Biology subjects

Russo, E.

Publications and source records attributed to Russo, E..

12 recordsLinked to original sources

bioRxiv2026

Live immunogenic melanoma cells generated by etoposide treatment upregulate B2M and lose tumor-forming potential

Cytotoxic chemotherapy has been the primary cancer treatment modality for decades, however, chemotherapy drugs do not selectively target cancer cells. These drugs are toxic to all proliferating cells including immune cells that constitute the host-defense system against pathogens and cancer cells. In an effort to develop non-toxic combinations of chemotherapy and immunotherapies for cancer, we previously reported in Sriram et al. 2021 that etoposide-treated B16 melanoma cells expressing ovalbumin, when co-cultured in vitro with dendritic cells and T-cells, enhance T-cell activation. The live fraction of melanoma cells after etoposide treatment was critical to promote T-cell activation as dead cells alone or in combination with cell-free supernatants were not effective. In this study, we show that the live fraction of etoposide-treated B16-Ova cells, which gain the ability to stimulate T-cells, are growth-arrested, but remain viable past the co-incubation period with dendritic cells and T-cells post etoposide washout. Furthermore, using a soft-agar colony-formation assay as a proxy for tumor-forming potential, we show that these live etoposide-treated B16-Ova cells have drastically reduced ability to form colonies displaying a near-complete loss of anchorage-independent growth. We also show that etoposide treatment upregulates the production of Beta-2-microglobulin (B2M), a subunit of Class I MHC. Intriguingly, we observed using immunofluorescence that the live etoposide-treated B16-Ova cells show enhanced intracellular perinuclear B2M accumulation but B2M surface staining, while detectable, is not enhanced by etoposide treatment. Furthermore, while the live etoposide-treated B16-Ova cells express Class I MHC protein, there is only a marginal drug treatment-induced increase observed in the expression levels by western blotting. Our results suggest that T-cell activation by live etoposide-treated B16-Ova cells is likely not driven by drug treatment-induced enhancement in cell surface levels of Class I MHC and point to other mechanisms.

cancer biology↗

bioRxiv2026

The Pentose Phosphate Pathway Regulates Myelo-Lymphoid Lineage Specification

Following infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we combined in situ RNA barcoding and metabolomics approaches to perform metabolic state-fate mapping in vivo. This approach revealed a subset of myeloid-biased HSPCs that express a distinct set of metabolic enzymes and transporters as well as the surface marker CD62L. Metabolically, CD62Lhigh HSPCs have differential activity of the pentose phosphate pathway (PPP), OXPHOS and translation, as well as differential levels of S-adenosylmethionine (SAM) cycle metabolites associated with epigenetic modifications. Inhibition of the PPP skews HSPC lineage fate decisions by disrupting myeloid associated enhancers, while simultaneously increasing enhancer activity for the master B-lymphoid regulator Ikaros. In vivo, overexpression of glucose-6-phosphate dehydrogenase, a rate limiting enzyme of the PPP, skewed HSPC output from B-lymphocytes. In summary, our data shows that HSPCs undergo significant metabolic changes to facilitate the bioenergetic and epigenetic demands of myeloid versus lymphoid lineage specification. We highlight a key role for the pentose phosphate pathway which modulates myeloid rather than lymphoid commitment by shaping the HSPC enhancer landscape, providing proof of principle that HSPC metabolism can be targeted to modulate immune system dynamics.

immunology↗

bioRxiv2025

Decoupling simultaneous motor imagination and execution via orthogonal ECoG neural representations

The brain coordinates multiple parallel motor programs, ensuring synergy and preventing interference during movements. Yet, performance often degrades when brain-machine interfaces are used during concurrent tasks or ongoing movements. We suggest that latent neural representations may represent a strategy to solve this issue. In this study, we addressed this question using neural signals from a tetraplegic individual with partial residual motor function, implanted with a wireless epidural electrocorticography (ECoG) device. By adapting dimensionality reduction techniques, we found that motor execution and motor imagery span partially overlapping subspaces in mesoscale neural signals, shaped by specific frequency band contributions. Despite substantial shared variance, we show that identifying orthogonal, condition-specific dimensions enables successful decoding of executed and imagined movements, even when performed simultaneously. These findings show that ECoG signals can expose separable neural subspaces, allowing executed and imagined actions to be harnessed independently and in concert. This opens a promising avenue to develop brain-machine interfaces that can simultaneously control multiple external devices or operate alongside natural movements.

