-0002-9284-5953], García-Alberca, Jose Maria [0000-0003-2951-6644], Goate, Alison M [0000-0002-0576-2472], González-Pérez, Antonio [0000-0001-9771-5982], Green, Emma [0000-0002-8687-5590], Grünblatt, Edna [0000-0001-8505-7265], Gudnason, Vilmundur [0000-0001-5696-0084], Haapasalo, Annakaisa [0000-0003-0959-2957], Harwood, Janet [0000-0002-3225-0069], Heilmann-Heimbach, Stefanie [0000-0003-1057-465X], Herrmann, Martin J [0000-0001-9970-2122], Holstege, Henne [0000-0002-7688-3087], Biessels, Geert Jan [0000-0001-6862-2496], Jian, Xueqiu [0000-0002-0313-6494], Johansson, Charlotte [0000-0002-5351-1950], Jun, Gyungah R [0000-0002-3230-8697], Kastumata, Yuriko [0000-0002-0188-8094], Kehoe, Patrick G [0000-0002-7542-1139], Kornhuber, Johannes [0000-0002-8096-3987], Kosmidis, Mary H [0000-0001-8790-1220], Lage, Carmen [0000-0003-1703-121X], Launer, Lenore [0000-0002-3238-7612], Lee, Chien-Yueh [0000-0002-4304-974X], Lleó, Alberto [0000-0002-2568-5478], Lopez, Oscar [0000-0002-8546-8256], de Munain, Adolfo Lopez [0000-0002-9509-4032], Lunetta, Kathryn L [0000-0002-9268-810X], Ma, Yiyi [0000-0002-3609-8877], MacLeod, Catherine A [0000-0002-9314-7380], Marquié, Marta [0000-0002-0660-0950], Montes, Angel Martín [0000-0002-1694-786X], Mead, Simon [0000-0002-4326-1468], Medina, Miguel [0000-0002-7016-5340], Menéndez-González, Manuel [0000-0002-5218-0774], Mol, Merel [0000-0003-2533-2530], Morgan, Kevin [0000-0002-8217-2396], Nöthen, Markus M [0000-0002-8770-2464], Muchnik, Carolina [0000-0002-1542-3706], Nacmias, Benedetta [0000-0001-9338-9040], Nicolas, Gael [0000-0001-9391-7800], Nordestgaard, Børge G [0000-0002-1954-7220], Pasquier, Florence [0000-0001-9880-9788], Pastor, Pau [0000-0002-7493-8777], Peloso, Gina [0000-0002-5355-8636], Pérez-Cordón, Alba [0000-0002-6028-0791], Pérez-Tur, Jordi [0000-0002-9111-1712], Pericard, Pierre [0000-0001-8167-6448], Pineda, Juan A [0000-0002-3751-0296], Pisanu, Claudia [0000-0002-9151-4319], Posthuma, Danielle [0000-0001-7582-2365], Puerta, Raquel [0000-0002-1191-5893], Quenez, Olivier [0000-0002-8273-8505], Thomassen, Jesper Qvist [0000-0003-3484-9531], Real, Luis M [0000-0003-4932-7429], Reinders, Marcel JT [0000-0002-1148-1562], Reitz, Christiane [0000-0001-8757-7889], Riedel-Heller, Steffi [0000-0003-4321-6090], Rodriguez-Rodriguez, Eloy [0000-0001-7742-677X], Rongve, Arvid [0000-0002-0476-4134], Sáez, María Eugenia [0000-0001-9299-2534], Saltvedt, Ingvild [0000-0002-7897-9808], Juan, Pascual Sánchez [0000-0002-6081-8037], Sarnowski, Chloé [0000-0002-6090-7099], Satizabal, Claudia L [0000-0002-1115-4430], Schott, Jonathan M [0000-0003-2059-024X], Selbæk, Geir [0000-0001-6511-8219], Shadrin, Alexey A [0000-0002-7467-250X], Soininen, Hilkka [0000-0002-2785-9937], Solfrizzi, Vincenzo [0000-0002-8524-0315], Song, Yeunjoo [0000-0002-7452-3731], Sotolongo-Grau, Oscar [0000-0002-9679-0670], Spalletta, Gianfranco [0000-0002-7432-4249], Squassina, Alessio [0000-0001-7415-7607], Stordal, Eystein [0000-0002-2443-7923], Tosto, Giuseppe [0000-0001-7075-8245], Uitterlinden, Andre [0000-0002-7276-3387], Valladares, Otto [0000-0001-8055-2187], Broeckhoven, Christine Van [0000-0003-0183-7665], Vidal, Jean-Sébastien [0000-0001-6770-0720], Vogelgsang, Jonathan [0000-0001-9326-8193], Wagner, Michael [0000-0003-2589-6440], Wallon, David [0000-0002-2634-7198], Wiltfang, Jens [0000-0003-1492-5330], Woods, Bob [0000-0002-6781-651X], Yannakoulia, Mary [0000-0003-2171-7337], Zare, Habil [0000-0001-5902-6238], Zhang, Xiaoling [0000-0001-8237-1857], Farrer, Lindsay A [0000-0001-5533-4225], Psaty, Bruce M [0000-0002-7278-2190], Ghanbari, Mohsen [0000-0002-9476-7143], Raj, Towfique [0000-0002-9355-5704], Sachdev, Perminder [0000-0002-9595-3220], Mather, Karen [0000-0003-4143-8941], Ikram, M Arfan [0000-0003-0372-8585], Tsolaki, Magda [0000-0002-2072-8010], Pericak-Vance, Margaret A [0000-0001-7283-8804], Amouyel, Philippe [0000-0001-9088-234X], Williams, Julie [0000-0002-4069-0259], Frikke-Schmidt, Ruth [0000-0003-4084-5027], Seshadri, Sudha [0000-0001-6135-2622], Andreassen, Ole A [0000-0002-4461-3568], Sleegers, Kristel [0000-0002-0283-2332], van Duijn, Cornelia M [0000-0002-2374-9204], Sims, Rebecca [0000-0002-3885-1199], van der Flier, Wiesje M [0000-0001-8766-6224], Ramirez, Alfredo [0000-0003-4991-763X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Complex Trait Genetics, Clinical sciences, Neuroprotection & Neuromodulation, Pathologic Biochemistry and Physiology, Clinical Biology, Epidemiology, Internal Medicine, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UAM. Departamento de Biología Molecular, University of Helsinki, Department of Neurosciences, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, HUS Neurocenter, Neurologian yksikkö, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale (France), European Commission, LabEx DISTALZ, Pérez-Tur, Jordi, University Children’s Hospital Basel (Suiza), INSERM (Francia), Lille Métropole Communauté Urbaine, Government of France (Francia), EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Holmans, Peter A. [0000-0003-0870-9412], van der Lee, Sven J. [0000-0003-1606-8643], Costa, Marcos R. [0000-0002-4928-2163], Bis, Joshua C. [0000-0002-3409-1110], Brookes, Keeley J. [0000-0003-2427-2513], Bush, William S. [0000-0002-9729-6519], de Witte, Lot D. [0000-0002-7235-9958], del Ser, Teodoro [0000-0001-9806-7083], Fox, Nick C. [0000-0002-6660-657X], Bullido, María J. [0000-0002-6477-1117], Goate, Alison M. [0000-0002-0576-2472], Herrmann, Martin J. [0000-0001-9970-2122], Jun, Gyungah R. [0000-0002-3230-8697], Kehoe, Patrick G. [0000-0002-7542-1139], Kosmidis, Mary H. [0000-0001-8790-1220], Lunetta, Kathryn L. [0000-0002-9268-810X], MacLeod, Catherine A. [0000-0002-9314-7380], Nöthen, Markus M. [0000-0002-8770-2464], Nordestgaard, Børge G. [0000-0002-1954-7220], Pineda, Juan A. [0000-0002-3751-0296], Real, Luis M. [0000-0003-4932-7429], Reinders, Marcel J. T. [0000-0002-1148-1562], Satizabal, Claudia L. [0000-0002-1115-4430], Schott, Jonathan M. [0000-0003-2059-024X], Shadrin, Alexey A. [0000-0002-7467-250X], Farrer, Lindsay A. [0000-0001-5533-4225], Psaty, Bruce M. [0000-0002-7278-2190], Ikram, M. Arfan [0000-0003-0372-8585], Pericak-Vance, Margaret A. [0000-0001-7283-8804], Andreassen, Ole A. [0000-0002-4461-3568], van Duijn, Cornelia M. [0000-0002-2374-9204], van der Flier, Wiesje M. [0000-0001-8766-6224], and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: tau Proteins/genetics, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurologi, MED/03 - GENETICA MEDICA, 45/43, Medizin, Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13], genetics [Alzheimer Disease], Genome-Wide Association Study, Humans, tau Proteins, Alzheimer Disease, Cognitive Dysfunction, VARIANTS, pathology [Alzheimer Disease], Tau Proteins, Settore BIO/13 - Biologia Applicata, Cognitive Dysfunction/psychology, 692/699/375/365/1283, IMPUTATION, article, 1184 Genetics, developmental biology, physiology, Biología y Biomedicina / Biología, AMYLOID-BETA, Settore MED/26 - NEUROLOGIA, Neurology, psychology [Cognitive Dysfunction], Medical Genetics, Human, Neuroscience(all), 631/208/205/2138, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, ddc:570, Genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Medicinsk genetik, MED/26 - NEUROLOGIA, Alzheimer Disease/genetics, neurology, tau Protein, NECROSIS-FACTOR-ALPHA, RISK LOCI, genetics [tau Proteins], PREDICTION MODELS, Human medicine, GENERATION, RESPONSES
Abstract: 25 páginas, 6 figuras, 2 tablas, Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not
Published: 2022

