Deutsche Forschungsgemeinschaft Research Articles

GLP-2 as an indicator and modulator of acute inflammation improves cardiac function and survival in sepsis

Abstract Purpose GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut hormones secreted in response to food. While GLP-1 controls glucose metabolism, GLP-2 is a local gut growth factor regulating intestinal nutrient absorption. GLP-2 has been found to be upregulated in patients with colitis. We hypothesize that beyond its local intestinal function GLP-2 might be involved in systemic immune responses. Methods and results To analyze whether GLP-2 secretion is modulated by the immune system, we measured circulating GLP-2 levels in 2 clinical cohorts. In the first cohort (n=34) GLP-2 levels increased over time following cardiac surgery as an inflammatory stimulus. In the second cohort 223 patients with sepsis had a 3.9 fold increase of GLP-2 plasma levels vs. 53 healthy controls (3.0 ng/mL vs. 11.4 ng/mL; p<0.001). High GLP-2 levels were associated with markers of inflammation (IL-6, PCT, CRP), septic cardiomyopathy (NT-proBNP) and independently predicted mortality in humans with sepsis. Induction of sepsis in mice by endotoxin or cecal ligation puncture strongly increased GLP-2 levels independent from food intake. By injecting various proinflammatory cytokines and inducing sepsis in IL1R−/− and IL6−/− mice we identified that inflammation upregulates GLP-2 secretion through IL-6. To identify the source of GLP-2 secretion under inflammation, we induced sepsis in Gcg−/− mice lacking endogenous GLP-2 production with a tissue-specific reactivation of Gcg in gut L-cells (GcgRAΔvilCre) or pancretic alpha cells (GcgRAΔPDX1-Cre). We observed sepsis-induced GLP-2 secretion to be derived from the pancreas and not from the gut. Additional in-vitro and ex-vivo approaches revealed that IL-6 directly activates GLP-2 secretion from pancreatic alpha cells. Gcg−/− mice lacking GLP-2 production and Glp2r−/− mice show aggravated sepsis indicating that endogenous upregulation of GLP-2 is protective. Finally, we analyzed whether inflammatory upregulation of GLP-2 has immunomodulatory relevance. We administered GLP-2 or saline as control per central jugular vein catheter mice who underwent CLP. GLP-2 treatment improved LV-contractility (dp/dtmax) in septic cardiomyopathy (control 7361 vs. GLP-2 9500 mmHg/s; p<0.01), inhibited sepsis-induced hypotension and reduced mortality (p=0.018). Mechanistically GLP-2 reduced myeloid immune cell infiltration into heart and liver tissue and decreased proinflammatory cytokine levels in various organs and the blood (TNF-α, IL-6 and IL-1β). After broad GLP-2 receptor profiling we found maximum mRNA expression in gut tissues with no expression on immune cells. By further mechanistic studies we found GLP-2 to protect against sepsis-induced gut barrier dysfunction. Conclusions Here we identified a counter-regulatory control system in which IL-6 derived upregulation of GLP-2 secretion limits excessive innate immune responses and protects against sepsis. These findings might open new avenues for the treatment of patients with inflammatory diseases. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): European Foundation for the Study of Diabetes, European Research Area Network on Cardiovascular Diseases (ERA-CVD and BMBF), Deutsche Forschungsgemeinschaft (DFG)

A novel direct inducible nongenetic murine model of diabetes-aggravated atherosclerosis

Abstract Background and aims Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients (1,2). Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s) on any genetic background. Methods and results Wild type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin (STZ) and fed either a high-fat diet (HFD) or high-cholesterol/high fat-diet (Paigen diet, PD) for 12 and 20 weeks. LDLR KO mice were used as reference control. Combined hyperlipidemic and hyperglycemic mice (HGHCi), but not hyperlipidemia (HCi) alone, displayed characteristic features of aggravated atherosclerosis characterized by larger and less stable plaques (necrotic core area in HGHCi HFD: 24% vs HCi HFD: 13% vs LDLR KO HFD: 18% area, at 20 weeks p<0.05; fibrous cap thickness in HGHCi: 13 μm vs HCi HFD: 23 μm vs LDLR KO HFD: 17 μm, at 20 weeks, p<0.05) which contained more macrophages (MOMA-2 in HGHCi HFD: 27% vs HCi HFD: 19% vs LDLR KO HFD: 46% area/plaque, at 20 weeks, p<0.05) and less smooth muscle cells (α-SMA in HGHCi HFD: 12% vs HCi HFD: 25% vs LDLR KO HFD: 18% area/plaque, at 20 weeks, p<0.05), on both HFD or PD diet. Diabetic atherosclerotic mice (HGHCi) fed a HFD showed 37% plaque area (of total lumen) compared to 16% plaque area in non-diabetic mice (HCi HFD) and 17% in LDLR KO HFD after 12 weeks; and 43% (HGHCi HFD) vs. 29% (HCi HFD) vs 39% plaque area (LDLR KO HFD) after 20 weeks (Figure 1A, B). Differences between the diabetic HGHCi and non-diabetic HCi HFD mice were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14) (Figure 1C). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks (HGHCi PD: 48% plaque area vs. HCi PD: 30% plaque area), therefore, representing a direct inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. Conclusion We established a nongenetic direct inducible mouse model of diabetes-aggravated atherosclerosis allowing comparative analyses of atherosclerosis in diabetic and non-diabetic conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Leptin mediates protective effects on the vasculature

