Biology subjects

Petersen, S.

Publications and source records attributed to Petersen, S..

14 recordsLinked to original sources

bioRxiv2026

Nanoluciferase reporter preserves immunocompetent glioma model fidelity while facilitating longitudinal molecular imaging

Glioblastoma studies employ syngeneic orthotopic models to preserve tumor-immune interactions, but intracranial tumor burden is challenging to monitor longitudinally. Bioluminescence imaging enables non-invasive assessment, although reporter immunogenicity may compromise model fidelity. We engineered murine GL261 glioma cells to stably express nanoluciferase (NLuc) and compared them with parental GL261 (WT) and GL261 cells expressing red-shifted firefly luciferase (Red-FLuc). In vitro, GL261-NLuc retained growth kinetics and morphology comparable to GL261-WT and produced >100-fold stronger bioluminescence than GL261-Red-FLuc. In immunocompetent mice, GL261-NLuc formed lethal brain tumors with survival and tumor histopathology, immune profile, and response patterns to experimental oncolytic virus therapy broadly resembling GL261-WT. In contrast, GL261-Red-FLuc tumors regressed and exhibited heightened inflammation and increased infiltration of activated CD8+ T-cells. Longitudinal imaging of GL261-NLuc tumors detected treatment-associated changes in growth kinetics not captured by survival alone. These establish GL261-NLuc as a practical reporter for longitudinal immunocompetent glioblastoma studies amenable to immunotherapy evaluations.

molecular biology↗

bioRxiv2025

Patterns of brain-wide associations reflect socioeconomics

Previous brain-wide association studies (BWAS) cross-sectionally linked a specific behavioral trait, most commonly IQ or psychopathology, to variation in brain function or structure. Here, we expanded the focus of BWAS from effect sizes to interpretability and generalizability by mapping 649 variables to brain function and structure. We compared the resultant BWAS maps to other types of brain data to annotate the BWAS patterns. Socioeconomic status (SES) -- not IQ or psychopathology -- showed the strongest associations with both resting-state functional connectivity (RSFC) and cortical thickness in the Adolescent Brain Cognitive Development (ABCD) Study. A principal exposome brain pattern, anchored to sensory and motor cortex, captured 34% of the variance across all BWAS maps. This exposome pattern was strongly correlated with the SES and IQ BWAS maps and non-BWAS maps of sleep (EEG), norepinephrine (PET), and stimulants (drug trial), but not cognitive activation maps (task fMRI). Adjusting for SES, reduced brain-IQ associations by 40%. Brain with IQ associations did not generalize, as they could no longer be detected in subsamples drawn from only higher SES backgrounds, while brain with SES associations remained strong in higher-IQ-only subsamples. These findings reveal SES as the principal axis of population-level brain variation, possibly stemming from the sleep deprivation and heightened stress associated with lower SES, since socioeconomics can only indirectly affect the brain.

neuroscience↗

bioRxiv2025

In silico discovery of pathogenic PD-L1 nsSNVs with altered glycosylation and immunotherapy binding

Immune checkpoint inhibitors (ICIs), particularly anti-PD-L1 monoclonal antibodies, block extracellular interactions between programmed death ligand-1 (PD-L1) and programmed cell death protein-1 (PD-1) to enhance antitumour immunity. Here, we present a streamlined workflow integrating public databases, bioinformatics tools, and in silico molecular dynamics (MD) simulations and in vitro experimental assays to identify consequential pathogenic nonsynonymous PD-L1 variants (PD-L1SNVs). Four variants predicted as pathogenic across six bioinformatic tools (SIFT, PolyPhen-2, PANTHER, SNP-PhD, SNP&GO, and Pmut) destabilized the anti-PD-L1 ICI atezolizumab-drug binding epitope in MD studies, correlating with reduced drug affinity. Live-cell assays directly linked PD-L1SNVs to intracellular trafficking defects and aberrant glycosylation, even distal from N-glycosylation sites. Allostery modeling (AlloSigMA) linked these disruptions to long-range structural perturbations. Our work establishes bioinformatics-driven predictions of functionally impactful pathogenic PD-L1SNVs and highlight how glycosylation/trafficking defects may serve as key mechanisms compromising therapeutic efficacy. These insights in predicting and validating pathogenic PD-L1SNVs has significant implications for guiding the personalized selection of effective PD-L1-targeted therapies in clinical settings. One Sentence Summary: Uncovering the implication of non-synonymous single nucleotide variants (nsSNVs) on the structure and function of Programmed Death Ligand-1.

