Single hole dynamics in the Kondo Necklace and Bilayer Heisenberg models on a square lattice

We study single hole dynamics in the bilayer Heisenberg and Kondo Necklace models. Those models exhibit a magnetic order-disorder quantum phase transition as a function of the interlayer coupling J_perp. At strong coupling in the disordered phase, both models have a single-hole dispersion relation with band maximum at p = (\pi,\pi) and an effective mass at this p-point which scales as the hopping matrix element t. In the Kondo Necklace model, we show that the effective mass at p = (\pi,\pi) remains finite for all considered values of J_perp such that the strong coupling features of the dispersion relation are apparent down to weak coupling. In contrast, in the bilayer Heisenberg model, the effective mass diverges at a finite value of J_perp. This divergence of the effective mass is unrelated to the magnetic quantum phase transition and at weak coupling the dispersion relation maps onto that of a single hole doped in a planar antiferromagnet with band maximum at p = (\pi/2,\pi/2). We equally study the behavior of the quasiparticle residue in the vicinity of the magnetic quantum phase transition both for a mobile and static hole. In contrast to analytical approaches, our numerical results do not unambiguously support the fact that the quasiparticle residue of the static hole vanishes in the vicinity of the critical point. The above results are obtained with a generalized version of the loop algorithm to include single hole dynamics on lattice sizes up to 20 X 20.Comment: 12 pages, 13 Fig

Bioinformatic approaches to determine pathogenicity and function of clinical genetic variants across ion channels and neurodevelopmental disorder associated genes

Clinical genetic testing for rare monogenic diseases has the scope of identifying the disease-causing variants. Identification of the molecular etiology of the disease can already today improve clinical care and is essential for the administration of precision medicines that are currently in development for many disorders. However, distinguishing pathogenic variants from benign genetic variants remains a challenge – in particular for missense variants where a single amino acid is substituted. The effects of a pathogenic variant on the protein function, for example, whether it causes a gain (GoF) or a loss (LoF) of the protein function, is most of the time not understood since most genetic variants are ultra-rare and have not been molecularly tested. In particular, for genes associated with severe developmental disorders, first-generation symptomatic treatments offer often only limited relief. Consequently, the development and application of targeted treatments that promise improvement is urgently needed. Identifying the disease-causing pathogenic and predicting their function is crucial as targeted therapies can only be administered to patients with classified pathogenic variants whose functional effects are known to avoid adverse treatment outcomes. In this dissertation, I present bioinformatic approaches to enhance the assessment of variant pathogenicity and understanding of the functional effects of genetic variants. The developed approaches were applied on an exome-wide scale using public datasets and for selected disorders for which I had expert-curated clinical-genetic data available from collaborators. The major focus of this thesis is on genes implicated in neurodevelopmental disorders and diseases associated with ion channel dysfunction for which collaboration with other research groups enabled the aggregation of required genetic, clinical, and functional datasets to develop and test the bioinformatic approaches. In the first study (Bruenger and Ivaniuk et al., in preparation for submission to Genetics in Medicine), we developed a novel approach to extend the application of current variant interpretation guidelines as proposed by the American College of Medical Genetics and Genomics (ACMG). Currently, a major limitation of interpreting the pathogenicity of variants with the ACMG guidelines presents the rare applicability of some of the proposed evidence criteria. We evaluated the potential of incorporating individual pathogenic variants observed in paralogous genes to extend the applicability of two criteria of the guidelines. Our results demonstrated that pathogenic variants in evolutionarily conserved paralogous genes can serve as evidence for a variant's pathogenicity and thus extend the current criteria's applicability by more than four times. We further explored whether the selection of the paralogous pathogenic variants can be improved by incorporating phenotype information. We assembled a clinically well-defined cohort of patients with variants in voltage-gated sodium channels (VGSC) and identified phenotype correlations among paralogous genes based on the shared variant properties. By integrating these phenotype correlations into our proposed extension of the ACMG criteria, we demonstrated an enhanced ability to provide evidence for the pathogenicity of genetic variants in VGSC-encoding genes. In the second study (Brunklaus, Feng, and Bruenger et al., Brain, 2022), we examined whether experimentally obtained functional effects of variants in one VGSC encoding gene could predict function in conserved variants in paralogous genes with high sequence similarity. We aggregated 437 in-vitro functionally tested variants from an intensive literature search and found that the functional effect across conserved variants in paralogous genes was conserved in 94% of cases. Our findings represent the first GoF versus LoF topological map of VGSC proteins, which could guide precision therapy as functionally tested variants are rare across VGSC. We integrated our findings into a publicly accessible webtool (http://SCN-viewer.broadinstitute.org) to facilitate functional variant interpretation across VGSC. In the third study (Bruenger et al., Brain, 2022), we systematically identified biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were significantly enriched for pathogenic variants compared to population variants across all ion channels. Using a newly developed structural framework, we provide quantitative evidence that variants at the pore showed the strongest pathogenic variant enrichment. Moreover, we found that a hydrophobic pore environment was most strongly associated with variant pathogenicity. Finally, we showed that the identified biological properties correlated with in-vitro functional readouts from 679 variants and clinical phenotypes in 1,422 patients with neurodevelopmental disorders which were collected through collaboration with other research groups. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future. In the fourth study (Iqbal and Bruenger et al., Brain, 2022), we developed a novel consensus approach that combines evolutionary and population-based genomic scores to identify 3D essential sites (Essential3D) on protein structures encoded by genes associated with neurodevelopmental disorders (NDDs). NDDs encompass severe clinical conditions caused by pathogenic variants in different genes. However, many of those genes were just recently associated with NDDs and are not well studied. We identified 14,377 Essential3D sites on protein structures encoded by 189 genes and found that these sites were eight-fold enriched for pathogenic versus population controls in an independent cohort of over 360,000 patient and population variants. The Essential3D sites offer insights into molecular mechanisms of protein function, such as key protein-protein interaction sites. The provided annotations are available at https://es-ndd.broadinstitute.org and will guide clinical variant interpretation. In summary, within these major studies in my Ph.D., we aggregated genetic, clinical, and functional datasets and developed bioinformatic approaches to enhance the assessment of variant pathogenicity and improve understanding of the functional effects of genetic variants on protein function. The advances made during my Ph.D. research demonstrate the power of integrating multiple data sources to study novel genetic variants and their implication for rare monogenic diseases. Our approaches specifically improve variant function and pathogenicity assessment in genes implicated in several severe diseases for which currently applied first-generation therapies cannot adequately lower the disease burden. Thus, our results contribute to a new era in precision medicine, where personalized treatments and improved clinical care become increasingly accessible to patients. Finally, the annotations developed in these can serve as a foundation for further studies, including the application of machine learning methods to predict variant pathogenicity and protein functional effects more accurately