neuroscience↗

bioRxiv2025

Characterization of a novel mouse model of Dopamine Transporter Deficiency Syndrome and pharmacological therapeutic strategies

The dopamine transporter (DAT) is an essential protein in the maintenance of dopamine homeostasis in the brain. Thus, single amino acid changes in the gene that encodes for DAT can be sufficient to induce disease, such as Dopamine Transporter Deficiency Syndrome (DTDS). DTDS-associated variants are posited to cause DAT protein misfolding, retention in the endoplasmic reticulum, and a consequent depletion or loss of DAT at the cell surface. In turn, proper dopaminergic regulation is lost. Current treatments for DTDS are largely ineffective, and improved therapeutic options are greatly needed. To this end, we have created a novel mouse model of DTDS harboring the A313V knock-in DAT variant, a proxy for the DTDS-causing A314V variant in humans. We show that the A313V knock-in DAT mice are hyperactive, have increased striatal tissue content of dopamine and its metabolites homovanillic acid (HVA) and DOPAC, and impaired dopamine uptake. We demonstrate that FDA approved compounds alpha-methyl-para-tyrosine ([a]MPT) and amphetamine (AMPH) ameliorate hyperactivity in this mouse model. Moreover, [a]MPT may be a disease-modifying treatment by addressing the hyperdopaminergic tone underlying this hyperactivity. In contrast, noribogaine, a pharmacological chaperone for DAT, is unable to rescue DAT expression. Taken together, these findings show that the A313V knock-in DAT variant mice recapitulate several defining phenotypes seen in patients with DTDS, and provide evidence for two novel treatments for the disease.

pharmacology and toxicology↗

bioRxiv2024

Out of the single-neuron straitjacket: neurons within assemblies change selectivity and their reconfiguration underlies dynamic coding

We investigated cell assemblies in the frontal cortex of macaques during two discrimination tasks. Focusing on the period of goal-action transformation, we extracted spikes fired during assembly activation from the full neural activity and showed that the contribution of a neuron to assembly coding, when it coordinates with other assembly neurons, differs from its coding in isolation. Neurons with their flexible participation to multiple assemblies contributed to the encoding of new information not encoded by the neurons alone. Even non-discriminative neurons acquired selectivity as part of the collective activity of the assemblies. Thus, neurons in their assemblies process distinct information for various purposes as a chess simul master, playing on multiple chessboards. The reconfiguration of the participation of the neurons into different assemblies in the goal-action transformation process translated into a dynamic form of coding, whereas minimal reconfiguration was associated with the static goal coding of the memory period.

neuroscience↗

bioRxiv2023

Integration of rate and temporal codes by hippocampal cell-assemblies supports theta phase coding of episodic information

Spatial information is encoded by location-dependent hippocampal place cell firing rates and sub-second, rhythmic entrainment of spike times. These rate and temporal codes have primarily been characterized in low-dimensional environments under limited cognitive demands; but how is coding configured in complex environments when individual place cells signal several locations, individual locations contribute to multiple routes and functional demands vary? Quantifying rat CA1 population dynamics during a decision-making task, we show that the phase of individual place cells spikes relative to the local theta rhythm shifts to differentiate activity in different place fields. Theta phase coding also disambiguates repeated visits to the same location during different routes, particularly preceding spatial decisions. Using unsupervised detection of cell assemblies alongside theoretical simulation, we show that integrating rate and phase coding mechanisms dynamically recruits units to different assemblies, generating spiking sequences that disambiguate episodes of experience and multiplexing spatial information with cognitive context.

