Biology subjects

Hansen, N.

Publications and source records attributed to Hansen, N..

11 recordsLinked to original sources

bioRxiv2026

Disrupted mannosidase enzymes in C9orf72 ALS/FTD

Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder resulting from the loss of motor neurons in the brain and spinal cord. Neuroinflammation, induced by glial cells including microglia (MG) and astrocytes, is an acknowledged aspect of this neurodegeneration. Generating induced pluripotent stem cell (iPSC) neuroinflammatory models of ALS may help elucidate non-neuronal mechanisms of disease. Here, we analyze human postmortem tissue and an iPSC derived glia-crosstalk model identifying a reduction in Golgi enzymes MAN1A1 and MAN1A2 in addition to other glycan enzymes from ALS-associated microglia and astrocytes. Impaired Golgi and glycan metabolism is linked to inflammation and other related ALS disease mechanisms including impaired lysosomal proteostasis, altered extracellular matrix, disrupted secretion, and altered cell-cell signaling.

neuroscience↗

bioRxiv2026

Precision Targeting of Heparan Sulfate Proteoglycans Broadly Dysregulates Survival Signaling and Metabolic Adaptation in Pancreatic Cancer

Treatments for pancreatic ductal adenocarcinoma (PDAC) often fail because of the cancer's ability to adapt its signaling and metabolic pathways to circumvent treatment mechanisms. PDAC hallmarks that promote treatment resistance (increased fatty acid metabolism, survival signaling, desmoplasia, and macropinocytosis) are extensively regulated by heparan sulfate proteoglycans (HSPGs) and their binding partners. The pro-tumor functions of HSPGs are controlled by site-specific cleavage of their heparan sulfate chains by mammalian heparanase; however, cleavage by bacterial heparinase III (HepIII) represses these functions and prevents downstream, pro-tumor signaling. Using tumor-targeting, attenuated Salmonella typhimurium (strain YS1646), we have limited HepIII transgene expression to tumor tissue. Degradation of tumor cell heparan sulfates by HepIII resulted in decreased macropinocytosis, reduced survival signaling, lipid storage depletion, and decreased expression of translational machinery. This tumor-targeting treatment has the potential to improve the efficacy of several approved pancreatic cancer therapies, which is predicted to increase patient survival.

cancer biology↗

bioRxiv2025

Molecular profiling of glioblastoma-derived extracellular vesicles identifies small nucleolar RNAs as candidate liquid biomarkers for radiation-induced senescence

Radiation-induced senescence (RIS) in glioblastoma (GBM) is an undesirable cell fate that reduces tumor cell death and supports resistance and outgrowth. While senescence-targeting drugs are promising adjuvants, their clinical application will require proper patient selection based on post-treatment RIS burden. Current methods to evaluate senescence, however, are tissue-based, and given GBMs difficult anatomical location, post-treatment biopsies are impractical. Innovative and less invasive biomarkers for RIS are urgently needed. To this end, we aimed to identify candidate extracellular vesicle (EV) liquid biomarkers for RIS by profiling senescence-associated cargo changes within GBM EVs. Using a panel of GBM patient-derived cell cultures, we show that RIS is the primary functional state following radiation exposure and is associated with significant alterations in the cargo of senescent-derived EVs (senEVs). In particular, senEV transcriptomes have an increased abundance of senescence-associated RNA genes and gene sets. Most striking, however, was that senEVs are most differentiated by the significant enrichment of a panel of snoRNAs. This signature was conserved in 4/5 GBM models of RIS and was validated by qRT-PCR. We further confirmed snoRNA enrichment in the senEVs of a breast cancer cell line, as well as the lack of snoRNA enrichment following senescence-independent drug exposure. Analysis by mass spectrometry revealed that snoRNAs are likely co-packaged with their associating proteins, as senEVs had concurrent increases in these binding partners. We examined whether packaging is associated with nucleolar stress during RIS, but found that upregulation in senEVs is likely due to a tightly controlled cellular abundance rather than nucleoli fragmentation and release of nucleolar components to the cytoplasm. Finally, using a preliminary cohort of longitudinal plasma samples from four GBM patients, we determined the feasibility of detecting senescence-associated and snoRNA species in the extracellular vesicles of patient biofluids. Of interest, post-treatment EVs had increased senescence-associated RNAs like CDKN2B and GLB1 and the snoRNA SNORA49. Altogether, this data suggests that senEV RNA species, and particularly snoRNAs, are a promising analyte for RIS-biomarker development. With further study, this work may open avenues for a companion diagnostic for senotherapeutics.