bioinformatics↗

bioRxiv2025

Acoustic Prediction and Biomechanical Validation of Primary Stability in Uncemented Short-Stem Hip Prostheses: An In Vitro Study

BackgroundIn uncemented hip arthroplasty, achieving sufficient primary stability is essential for long-term implant success. However, objective intraoperative assessment of fixation quality remains challenging. Acoustic analysis of stem impaction sounds offers a promising tool for real-time evaluation, but its diagnostic accuracy and biomechanical correlation require further validation. MethodsTwelve formalin-fixed human femora were implanted with cementless Metha(R) short stems under three predefined anchorage conditions: loose, optimal (fit), and fracture-inducing press-fit. Impaction sounds were recorded using calibrated microphones and processed via frequency-domain analysis. Relative micromotions were quantified under torsional loading to biomechanically assess primary stability. ResultsSpectral markers reliably differentiated between anchorage states. The transition from loose to fit showed minimal spectral change, while fit-to-fracture was characterized by a significant increase in low-frequency energy (<2.5 kHz) and pronounced attenuation in high-frequency bands (>15 kHz). These acoustic signatures closely correlated with biomechanically measured micromotions, which showed a distinct hierarchy: fracture < fit < loose. Cluster permutation analysis confirmed statistically significant differences, particularly in the fracture group. ConclusionThis in vitro study demonstrates that frequency-based acoustic analysis can distinguish between stable, insufficient, and over-press-fit conditions during stem implantation. The findings support the potential of intraoperative acoustic monitoring as a real-time, objective tool to enhance implant safety and detect cortical compromise before it becomes clinically apparent.

bioengineering↗

bioRxiv2025

Evolution of β-lactam resistance causes fitness reductions and several cases of collateral sensitivities in the human pathogen Haemophilus influenzae

The evolution of antimicrobial resistant (AMR) pathogens poses a global health threat and it is unclear if evolutionary trajectories to resistance lead to predictable phenotypes. We analyzed AMR-evolution in the human pathogen Haemophilus influenzae in controlled evolution experiments with increasing concentrations of either ampicillin, cefotaxime, or ceftriaxone. We isolated 315 clones from different time points of six independent experiments and characterized changes in genome sequences, bacterial fitness, and minimum inhibitory concentrations (MICs) to 14 antibiotics. Resistance evolution under ampicillin and cefotaxime was mainly driven by mutations in the ftsI gene, encoding the penicillin-binding protein 3. However, ceftriaxone exposure repeatedly selected for amino acid substitutions in the outer membrane protein P2 (OmpP2). Some OmpP2-mutants reproducibly showed phenotypic heterogeneity for ceftriaxone but also for fluoroquinolones, rifampicin and tetracycline. Bacterial fitness assessments revealed trade-offs between resistance-associated mutations and growth, though no systematic correlation of MIC increase and growth deficit was detected. Over 50% of the selected clones became more susceptible to aminoglycosides, clarithromycin, and colistin, while some mutation patterns resulted in cross-resistance to meropenem and fluoroquinolones. Overall, beta-lactam antibiotics reproducibly selected mutants with increased MICs, but evolutionary pathways and resulting phenotypes remain unpredictable. These findings highlight the complexity of resistance evolution and suggest that future AMR treatment strategies may need to consider strain-specific and collateral effects more closely.