41. Corallopyronin A: antimicrobial discovery to preclinical development

Author: Anna K. Krome, Tim Becker, Stefan Kehraus, Andrea Schiefer, Michael Gütschow, Lillibeth Chaverra-Muñoz, Stephan Hüttel, Rolf Jansen, Marc Stadler, Alexandra Ehrens, Domen Pogorevc, Rolf Müller, Marc P. Hübner, Thomas Hesterkamp, Kenneth Pfarr, Achim Hoerauf, Karl G. Wagner, and Gabriele M. König
Subjects: Biological Products, Lactones, Anti-Infective Agents, Organic Chemistry, Drug Discovery, Humans, Water, Biochemistry, Anti-Bacterial Agents
Abstract: Covering: August 1984 up to January 2022Worldwide, increasing morbidity and mortality due to antibiotic-resistant microbial infections has been observed. Therefore, better prevention and control of infectious diseases, as well as appropriate use of approved antibacterial drugs are crucial. There is also an urgent need for the continuous development and supply of novel antibiotics. Thus, identifying new antibiotics and their further development is once again a priority of natural product research. The antibiotic corallopyronin A was discovered in the 1980s in the culture broth of the Myxobacterium
Published: 2022

42. Combining phase contrast and immunofluorescence images using geometric hashing.

Author: Tim Becker, Sandra Schultz, Daniel H. Rapoport, and Amir Madany Mamlouk
Published: 2013
Full Text: View/download PDF

43. From time lapse-data to genealogic trees: Using different contrast mechanisms to improve cell tracking.

Author: Tim Becker, Daniel H. Rapoport, and Amir Madany Mamlouk
Published: 2012
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44. Prior fluid and electrolyte imbalance is associated with COVID-19 mortality

