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Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation
No full textAutologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A . A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring
Social contact patterns derived from an epidemiological survey and GPS-based co-location data – A systematic comparison using parallel data collections during the COVID-19 pandemic in Germany
No full textThe parametrisation of contact behaviour is crucial for infectious disease transmission models. Contact information derived from self-reported surveys and from co-location in space and time (GPS-based) may reflect different dimensions of contact behaviour, which might be associated with distinct epidemiological risks depending on the contagion of interest. This study explores whether and how contacts measured using these distinct approaches exhibit similar or complementary contact patterns. We compare the mean number of contacts and the mean excess number of contacts (i.e. the ratio of mean squared contacts to mean contacts) from the COVIMOD survey and NETCHECK GPS co-location data between April 2020 and December 2021. While mean contacts measure contact intensity, mean excess contacts reflect dispersion, which is important for understanding superspreading behaviour. Mean contacts were considerably higher in co-location data (11.04; 95 %CI: 10.90–11.19) than in survey data (3.38; 95 % CI: 3.30–3.47); however, both data sources correlated well with each other. Mean excess contacts were similar during periods of strict non-pharmaceutical interventions (NPIs) but diverged when NPIs were lifted, with co-location data values rising more markedly. Setting-specific contact patterns also differed, potentially due to methodological differences in setting classification and data capture. Furthermore, regional variation was more pronounced in co-location data, with densely populated city-states showing higher contact numbers. Comparative insights from the two data sources demonstrate that GPS-based and survey-based contact data capture complementary and distinct aspects of human interaction. Combining both sources could provide a more comprehensive picture of human interactions relevant to infectious disease modelling
Polystyrene micro- and nanoplastics in a colitis mouse model – effects on biodistribution, macrophage polarization, and gut microbiome
No full textThe increasing prevalence of inflammatory bowel disease (IBD) and rising pollution from micro- and nanoplastic (MNP) particles has prompted investigations on their potential interconnection. To elucidate the complex relationship between IBD and exposure to MNPs, we induced colitis in mice using dextran sodium sulfate (DSS) and orally administered a mixture of polystyrene (PS) MNPs (diameter 10, 1, and 0.29 µm). These particles enabled a detailed examination of MNP biodistribution, innate immune cell response and gut microbiome alterations under inflammatory conditions. Specifically, the nanosized PS particles predominantly accumulated in the bloodstream and excretory organs, with enhanced accumulation in the inflamed gut/colon. Proteomic analysis of the colon revealed alterations in molecular pathways related to protein transport, metabolism, and immune responses. Specifically, we found macrophage proteome signatures with pro-inflammatory polarization, highlighting the intricate effects of MNPs on inflammation and immune cell behavior. Moreover, MNPs significantly disrupted the gut microbiome, reducing microbial diversity and shifting bacterial populations towards pro-inflammatory and potentially pathogenic species. These changes suggest that MNP exposure could exacerbate colitis through complex interactions involving MNPs, immune responses, and microbial dynamics. The widespread presence of MNPs underscores the urgent need for comprehensive strategies to address MNP pollution, its implications for disease, and potential impacts on public health
Transformative learning: noticing student strengths through frame shifting
No full textThis exploratory study investigates the dynamics of frame shifting in teacher noticing, examining how structured pedagogical interventions support the development of strength-based noticing practices. The research offers theoretical insights by exploring mechanisms of professional transformation through an integrated framework synthesising professional noticing, transformative learning theory, and frame analysis. During an intensive two-week teacher education course, twenty-six prospective secondary mathematics teachers engaged with a structured coding scheme designed as both an analytical tool and pedagogical scaffold. Analysis of written responses to a standardised noticing task revealed decreases in deficit-based orientations and increases in strength-based orientations. These findings suggest that structured frame shifting—the deliberate practice of changing interpretive frameworks—supports teachers in developing more sophisticated ways of recognising and building upon student thinking. This study contributes evidence for mechanisms through which teachers develop new ways of attending, interpreting, and responding to students’ mathematical thinking, with implications for designing teacher education programs that promote equity-oriented teaching practices
Between Symptoms and Complications: Innovative Concepts of Visceral Pain Inhibition in IBD and Characteristics of IBD-related Colorectal Carcinoma
No full textIBD represents a relevant inflammatory disorder of the gastrointestinal tract that requires an interdisciplinary collaboration of gastroenterologists and visceral surgeons to provide precise and individualized treatment options. Especially adequate management of chronic symptoms and an effective therapy of complications are crucial, but also highly challenging in the overall treatment plan of these patients. Therefore, the present study focused on abdominal pain typically resulting from intestinal inflammation and displaying one of the leading symptoms in IBD and on the other hand on malignant transformation, especially the occurrence of CRC as one of the most incisive complications in this inflammatory disorder.