genomics↗

bioRxiv2024

Serotonin-2B receptor (5-HT2BR) expression and binding in the brain of ageing APPswe/PS1de9 transgenic mice and in human Alzheimer's disease brain tissue

Although evidence of dysregulation in central serotonergic signaling is widespread in Alzheimers disease (AD), relatively little is known about the specific involvement of the serotonin-2B receptor (5-HT2BR) subtype. Here, we assessed 5-HT2BR expression and binding in brain tissue from APPswe/PS1dE9 transgenic (TG) mice and AD patients. 5-HT2BR mRNA was measured by RT-qPCR in 3-to >18-month-old TG and wild-type (WT) littermate mice (n=3-8), and in middle frontal gyrus samples from female, AD and control subjects (n=7-10). The density of 5-HT2BRs was measured by autoradiography using 1 nM [3H]RS127445 and 1 M LY266097. In both mouse and human samples, 5-HT2BR mRNA was detectable after 33 amplification cycles. Levels in WT mice, not TG mice, increased with age, and were higher in AD patients compared to control subjects. [3H]RS127445 binding was low in the mouse brain, detected after 3 months of age. 5-HT2BR density was overall lower in the hippocampus of TG compared to WT mice. Specific binding was too low to be reliably quantified in the human samples. These data provide evidence of a different 5-HT2BR expression and binding in the APPswe/PS1dE9 TG model of AD and AD patients. Studies investigating the functional involvement of the 5-HT2BR in AD are warranted.

neuroscience↗

bioRxiv2023

Specialized cingulo-opercular network activation in judging ambiguity of facial expressions in a slow reveal fMRI paradigm

Cortical task control networks, including the cingulo-opercular (CO) network play a key role in decision-making across a variety of functional domains. In particular, the CO network functions in a performance reporting capacity that supports successful task performance, especially in response to errors and ambiguity. In two studies testing the contribution of the CO network to ambiguity processing, we presented a valence bias task in which masked clearly and ambiguously valenced emotional expressions were slowly revealed over several seconds. This slow reveal task design provides a window into the decision-making mechanisms as they unfold over the course of a trial. In the main study, the slow reveal task was administered to 32 young adults in the fMRI environment and BOLD time courses were extracted from regions of interest in three control networks. In a follow-up study, the task was administered to a larger, online sample (n = 81) using a more extended slow reveal design with additional unmasking frames. Positive judgments of surprised faces were uniquely accompanied by slower response times and strong, late activation in the CO network. These results support the initial negativity hypothesis, which posits that the default response to ambiguity is negative and positive judgments are associated with a more effortful controlled process, and additionally suggests that this controlled process is mediated by the CO network. Moreover, ambiguous trials were characterized by a second CO response at the end of the trial, firmly placing CO function late in the decision-making process.

neuroscience↗

bioRxiv2022

Adgrg6/Gpr126 is required for myocardial Notch activity and N-cadherin localization to attain trabecular identity

How adhesion G protein-coupled receptors (aGPCRs) control development remains unclear. The aGPCR Adgrg6/Gpr126 has been associated with heart trabeculation. Defects in this process cause cardiomyopathies and embryonic lethality. Yet, how cardiomyocytes attain trabecular identity is poorly understood. Here, we show that Gpr126 regulates Notch activity and N-cadherin localization that are necessary for attaining trabecular identity in zebrafish. Maternal zygotic gpr126stl47 early truncation mutants exhibit hypotrabeculation whereby N-cadherin distributes randomly at apical/basal membranes of compact layer cardiomyocytes. In contrast, gpr126st49 mutants expressing a N-terminal fragment lacking the GPS motif (NTF{Delta}GPS) exhibit a multilayered ventricular wall consisting of polarized cardiomyocytes with normal N-cadherin expression and increased Notch signaling. Notably, endocardially expressed C-terminal fragment (CTF) reinstates trabeculation in gpr126st49 mutants. Collectively, our data indicate domain-specific roles of Gpr126 during trabeculation whereby the NTF maintains cell-cell adhesion and is required for compact wall integrity, while the CTF is essential to provide trabecular identity

developmental biology↗

bioRxiv2022

A Precision Functional Atlas of Network Probabilities and Individual-Specific Network Topography