Abstract Introduction and purpose Lipodystrophy (LD) syndromes are characterized by the loss of adipose tissue resulting in metabolic complications and accelerated atherosclerosis. The systemic concentration of the adipokine leptin is reduced in LD as a result of adipose tissue deficiency. A therapeutical option to treat LD is the substitution of leptin, which improves metabolic complications and reduces mortality. However, the vascular effects of leptin remain largely unknown. Here we analyze the direct effects of leptin on the vascular system and the development of atherosclerosis. Methods and results Treatment of human endothelial cells (ECs) with leptin reduced endothelial inflammation and the process of endothelial-to-mesenchymal transition (EndMT) (CNN1, −41.4%, p<0.05, n=4). In addition, leptin administration prevented the EndMT-induced increase of endothelial permeability. The protective effect of leptin on EndMT was confirmed in vivo in a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR−/−; aP2-nSrebp1c). Treatment of the mice with leptin (3.0 mg/kg body weight daily for 8 weeks) decreased EndMT. Leptin showed no effect on plaques size but reduced the protrusion of plaques in atherosclerotic areas of the aortic roots (−31%, p<0.05, n=4–6). Cytokine screening revealed an increase of the growth differentiation factor 15 (GDF15) in serum of LD patients (+26.2%, p<0.05, n=53–58) and in ECs after EndMT (+138%, p<0.05, n=6743–10920). This increase was reversed using leptin treatment in ECs undergoing EndMT, in the LD mice model, and in LD patients after 4 weeks of leptin administration. Indeed, treatment of endothelial cells with GDF15 induced EndMT (CNN1, +7.7-fold-control, p<0.05, n=3), and impaired EC barrier function. Neutralizing antibodies targeting GDF15 inhibited EndMT-mediated expression of mesenchymal genes (CNN1, −54%, p<0.05, n=4). The treatment of ECs with serum from LD patients induced EndMT and the increase of mesenchymal marker expression was inhibited with additional administration with neutralizing antibodies targeting GDF15 (CNN1, −28%, p<0.05, n=3). Conclusion Our findings indicate that EndMT is part of the cardiovascular disease progression in lipodystrophy syndromes. Leptin treatment has direct protective vascular effects by preventing inflammation, EndMT, and maintaining endothelial integrity. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)

The effect of distinct dietary interventions on proximal aortic stiffness; the DIRECT-PLUS randomized controlled trial