Author: Anna Bauer-Mehren, Vitalia Schueller, Tim Becker, Steffen Massberg, and Satu Nahkuri
Subjects: medicine.medical_specialty, business.industry, Public health, Renal function, Disease, medicine.disease, Diabetes mellitus, Pandemic, medicine, Dementia, Medicine, Medical history, Observational study, Intensive care medicine, business
Abstract: The COVID-19 pandemic represents a major public health threat. Risk of death from the infection is associated with age and pre-existing comorbidities such as diabetes, dementia, cancer, and impairment of immunological, hepatic or renal function. It remains incompletely understood why some patients survive the disease, while others do not. As such, we sought to identify novel prognostic factors for COVID-19 mortality. We performed an unbiased, observational retrospective analysis of real world data. Our multivariable and univariable analyses make use of U.S. electronic health records from 122,250 COVID-19 patients in the early stages of the pandemic. Here we show that a priori diagnoses of fluid, pH and electrolyte imbalance during the year preceding the infection are associated with an increased risk of death independently of age and prior renal comorbidities. We propose that future interventional studies should investigate whether the risk of death can be alleviated by diligent and personalized management of the fluid and electrolyte balance of at-risk individuals during and before COVID-19. Nahkuri et al. evaluate potential prognostic factors for COVID-19 mortality in a large US database of electronic health records. They find that fluid, pH and electrolyte imbalances – diagnosed at least one month prior to COVID-19 diagnosis – are associated with mortality. The clinical course of patients with COVID-19 is highly variable, with some patients barely affected and others dying. We wanted to better understand why this is the case and identify markers of COVID-19-associated mortality. To this end, we looked into the entire available medical history of more than 100,000 COVID-19 patients from the United States. We found that patients who had experienced a disturbance of electrolyte or fluid levels in the year before they contracted SARS-CoV-2 were more likely to die than patients without such a history. This observation suggests that careful monitoring and balancing of the hydration and electrolyte status during and even before a SARS-CoV-2 infection may be beneficial and possibly reduce the risk of death with COVID-19.
Published: 2021

45. Theatralität

Author: Martin Zenck, Tim Becker, and Raphael Woebs
Subjects: Music
Abstract: Die Alltags sprache kennt bereits Redewendungen wie „mach blos kein Theater! / keine Szene! ", womit Verhaltensweisen gekennzeichnet werden, die in ihrer Ubersteigerung und Verdichtung an theâtrale Handlungen auf der Buhne erinnern (nicht im Sinne einer Steigerung, aber als mediale Komplementaritat hat Immanuel Kant den Begriff der theatralischen Darstellung'2 auf die Kunste bezogen, die etwa bei den zusammengesetzten Kunsten des Melodrams und der Oper zusammenwirken) . Zugleich benennen diese alltaglich habituellen und vergleichsweise theatralen Verhaltenseisen3 die doppelte Perspektive von der sozialen Normerwartung eines Publikums auf eine besondere asthetisch ausgezeichnete der Szene (des Theaters, dem Szenarium einer Versammlung, Podiumsdiskussion oder eines Fernsehduells zwischen Politikern), wie umgekehrt bereits in den fruhen Theaterkonzeptionen die Szene in ihrer Ausrichtung auf den Rezipienten in die Wirkung einbezogen wurde, so dass gewissermasen das auf der Buhne gespielt wurde, was die Szene etwa im ,theatrum mundi' vom panoramatischen Blick auf die Wirklichkeit und die Schauspieler von den Zuschauern empfangen hatten. Dieses Spiegelverhaltnis von Theater und Wirklichkeit, von noch bis ins 1 7. Jahrhundert unverdunkeltem Zuschauerraum und Szene hat Jacques Lacan treffend zusammengefasst: „Ich meine, und Merleau-Ponty gibt uns den Hinweis, das wir im Schauspiel der Welt angeschaute Wesen sind. Was uns zum Bewustsein macht, das setzt uns auch mit demselben Schlag ein als , speculum mundi'. "4 Konsumtiv war also eine Reziprozitat des Blickes. Zentral fur diesen Austausch von Realitat und Fiktionalitat ist die Tatsache, dass das barocke Welttheater sich auch immer als Schaubuhne auf offentlichen Platzen verstand (wie heute noch allerdings ziemlich depraviert die obligatorischen federmann -Auffuhrungen bei den Salzburger Festspielen, neuerdings sogar besetzt mit Veronica Ferres,vgl. die Kritik in der F. A.Z. im Feuilleton vom 30. Juli 2002). In diesem Zusammenhang sind auch die ersten entscheidenden Veroffentlichungen sowohl von Seiten der Theateranthropologie (Richard Schechner, Eugenio Barba, Victor Turner), der Mediensoziologie (Erving Goff man) und der Organisationssoziologie und Gesellschaftsphilosophie (Niklas Luhmann, Hans-Georg Soeffner) entstanden, die in ihren Forschungen das interaktive Aushandeln sozialer und individueller Identitaten zumindest teilweise vor dem Hintergrund der theatralen und medialen Selbstinszenierung herausgearbeitet haben. Von
Published: 2021