In the first part of the present work, we therefore started to investigate nociceptive signaling which comprises a complex network of diverse areas, neurons and interacting neurotransmitter systems with special regard to the GABAergic and the opioidergic system. We initially examined the role of GABAergic neurotransmission with respect to GABABR-mediated effects in multiple in vitro experiments which should serve as a basis for future in-depth studies. However, besides GABAergic transmission, administration of opioids and subsequent activation of the opioidergic system still represents the mainstay in clinical practice to inhibit nociceptive signaling thus providing adequate pain relief in many inflammatory disorders, especially in IBD. Nevertheless, the powerful analgesic actions of opioids are counteracted by their severe side effects which markedly limit their prevalent use hence indicating the need for new potent analgesic drugs with low side effect profiles. NFEPP, a fentanyl analogue, typifies such a novel compound which was designed to activate MORs only in acidic microenvironments thereby providing potent analgesia without opioid-typical side effects (Spahn et al., 2017). We next examined the actions of the potential alternative NEPP in a murine model of colonic inflammation employing multiple in vivo and in vitro experiments combined with a translational approach in human colonic tissue. Interestingly, we found that during a colonic inflammation which closely mimics the inflammatory state of ulcerative colitis, repeated treatment with NFEPP effectively inhibited visceral nociception without inducing opioid-typical adverse events and its actions were strictly confined to acidic areas which corresponded to sites of histologically verified inflammation within the inflamed colonic wall.
Moreover, in our murine model of IBD, we additionally revealed that NFEPP maintained its antinociceptive actions over time and did not induce analgesic tolerance compared to fentanyl when applied at the same dose and dosing intervals. Finally, we substantiated our results by proving that NFEPP was also able to inhibit human colonic nociceptors under acidic conditions likely indicating its potential future transition into clinical practice as a novel safe and effective analgesic drug for adequate pain control in inflammatory gastrointestinal disorders such as IBD.
In the second part, we then investigated sporadic and IBD-related CRC. Identification of distinctive tumor characteristics will likely codetermine therapeutical procedures and survival predictions. In this context, primary tumor sidedness is assumed to be of predictive value based on diverse clinicopathological characteristics found in right- and left-sided tumor localizations. Thus, we first examined an unselected population of patients with sporadic CC stage I-IV at our institution and did not reveal an association of primary tumor sidedness with survival outcomes in our cohort although demonstrating diverse clinicopathological characteristics in the right- and left-sided group. We next conducted a multicentric study of IBD-related non-metastatic CRC and similarly disclosed that primary tumor sidedness did not affect overall and recurrence-free survival, but also found that clinicopathological features were equally distributed among a right- and left-sided tumor localization in these patients likely referring to a unique nature of IBD-related CRC. Interestingly, CEA levels and parameters that were related to lymph node status significantly impacted the overall outcome in sporadic and IBD-related CRC highlighting the relevance of common tumor load and affection of lymph nodes for patient mortality. Nevertheless, our results point out the imperative of future high-power and in-depth studies to clarify the question if primary tumor sidedness could ultimately dictate diverse therapeutical approaches in patients with sporadic and IBD-related CRC
The soil microbiome as an indicator of ecosystem multifunctionality in European soils
No full textThe role of soil microorganisms in supporting multiple ecosystem functions (multifunctionality) remains poorly understood across diverse environmental conditions. Here, we investigate 484 soils from 27 European countries spanning a range of climatic and edaphic contexts. We assess the contribution of climate, soil properties, and soil microbiome traits (i.e., the relative abundance of co-occurring taxa) to explain six key functional proxies related to soil structure, biochemical activity, and productivity. We find the highest multifunctionality values in grasslands, woodlands, loamy and acidic soils, and temperate humid regions, and the lowest in croplands, alkaline soils, and drier regions. Soil properties explain 12–31% of variation in multifunctionality, with microbial biomass and nitrogen content emerging as the strongest predictors. The soil microbiome accounts for 2–14% of unique variance in multifunctionality but explains more than 25% of variation in enzymatic activities and primary productivity in clay-rich soils and soils originating from temperate dry regions. Specific taxa, particularly within Actinobacteria, Acidobacteria, and the fungal genus Mortierella consistently emerge as strong predictors of ecosystem multifunctionality. Our findings highlight that ecosystem multifunctionality is jointly shaped by soil properties and microbial communities. We argue that specific taxa hold potential as context-dependent indicators for multifunctionality monitoring across environmental gradients
A unified 3D reconstruction of microscopy and MRI in a brain showing Alzheimer's disease-related neuropathology
