Biology subjects

Virta, J.

Publications and source records attributed to Virta, J..

8 recordsLinked to original sources

bioRxiv2026

Seasonal photoperiod cycling reduces inter-individual variability in mu-opioid receptor density in rats

RationaleThe -opioid receptor (MOR) is widely expressed across tissues and plays crucial roles in pain and stress responses, social behaviour, and immune regulation. Recent evidence indicates seasonal variation in in vivo MOR signalling; for example, short photoperiods are associated with reduced central MOR availability, increased MOR expression in brown adipose tissue (BAT), and strengthened brain-BAT interactions. However, despite this coupling with photoperiod, it remains unclear whether static daylength and dynamically changing photoperiods exert distinct effects, as adaptation to photoperiod transitions may itself induce stress-related modulation of the MOR system. Elucidating how seasonal, stress-related adaptations influence MOR signalling is essential for advancing our understanding of seasonal fluctuations in mood and stress regulation. MethodsWe compared rats housed under seasonal photoperiod cycling with those maintained under constant photoperiod conditions, using ex vivo radioligand binding to directly assess MOR density in central and peripheral tissues. ResultsRats exposed to seasonal photoperiod cycling showed markedly reduced inter-individual variability in MOR density in both the brain (including the cerebellum and striatum) and peripheral tissues (adrenal glands), whereas no tissues exhibited substantially increased variability. ConclusionsThese findings demonstrate that seasonal photoperiod cycling stabilizes MOR dynamics at the population level, suggesting stress-related synchronization of MOR signalling. The findings deepen our understanding of seasonal effects on endogenous MOR signalling, and further underscore the role of seasonal light variation in modulating mood-related processes.

neuroscience↗

bioRxiv2025

Targeting Macrophage Folate Receptor-β for Diagnosis and Treatment of Autoimmune Myocarditis

We investigated folate receptor-{beta} (FR-{beta}) expressed on activated macrophages as a therapeutic and imaging target in autoimmune myocarditis (AIM). Treatment with a folate-aminopterin conjugate (EC2319) targeting FR-{beta}-positive macrophages significantly reduced macrophage infiltration compared to saline (5.23 {+/-} 2.84% vs. 1.24 {+/-} 0.66%, P < 0.001) in rat experimental AIM. After immunization, FR-{beta} targeting positron emission tomography (PET) tracer [18F]FOL detected myocardial inflammatory lesions and revealed reduction in inflammation following EC2319 treatment relative to saline or tumor necrosis factor-alpha inhibitor Etanercept [standardized uptake value (SUV) 1.07 {+/-} 0.22 vs. 2.38 {+/-} 0.90 vs. 2.59 {+/-} 0.56, P < 0.001]. [18F]FOL PET signal correlated with myocardial CD68-positive macrophage content (r = 0.720, P < 0.001). These findings demonstrate that EC2319 attenuates myocardial inflammation in AIM and underscore the pathogenic role of FR-{beta}-positive macrophages. [18F]FOL PET provides a noninvasive means of detecting myocardial inflammatory activity and therapeutic response. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/686077v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@18e9296org.highwire.dtl.DTLVardef@139b8b3org.highwire.dtl.DTLVardef@8d1a74org.highwire.dtl.DTLVardef@1c3f06d_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Estrogen Receptor alpha/14-3-3 molecular glues as alternative treatment strategy for endocrine resistant breast cancer

Endocrine resistance in breast cancer treatment is a major clinical hurdle, causing an urgent need for alternative treatment modalities. The suppressive protein-protein interaction (PPI) between Estrogen Receptor alpha (ER) and the adaptor protein 14-3-3 offers such a strategy. Here, we report the biological impact of small-molecule molecular glues of this ER/14-3-3 PPI by using both fusicoccin-derived semi-synthetic natural products and fully synthetic covalent drug-like molecules. We show that the ER/14-3-3 PPI is stabilized by both the natural- and synthetic glues, resulting in a suppression of ER transcriptional activity and a blockade of breast cancer cell proliferation, both in cell lines and in organoids derived from endocrine therapy resistant breast cancer patients. Importantly, the molecular glues effectively blocked ER action even in case of constitutively active clinical ER mutations, providing the foundations for developing alternative classes of ER targeting compounds to improve treatment of patients with endocrine-therapy resistant breast cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/591105v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@173545corg.highwire.dtl.DTLVardef@a78ab7org.highwire.dtl.DTLVardef@183f4b6org.highwire.dtl.DTLVardef@371606_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Cell-type-specific characterization of miRNA gene dynamics in immune cell subpopulations during aging and atherosclerosis disease development at single-cell resolution