Abstract Background Proximal aortic stiffness (PAS) reflects arterial aging and is strongly associated with increased cardiovascular risk. Plant-rich, specifically Mediterranean-style, diets are associated with reduced cardiovascular risk. The effect of dietary interventions on PAS remains unclear. Methods We randomized participants with abdominal-obesity/dyslipidemia to healthy-dietary-guidelines (HDG), Mediterranean, or green-Mediterranean diets combined with physical activity (PA). Both Mediterranean diets were similarly hypocaloric and included 28g/day walnuts. The green-Mediterranean group also consumed green tea (3–4 cups/day) and a Wolffia-globosa (Mankai) plant green-shake. PAS was estimated based on aortic-arch pulse-wave-velocity using magnetic resonance imaging (MRI) at baseline and after 18-months. Results Among 294 participants [age=51±10.6 years, body-mass-index 31.3±4.0 kg/m2, PAS = 6.1±2.7 m/sec, retention rate = 89.8%], 281 had valid PAS measurements. Higher PAS was mostly associated with aging, hypertension, dyslipidemia, diabetes, and increased visceral adiposity (p<0.05 for all). After 18-months of intervention, all diet groups significantly reduced their PAS ([HDG: −4.8% (interquartile-range [IQR]: −22.3 to 8.7); Mediterranean: −7.3%, IQR (−20.8 to 11.9); green-Mediterranean: −14.0%, IQR (−27.0 to 2.4); p<0.05 for within-groups changes). Green-Mediterranean dieters had significantly greater PAS reduction than HDG dieters (p=0.007), also after controlling for age, sex, baseline-PAS, and Δweight. Further adjustment to baseline dyslipidemia, diabetes, and hypertension also revealed significant differences in PAS reduction between green-Mediterranean and Mediterranean groups (p=0.027). Specifically, greater green tea consumption was associated with greater PAS regression (p=0.04). ΔPAS was significantly associated with improvements in Δlow-density-lipoprotein cholesterol and Δtotal-cholesterol (p<0.05, multivariable models). All lifestyle intervention showed aortic age regression as compared to the expected (1.8±0.14 years vs.: HDG: −2.9±7.5 years; MED: −4.1±7.4 years; green-MED:-4.9±8.0 years; p<0.001). Conclusions Higher PAS is strongly related to aging and is associated with traditional cardiovascular risk factors. Lifestyle intervention promotes PAS reduction. Green-Mediterranean diet may be associated with more remarkable aortic rejuvenation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation); the Israel Ministry of Health

Oxidative activation of CaMKII mediates arrhythmias and contractile dysfunction in an obstructive sleep apnea mouse model

Abstract Background/Introduction Atrial arrhythmias frequently occur in patients with obstructive sleep apnea (OSA), but the underlying mechanisms remain insufficiently understood. We recently demonstrated that CaMKII-dependent pro-arrhythmic activity is increased in patients with OSA, but the mechanisms of CaMKII activation remain unknown. Interestingly, OSA can lead to increased reactive oxygen species production, which may facilitate CaMKII activation by oxidation at methionine residues 281/282. Purpose We tested if oxidation of CaMKII is involved in the development of arrhythmias and contractile dysfunction in vitro and in vivo in a mouse model of obstructive sleep apnea by tongue enlargement. Methods Experiments were performed using 41 wild-type (WT) and 25 genetically modified mice lacking oxidative CaMKII activation due to mutation of methionine 281/282 to valine (MMVV mice). Polytetrafluorethylene (PTFE, 100 μl) was injected into the tongue of 23 WT and 12 MMVV mice to induce OSA by sustained tongue enlargement as previously established. Whole body plethysmography was performed to confirm success of intervention. Echocardiography was performed at baseline and after 8 weeks to assess left-ventricular function. After 8 weeks, isolated atrial and ventricular cardiomyocytes were incubated with the Ca-sensitive dye FURA-2 AM (5 μM, 15 min) and analyzed with epifluorescence microscopy under regular electrical field stimulation (1 Hz). Results PTFE injection resulted in an increased frequency of inspiratory flow limitations (IFLs/h) from 27.4±5.95 to 59.6±6.22 in PTFE mice (p<0.001, fig. 1A). Interestingly, in WT PTFE mice, left ventricular ejection fraction (LVEF, in %) was reduced at 8 weeks post procedure from 57.0±1.36 to 51.5±1.85 (p=0.001, fig. 1B). Importantly, mice lacking oxidative CaMKII activation were protected from such decline in contractile function, and LVEF was higher at 8 weeks vs. WT PTFE (p<0.001, fig. 1B). Congruent with deterioration of contractility in vivo, the Ca transient amplitude after 30s pause (normalized to steady-state before pause) was decreased in ventricular cardiomyocytes of WT PTFE mice indicating increased SR Ca leak (p for interaction genotype x PTFE = 0.014, fig. 1C). In contrast to WT, the post-pause ratio was increased in MMVV PTFE mice (p=0.018, fig. 1C). In addition to contractile function, cellular arrhythmic events were analyzed as non-stimulated pro-arrhythmic events (NSEs) during steady-state electrical field stimulation at 1 Hz (fig. 1D, red arrows). NSE frequency was increased in atrial cardiomyocytes from WT PTFE mice with 0.050±0.005 compared to 0.018±0.003 s–1 in WT CTRL (p<0.001, fig. 1D). Intriguingly, MMVV mice were protected from NSEs after PTFE treatment (0.020±0.004, p<0.001 vs. WT PTFE, Fig. 1D). Conclusion In a mouse model of obstructive sleep apnea, contractile dysfunction and pro-arrhythmic activity are modulated by oxidative CaMKII activation, which may have therapeutic implications. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft; Medical Faculty at University of Regensburg