cancer biology↗

bioRxiv2025

Evaluating a structured expert elicitation approach for adaptive conservation: Lessons from five years in practice

Threatened species management relies on Ex ante estimates of species responses to different interventions to generate meaningful predictions. Structured expert elicitation is often used to generate these estimates, but comparisons of these expert-predicted outcomes with observed results are rare. This study aims to evaluate the utility of expert elicitation for adaptive management in the New South Wales Saving our Species (SoS) program in Australia by revisiting six species management plans that were generated from bespoke structured elicitation guidelines five years prior. Each species management plan included a defined scope, conceptual model, monitoring indicators and estimated response to management curves under different scenarios. Experts reviewed the conceptual models after five years of management and monitoring and compared the predicted response to management with observed monitoring data. In three of the six case studies, observed outcomes closely matched predictions. Where predictions diverged, factors such as unanticipated new threats and unexpected responses to interventions contributed to discrepancies. However, in all cases, the structured approach provided a clear logic for planning, enabling managers to systematically refine their understanding. The conceptual models and response curves proved valuable for collaboration, communication, and generating hypotheses for unexpected results. This work demonstrates the value of the bespoke guidelines in supporting adaptive management processes, strengthening the knowledge base for threatened species conservation while improving alignment between predictions and real-world outcomes.

ecology↗

bioRxiv2025

Single JAK2-V617F hematopoietic stem cells can initiate MPN in transplantations into non-conditioned recipient mice

Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem cells (HSC) that are most frequently caused by acquired somatic mutations in JAK2. A number of conditional mouse models of JAK2-V617F-driven MPN have been generated that rely on Cre-LoxP mediated activation, resulting in polyclonal disease. To more closely mimic the monoclonal origin of human MPN, transplantations of single purified JAK2-mutant HSCs or bone marrow (BM) at limiting dilutions into lethally irradiated recipient mice have been previously performed. However, irradiation is known to alter the BM microenvironment and also to induce transient aplasia accompanied by elevated cytokine levels that promotes the expansion of the mutant clone. To overcome these limitations, we examined whether JAK2-V617F-mutant HSCs are able to engraft and initiate MPN in non-conditioned recipients. We found that BM from two different MPN models, one expressing the human JAK2-V617F, and another expressing the mouse Jak2-V617F, efficiently engrafted and initiated MPN in non-irradiated immunocompromised Rag2-/- recipients. MPN evolved even in transplantations at limiting dilutions, showing high competitiveness of single JAK2-mutant HSCs. Thus, JAK2-V617F mutant HSCs can outcompete resident non-mutated HSCs in the absence of elevated cytokine levels and without the need of emptying stem cell niches by irradiation. However, only BM from mice expressing the mouse Jak2-V617F engrafted and initiated disease in non-conditioned C57BL/6 mice, while BM from mice expressing the human JAK2-V617F was rejected, indicating that mouse Jak2-V617F is ignored by the immune surveillance. These results provide a possible explanation why JAK2-V617F is so frequently found in healthy individuals with clonal hematopoiesis.