The brain is organized into a broad set of functional neural networks. These networks and their various characteristics have been described and scrutinized through in vivo resting state functional magnetic resonance imaging (rs-fMRI). While the basic properties of networks are generally similar between healthy individuals, there is vast variability in the precise topography across the population. These individual differences are often lost in population studies due to population averaging which assumes topographical uniformity. We leveraged precision brain mapping methods to establish a new open-source, method-flexible set of precision functional network atlases: the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. Using participants from the Adolescent Brain Cognitive Development (ABCD) study, single subject precision network maps were generated with two supervised network-matching procedures (template matching and non-negative matrix factorization), an overlapping template matching method for identifying integration zones, as well as an unsupervised community detection algorithm (Infomap). From these individualized maps we also generated probabilistic network maps and integration zones for two demographically-matched groups of n[~]3000 each. We demonstrate high reproducibility between groups (Pearsons r >0.999) and between methods (r=0.96), revealing both regions of high invariance and high variability. Compared to using parcellations based on groups averages, the MIDB Precision Brain Atlas allowed us to derive a set of brain regions that are largely invariant in network topography across populations, which provides more reproducible statistical maps of executive function in brain-wide associations. We also explore an example use case for probabilistic maps, highlighting their potential for use in targeted neuromodulation. The MIDB Precision Brain Atlas is expandable to alternative datasets and methods and is provided open-source with an online web interface to encourage the scientific community to experiment with probabilistic atlases and individual-specific topographies to more precisely relate network phenomenon to functional organization of the human brain.

neuroscience↗

bioRxiv2021

Human Fronto-Striatal Connectivity is Organized into Discrete Functional Subnetworks

The striatum is interconnected with the cerebral cortex via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate cortico-striatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited by the practice of averaging neuroimaging data across individuals. Here we utilized highly-sampled resting-state functional connectivity MRI for individually-specific precision functional mapping of cortico-striatal connections. We identified ten discrete, individual-specific subnetworks linking cortex--predominately frontal cortex--to striatum. These subnetworks included previously unknown striatal connections to the human language network. The discrete subnetworks formed a stepped rostral-caudal gradient progressing from nucleus accumbens to posterior putamen; this organization was strongest for projections from medial frontal cortex. The stepped gradient organization fit patterns of fronto-striatal connections better than a smooth, continuous gradient. Thus, precision subnetworks identify detailed, individual-specific stepped gradients of cortico-striatal connectivity that include human-specific language networks.

neuroscience↗

bioRxiv2020

Network variants are similar between task and rest states

Recent work has demonstrated that individual-specific variations in functional networks (that we call "network variants") can be identified in individuals using functional magnetic resonance imaging (fMRI). These network variants exhibit reliability over time with resting-state fMRI data. These properties have suggested that network variants may be trait-like markers of individual differences in brain organization. Another test of this conclusion would be to examine if network variants are stable between task and rest states. Here, we use precision data from the Midnight Scan Club (MSC) to demonstrate that (1) task data can be used to identify network variants reliably, (2) these network variants show substantial spatial overlap with those observed in rest, although state-specific effects are present, (3) network variants assign to similar canonical functional networks in different states, and (4) single tasks or a combination of multiple tasks produce similar network variants to rest. Together, these findings further reinforce the trait-like nature of network variants and demonstrate the utility of using task data to define network variants.