Inactivation of catalytic and non-catalytic PI3 kinase gamma functions enhances hypoxia-induced pulmonary hypertension in mice

Abstract Rationale Pulmonary hypertension (PH) is a pulmonary vascular disease characterised by chronically elevated pulmonary arterial mean pressure, increased pulmonary vascular resistance and right ventricular (RV) dysfunction and hypertrophy. The pathogenesis includes vasoconstriction of pulmonary vessels and pulmonary vascular remodelling. Phosphatidylinositol 3'-kinase γ (PI3Kγ) is highly expressed in leukocytes, endothelial cells (EC) and cardiomyocytes, which are involved in the pathogenesis of PH. The catalytic function of PI3Kγ has been shown to be associated with numerous processes that are potentially important for both vascular remodelling and maladaptive cardiac hypertrophy, including leukocyte recruitment and endothelial cell proliferation and survival. However, inhibition of non-catalytic PI3Kγ function results in reduced nitric oxide (NO) production by endothelial NO synthase (eNOS), which may lead to increased vascular resistance. Therefore, the aim of our study was to investigate the role of both catalytic and non-catalytic PI3Kγ functions in the pathogenesis of PH. Methods The importance of PI3Kγ in the pathogenesis of PH was analysed in vivo using the hypoxia-induced mouse model of PH (21 days at 10% O2 hypoxia (HOX)). PI3Kγ knockout mice (PI3Kγ−/−), as well as mice expressing a catalytically inactive form of PI3Kγ (PI3KγKD/KD) were investigated. To specifically inhibit the non-catalytic function of PI3Kγ, C57BL/6N mice were treated with a blocking peptide via intratracheal instillation and studied in the same model. Subsequently, systolic right ventricular pressure (RVSP) was measured using a Millar pressure catheter inserted via the jugular vein. In vitro, western blotting was used to investigate the phosphorylation of eNOS (Ser1177) in pulmonary ECs from wild type (WT), PI3Kγ−/− and PI3KγKD/KD mice. Results PI3Kγ−/− mice showed significantly increased RVSP after three weeks of hypoxia compared with WT controls (HOX WT 34.16±3.47mmHg vs. HOX PI3Kγ−/− 37.04±2.43mmHg; p=0.005; n≥7). A significant increase in RVSP was also detected in PI3KγKD/KD and blocking peptide-treated mice (HOX WT 34.67±2.02mmHg vs. HOX PI3KγKD/KD 37.95±1.39mmHg; p=0.023; n≥5 and HOX vehicle 34.19±2.74mmHg vs. HOX blocking peptide 37.61±2.46mmHg; p=0.011; n≥9). Heart rate, as well as systemic blood pressure, remained unchanged. Under normoxic conditions, no difference in RVSP between the groups could be measured. Interestingly, western blot detected reduced phosphorylation of eNOS after stimulation with fetal calf serum in PI3Kγ−/− ECs compared to WT and PI3KγKD/KD. Conclusion These results show that blunting of both catalytic and non-catalytic functions of PI3Kγ in vivo do not prevent the pathogenesis of PH, but conversely enhance hypoxia-induced elevation of RVSP. In this context, reduced phosphorylation of eNOS may play a crucial role, leading to increased vasoconstriction. Additional studies are required to evaluate the underlying mechanisms in detail. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): DFG Deutsche Forschungsgemeinschaft

Machine learning for classification of hypertension subtypes using multi-omics: A multi-centre, retrospective, data-driven study.