46. Adaptive Mitosis Detection in Large in vitro Stem Cell Populations using Timelapse Microscopy.

Author: Tim Becker, Daniel H. Rapoport, and Amir Madany Mamlouk
Published: 2011
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47. Pharmacology and early ADMET data of corallopyronin A, a natural product with macrofilaricidal anti-wolbachial activity in filarial nematodes

Author: Alexandra Ehrens, Andrea Schiefer, Anna K. Krome, Tim Becker, Katharina Rox, Helene Neufeld, Tilman Aden, Karl G. Wagner, Rolf Müller, Miriam Grosse, Marc Stadler, Gabriele M. König, Stefan Kehraus, Silke Alt, Thomas Hesterkamp, Marc Peter Hübner, Kenneth Pfarr, and Achim Hoerauf
Abstract: Corallopyronin A (CorA), a natural product antibiotic of Corallococcus coralloides, inhibits the bacterial DNA-dependent RNA polymerase. It is active against the essential Wolbachia endobacteria of filarial nematodes, preventing development, causing sterility and killing adult worms. CorA is being developed to treat the neglected tropical diseases onchocerciasis and lymphatic filariasis caused by Wolbachia-containing filariae. For this, we have completed standard Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) studies. In Caco-2 assays, CorA had good adsorption values, predicting good transport from the intestines, but may be subject to active efflux. In fed-state simulated human intestinal fluid (pH 5.0), CorA half-life was >139 minutes, equivalent to the stability in buffer (pH 7.4). CorA plasma-stability was >240 minutes, with plasma protein binding >98% in human, mouse, rat, dog, mini-pig and monkey plasma. Clearance in human and dog liver microsomes was low (35.2 and 42 µl/min/mg, respectively). CorA was mainly metabolized via phase I reactions, i.e., oxidation, and to a minimal extent via phase II reactions. In contrast to rifampicin, CorA does not induce CYP3A4 resulting in a lower drug-drug-interaction potential. Apart from inhibition of CYP2C9, no impact of CorA on enzymes of the CYP450 system was detected. Off-target profiling resulted in three hits (inhibition/activation) for the A3 and PPARγ receptors and COX1 enzyme; thus, potential drug-drug interactions could occur with antidiabetic medications, COX2 inhibitors, angiotensin AT1 receptor antagonists, vitamin K-antagonists, and antidepressants. In vivo pharmacokinetic studies in Mongolian gerbils and rats demonstrated excellent intraperitoneal and oral bioavailability (100%) with fast absorption and high distribution in plasma. No significant hERG inhibition was detected and no phototoxicity was seen. CorA did not induce gene mutations in bacteria (Ames test) nor chromosomal damage in human lymphocytes (micronucleus test). Thus, CorA possesses an acceptable in vitro early ADMET profile; supported by previous in vivo experiments in mice, rats and Mongolian gerbils in which all animals tolerated CorA daily administration for 7-28 days. The non-GLP package will guide selection and planning of regulatory-conform GLP models prior to a first-into-human study.
Published: 2022

48. PSEUDo: Interactive Pattern Search in Multivariate Time Series with Locality-Sensitive Hashing and Relevance Feedback

