Multithreaded parallelism for heterogeneous clusters of QPUs

In this work, we present MILQ, a quantum unrelated parallel machines scheduler and cutter. The setting of unrelated parallel machines considers independent hardware backends, each distinguished by differing setup and processing times. MILQ optimizes the total execution time of a batch of circuits scheduled on multiple quantum devices. It leverages state-of-the-art circuit-cutting techniques to fit circuits onto the devices and schedules them based on a mixed-integer linear program. Our results show a total improvement of up to 26 % compared to a baseline approach.Comment: 7 pages, 4 figures, 1 table, 1 algorith

Retinal Gene Therapy: Bridging the Gap

After 50 years of gradual progress, the last decade has seen gene therapy shaping up to be a transformational technology for the treatment of previously untreatable monogenetic disorders. After being set back by several decades, crucial improvements to vector safety have again propelled gene augmentation therapy into translational reality, with monogenetic retinal disorders on the forefront of the development. This dissertation aimed to inform translational efforts towards Germany's first ocular gene therapy trials, which were conducted at the Centre for Ophthalmology in Tübingen. The individual chapters discuss the candidate's work along a trajectory from pre-clinical to clinical stages of these trials. It starts with the analysis and interpretation of comprehensive findings regarding patient, germline, and environmental safety of gene augmentation therapy, gathered from non-human primates, which led to important new hypotheses, regarding vector development and delivery, as well as patient management. Moving closer to Germany's first ocular gene therapy surgery, the thesis presents a careful, multi-modal analysis of Choroideremia patients' phenotypes, that factored into subject selection, validated the trial design, and helped to further define this rare disease. Spurred by the challenge to define novel clinical endpoints, and based on the phenotype, which was characterized in the second section, this work concludes with the investigation of a recent, computer-based colour vision test in treatment candidates, to establish its adequacy as an endpoint in retinal gene therapy trials. This dissertation is complemented by multiple reviews regarding inherited retinal disorders, as well as multiple second- and co- authorships in related literature. In its entirety, this thesis aims to paint a comprehensive picture of translational efforts in the dawn of potentially transformational advances in gene therapy

Strategies for Site‐Specific Labeling of Receptor Proteins on the Surfaces of Living Cells by Using Genetically Encoded Peptide Tags

Fluorescence microscopy imaging enables receptor proteins to be investigated within their biological context. A key challenge is to site-specifically incorporate reporter moieties into proteins without interfering with biological functions or cellular networks. Small peptide tags offer the opportunity to combine inducible labeling with small tag sizes that avoid receptor perturbation. Herein, we review the current state of live-cell labeling of peptide-tagged cell-surface proteins. Considering their importance as targets in medicinal chemistry, we focus on membrane receptors such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). We discuss peptide tags that i) are subject to enzyme-mediated modification reactions, ii) guide the complementation of reporter proteins, iii) form coiled-coil complexes, and iv) interact with metal complexes. Given our own contributions in the field, we place emphasis on peptide-templated labeling chemistry.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Leipzig School of Natural SciencesPeer Reviewe

Isogeometric dual mortar methods for computational contact mechanics

International audienceIn recent years, isogeometric analysis (IGA) has received great attention in many fields of computational mechanics research. Especially for computational contact mechanics, an exact and smooth surface representation is highly desirable. As a consequence, many well-known finite e lement m ethods a nd a lgorithms f or c ontact m echanics h ave b een t ransferred t o I GA. I n t he present contribution, the so-called dual mortar method is investigated for both contact mechanics and classical domain decomposition using NURBS basis functions. In contrast to standard mortar methods, the use of dual basis functions for the Lagrange multiplier based on the mathematical concept of biorthogonality enables an easy elimination of the additional Lagrange multiplier degrees of freedom from the global system. This condensed system is smaller in size, and no longer of saddle point type but positive definite. A very simple and commonly used element-wise construction of the dual basis functions is directly transferred to the IGA case. The resulting Lagrange multiplier interpolation satisfies discrete inf–sup stability and biorthogonality, however, the reproduction order is limited to one. In the domain decomposition case, this results in a limitation of the spatial convergence order to O(h 3 /2) in the energy norm, whereas for unilateral contact, due to the lower regularity of the solution, optimal convergence rates are still met. Numerical examples are presented that illustrate these theoretical considerations on convergence rates and compare the newly developed isogeometric dual mortar contact formulation with its standard mortar counterpart as well as classical finite elements based on first and second order Lagrange polynomials