No full textTo bridge between detailed post-mortem neuropathological assessments and Magnetic Resonance Imaging (MRI), we have created and share a three-dimensional (3D) account of an entire human brain with an intermediate Alzheimer's disease neuropathologic change. We combined multimodal imaging, using cryosectioning, histology, immunocytochemistry, and quantitative ultra-high field 7 Tesla (T) magnetic resonance imaging (MRI) at submillimeter resolution. Amyloid-β and phosphorylated-tau immunoreactivity, cell soma, and nerve fibers were visualized, together with quantitative MR parameters. All data were coaligned with at 200 μm resolution and are openly shared. The use of whole-brain sections allows for a detailed assessment of neuropathological alterations, revealing clear differences between the left and right hemispheres in terms of pathological load of amyloid-β and phosphorylated-tau in a single brain showing Alzheimer's disease neuropathologic change. This resource opens the door for a combination of detailed correlations between neuroimaging and neuropathological microscopy observations, as well as for detailed MRI validation
DNA methylation changes during acute COVID-19 are associated with long-term transcriptional dysregulation in patients’ airway epithelial cells
No full textMolecular changes underlying the persistent health effects after SARS-CoV-2 infection remain poorly understood. To discern the gene regulatory landscape in the upper respiratory tract of COVID-19 patients, we performed enzymatic DNA methylome and single-cell RNA sequencing in nasal cells of COVID-19 patients ( n = 19, scRNA-seq n = 14) and controls ( n = 14, scRNA-seq n = 10). In addition, we resampled a subset of these patients for transcriptome analyses at 3 ( n = 7) and 12 months ( n = 5) post infection and followed the expression of differentially regulated genes over time. Genome-wide DNA methylation analysis revealed 3112 differentially methylated regions between COVID-19 patients and controls. Hypomethylated regions affected immune regulatory genes, while hypermethylated regions were associated with genes governing ciliary function. These genes were not only downregulated in the acute phase of the disease but sustained repressed up to 12 months post infection in ciliated cells. Validation in an independent cohort collected 6 months post infection ( n = 15) indicated symptom-dependent transcriptional repression of ciliary genes. We therefore propose that hypermethylation observed in the acute phase may exert a long-term effect on gene expression, possibly contributing to post-acute COVID-19 sequelae
Mapping high-income taxpayers in Berlin using kernel-smoothed proportions from aggregated georeferenced data
No full textThe rare access to exact official geocoordinates opens new methodological possibilities for analyzing highly
sensitive tax data. We explore their visualization potential and systematically evaluate aggregation as an
anonymization strategy, with particular attention to its methodological and analytical implications. For an
analysis of high-income taxpayers in Berlin, Germany, the focus is on the presentation of regional shares. In
addition to frequency maps, smoothed representations using kernel density estimation are analyzed in particular,
and their cartographic characteristics are discussed. Due to the high sensitivity of individual-level data, such data
are generally not published, which is why anonymization is required in official statistics. This applies in particular
to the group of high-income taxpayers. Using exact data as a gold standard makes it possible to systematically
analyze the distortions caused by aggregation, one of the most commonly used anonymization methods in official
statistics. In order to correct these distortions, a measurement error model is employed that explicitly accounts
for the aggregation process and produces smoothed kernel density estimates for interpretable cartographic
representations. In addition, the measurement error model is linked with census information to demonstrate
a realistic application scenario. Local and global error measures are intended to empirically substantiate the
improvement achieved through the use of the measurement error model
On the split closure of the periodic timetabling polytope
No full textThe Periodic Event Scheduling Problem (PESP) is the central mathematical tool for periodic timetable optimization in public transport. PESP can be formulated in several ways as a mixed-integer linear program with typically general integer variables. We investigate the split closure of these formulations and show that split inequalities are identical with the recently introduced flip inequalities. While split inequalities are a general mixed-integer programming technique, flip inequalities are defined in purely combinatorial terms, namely cycles and arc sets of the digraph underlying the PESP instance. It is known that flip inequalities can be separated in pseudo-polynomial time. We prove that this is best possible unless P = NP, but also observe that the complexity becomes linear-time if the cycle defining the flip inequality is fixed. Moreover, introducing mixed-integer-compatible maps, we compare the split closures of different formulations, and show that reformulation or binarization by subdivision do not lead to stronger split closures. Finally, we estimate computationally how much of the optimality gap of the instances of the benchmark library PESPlib can be closed exclusively by split cuts, and provide better dual bounds for five instances