Author: Yuncong Yu, Dylan Kruyff, Jiao Jiao, Tim Becker, and Michael Behrisch
Subjects: Signal Processing, Computer Vision and Pattern Recognition, Computer Graphics and Computer-Aided Design, Software
Abstract: We present PSEUDo, a visual pattern retrieval tool for multivariate time series. It aims to overcome the uneconomic (re-)training problem accompanying deep learning-based methods. Very high-dimensional time series emerge on an unprecedented scale due to increasing sensor usage and data storage. Visual pattern search is one of the most frequent tasks on time series. Automatic pattern retrieval methods often suffer from inefficient training data, a lack of ground truth labels, and a discrepancy between the similarity perceived by the algorithm and required by the user or the task. Our proposal is based on the query-aware locality-sensitive hashing technique to create a representation of multivariate time series windows. It features sub-linear training and inference time with respect to data dimensions. This performance gain allows an instantaneous relevance-feedback-driven adaption to converge to users' similarity notion. We demonstrate PSEUDo's performance in terms of accuracy, speed, steerability, and usability through quantitative benchmarks with representative time series retrieval methods and a case study. We find that PSEUDo detects patterns in high-dimensional time series efficiently, improves the result with relevance feedback through feature selection, and allows an understandable as well as user-friendly retrieval process.
Published: 2022

49. RoadMap to understand the role of dust in the atmosphere of Mars

Author: Ann Carine Vandaele, Jon Merrison, Gerhard Wurm, Olga Munoz, Teresa Jardiel, Hannakaisa Lindqvist, Mike Wolff, Lori Neary, Yannick Willame, Arianna Piccialli, Loïc Trompet, Zachary Flimon, Andebo Abesha, Tim Becker, Julia Martikainen, Juan Carlos Gomez-Martin, and Marco Peiteado
Abstract: The atmosphere of Mars is driven by different cycles – seasonal cycles of temperature, dust, ice, water vapour, CO2, etc. – which are coupled through transport: dust is blown from the surface by winds, carried aloft where it absorbs solar radiation and heats the atmosphere, impacting temperature, composition and winds. Formation of water ice crystals scavenges dust back from the surface. Water, being involved in the creation processes of clouds, is one of the most important species in the atmosphere. It controls the stability of the atmosphere, dominates its chemistry, and has a radiative impact through the formation of clouds. Dust is present everywhere on Mars, yet its abundance, physical properties, size distribution as well as impact on the composition, structure and dynamics of the atmosphere has today only barely been addressed and understood. However, knowledge of the characteristics of aerosols (such as dust, ices, clouds and haze) is crucial for the interpretation of the IR and UV spectra because they absorb in these spectral regions, and their absorption signature overlaps the absorption features of other species (such as O3 in the UV), and they regulate the travelling path of light in the atmosphere through absorption and (multiple) scattering. Their impact is difficult to accurately estimate because their spectral characteristics are not known with enough accuracy. The goal of the ROADMAP project (ROle and impAct of Dust and clouds in the Martian AtmosPhere) is to better characterize the Martian dust and clouds in terms of size, shape and loading within the atmosphere, but also to provide laboratory reference data which will be used to improve our knowledge on the genesis, transport and impact of dust and clouds on the Martian atmosphere. The team behind the RoadMap project brings together the laboratory community, scientists involved in space missions and numerical modellers to promote synergies through their different perspectives and experiences: laboratory scientists understand the reference data and know-how to extract the most value from their experiments; mission scientists know the intricacies and potential of the instruments and the details of their calibration; numerical modellers know what data, information and parameters are most pertinent to their simulations and how best to interpret the results. We will describe the methodology behind the project and show how we intend to improve space exploration (observation and modelling of the atmosphere) using new laboratory results (dust resuspension induced by saltation, scattering properties, etc). The RoadMap (ROle and impAct of Dust and clouds in the Martian AtmosPhere) project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101004052.
Published: 2022

50. Polynomial Embeddings and Representations.

Author: Tim Becker
Published: 2007
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