Biology subjects

Nielsen, A.

Publications and source records attributed to Nielsen, A..

10 recordsLinked to original sources

bioRxiv2026

A Visually Interpretable Histopathology-Based Immune Model Predicts T-effector Biology and Response to Immune checkpoint inhibition in Clear Cell Renal Cell Carcinoma Clinical Trial and Contemporary Real-World Datasets

Immune checkpoint inhibitors (ICI) are central to the treatment of metastatic clear cell renal cell carcinoma (ccRCC), yet only a subset of patients derive durable benefit, and clinically deployable predictive biomarkers remain an unmet need. RNA-based T-effector signatures capture cytotoxic immune biology and have been associated with ICI response in clinical trial cohorts; however, their clinical implementation is limited by the marked spatial heterogeneity of ccRCC, as well as cost, long turnaround time, sample quality requirements, and limited accessibility. Here, we developed a visually interpretable deep learning (DL) model that predicts a T-cell-enriched immune score directly from hematoxylin and eosin (H&E)-stained whole-slide images. To overcome the inability of H&E morphology alone to distinguish lymphocyte subsets, we trained the model using multimodal spatial supervision from CD8, PAX8, and ERG IHC, which respectively identified cytotoxic T-cell-rich regions, tumor cells, and endothelial cells, thereby constraining immune predictions to relevant tumor microenvironmental niches. The resulting H&E DL Immune score was validated by pathologist review, comparison with held-out CD8 IHC annotations, and independent datasets. The H&E DL Immune score correlated with T-effector RNA scores across independent institutional and IMmotion150 clinical trial cohorts (spearman correlations of 0.726; p=5.90x10-15 and 0.706; p=4.04x10-19). As a proof of principle, the score was used to characterize associations with key biological features across large cohorts, including sarcomatoid differentiation, BAP1 and PBRM1 mutation status, and additional transcriptomic signatures. In IMmotion150 clinical trial cohort, a median-dichotomized H&E DL Immune score, similar to RNA-based T-effector score, was significantly associated with clinical benefit from atezulumab therapy. In contemporary institutional cohorts of patients treated with frontline ipilimumab plus nivolumab or in initial 3 lines of nivolumab monotherapy, patients in the top quartile of H&E DL Immune score had significantly longer progression-free survival. Collectively, these findings support a scalable and interpretable H&E-based biomarker that captures T-effector biology and can help identify patients with ccRCC more likely to benefit from ICIs.

bioinformatics↗

bioRxiv2025

Heterochromatin-based silencing of a foreign tandem repeat in Drosophila melanogaster shows unusual biochemistry and temperature sensitivity

Eukaryotic genomes are packaged into chromatin, a regulatory nucleoprotein assembly. Establishment, maintenance, and interconversion of chromatin states is required for correct patterns of gene expression, genome integrity, and survival. Transcriptionally repressive heterochromatin minimizes mobilization of transposable elements and limits expansion of other repetitive DNA, but mechanisms for recognition of the latter sequences are not well established. We previously demonstrated in Drosophila melanogaster that transcripts derived from 1360 and Invader4 transposon insertions can trigger local conversion of transcriptionally permissive euchromatin to heterochromatin through the piRNA system, but only in a subset of genomic locations near existing blocks of heterochromatin. Here we show that a ~9 kb tandem array of the 36-nucleotide lac operator (lacO) sequence of Escherichia coli can form ectopic heterochromatin at a similar subset of sites, resulting in variegating expression of an adjacent reporter gene. Heterochromatin Protein 1a (HP1a) and histone deacetylation are required for lacO repeat-induced silencing, but, contrasting with previously described Position Effect Variegation (PEV), we do not observe increased histone H3 lysine 9 methylation. Silencing is effective at 25{degrees}C and suppressed at 18{degrees}C (in contrast to canonical PEV, which is enhanced at 18{degrees}C), indicating involvement of a temperature-sensitive component. Temperature switching experiments show that lacO repeat-induced heterochromatin formation is reversible throughout larval development following an HP1a-dependent initiation step in the early embryo. We conclude that the Drosophila nucleus can recognize a completely foreign tandem repeat as a target for heterochromatin formation, and that the heterochromatin structure established is distinct from that of endogenous tandem arrays.

genetics↗

bioRxiv2024

Forest edges and other semi-natural habitat edges increase wild bee species richness and habitat connectivity in intensively managed temperate landscapes.