Indwelling pleural catheters for non-malignant pleural effusions: report on a single centre's 10 years of experience

BACKGROUND: Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of infectious pleurisy and non-malignant diseases like congestive heart failure (CHF) or liver cirrhosis with hepatic hydrothorax (HH). With regard to the chronic character of the underlying diseases, indwelling pleural catheters (IPC) are increasingly used, not only assuring immediate symptom relief but also potentially leading to pleurodesis without sclerosing agents. PATIENTS AND METHODS: In this single-centre retrospective observational study, patient characteristics, procedural variables and outcome in patients with IPC in non-malignant pleural effusion (NMPE) were evaluated and prognostic factors for pleurodesis were identified. RESULTS: From 2006 to 2017, 54 patients received 62 IPC, of whom 48.4% with CHF and 43.5% with HH. The median length of insertion was 1.5 months (IQR 0.6-2.9 months), the median survival time after insertion 3.2 months (IQR 1.1-16.0). An adequate symptom relief was achieved in 93.2% with no need for subsequent interventions. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 45.9%, being associated to age (<55 years, p=0.02), the primary diagnosis (p=0.03) and interventions for the underlying disease (p<0.001). Complications occurred in 24.2% of all procedures (n=15), the majority concerning mechanical obstructions (n=10) and infections (n=4). Patients with HH had an excess risk for complications (37.3%). CONCLUSION: Efficacy in symptom relief and a generally manageable safety profile recommend IPC as a first-line treatment option in NMPE, where disease-specific treatments are exhausted. Caution is warranted in patients with HH due to an excess risk for complications

Asymmetric spin-1/2 two-leg ladders

We consider asymmetric spin-1/2 two-leg ladders with non-equal antiferromagnetic (AF) couplings J_|| and \kappa J_|| along legs (\kappa <= 1) and ferromagnetic rung coupling, J_\perp. This model is characterized by a gap \Delta in the spectrum of spin excitations. We show that in the large J_\perp limit this gap is equivalent to the Haldane gap for the AF spin-1 chain, irrespective of the asymmetry of the ladder. The behavior of the gap at small rung coupling falls in two different universality classes. The first class, which is best understood from the case of the conventional symmetric ladder at \kappa=1, admits a linear scaling for the spin gap \Delta ~ J_\perp. The second class appears for a strong asymmetry of the coupling along legs, \kappa J_|| << J_\perp << J_|| and is characterized by two energy scales: the exponentially small spin gap \Delta ~ J_\perp \exp(-J_|| / J_\perp), and the bandwidth of the low-lying excitations induced by a Suhl-Nakamura indirect exchange ~ J_\perp^2 /J_|| . We report numerical results obtained by exact diagonalization, density matrix renormalization group and quantum Monte Carlo simulations for the spin gap and various spin correlation functions. Our data indicate that the behavior of the string order parameter, characterizing the hidden AF order in Haldane phase, is different in the limiting cases of weak and strong asymmetry. On the basis of the numerical data, we propose a low-energy theory of effective spin-1 variables, pertaining to large blocks on a decimated lattice.Comment: 18 pages, 11 figure