SummaryBackgroundArterial hypertension is a major cardiovascular risk factor. Identification of secondary hypertension in its various forms is key to preventing and targeting treatment of cardiovascular complications. Simplified diagnostic tests are urgently required to distinguish primary and secondary hypertension to address the current underdiagnosis of the latter.MethodsThis study uses Machine Learning (ML) to classify subtypes of endocrine hypertension (EHT) in a large cohort of hypertensive patients using multidimensional omics analysis of plasma and urine samples. We measured 409 multi-omics (MOmics) features including plasma miRNAs (PmiRNA: 173), plasma catechol O-methylated metabolites (PMetas: 4), plasma steroids (PSteroids: 16), urinary steroid metabolites (USteroids: 27), and plasma small metabolites (PSmallMB: 189) in primary hypertension (PHT) patients, EHT patients with either primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) or Cushing syndrome (CS) and normotensive volunteers (NV). Biomarker discovery involved selection of disease combination, outlier handling, feature reduction, 8 ML classifiers, class balancing and consideration of different age- and sex-based scenarios. Classifications were evaluated using balanced accuracy, sensitivity, specificity, AUC, F1, and Kappa score.FindingsComplete clinical and biological datasets were generated from 307 subjects (PA=113, PPGL=88, CS=41 and PHT=112). The random forest classifier provided ∼92% balanced accuracy (∼11% improvement on the best mono-omics classifier), with 96% specificity and 0.95 AUC to distinguish one of the four conditions in multi-class ALL-ALL comparisons (PPGL vs PA vs CS vs PHT) on an unseen test set, using 57 MOmics features. For discrimination of EHT (PA + PPGL + CS) vs PHT, the simple logistic classifier achieved 0.96 AUC with 90% sensitivity, and ∼86% specificity, using 37 MOmics features. One PmiRNA (hsa-miR-15a-5p) and two PSmallMB (C9 and PC ae C38:1) features were found to be most discriminating for all disease combinations. Overall, the MOmics-based classifiers were able to provide better classification performance in comparison to mono-omics classifiers.InterpretationWe have developed a ML pipeline to distinguish different EHT subtypes from PHT using multi-omics data. This innovative approach to stratification is an advancement towards the development of a diagnostic tool for EHT patients, significantly increasing testing throughput and accelerating administration of appropriate treatment.FundingEuropean Union's Horizon 2020 Research and Innovation Programme under Grant Agreement No. 633983, Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE (to Z.E. and F.B.), and Deutsche Forschungsgemeinschaft (CRC/Transregio 205/1).

Sub-percent precision measurement of neutrino oscillation parameters with JUNO* *Supported by the Chinese Academy of Sciences, the National Key R&D Program of China, the CAS Center for Excellence in Particle Physics, Wuyi University, and the Tsung-Dao Lee Institute of Shanghai Jiao Tong University in China, the Institut National de Physique Nucléaire et de Physique de Particules (IN2P3) in France, the

JUNO is a multi-purpose neutrino observatory under construction in the south of China. This publication presents new sensitivity estimates for the measurement of the , , , and oscillation parameters using reactor antineutrinos, which is one of the primary physics goals of the experiment. The sensitivities are obtained using the best knowledge available to date on the location and overburden of the experimental site, the nuclear reactors in the surrounding area and beyond, the detector response uncertainties, and the reactor antineutrino spectral shape constraints expected from the TAO satellite detector. It is found that the and oscillation parameters will be determined to 0.5% precision or better in six years of data collection. In the same period, the parameter will be determined to about % precision for each mass ordering hypothesis. The new precision represents approximately an order of magnitude improvement over existing constraints for these three parameters.

Don’t Judge a Book by Its Cover: Aenne Biermann’s 60 Photos

“A child’s hands” was chosen as the cover image for a monograph by photographer Aenne Biermann (1898–1933), published in Weimar Germany (1930) as part of a small series of paperback publications edited by Franz Roh and Jan Tschichold. Volume 1 of the same series, also published in 1930, was dedicated to photography by László Moholy-Nagy, who in a different context had advocated for photographic literacy. Even though Biermann was published amongst the forerunners of the New Vision, as evidenced by her photobook 60 Photos, she had been forgotten for a long time. By calling attention to her photographic oeuvre, my essay poses questions about the mechanisms of writing photobook history (and which books are omitted from it). In the discourse surrounding the photobook, the child’s hand as depicted on the cover is viewed as a symbol of the activity that the photobook unleashes, both as a tangible object and as a thinking device. Biermann’s photo-constellations oscillate between training manual and atlas for seeing, between perception primer and picture book; they offer a surprisingly humorous complexity, taking full advantage of the photobook as a medium of artistic expression.
 Acknowledgments: This paper is based in part on arguments first developed in my PhD dissertation Schools for Seeing: German Photobooks between 1924 and 1937 as Perception Primers and Sites of Knowledge (Princeton University, 2015), as well as my ABC der Photographie. Photobücher der Weimarer Republik als Schulen des Sehens [ABC of Photography. Photobooks of the Weimar Republic as Schools for Seeing] (Cologne: Walther König, 2018). Thanks to Vreni Hockenjos for the invitation to present at FotoWien in March 2022, where I took part in a panel entitled “Beyond the Margins: on Photobooks by Women”. Her research and thoughts on photobooks are invaluable. Thanks also to Michael Jennings, Sigrid Weigel, Devin Fore, Eduardo Cadava, and Barbara N. Nagel for supporting earlier thoughts on this topic in my dissertation, and to Catherine Abou-Nemeh for reading a draft version of this paper. I am grateful to Annette Kicken and the late Rudolf Kicken, as well as Petra Helck, Anna Kröger and Ina Schmidt-Runke of Gallery Kicken Berlin for introducing me to Aenne Biermann’s photographs already in 2006. The author acknowledges the support of the Cluster of Excellence “Matters of Activity. Image Space Material” funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2025 – 390648296.
 Article received: April 15, 2022; Article accepted: June 21, 2022; Published online: September 15, 2022; Original scholarly paper