Pollinator conservation schemes are typically focused on conserving existing-, restoring degraded- or establishing new wild bee habitats. The effectiveness of such conservation schemes depends on the presence of dispersal corridors that allow habitat colonization by bees. Nonetheless, we lack an understanding of the role of semi-natural habitats edges on the connectivity of pollinator communities across intensively managed landscapes. Here, we use data from wild bee communities comprising 953 occurrences from 79 species of non-parasitic bees, sampled at 68 locations distributed across a Norwegian and a Danish landscape to show that the proportion of semi-natural habitat edges is positively correlated to bee species richness and habitat connectivity. Specifically, we found that wild bee species richness sampled along roadsides increased with the proportion of semi-natural habitat edges within1.5 km of the study sites and with local plant species richness. We combined maps showing the proportion of seminatural habitat edges with least cost path analysis to find the most likely dispersal route between our bee communities. We find that these least cost path lengths provide better models of bee species compositional similarity than geographic distance (|{Delta}AICc| > 2), suggesting that seminatural habitat edges act as dispersal corridors in intensively managed landscapes. However, we also find that compositional similarity between communities depend on site-specific plant species richness stressing the importance of improving the habitat quality of edge habitats if they are to function as dispersal corridors. We discuss potential management options for improving wild bee habitat conditions along seminatural habitat edges and illustrate how maps of least cost paths can be used to identify dispersal corridors between pollinator habitats of conservation priority. Maps of dispersal corridors can be used to direct wild bee habitat management actions along seminatural habitat edges to facilitate the dispersal of bees between larger grassland habitats.

ecology↗

bioRxiv2024

Distinct genome architecture underlies fine-scale population differentiation in two common European bumblebees (Bombus pascuorum and Bombus lapidarius)

Bumblebees are keystone pollinators which facilitate the reproduction of a wide range of wild and agricultural plants. Their abundance and diversity have been severely reduced by anthropogenic stressors such as land-use change and widespread habitat fragmentation. However, we lack a comprehensive understanding of bumblebee population structure and local adaptation in response to human-altered landscapes. We here discover surprisingly fine-scaled population structure (e.g. [~]300km) within two widely occurring bumblebee species, Bombus lapidarius and Bombus pascuorum, by analysing whole genome data of 106 specimens from 7 sites in Northern Europe. Our sample range encompasses a mosaic of land-use types with varying levels of habitat fragmentation and natural oceanic barriers. While the observed population structure is largely associated with reduced gene flow across natural barriers, we also detect significant divergence between populations sampled from more fragmented, agricultural landscapes. Furthermore, we identify species-specific patterns of population structure which are underpinned by distinct genomic architecture. Whereas genetic divergence in B. lapidarius is spread relatively evenly across the genome, divergence in B. pascuorum is concentrated within several megabase-sized genomic regions with significantly elevated differentiation - including a putative chromosomal inversion - which may underlie well-known colour polymorphisms across its range. Our observations reveal unexpectedly high levels of inter- and intraspecific genomic diversity within the bumblebee genus, and highlight the necessity of increasing our understanding of bumblebee population structure and connectivity to design optimal bumblebee conservation strategies. Significance statementAnthropogenic stressors such as habitat fragmentation have severe impacts on bumblebee abundance and diversity, yet little is known about how bumblebee populations are structured in human-altered landscapes. We analyse whole-genome data from two common bumblebee species (Bombus lapidarius and Bombus pascuorum) across Northern Europe to uncover species-specific patterns of spatial population differentiation and local adaptation, including a chromosomal rearrangement in B. pascuorum. Importantly, our results imply that many of the fragmented bumblebee habitats in Europe comprise locally distinct populations with limited gene flow in between. These findings are therefore of major importance for our overall understanding of bumblebee genomic variation, connectivity and adaptation, offering fundamental insights that are required to effectively mitigate the effects of human activities on wild bee biodiversity.