Ligand-binding and -scavenging of the chemerin receptor GPR1

Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: as a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other. Graphic abstractDeutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Universität Leipzig (1039)Peer Reviewe

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy

Background Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. Methods Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. Results 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION− compared to VISION+ (OS: VISION−: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0–9.1, p < 0.01; PFS: VISION−: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0–7.8, p < 0.01). For patients rated TheraP−, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP−: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8–3.3, p = 0.2; PFS: TheraP−: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0–4.5, p < 0.01). Conclusion Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients

Any decline in prostate‐specific antigen levels identifies survivors scheduled for prostate‐specific membrane antigen‐directed radioligand therapy

Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS). Materials and Methods In this bicentric analysis, we included 184 mCRPC patients treated with $^{177}$Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan–Meier curves and log-rank comparison. Results A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44–0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25–0.60; p < 0.001). Conclusions In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis

Background:Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods:Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients (n = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes. Results:In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients (B = −0.016, SE = 0.006, p = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients (B = −6.734, SE = 2.514, p = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy (B = 5.974, SE = 2.420, p = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning. Conclusions:In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration

Combined Coronary CT-Angiography and TAVI-Planning: A Contrast-Neutral Routine Approach for Ruling-Out Significant Coronary Artery Disease

Background: Significant coronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). Assessment of CAD prior to TAVI is recommended by current guidelines and is mainly performed via invasive coronary angiography (ICA). In this study we analyzed the ability of coronary CT-angiography (cCTA) to rule out significant CAD (stenosis ≥ 50%) during routine pre-TAVI evaluation in patients with high pre-test probability for CAD. Methods: In total, 460 consecutive patients undergoing pre-TAVI CT (mean age 79.6 ± 7.4 years) were included. All patients were examined with a retrospectively ECG-gated CT-scan of the heart, followed by a high-pitch-scan of the vascular access route utilizing a single intravenous bolus of 70 mL iodinated contrast medium. Images were evaluated for image quality, calcifications, and significant CAD; CT-examinations in which CAD could not be ruled out were defined as positive (CAD+). Routinely, patients received ICA (388/460; 84.3%; Group A), which was omitted if renal function was impaired and CAD was ruled out on cCTA (Group B). Following TAVI, clinical events were documented during the hospital stay. Results: cCTA was negative for CAD in 40.2% (188/460). Sensitivity, specificity, PPV, and NPV in Group A were 97.8%, 45.2%, 49.6%, and 97.4%, respectively. Median coronary artery calcium score (CAC) was higher in CAD+-patients but did not have predictive value for correct classification of patients with cCTA. There were no significant differences in clinical events between Group A and B. Conclusion: cCTA can be incorporated into pre-TAVI CT-evaluation with no need for additional contrast medium. cCTA may exclude significant CAD in a relatively high percentage of these high-risk patients. Thereby, cCTA may have the potential to reduce the need for ICA and total amount of contrast medium applied, possibly making pre-procedural evaluation for TAVI safer and faster

Chemical genetic screen identifies Gapex-5/GAPVD1 and STBD1 as novel AMPK substrates

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis, acting as a sensor of energy and nutrient status. As such, AMPK is considered a promising drug target for treatment of medical conditions particularly associated with metabolic dysfunctions. To better understand the downstream effectors and physiological consequences of AMPK activation, we have employed a chemical genetic screen in mouse primary hepatocytes in an attempt to identify novel AMPK targets. Treatment of hepatocytes with a potent and specific AMPK activator 991 resulted in identification of 65 proteins phosphorylated upon AMPK activation, which are involved in a variety of cellular processes such as lipid/glycogen metabolism, vesicle trafficking, and cytoskeleton organisation. Further characterisation and validation using mass spectrometry followed by immunoblotting analysis with phosphorylation site-specific antibodies identified AMPK-dependent phosphorylation of Gapex-5 (also known as GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1)) on Ser902 in hepatocytes and starch-binding domain 1 (STBD1) on Ser175 in multiple cells/tissues. As new promising roles of AMPK as a key metabolic regulator continue to emerge, the substrates we identified could provide new mechanistic and therapeutic insights into AMPK-activating drugs in the liver