Investigating color screening in proton-nucleus collisions with complex potentials* *Supported by the National Natural Science Foundation of China (NSFC) (12175165, 11705125); S.S. acknowledges support from U.S. Department of Energy, Office of Science, Office of Nuclear Physics, (DE-FG88ER40388); X.D acknowledges support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through the CRC-TR 211 'Strong-interaction matter under extreme conditions’– project number 315477589

Color screening and parton inelastic scattering modify the heavy-quark antiquark potential in mediums consisting of particles from quantum chromodynamics (QCD), leading to the suppression of quarkonium production in relativistic heavy-ion collisions. Owing to the small charm/anti-charm () pair production number in proton-nucleus (pA) collisions, the correlation between different pairs is negligible, which makes the Schrödinger equation viable for tracking the evolution of only one pair. We employ the time-dependent Schrödinger equation with an in-medium potential to study the evolution of charmonium wave functions in a hydrodynamic-like QCD medium produced in pA collisions. We explore different parametrizations of real and imaginary parts of the potential and calculate the nuclear modification factors () of and in TeV energy p-Pb collisions at the Large Hadron Collider (LHC). Comparing strong and weak screening scenarios with experimental data in this approach, we arrive at the conclusion that color screening is weak at temperatures close to the deconfined phase transition. Moreover, the imaginary part of the potential is crucial in describing the experimental data, which is consistent with widely studied semi-classical approaches, where dissociation rates are essential.

Presolving for Mixed-Integer Semidefinite Optimization

This paper provides a discussion and evaluation of presolving methods for mixed-integer semidefinite programs. We generalize methods from the mixed-integer linear case and introduce new methods that depend on the semidefinite condition. The methods considered include adding linear constraints, deriving bounds relying on 2 × 2 minors of the semidefinite constraints, tightening of variable bounds based on solving a semidefinite program with one variable, and scaling of the matrices in the semidefinite constraints. Tightening the bounds of variables can also be used in a node presolving step. Along the way, we discuss how to solve semidefinite programs with one variable using a semismooth Newton method and the convergence of iteratively applying bound tightening. We then provide an extensive computational comparison of the different presolving methods, demonstrating their effectiveness with an improvement in running time of about 22% on average. The impact depends on the instance type and varies across the methods. Funding: This work was supported by the EXPRESS II project within the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) priority program CoSIP (DFG-SPP 1798). It was also partly supported by the DFG within Project A4 in the SFB 805.

Erratum: From single to collective motion of social amoebae: A computational study of interacting cells

Moreno E, Großmann R, Beta C and Alonso S (2022) From Single to Collective Motion of Social Amoebae: A Computational Study of Interacting Cells. Front. Phys. 9:750187. doi: 10.3389/fphy.2021.750187Due to a production error, the funder CONACYT to CB was erroneously omitted. The funder Deutsche Forschungsgemeinschaft (DFG), Project-ID 318763901-SFB1294 project B02, to CB and RG was erroneously omitted.The updated funding statement can be found below: SA and EM thank grant PGC2018-095456-B-I00 funded by MCIN/AEI/10.13039/501100011033 and by "ERDF A way of making Europe", by the European Union. EM also acknowledges financial support from CONACYT. CB and RG acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG)-Project-ID 318763901-SFB1294, project B02.The publisher apologizes for this mistake.The original version of this article has been updated.

A Penalty Branch-and-Bound Method for Mixed Binary Linear Complementarity Problems