Positionen zivilgesellschaftlicher Akteure und von Parteien zu Wettbewerb im Gesundheitswesen

Eine zentrale Rolle in der gesundheitspolitischen Auseinandersetzung spielen Ausmaß und Ausgestaltung des Wettbewerbs im Gesundheitssystem. Schwerpunkt dieses Artikels ist die Darstellung der unterschiedlichen Standpunkte von Parteien und zivilgesellschaftlichen Akteuren zum Systemwettbewerb zwischen Gesetzlicher (GKV) und Privater Krankenversicherung (PKV) im dualen Krankenversicherungssystem.A central issue in current health policy debates is the role of competition and its organisation in the German health care system. This article focuses on the different positions of political parties and civil society actors on competition between statutory health insurance (SHI) and private health insurance (PHI) in the dual health insurance system

Positionen zivilgesellschaftlicher Akteure und von Parteien zu Wettbewerb im Gesundheitswesen

Eine zentrale Rolle in der gesundheitspolitischen Auseinandersetzung spielen Ausmaß und Ausgestaltung des Wettbewerbs im Gesundheitssystem. Schwerpunkt dieses Artikels ist die Darstellung der unterschiedlichen Standpunkte von Parteien und zivilgesellschaftlichen Akteuren zum Systemwettbewerb zwischen Gesetzlicher (GKV) und Privater Krankenversicherung (PKV) im dualen Krankenversicherungssystem.A central issue in current health policy debates is the role of competition and its organisation in the German health care system. This article focuses on the different positions of political parties and civil society actors on competition between statutory health insurance (SHI) and private health insurance (PHI) in the dual health insurance system

Berufstätigkeit als Proxy für Arbeitsbelastungen? Routinedatenanalyse am Beispiel der Rehabilitation

Aim of the study: Job exposures are associated with health-related outcomes including sick leave and reduction in earning capacity. Rehabilitation of persons in working age aims primarily to secure or restore work capacity. Information concerning job exposures is, however, not directly available in routine data of healthcare payers. Since exposures relate to specific occupations and the current occupation is part of routine data, job exposures may be determined indirectly via job-exposure matrices (JEM). The aim of the study is to describe the possibilities and challenges of the representation of job exposures by the occupation according to routine data using the example of rehabilitation. Methods: The Scientific Use File 'SUFRSDLV15B' of the German Pension Insurance was analysed. We used data from n=1 242 171 persons in work with at least one completed medical rehabilitation between 2008 and 2015 (dataset 1). The occupation is coded according to KldB 88 or KldB 2010 (German Classification of Occupations). In addition, data from a nationwide survey with 2530 rehabilitation patients was available (dataset 2). Job exposures are operationalized by the Job Exposure Index via JEM. The relationship to the return-to-work prognosis at the end of rehabilitation (dataset 1) and to patient reported outcome measures (dataset 2) is described. Results: Information concerning the occupation is available for about 91% of rehabilitation measures of employed patients for the year prior to rehabilitation. At high levels of job exposures, the proportion of persons with a predicted working capacity in the last job of fewer than 3 h per day increased by a factor of 4 compared to low-level job exposures (23.5 vs. 6.1%). On the other hand, there is a low association only to reduced working capacity in the general labour market (2.9 vs. 2.4%). High-level job exposures are associated with self-reported, work-related impairments. Conclusion: The Job Exposure Index may offer a valid approach to depict occupation-related exposures. The index can be used in the analysis of routine data of the pension insurance and other social security funds, as well as in the linkage of individual assessment data with routine data containing the occupation, without any additional data collection effort. Due to its construction based on job classifications, it will not replace the assessment of individual burdens

Comparative Study of Multicanonical and Simulated Annealing Algorithms in the Protein Folding Problem

We compare a few variants of the recently proposed multicanonical method with the well known simulated annealing for the effectiveness in search of the energy global minimum of a biomolecular system. For this we study in detail Met-enkephalin, one of the simplest peptides. We show that the new method not only outperforms simulated annealing in the search of the energy groundstate but also provides more statistical-mechanical information about the system.Comment: to be published in Physica A, LATEX 32 pages, figures available on reques

Panoptic Segmentation of Individual Pigs for Posture Recognition

Behavioural research of pigs can be greatly simplified if automatic recognition systems are used. Systems based on computer vision in particular have the advantage that they allow an evaluation without affecting the normal behaviour of the animals. In recent years, methods based on deep learning have been introduced and have shown excellent results. Object and keypoint detector have frequently been used to detect individual animals. Despite promising results, bounding boxes and sparse keypoints do not trace the contours of the animals, resulting in a lot of information being lost. Therefore, this paper follows the relatively new approach of panoptic segmentation and aims at the pixel accurate segmentation of individual pigs. A framework consisting of a neural network for semantic segmentation as well as different network heads and postprocessing methods will be discussed. The method was tested on a data set of 1000 hand-labeled images created specifically for this experiment and achieves detection rates of around 95% (F1 score) despite disturbances such as occlusions and dirty lenses