cancer biology↗

bioRxiv2024

SMAS: Structural MRI-Based AD Score using Bayesian VAE

This study introduces the Structural MRI-based Alzheimers Disease Score (SMAS), a novel index intended to quantify Alzheimers Disease (AD)-related morphometric patterns using a deep learning Bayesian-supervised Variational Autoencoder (Bayesian-SVAE). SMAS index was constructed using baseline structural MRI data from the DELCODE study and evaluated longitudinally in two independent cohorts: DEL-CODE (n=415) and ADNI (n=190). Our findings indicate that SMAS has strong associations with cognitive performance (DELCODE: r=-0.83; ADNI: r=-0.62), age (DEL-CODE: r=0.50; ADNI: r=0.28), hippocampal volume (DEL-CODE: r=-0.44; ADNI: r=-0.66), and total grey matter volume (DELCODE: r=-0.42; ADNI: r=-0.47), suggesting its potential as a biomarker for AD-related brain atrophy. Moreover, our longitudinal studies suggest that SMAS may be useful for early identification and tracking of AD. The model demonstrated significant predictive accuracy in distinguishing cognitively healthy individuals from those with AD (DELCODE: AUC=0.971 at baseline, 0.833 at 36 months; ADNI: AUC=0.817 at baseline, improving to 0.903 at 24 months). Notably, over a 36-month period, SMAS index outperformed existing measures such as SPARE-AD and hippocampal volume. Relevance map analysis revealed significant morphological changes in key AD-related brain regions--including the hippocampus, posterior cingulate cortex, precuneus, and lateral parietal cortex--highlighting that SMAS is a sensitive and interpretable biomarker of brain atrophy, suitable for early AD detection and longitudinal monitoring of disease progression.

neuroscience↗

bioRxiv2024

Human placental organoids as a model to probe early gestation maternal immune dynamics

During pregnancy, the human placenta establishes tolerance toward fetal allogeneic tissue, where specialized trophoblast subtypes play a complex role in local and peripheral immunomodulation. However, due to inadequate models to study the early gestation of the human placenta, each trophoblast subtypes role in modulating the maternal immune response has remained elusive. Here, we derived human placental organoids from early gestation trophoblast stem cells to (1) identify patterns of immunomodulatory protein expression by trophoblast subtype and (2) evaluate the effects of the placental organoid secretome on immune cell activation and regulation. We show that the three primary trophoblast phenotypes had distinct influences on immune cell phenotype and activation and that three-dimensional culture significantly alters trophoblast immunomodulation relative to traditional two-dimensional trophoblast culture.

bioengineering↗

bioRxiv2024

Engineered 3D Hydrogel Matrices to Modulate Trophoblast Stem Cell-Derived Placental Organoid Phenotype

Placental organoid models are a promising platform to study human placental development and function. Organoid systems typically use naturally derived hydrogel extracellular matrices (ECM), resulting in batch-to-batch variability that limits experimental reproducibility. As an alternative, synthetic ECM-mimicking hydrogel matrices offer greater consistency and control over environmental cues. Here, we generated trophoblast stem cell-derived placental organoids using poly(ethylene glycol) (PEG) hydrogels with tunable degradability and placenta-derived ECM cues to evaluate trophoblast differentiation relative to Matrigel and two-dimensional (2D) culture controls. Our data demonstrate that PEG hydrogels support trophoblast viability and metabolic function comparable to gold standard Matrigel. Additionally, phenotypic characterization via proteomic analysis revealed that PEG and Matrigel matrices drive syncytiotrophoblast and extravillous trophoblast-dominant placental organoid phenotypes, respectively. Further, three-dimensional (3D) environments promoted greater integrin expression and ECM production than 2D culture. This study demonstrates that engineered 3D culture environments can be used to reliably generate placental organoids and guide trophoblast differentiation.

bioengineering↗

bioRxiv2023

IL-1β promotes MPN disease initiation by favoring early clonal expansion of JAK2-mutant hematopoietic stem cells

JAK2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). However, JAK2-V617F can also be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the prevalence of MPN. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that IL-1{beta} mediated inflammation is one of the factors that favors this progression. We examined mono- or oligoclonal evolution of MPN by performing bone marrow transplantations at limiting dilutions with only 1-3 JAK2-mutant HSCs per recipient. Genetic loss of IL-1{beta} in JAK2-mutant hematopoietic cells or inhibition by a neutralizing anti-IL-1{beta} antibody restricted the early clonal expansion of these JAK2-mutant HSCs resulting in a reduced frequency of a CHIP-like state and a lower rate of conversion to MPN. The MPN disease-promoting effects of IL-1{beta} were associated with damage to sympathetic innervation leading to loss of nestin-positive mesenchymal stromal cells and required the presence of IL-1R1 on bone marrow stromal cells. The anti-IL-1{beta} antibody protected these mesenchymal stromal cells from IL-1{beta} mediated damage and limited the expansion of the JAK2-mutant clone. Our results identify IL-1{beta} as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPN. Brief summaryIn a mouse model of oligo-clonal myeloproliferative neoplasm (MPN), IL-1{beta} produced by JAK2-mutant cells favored expansion of sub-clinical JAK2-V617F clones and initiation of MPN disease.