Linear complementarity problems (LCPs) are an important modeling tool for many practically relevant situations and also have many important applications in mathematics itself. Although the continuous version of the problem is extremely well-studied, much less is known about mixed-integer LCPs (MILCPs) in which some variables have to be integer-valued in a solution. In particular, almost no tailored algorithms are known besides reformulations of the problem that allow us to apply general purpose mixed integer linear programming solvers. In this paper, we present, theoretically analyze, enhance, and test a novel branch-and-bound method for MILCPs. The main property of this method is that we do not “branch” on constraints as usual but by adding suitably chosen penalty terms to the objective function. By doing so, we can either provably compute an MILCP solution if one exists or compute an approximate solution that minimizes an infeasibility measure combining integrality and complementarity conditions. We enhance the method by MILCP-tailored valid inequalities, node selection strategies, branching rules, and warm-starting techniques. The resulting algorithm is shown to clearly outperform two benchmark approaches from the literature. History: Accepted by Andrea Lodi, Area Editor for Design & Analysis of Algorithms – Discrete. Funding: M. De Santis acknowledges support within the project RM120172A2970290, which has received funding from Sapienza, University of Rome. M. Schmidt thanks the Deutsche Forschungsgemeinschaft (DFG) for its support within project A05 and B08 in the “SFB TRR 154 Mathematical Modelling, Simulation and Optimization using the Example of Gas Networks.” L. Winkel is supported by the DFG within the Research Training Group 2126: “Algorithmic Optimization.” Supplemental Material: The online supplementary material is available at https://doi.org/10.1287/ijoc.2022.1216 .

Mobilizing and Enhancing Legacy Biodiversity Data: The case of Karl Wilhelm Verhoeff's correspondence

A considerable amount of biological data is preserved as physical documents, the legacy of former explorers, collectors, researchers, and others. Mobilizing data from handwritten documents has been considered particularly challenging, with well-known cases such as the manual transcription of specimen labels and herbarium sheets by museum staff, or crowdsourced transcription of data card collections through online platforms. Here we present a pipeline of open-source software that can be used to automatically transcribe handwritten text, make it publicly available, annotate it with e.g., scientific names, extract names in Darwin Core Archive (DwC-A) for third-party reuse, and automatically recognize named entities in the machine-readable text. automatically transcribe handwritten text, make it publicly available, annotate it with e.g., scientific names, extract names in Darwin Core Archive (DwC-A) for third-party reuse, and automatically recognize named entities in the machine-readable text. We based our use case on the correspondence of the German zoologist Karl Wilhelm Verhoeff, related to the Myriapoda collection held at the Musée Zoologique de Strasbourg. The documents were processed with Transkribus (Muehlberger et al. 2019), a mostly open-source virtual research environment (OS VRE), which allows text in images to be converted into machine-readable text amenable to semantic enrichment. We achieved a character error rate as low as 5%, a remarkable result for handwritten material, as an accuracy higher than 95% for printed material is acceptable (Deutsche Forschungsgemeinschaft 2016). We then used Myriatrix (Martínez-Muñoz 2019), an instance of the Scratchpads OS VRE (Smith et al. 2011), to create bibliographic references, publish the full text, and annotate the correspondence with scientific names of myriapods. During the process, we added new scientific name spellings and combinations to the taxonomic backbone of Myriatrix and exported the full taxon classification in DwC-A via the Global Biodiversity Information Facility (GBIF) for reuse by the Global Names Architecture and its open-source tools (Patterson et al. 2016, Mozzherin et al. 2017). As a next step we are planning to subject the corrected text from Transkribus to a specific text-preprocessing workflow combining natural language processing (NLP) and machine learning (ML) techniques (Lücking et al. 2021). This includes, inter alia, a multiple annotation approach for general and bioscientific term classification in order to detect the respective entities automatically. The workflow has been developed in the framework of the Specialized Information Service Biodiversity Research (Koch et al. 2017) to make biodiversity information available via a customized and (bio-)ontology-based semantic search engine (Pachzelt et al. 2021). We recommend our comprehensive approach to natural history institutions seeking to efficiently digitize and mobilize the rich biological data present in their archival documents.

On Airport Time Slot Auctions: A Market Design Complying with the IATA Scheduling Guidelines

