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Identifizierung seltener genetischer Varianten als Ursache für schweres COVID-19
Get PDFDiese Arbeit untersucht den bisher nur zum Teil verstandenen Zusammenhang zwischen seltenen Wirts-genetischen Varianten und schwerem COVID-19 in 52 Kandidatengenen in einer spanisch/italienischen Kohorte mit 1.772 schwer an COVID-19 Erkrankten und 5.347 Populations-basierten Kontrollen. Insbesondere unter Stratifizierung nach Risikofaktoren wie Alter und Vorerkrankungen zeigten seltene, schädliche Varianten im Gen TLR7 eine signifikante Assoziation zu schwerem COVID-19. Zusätzliche funktionelle sowie 3D-Proteinstruktur-basierte Daten zu Varianten-Pathogenität führten zu höheren Effektstärken. Während bei Männern in Vorarbeiten insbesondere ein X-chromosomal rezessiver Mechanismus diskutiert wurde, stellt diese Arbeit eine neue Hypothese für einen Pathomechanismus bei Frauen auf. Demnach könnten bei Frauen Varianten in Nähe des Dimerisierungs-Interface einen dominant-negativen Effekt durch Beeinträchtigung der Dimerisierung von TLR7 zeigen. Weiterhin wurden in den Genen IFIH1, IFNAR2 und TBK1 Hinweise auf Assoziationen zwischen seltenen Varianten und schwerem COVID-19 gefunden. Insgesamt bietet diese Arbeit deutliche Evidenz für eine Beteiligung von seltenen pathogenen TLR7-Varianten in der Ätiologie von schwerem COVID-19 und zeigt, dass Risikostratifizierung sowie differenzierte Variantenbewertung durch funktionelle in vitro Untersuchungen oder 3D-Proteinstruktur-Analysen die statistische Power von Studien zu seltenen genetischen Varianten erhöhen können
Investigation of the effect of posttranslational modification of lipoproteins in TLR2-mediated recognition of <em>Staphylococcus aureus</em>
Get PDFS. aureus has been postulated to change its lipoprotein acylation patterns under varying environmental conditions. Whether lipoproteins are posttranslationally di- or tri-acylated results in differences in recognition by human Toll-like receptors. In 2012, Kurokawa et al. observed a shift from tri- to di-acylated S. aureus lipoproteins by growth in a decreased pH environment in the stationary phase of growth. The underlying mechanisms, especially the genes involved in tri-acylation of S. aureus lipoproteins, were unknown at that time. Eight years later, Gardiner et al. discovered that two genes lnsA and lnsB encoded enzymes responsible for tri-acylation. LnsA and LnsB activity decreased bacterial recognition by TLR2 and shifted its dimerization partner from TLR6 to TLR1.
Based on these findings, the aim of this study was to investigate whether S. aureus-mediated posttranslational lipoprotein modification under stress conditions is conserved across the S. aureus species. In particular, we hypothesized that regulation of lnsA and lnsB expression under stress conditions results in altered TLR2 recognition and immunogenicity, which could account for host adaptation of S. aureus to colonization and infection
Role of the NLRP3 inflammasome in bone marrow fibrosis, neural damage, and mesenchymal stem cell survival in Myeloproliferative Neoplasms
Get PDFInflammation is a hallmark of BCR-ABL-negative myeloproliferative neoplasms (MPN), driven by mutations in JAK2, CALR, and MPL that activate JAK-STAT signaling and induce pro-inflammatory cytokines. Interleukin-1β (IL-1β), regulated by the NLRP3 inflammasome, has been implicated in key pathological features of MPN, including bone marrow (BM) fibrosis, neuropathy, and mesenchymal stem cell (MSC) loss.
This thesis investigated the role of the NLRP3 inflammasome in IL-1β-dependent disease manifestations in MPN through three main objectives. First, murine Jak2V617F- and CALR-mutant MPN cell lines were analyzed and exhibited increased Caspase-1 activation and reactive oxygen species (ROS), indicating inflammasome activity. Second, a Jak2V617F MPN mouse model was used to compare wildtype and Nlrp3-deficient animals. Nlrp3 deficiency resulted in reduced BM fibrosis, decreased COL1A1 expression, and normalization of megakaryopoiesis, while osteosclerosis showed a non-significant trend toward reduction. Third, Nlrp3 deficiency ameliorated neuropathy, preserved MSCs, and increased β3-adrenergic receptor (Adrb3) expression in the BM.