genomics↗

bioRxiv2022

A mind-body interface alternates with effector-specific regions in motor cortex

Primary motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down precentral gyrus from foot to face representations1,2. The motor homunculus has remained a textbook pillar of functional neuroanatomy, despite evidence for concentric functional zones3 and maps of complex actions4. Using our highest precision functional magnetic resonance imaging (fMRI) data and methods, we discovered that the classic homunculus is interrupted by regions with sharpy distinct connectivity, structure, and function, alternating with effector-specific (foot, hand, mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, and to prefrontal, insular, and subcortical regions of the Cingulo-opercular network (CON), critical for executive action5 and physiological control6, arousal7, and processing of errors8 and pain9. This interdigitation of action control-linked and motor effector regions was independently verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant, child) precision fMRI revealed potential cross-species analogues and developmental precursors of the inter-effector system. An extensive battery of motor and action fMRI tasks documented concentric somatotopies for each effector, separated by the CON-linked inter-effector regions. The inter-effector regions lacked movement specificity and co-activated during action planning (coordination of hands and feet), and axial body movement (e.g., abdomen, eyebrows). These results, together with prior work demonstrating stimulation-evoked complex actions4 and connectivity to internal organs (e.g., adrenal medulla)10, suggest that M1 is punctuated by an integrative system for implementing whole-body action plans. Thus, two parallel systems intertwine in motor cortex to form an integrate-isolate pattern: effector-specific regions (foot, hand, mouth) for isolating fine motor control, and a mind-body interface (MBI) for the integrative whole-organism coordination of goals, physiology, and body movement.

neuroscience↗

bioRxiv2021

Functional characterization of the biogenic amine transporter system on human macrophages

Monocyte-derived macrophages are key players in tissue homeostasis and disease regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling on and around immune cells remains nebulous. In the central nervous system, biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown macrophages express these transporters, relatively little is known of their function on these cells. To address these knowledge gaps, we interrogated the function of norepinephrine (NET) and dopamine (DAT) transporters on human monocyte-derived macrophages. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured macrophages, but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immuno-modulatory mechanism in response to lipopolysaccharide (LPS). LPS induced reverse transport of dopamine through DAT, engaging autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the pro-inflammatory response to LPS. Finally, we found that this DAT-immune axis was disrupted in disease. Collectively, our data introduce a novel role for DAT in the regulation of innate immunity during health and disease.

neuroscience↗

bioRxiv2021

Can we fish on stocks that need rebuilding? Illustrating the trade-offs between stock conservation and fisheries considerations

In the Northeast Atlantic, advice for many fish stocks follows the ICES MSY approach, where a zero catch will be recommended if the stock is below its limit reference point, Blim, and cannot rebuild in the short-term. How-ever, zero catch advice are rarely implemented by managers. This study used medium-term stochastic forecasts with harvest control rules (HCRs) to investigate the consequences of allowing reduced fishing below Blim. We applied the method to western Baltic herring and North Sea cod, two contrasting species currently estimated below Blim. We show that the minimum rebuilding probability of 95% required by the MSY approach could be impossible to reach in the short-to medium-term. When this is the case, a lower probability may need to be considered instead in the short-term. Recruitment is the largest source of uncertainty in stock response to management, and can exceed differences between HCRs. Reference points should be estimated in accordance with current recruitment levels if they are to be used for short-term advice or as realistic rebuilding targets. For both stocks, it is possible to keep fishing at reduced levels for similar cumulative catch, SSB and risk on the stock in the medium-term compared to no catch below Blim. Medium-term trade-offs between stock conservation and fisheries considerations may be needed when fishery closure cannot be implemented in practice.