cancer biology↗

bioRxiv2022

Individualized Gaussian Process-based Prediction of Memory Performance and Biomarker Status in Ageing and Alzheimer's disease

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as informative covariates, vascular risks, brain activity, neuropsychological test etc.,) might provide useful predictions of clinical outcomes during progression towards Alzheimers disease (AD). The Bayesian approach aims to provide a trade-off by employing relevant features combinations to build decision support systems in clinical settings where uncertainties are relevant. We tested the approach in the MRI data across 959 subjects, aged 59-89 years and 453 subjects with available neuropsychological test scores and CSF biomarker status (amyloid-beta (A{beta})42/40 & and phosphorylated tau (pTau)) from a large sample multi-centric observational cohort (DELCODE). In order to explore the beneficial combinations of information from different sources, we presented a MRI-based predictive modelling of memory performance and CSF biomarker status (positive or negative) in the healthy ageing group as well as subjects at risk of Alzheimers disease using a Gaussian process multikernel framework. Furthermore, we systematically evaluated predictive combinations of input feature sets and their model variations, i.e. (A) combinations of brain tissue classes and feature type (modulated vs. unmodulated), choices of filter size of smoothing (ranging from 0 to 15 mm full width at half maximum), and image resolution (1mm, 2mm, 4mm and 8mm); (B) incorporating demography and covariates (C) the impact of the size of the training data set (i.e., number of subjects); (D) the influence of reducing the dimensions of data and (E) choice of kernel types. Finally, the approach was tested to reveal individual cognitive scores at follow-up (up to 4 years) using the baseline features. The highest accuracy for memory performance prediction was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF-biomarkers explaining 57% of outcome variance in out of sample predictions. The best accuracy for A{beta}42/40 status classification was achieved for combination demographics, ApoE4 and memory score while usage of structural MRI improved the classification of individual patients pTau status.

neuroscience↗

bioRxiv2020

A long read mapping method for highly repetitive reference sequences

About 5-10% of the human genome remains inaccessible for functional analysis due to the presence of repetitive sequences such as segmental duplications and tandem repeat arrays. To enable high-quality resequencing of personal genomes, it is crucial to support end-to-end genome variant discovery using repeat-aware read mapping methods. In this study, we highlight the fact that existing long read mappers often yield incorrect alignments and variant calls within long, near-identical repeats, as they remain vulnerable to allelic bias. In the presence of a non-reference allele within a repeat, a read sampled from that region could be mapped to an incorrect repeat copy because the standard pairwise sequence alignment scoring system penalizes true variants. To address the above problem, we propose a novel, long read mapping method that addresses allelic bias by making use of minimal confidently alignable substrings (MCASs). MCASs are formulated as minimal length substrings of a read that have unique alignments to a reference locus with sufficient mapping confidence (i.e., a mapping quality score above a user-specified threshold). This approach treats each read mapping as a collection of confident sub-alignments, which is more tolerant of structural variation and more sensitive to paralog-specific variants (PSVs) within repeats. We mathematically define MCASs and discuss an exact algorithm as well as a practical heuristic to compute them. The proposed method, referred to as Winnowmap2, is evaluated using simulated as well as real long read benchmarks using the recently completed gapless assemblies of human chromosomes X and 8 as a reference. We show that Winnowmap2 successfully addresses the issue of allelic bias, enabling more accurate downstream variant calls in repetitive sequences. As an example, using simulated PacBio HiFi reads and structural variants in chromosome 8, Winnowmap2 alignments achieved the lowest false-negative and false-positive rates (1.89%, 1.89%) for calling structural variants within near-identical repeats compared to minimap2 (39.62%, 5.88%) and NGMLR (56.60%, 36.11%) respectively. Winnowmap2 code is accessible at https://github.com/marbl/Winnowmap

bioinformatics↗