neuroscience↗

bioRxiv2018

Tauopathy in the APPswe/PS1ΔE9 mouse model of familial Alzheimer’s disease

Despite compelling evidence that the accumulation of amyloid-beta (A{beta}) promotes cortical MAPT (tau) aggregation in familial and idiopathic Alzheimers disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. The absence of neurofibrillary lesions in amyloidosis mice remains a challenge for the amyloidocentric paradigm of AD pathogenesis. It has resulted in the generation of transgenic mice harboring mutations in their tau gene, which may be inappropriate for studying a disease with no known TAU mutations, such as AD. Here, we have used APPswe/PS1{Delta}E9 mice to show that tau pathology can develop spontaneously in murine models of familial AD. Tauopathy was abundant around A{beta} deposits, with Gallyas- and thioflavin-S-positive perinuclear inclusions accumulating in the APPswe/PS1{Delta}E9 cortex by 18 months of age. Age-dependent increases in Gallyas signal correlated positively with binding levels of the paired helical filament (PHF) ligand [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Tandem mass tag proteomics identified sequences of hyperphosphorylated tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Human frontal gyrus tissue was used to validate these findings, revealing primarily quantitative differences between the tauopathy observed in AD patient vs. transgenic mouse tissue. Levels of tau mRNA were not different between APPswe/PS1{Delta}E9 and littermate control animals. As physiological levels of endogenous, wild-type tau aggregate secondarily to A{beta} in transgenic mice, this study demonstrates that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.

neuroscience↗

bioRxiv2017

A rainfall-manipulation experiment with 517 Arabidopsis thaliana accessions

The gold standard for studying natural selection and adaptation in the wild is to quantify lifetime fitness of individuals from natural populations that have been grown together in a common garden, or that have been reciprocally transplanted. By combining fitness values with species traits and genome sequences, one can infer selection coefficients at the genetic level. Here we present a rainfall-manipulation experiment with 517 whole-genome sequenced natural accessions of the plant Arabidopsis thaliana spanning the global distribution of the species. The experiments were conducted in two field stations in contrasting climates, in the Mediterranean and in Central Europe, where we built rainout shelters and simulated high and low rainfall. Using custom image analysis we quantified fitness- and phenology-related traits for 23,154 pots, which contained about 14,500 plants growing independently, and over 310,000 plants growing in small populations (max. 30 plants). This large field experiment dataset, which associates fitness and ecologically-relevant traits with genomes, will provide an important resource to test eco-evolutionary genetic theories and to understand the potential evolutionary impacts of future climates on an important plant model species.

evolutionary biology↗

bioRxiv2017

Parasympathetic and sympathetic activity are associated with individual differences in neural indices of selective attention in adults

Multiple theoretical frameworks posit that interactions between the autonomic nervous system and higher-order neural networks are crucial for cognitive regulation. However, few studies have directly examined the relationship between measures of autonomic physiology and brain activity during cognitive tasks, and fewer studies have examined both the parasympathetic and sympathetic autonomic branches when doing so. Here, 93 adults completed an event-related potential (ERP) auditory selective attention task concurrently with measures of parasympathetic activity (high-frequency heart rate variability; HF-HRV) and sympathetic activity (pre-ejection period; PEP). We replicate previous findings showing effects of selective attention on mean amplitude of the N1 ERP component (Hillyard et al., 1973; Coch et al., 2005), and extend this result to show that the effects of selective attention were associated with baseline values of HF-HRV and PEP. Individuals with higher resting HF-HRV and shorter resting PEP showed larger effects of selective attention on their ERPs. Follow-up regression models demonstrated that HF-HRV and PEP accounted for unique variance in selective attention effects on N1 mean amplitude. These results are consistent with the neurovisceral integration model, which posits that greater parasympathetic activity is a marker of increased cognitive capacity, as well as other theoretical models which emphasize the role of heightened sympathetic activity in more efficient attention-related processing. The present findings highlight the importance of autonomic physiology in the study of individual differences in neurocognitive function, and given the foundational role of selective attention across cognitive domains, suggest that both parasympathetic and sympathetic activity may be key to understanding variability in brain function across a variety of cognitive tasks.

neuroscience↗