MicroRNAs (miRNAs) are a class of regulatory non-coding RNAs that finetune cellular functions by modulating the stability and abundance of their target mRNAs, thereby contributing to regulation of tissue homeostasis. MiRNA genes are transcribed similarly to protein-coding genes and recent studies have enabled their annotation and quantification genome-wide from bulk nascent transcriptomes. Here, we developed an approach to quantify and integrate miRNA gene signatures into single-cell studies. To characterize miRNA gene expression dynamics, we first compared the suitability of droplet and plate-based single-cell RNA-sequencing (scRNA-seq) platforms using the matched datasets provided by the Tabula Muris Senis and Tabula Sapiens consortiums. We found high concordance between the platforms and with cell type-specific bulk expression data. Based on the comprehensive aging profiles, our analysis comparing spleen immune cells between young and old mice revealed a concordant regulation of miRNAs involved in senescence and inflammatory pathways in multiple immune cell types, including up-regulation of mmu-mir-146a, mmu-mir-101a and mmu-mir-30 family genes. To study the aberrant regulation of immune cell homeostasis and tissue inflammation that pre-dispose to aging-related disease development, we collected transcriptome profiles from atherosclerosis development in LDLR-/-ApoB100/100 mice. We found an elevated myeloid cell proportion in the adipose tissue and further characterized the cell subtypes based on reproducible transcriptome clusters. We then compared miRNA gene expression in early versus late disease and upon inflammatory challenge to monitor different stages during disease progression. At atherosclerotic stage, pro-inflammatory mmu-mir-511 expression increased in several macrophage subtypes, while immunosuppressive mmu-mir-23b[~]mir-24-2[~]mir-27b up-regulation was specific to Trem2+ lipid-associated macrophages. The infiltrating monocytes up-regulated mmu-mir-1938 and mmu-mir-22 expression and in classical monocytes maturation further increased mmu-mir-221[~]222, mmu-mir-511 and mmu-mir-155 expression. To validate that these changes detected from single cell profiles represent miRNA gene transcriptional regulation, we used nascent transcriptomics data from ex vivo macrophage cultures with pro-inflammatory stimulation, confirming both rapid and long-lasting transcriptional activation of the miRNA loci studied. Collectively, our work enables integrating miRNA gene analysis to current single cell genomics pipelines and facilitates characterization of miRNA regulatory networks during aging and disease development.

molecular biology↗

bioRxiv2022

Photoperiod modulates mu-opioid receptor availability in brown adipose tissue

Photoperiod drives metabolic activity of brown adipose tissue (BAT), and affects food intake and weight gain in mammals. Sympathetic innervation in BAT controls thermogenesis and facilitates physiological adaption to seasons, but the exact mechanism remains elusive. Previous studies show that the central opioid signaling tunes BAT heating and the brain muopioid receptor (MOR) levels have seasonal patterns. It is hence intriguing to know whether the peripheral MOR signaling shows seasonal variation. Here, we examined the effect of photoperiod on BAT MOR availability using [11C]carfentanil positron emission topography (PET). Adult rats (n = 9) were repeatedly imaged under changing photoperiods which simulates the local seasons. Long photoperiod downregulated MOR availability in BAT, while MOR availability in the muscles was unaffected. We confirmed the expression of MOR in BAT and muscle using immunofluorescence imaging. We conclude that photoperiod causally affects MOR availability in BAT, and sympathetic innervation of BAT may influence thermogenesis via the peripheral MOR system. Significance of the studyPhotoperiod impacts the metabolic activity of brown adipose tissue (BAT) with the exact mechanism still unclear. The current study shows that photoperiod causally affects the mu-opioid receptor (MOR) levels in BAT, with longer photoperiod leading to lower MOR availability. This possibly indicates down-regulated innervation during bright seasons. Immunofluorescence staining data reveal expression of MOR in both brain and peripheral tissues, drawing attention to the under-investigated peripheral MOR system. Also, the study highlights the feasibility of [11C]carfentanil PET in studying the peripheral MOR signaling.