Together, these findings identify the NLRP3 inflammasome as a critical contributor to MPN pathology and support its potential as a therapeutic target. Inhibiting inflammasome activity may represent a novel strategy to improve outcomes for patients with BCR-ABL-negative MPN
Amtliche Bekanntmachungen, 55. Jahrgang, Nr. 58
No full textPrüfungsordnung für den konsekutiven Masterstudiengang „Agricultural and Food Economics“ (AFECO) der Agrar-, Ernährungs- und Ingenieurwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vom 20. August 202
The role of primary cilia in adipose tissue
Get PDFThe primary cilium serves as a cellular antenna, transducing extracellular stimuli into an intracellular response. In white adipose tissue (WAT), adipocyte precursor cells (APCs) but not mature adipocytes display a primary cilium. APCs replenish the adipocyte pool by undergoing adipogenesis. Advances in single-cell analysis have revealed the heterogeneity of APCs as they consist of multiple functionally distinct subpopulations in the WAT. The regulation of cell fate and differentiation of APCs is key to maintaining WAT homeostasis. Primary cilia have been proposed to regulate APC function and, thereby, WAT physiology. The role of cilia in regulating whole-body energy metabolism is also reflected in the Bardet-Biedl syndrome (BBS), where primary cilia dysfunction leads to obesity due to hyperphagia and WAT remodeling. However, how ciliary signaling might impact APC fate decision making is not known.
To address that, I comprehensively investigated the APC subpopulations in WAT under physiological conditions and during primary cilia dysfunction in a BBS mouse model before the onset of obesity. In mice that recapitulated the ciliopathy BBS (Bbs8-/-), I demonstrated that loss of BBS8 reduced the stem cell-like P1 APC subpopulation due to a phenotypic switch towards a fibrogenic phenotype. This was accompanied by extracellular matrix remodeling of the WAT and an increase of the profibrotic CD9high APC subpopulation. Single-cell RNA sequencing revealed an altered trajectory of Bbs8-/- cells, as they directly transitioned into fibrogenic progenitors, bypassing the committed P2 APCs. Ciliary hedgehog (Hh) signaling emerged as a central driver of the molecular changes in Bbs8-/- APCs. Controlled activation of the Hh pathway is essential for maintaining stem cell fates. However, loss of BBS8 promoted ectopic Hh activation in APCs and, in turn, induced the fibrogenic fate change.
These findings reveal a novel role of primary cilia in APC fate determination, balancing adipogenesis and fibrogenesis. The identified molecular mechanisms can serve as a basis to refine potential therapeutic targets for obesity
Small and Fast LLMs on Commodity Hardware: Post-Training Quantization in llama.cpp
Get PDFLarge Language Models (LLMs) have demonstrated remarkable capabilities but their significant computational and memory demands hinder widespread deployment, especially on resource-constrained devices. Quantization, the process of reducing the numerical precision of model parameters, has emerged as a critical technique for compressing LLMs and accelerating inference. This paper provides an overview of LLM quantization, with a particular focus on the Post-Training Quantization (PTQ) methods implemented within the popular llama.cpp framework and its GGUF file format. We begin by covering quantization fundamentals, including the distinction between PTQ and Quantization-Aware Training (QAT). We then describe the specific PTQ schemes employed by llama.cpp, including legacy methods, advanced K-quants, and recent IQ-quants, along with their underlying mathematical principles. The paper also discusses the impact of these techniques on model fidelity, hardware requirements, inference speed, and traces the adoption of GGUF as a de facto standard in the open-source community. This work serves as a practical guide and comprehensive reference for researchers aiming to deploy LLMs on resource-constrained hardware. By systematically documenting and comparing the PTQ methods within llama.cpp, we provide the necessary insights to navigate the trade-offs between model fidelity, inference speed, and memory footprint. This enables informed decision-making for real-world applications, from local CPU-based inference to efficient edge deployment
Amtliche Bekanntmachungen, 55. Jahrgang, Nr. 88
No full textÄnderung und zugleich Neubekanntmachung der Ordnung für die Wahl zum Fakultätsrat der Agrar-, Ernährungs- und Ingenieurwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vom 4. November 202
A multi-group path analysis of medication documentation quality using cross-sectional survey data : Impact of leadership, job satisfaction, patient-related burnout, and patient safety culture