The growth in air traffic (before the Covid-19 pandemic) made airport time slots an increasingly scarce resource (and it is believed that this growth will continue after recovery). It is widely acknowledged that the grandfathering schemes used nowadays lead to inefficient allocations and that auctions would be a means to allocate valuable airport time slots efficiently. It has, however, also been pointed out that the design of such slot auctions is challenging due to the various constraints that need to be considered. The present paper proposes a market design for the sales of airport time slots at EU airports that complies with the Worldwide Scheduling Guidelines of the International Air Transport Association (IATA), most notably the reference value systems at level 3 airports. These guidelines need to be considered but lead to significant additional complexity in the market design. Capacity constraints are defined for overlapping time windows, which render the maximum welfare flight scheduling problem NP-hard. Auction formats with good incentive properties such as the Vickrey-Clarke-Groves mechanism or core-selecting auctions require an exact solution to the allocation problem. Given its hardness, it is far from obvious that the allocation problem can be solved to optimality sufficiently fast for practically relevant sizes of real-world problems. We introduce a mathematical model formulation for the maximum welfare flight scheduling problem that complies with all specified IATA constraints and evaluate it on near real-world data sets of flight requests for a full season of a major international airport. We show that the allocation can be computed within minutes and that all the payment computations for the winners can be done in less than two hours on average for realistic problem sizes. The consideration of values of airlines within the proposed auction mechanism leads to significant welfare gains of more than 35% as compared with benchmarks resulting from different standard objectives. These include the maximization of the number of movements, the minimization of the number of movements for which deviations from requested times occur, and the minimization of the total deviation of scheduled from requested times. Whereas the results indicate that auctions can be solved quickly for realistic problem sizes and promise significant welfare gains under the standard independent private values assumptions, the implementation of auctions in the field leads to additional serious challenges. For example, the regulator might have to impose allocation constraints to mitigate the market power of incumbent airlines. In addition, the valuation of slots and the interdependencies of the slot assignment with those at other coordinated airports need careful attention. Funding: This work was supported by the Deutsche Forschungsgemeinschaft [Grants BI-1057/I-9 and 405008493]. M. Bichler gratefully acknowledges funding by the German National Science Foundation [DFG BI 1057/9-1].

In Memoriam: Dr.-Ing. Walter Lachenmeier (1945–2022)—Reflections on a Life between Research Funding Administration, Electric Vehicle Development and Technology Transfer

These memoirs about Walter Lachenmeier (1945–2022) concentrate on his activities as head of the engineering sciences group of the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG), for which he worked from 1977 to 2007, and his following scientific activities in electric vehicle research and development, including a review of his patents in this area, which encompass topics from enhancement of the performance and lifetime of lithium-ion batteries, their arrangement, connection and configuration, as well as efficiency increase in supply and storage of energy.

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.

BackgroundConcerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules.MethodsSARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40.FindingsAmong 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50–13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23–5·77; mean difference 6·98; 5·92–8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07–13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33–12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01–2·69).InterpretationPeople with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases.FundingDeutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.

An Alternating Method for Cardinality-Constrained Optimization: A Computational Study for the Best Subset Selection and Sparse Portfolio Problems

Cardinality-constrained optimization problems are notoriously hard to solve in both theory and practice. However, as famous examples, such as the sparse portfolio optimization and best subset selection problems, show, this class is extremely important in real-world applications. In this paper, we apply a penalty alternating direction method to these problems. The key idea is to split the problem along its discrete-continuous structure to obtain two subproblems that are much easier to solve than the original problem. In addition, the coupling between these subproblems is achieved via a classic penalty framework. The method can be seen as a primal heuristic for which convergence results are readily available from the literature. In our extensive computational study, we first show that the method is competitive to a commercial mixed-integer program solver for the portfolio optimization problem. On these instances, we also test a variant of our approach that uses a perspective reformulation of the problem. Regarding the best subset selection problem, it turns out that our method significantly outperforms commercial solvers and it is at least competitive to state-of-the-art methods from the literature. History: Accepted by Andrea Lodi, Area Editor for Design &amp; Analysis of Algorithms–Discrete. Funding: The first author thanks the Deutsche Forschungsgemeinschaft (DFG) for its support within “Algorithmic Optimization” [Grant RTG 2126]. The third author thanks the DFG for its support within project A05 and B08 in the “Sonderforschungsbereich/Transregio 154 Mathematical Modeling, Simulation and Optimization using the Example of Gas Networks.” Supplemental Material: The supplementary material is available at https://doi.org/10.1287/ijoc.2022.1211 .

Repeated Games with Incomplete Information over Predictable Systems

Consider a stationary process taking values in a finite state space. Each state is associated with a finite one-shot zero-sum game. We investigate the infinitely repeated zero-sum game with incomplete information on one side in which the state of the game evolves according to the stationary process. Two players, named the observer and the adversary, play the following game. At the beginning of any stage, only the observer is informed of the state ξn and is therefore the only one who knows the identity of the forthcoming one-shot game. Then, both players take actions, which become publicly known. The paper shows the existence of a uniform value in a new class of stationary processes: ergodic Kronecker systems. Techniques from ergodic theory, probability theory, and game theory are employed to describe the optimal strategies of the two players. Funding: This work was supported by the Israel Science Foundation [Grant 591/21] and Deutsche Forschungsgemeinschaft [Grant KA 5609/1-1].

Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.

Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.