ecology↗

bioRxiv2020

An empirical attack tolerance test alters the structure and species richness of plant-pollinator networks

Ecological network theory hypothesizes a link between structure and stability, but this has mainly been investigated in-silico. In an experimental manipulation, we sequentially removed four generalist plants from real plant-pollinator networks and explored the effects on, and drivers of, species and interaction extinctions, network structure and interaction rewiring. Our results indicate that cumulative species and interaction extinctions increased faster with generalist plant loss than what was expected by co-extinction models, which predicted the survival or extinction of many species incorrectly. In addition, network nestedness decreased, modularity increased, and opportunistic random interactions and structural unpredictability emerged, which are all indicators of network instability and fragility. Conversely, interaction reorganization (rewiring) was high, asymmetries between network levels emerged as plants increased their centrality. From the experimental manipulations of real networks, our study shows how plant-pollinator network structure has low stability and changes towards a more fragile state when generalist plants are lost.

ecology↗

bioRxiv2018

Atypical functional connectivity in Tourette syndrome differs between children and adults

BackgroundTourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics that typically change over development. Whether and how brain function in TS also differs across development has been largely understudied. Here, we used functional connectivity MRI to examine whole brain functional networks in children and adults with TS.\n\nMethodsMultivariate classification methods were used to find patterns among functional connections that distinguish TS from controls separately for children and adults (total N = 202). We tested whether the patterns of connections that classify diagnosis in one age group (e.g., children) could classify diagnosis in another age group (e.g., adults). We also tested whether the developmental trajectory of these connections were altered in TS.\n\nResultsPatterns of functional connections that distinguished TS from controls were generalizable to an age-matched independent test set, but not to other age groups. While diagnostic classification was successful in children and adults separately, the connections that best distinguished TS from controls were age-specific. When contextualized with typical development, some functional connections exhibited accelerated maturation in childhood TS, while others exhibited delayed maturation in adulthood TS.\n\nConclusionsOur results demonstrate that brain networks are differentially altered in children and adults with TS, and that the developmental trajectory of affected connections is disrupted. These findings further our understanding of neurodevelopmental trajectories in TS and carry implications for future applications aimed at predicting the clinical course of TS in individuals over development.

neuroscience↗

bioRxiv2017

Modeling Zero-Inflated Count Data With glmmTMB

Ecological phenomena are often measured in the form of count data. These data can be analyzed using generalized linear mixed models (GLMMs) when observations are correlated in ways that require random effects. However, count data are often zero-inflated, containing more zeros than would be expected from the standard error distributions used in GLMMs, e.g., parasite counts may be exactly zero for hosts with effective immune defenses but vary according to a negative binomial distribution for non-resistant hosts.\n\nWe present a new R package, glmmTMB, that increases the range of models that can easily be fitted to count data using maximum likelihood estimation. The interface was developed to be familiar to users of the lme4 R package, a common tool for fitting GLMMs. To maximize speed and flexibility, estimation is done using Template Model Builder (TMB), utilizing automatic differentiation to estimate model gradients and the Laplace approximation for handling random effects. We demonstrate glmmTMB and compare it to other available methods using two ecological case studies.\n\nIn general, glmmTMB is more flexible than other packages available for estimating zero-inflated models via maximum likelihood estimation and is faster than packages that use Markov chain Monte Carlo sampling for estimation; it is also more flexible for zero-inflated modelling than INLA, but speed comparisons vary with model and data structure. Our package can be used to fit GLMs and GLMMs with or without zero-inflation as well as hurdle models. By allowing ecologists to quickly estimate a wide variety of models using a single package, glmmTMB makes it easier to find appropriate models and test hypotheses to describe ecological processes.

ecology↗