Biology subjects

Salomoni, P.

Publications and source records attributed to Salomoni, P..

6 recordsLinked to original sources

bioRxiv2026

MRI-Compatible Rigid Head Holders for Artifact-Free Multimodal Imaging in Mice

PurposeHigh-resolution intravital microscopy allows cellular-scale analysis of the brain in vivo but is greatly sensitive to physiological motion. Combining optical microscopy with magnetic resonance imaging (MRI) in the same animal could relate cellular and mesoscale functional readout to whole-brain structural information, but this requires head holders that are both mechanically rigid and MRI compatible. Conventional metallic head holders introduce MRI artifacts, whereas many nonmetallic alternatives lack sufficient stability for chronic microscopy. Thus, we developed rigid, MRI-compatible head holders engineered from 3D-printed zirconia ceramics to reduce motion during microscopy while preserving MRI image quality. MethodsHead holders were designed for mouse cranial fixation and fabricated from zirconia ceramics using additive manufacturing. We quantified motion artifacts during two-photon and multimodal widefield imaging of the mouse cortex and assessed their impact on neuronal calcium activity, functional connectivity, and hemodynamic readouts. MRI compatibility was evaluated by measuring image quality in the presence of the head holder. ResultsThe ceramic head holders provided mechanical stability to reduce motion artifacts to micrometer levels during intravital imaging. The head holders produced no detectable susceptibility artifacts in MRI, and image contrast was comparable to control acquisitions performed without head holder. Sequential optical and MRI imaging of the same brain regions established artifact-minimized multimodal data acquisition within the same animal. ConclusionsNon-metallic ceramic head holders support longitudinal multimodal studies that combine high-resolution optical microscopy with whole-brain MRI measurements in the same animal.

neuroscience↗

bioRxiv2025

DISC1-PML protein interaction for congenital CMV infection-induced cortical neural progenitor deficit: perturbance of host signaling via viral IE1

Congenital CMV infection is the most common perinatal infection, affecting up to 0.5% of infants. This elicits long-term disabilities that include neuropsychiatric manifestations, such as intellectual disability, microcephaly. Despite its high prevalence, the underlying mechanism of how congenitally acquired CMV infection causes brain pathology remains unknown. Here we discovered the molecular interplay of key host (DISC1 and PML) and viral (IE1) proteins within the neural progenitor cells, which underlay an attenuated neural progenitor proliferation. Abolishing the viral IE1 protein by delivering IE1-targeting CRISPR/Cas9 to fetal brain rescued this progenitor cell deficit, a key pathology in congenital CMV infection. A selective targeting to a viral-specific protein by the CRISPR/Cas9 system is minimal in off-target effects. Therefore, we believe that a pivotal role of IE1 in an attenuated neural progenitor proliferation in the developing cortex through its interfering with interaction between host DISC1 and PML proteins.

developmental biology↗

bioRxiv2024

Dynamics of microglia-glioblastoma crosstalk at the far infiltration zone

The interaction of glioblastoma (GB) and microglia is critical due to its implications for tumor progression, immune response modulation, and potential therapeutic strategies. However, the role of microglia in GB pathogenesis remains unclear, especially regarding the in vivo dynamics of their interplay. Performing three-photon imaging in an autochthonous, immunocompetent mouse GB model, we examined tumor/microglia dynamics within previously inaccessible regions at the GB far infiltration zone in the corpus callosum. Initially, microglia increased tissue surveillance upon encountering GB-cells in sparsely infiltrated areas. In contrast, when GB-cell density increased, microglia reduced surveillance, suggesting a biphasic response to tumor invasion. Additionally, microglia were not uniformly attracted to infiltrating GB-cells; only a subset moved directionally toward them within a defined spatial range. This study provides insight into the heterogeneity of the immune response to tumor invasion and the dynamics of microglia-GB interactions in vivo. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/614016v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@24b1d8org.highwire.dtl.DTLVardef@1180609org.highwire.dtl.DTLVardef@346dbforg.highwire.dtl.DTLVardef@1144dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

Current concepts regarding the biology of aging are based on studies aimed at identifying factors regulating natural lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific sets of pathologies, rather than by general physiological decline. Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans. We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging. HighlightsO_LIPhenotyping at scale defines lifetime trajectories of age-dependent changes in C57BL/6J mice C_LIO_LICentral genetic and environmental lifespan regulators (putative anti-aging interventions; PAAIs) influence age-sensitive phenotypes (ASPs) often long before the appearance of age-dependent changes in these ASPs C_LIO_LICorresponding genetic variants in humans also have age-independent effects C_LIO_LIMany PAAI effects shift the baseline of ASPs rather than slowing their rate of change C_LI

physiology↗

bioRxiv2021

Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGF{beta}-like soluble factor, SCUBE3. In turn, osteoclasts secrete unregulated amounts of SEMA4D enhancing proliferation of mutated osteoprogenitors and arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation upon denosumab treatment, a drug that depletes osteoclasts. In contrast, gain of hTERT activity, commonly found in malignant GCT, makes neoplastic cells insensitive to osteoclasts, predicting the unresponsiveness to denosumab. We provide a mechanism for GCT initiation and its response to current treatment, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells, emphasising the importance of tumor/microenvironment bidirectional interactions in tumorigenesis.

cancer biology↗

bioRxiv2021

Heterogeneity and excitability of BRAFV600E-induced tumors is determined by PI3K/mTOR-signaling state and Trp53-loss

BackgroundDevelopmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function. MethodsIntraventricular in utero electroporation in combination with the piggyBac transposon system is employed as a tool to generate developmental brain neoplasms. In vivo tumor growth is monitored by using the infrared fluorescent protein (iRFP). Lineage inference is carried out by using the Brainbow transgene. Neural activity from tumor slices is assessed by multielectrode array. RNA sequencing is exploited to analyze the induced neoplasms at the transcriptomic level. ResultsBRAFV600E in murine neural progenitors only in concert with active PI3K/mTOR-signaling through constitutively phosphorylated Akt-kinase (pAkt) elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG). Purely glial tumors partially resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to induce anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG-models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter. ConclusionmTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors. Key pointsO_LIIUE of BRAFV600E and activation of mTOR leads to ganglioglioma (GG)-like tumors, while BRAFV600E alone give rise to PLNTY-like neoplasms. C_LIO_LIAnaplastic GGs depend on the Trp53 deletion in combination to BRAFV600E and PI3K-mTOR signaling cascade. C_LI Importance of the StudyGlioneuronal tumors are challenging with respect to biological behavior and seizure emergence. While BRAFV600E in murine neural precursors induces oligoid tumors, it requires an overactivation of PI3K/mTOR-signaling for the development of hyperexcitable gangliogliomas and additional Trp53-loss for anaplastic transformation.

neuroscience↗