Get PDFMedication-related adverse events are a major problem for patient safety and quality of care. This study explored the effects of leadership, job satisfaction, patient-related burnout and patient safety culture, measured through surveys of frontline workers, on documentation quality. Perceptions of physicians and nurses were surveyed using established instruments including the Transformational Leadership Inventory, the Copenhagen Psychosocial Questionnaire, the Copenhagen Burnout Inventory, and the Hospital Survey on Patient Safety Culture. Documentation quality was evaluated using retrospective review of patient records with the MediDoq instrument. Data from 24 departments, covering 282 physicians, 417 nurses, and 802 patient records, were analysed through a multi-group (physicians and nurses) path analysis to evaluate the theoretical model. The theoretical model revealed satisfactory fit, explaining about 76–80% of the variance in Documentation Quality for physicians and nurses. Perceived Patient Safety had a significant effect on Documentation Quality only for nurses. The analyses revealed differences between professional groups. Based on these results, (i) medication documentation quality may be affected by various organizational factors; (ii) perceived Patient Safety reported by the nurses may mediate some of these effects; (iii) the effects of various organizational factors on documentation quality may vary significantly across professional groups
Evaluating Sorafenib (SORA-2) as Second-Line Treatment for Unresectable Hepatocellular Carcinoma : A European Retrospective Multicenter Study
Get PDFBackground/Objectives: Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients. Methods: This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit. Results: In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6–13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0–4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients. Conclusions: In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC
Glucose-weighted CEST MRI in Adipose Tissue and Sepsis induced AKI
Get PDFCEST is an advanced MRI technique that is widely used today in both clinical and research. In particular, glucoCEST can be alternative to the contrast enhancement MRI technique using gadolinium (M. Kim et al., 2022). In the scope of this thesis, the CEST and glucoCEST techniques are applied to two main topics: FAT and S-AKI. Within the FAT topic, two subtopics are explored: characterizing different types of adipose tissue and evaluating glucose uptake in BAT under both resting and activated conditions. For the S-AKI topic, glucoCEST is used to assess it as a promising biomarker. This experiment is conducted in several phases: in-vitro, ex-vivo, and then transferred to in-vivo. Sections 1 and 2 provide an overview of the research direction and the fundamental principles, including MRI physics, the principles of CEST, and glucoCEST. Section 3 focuses on the characterization of adipose tissue, while Section 4 evaluates the effectiveness of the glucoCEST technique in assessing the 6-hour S-AKI model. The first project aims to differentiate between BAT and WAT using CEST spectra, with glucose as a tracer to distinguish between the two. Additionally, it evaluates the potential of the glucoCEST technique to detect the activation status of BAT through a pharmacological activation method. In this project, based on the CEST spectrum, we have clearly distinguished between the spectra of WAT and BAT based on the characteristic structure of this type of adipose tissue. In Part 2 of the first project, the glucoCEST technique was applied with two infusion methods, i.v. and i.p., to observe the different absorption times of BAT with glucose. The i.v. method showed faster wash-in and wash-out compared to the i.p. method. This shows the reasonableness of applying the i.v technique for the BAT activation experiment because the drug activation time only lasts from 40-60 minutes after injection. In addition, ex-vivo experiments with the combination of activation drugs showed the ability of the glucoCEST technique to detect BAT before and after activation. It shows the potential of glucoCEST to evaluate the function of BAT.
The second project shows the results of the experiment applying the glucoCEST technique to evaluate S-AKI. We used a S-AKI mice model that was generated by PCI model. The results of kidney injury were confirmed by the change of some blood index such as creatine, HDL and urea. MRI assessments were performed 6h after S-AKI, including the application of D-GLC, 3-OMG as a contrast agent, T1 mapping, and T2 mapping. The results of glucoCEST showed that there was a change in signal between the control group and S-AKI in both types of glucose injection. The change was also observed in the T2 mapping results between healthy and disease groups. In contrast, the T1 mapping in the injured kidneys did not show a significant change compared with the healthy group. Additionally, the T2 values changed in the control group before and after injection, particularly in the pelvis region. This suggests that glucose injection alters the properties of urine. This finding aligns with the AACID results, where similar changes were observed in the pelvis, indicating a shift in the pH environment after glucose injection.
Our results show that glucoCEST MRI is more sensitive to the change in septic groups in the early time point at 20 minutes. It indicates that glucoCEST can be a potential biomarker to evaluate the early stage of S-AKI