molecular biology↗

bioRxiv2020

Seasonal variation in brain mu-opioid receptor availability

Seasonal rhythms influence mood and sociability. The brain -opioid receptor (MOR) system modulates a multitude of seasonally varying socioemotional functions, but its seasonal variation remains elusive with no previously reported in vivo evidence. Here, we studied the seasonal effects on brain MOR availability via analysing a dataset (n=204) of [11C]carfentanil positron emission tomography (PET) scans of healthy volunteers. We found that seasonally varying daylength had an inverted U-shaped functional relationship with brain MOR availability. Brain regions sensitive to daylength spanned the socio-emotional brain circuits, where MOR availability formed a spring-like peak. Causal effect of daylength on brain MOR availability was further verified by a post hoc experiment with repeated PET imaging of rats (n=9) under seasonal photoperiodic simulation. Therefore, the in vivo brain MOR availability in normal humans shows significant seasonal variation, which aligns with expected seasonal variation in mood and suicidality.

neuroscience↗

bioRxiv2020

Radiosynthesis and Preclinical Evaluation of Ga-NOTA-Folate for PET Imaging of Folate Receptor β Positive Macrophages

Folate receptor {beta} (FR-{beta}) is one of the markers expressed on macrophages and a promising target for imaging of inflammation. Here, we report the radiosynthesis and preclinical evaluation of [68Ga]Ga-NOTA-folate (68Ga-FOL). First, we determined the affinity of 68Ga-FOL using human FR-{beta} expressing cells. Then, we studied atherosclerotic mice with 68Ga-FOL and 18F-FDG PET/CT. After sacrifice, the tissues excised were measured with a {gamma}-counter for ex vivo biodistribution. Further, the tracer distribution and co-localization with macrophages in aorta cryosections were studied using autoradiography, hematoxylin-eosin staining and immunostaining with anti-Mac-3 antibody. Specificity of 68Ga-FOL was assessed in a blocking study with excess of folate glucosamine. As a last step, human radiation doses were extrapolated from rat PET data. We were able to produce 68Ga-FOL at high radioactivity concentration, with high molar activity and radiochemical purity. The cell binding studies showed high (5.1 {+/-} 1.1 nM) affinity of 68Ga-FOL to FR-{beta}. The myocardial uptake of 68Ga-FOL (SUV 0.43 {+/-} 0.06) was 20-folds lower compared to 18F-FDG (SUV 10.6 {+/-} 1.8, P = 0.001). The autoradiography and immunohistochemistry of aorta revealed that 68Ga-FOL radioactivity co-localized with Mac-3-positive macrophage-rich atherosclerotic plaques. The plaque-to-healthy vessel wall ratio of 68Ga-FOL (2.44 {+/-} 0.15) was significantly higher than that of 18F-FDG (1.93 {+/-} 0.22, P = 0.005). Blocking studies verified 68Ga-FOL specificity to FR. As estimated from rat data the human effective dose was 0.0105 mSv/MBq. The organ with highest absorbed dose was kidney (0.1420 mSv/MBq). In conclusion, 68Ga-FOL is a promising new FR-{beta}-targeted tracer for imaging macrophage-associated inflammation. TABLE OF CONTENT/ABSTRACT GRAPHIC O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biochemistry↗

bioRxiv2018

Tensorial Blind Source Separation for Improved Analysis of Multi-Omic Data

There is an increased need for integrative analyses of multi-omic data. Although several algorithms for analysing multi-omic data exist, no study has yet performed a detailed comparison of these methods in biologically relevant contexts. Here we benchmark a novel tensorial independent component analysis (tICA) algorithm against current state-of-the-art methods. Using simulated and real multi-omic data, we find that tICA outperforms established methods in identifying biological sources of data variation at a significantly reduced computational cost. Using two independent multi cell-type EWAS, we further demonstrate how tICA can identify, in the absence of genotype information, mQTLs at a higher sensitivity than competing multi-way algorithms. We validate mQTLs found with tICA in an independent set, and demonstrate that approximately 75% of mQTLs are independent of blood cell subtype. In an application to multi-omic cancer data, tICA identifies many gene modules whose expression variation across tumors is driven by copy number or DNA methylation changes, but whose deregulation relative to the normal state is independent such alterations, an important finding that we confirm by direct analysis of individual data types. In summary, tICA is a powerful novel algorithm for decomposing multi-omic data, which will be of great value to the research community.

bioinformatics↗