neuroscience↗

bioRxiv2023

Metabolically Primed Multipotent Hematopoietic Progenitors Fuel Innate Immunity

Following infection, hematopoietic stem and progenitor cells (HSPCs) support immunity by increasing the rate of innate immune cell production but the metabolic cues that guide this process are unknown. To address this question, we developed MetaFate, a method to trace the metabolic expression state and developmental fate of single cells in vivo. Using MetaFate we identified a gene expression program of metabolic enzymes and transporters that confers differences in myeloid differentiation potential in a subset of HSPCs that express CD62L. Using single-cell metabolic profiling, we confirmed that CD62Lhigh myeloid-biased HSPCs have an increased dependency on oxidative phosphorylation and glucose metabolism. Importantly, metabolism actively regulates immune-cell production, with overexpression of the glucose-6-phosphate dehydrogenase enzyme of the pentose phosphate pathway skewing MPP output from B-lymphocytes towards the myeloid lineages, and expansion of CD62Lhigh HSPCs occurring to support emergency myelopoiesis. Collectively, our data reveal the metabolic cues that instruct innate immune cell development, highlighting a key role for the pentose phosphate pathway. More broadly, our results show that HSPC metabolism can be manipulated to alter the cellular composition of the immune system.

immunology↗

bioRxiv2021

Prefrontal cortical contributions to working memory loading, maintenance and recall are parsed by hippocampal-prefrontal oscillatory assembly dynamics

Working memory enables incorporation of recent experience into subsequent decision-making. This processing recruits both prefrontal cortex and hippocampus, where neurons encode task cues, rules and outcomes. However, precisely which information is carried when, and by which neurons, remains unclear. Using population decoding of activity in rat medial prefrontal cortex (mPFC) and dorsal hippocampal CA1, we confirm that mPFC populations lead in maintaining sample information across delays of an operant nonmatch to sample task, despite individual neurons firing only transiently. During sample encoding, distinct mPFC subpopulations joined distributed CA1-mPFC cell assemblies hallmarked by 4-5Hz rhythmic modulation; CA1-mPFC assemblies re-emerged during choice episodes, but were not 4-5Hz modulated. Delay-dependent errors arose when attenuated rhythmic assembly activity heralded collapse of sustained mPFC encoding; pharmacological disruption of CA1-mPFC assembly rhythmicity impaired task performance. Our results map component processes of memory-guided decisions onto heterogeneous CA1-mPFC subpopulations and the dynamics of physiologically distinct, distributed cell assemblies.

neuroscience↗

bioRxiv2021

Hierarchical cross-scale analysis identifies parallel ventral striatal networks coding for dynamic and stabilized olfactory reward predictions

The unbiased identification of brain circuits responsible for behavior and their local cellular computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach from behavioral modeling and fMRI in task-performing mice to cellular network dynamics to identify how reward predictions are represented in the forebrain upon olfactory conditioning. fMRI identified functional segregation in reward prediction and error computations among olfactory cortices and subcortical circuits. Among them, the olfactory tubercle contributed both to dynamic reward predictions and prediction error. In this region, cellular recordings revealed two parallel neuronal populations for prediction coding. One population produced stabilized predictions as distributed stimulus-bound transient network activity; the other evolved during anticipatory waiting and fully reflected predicted value in single-units, dynamically integrating the recent cue-specific history of uncertain outcomes. Thus, the cross-scale approach revealed regional functional differentiation among the distributed forebrain circuits with a limbic hotspot for multiple non-redundant reward prediction coding.

neuroscience↗

bioRxiv2020

Significant and conflicting correlation of IL-9 with Prevotella and Bacteroides in human colorectal cancer

BackgroundColorectal cancer (CRC) is a widespread disease that represents an example of chronic inflammation-associated tumor. In fact, the immune system, besides protecting the host from developing tumors, can support the CRC progression. In this scenario, the gut microbiota (GM) is essential to modulate immune responses and a dysbiotic condition can favor chronic/abnormal immune activation that support the tumor growth. GM can elicit the production of cytokines, influencing the immunostimulatory or immunosuppressive reactions, such as the tendency to mount Th1, Th17, Tregs or Th9 responses that play different roles towards colon cancer. Paradigmatic is the role of IL-9 that can both promote tumor progression in hematological malignancies and inhibit tumorigenesis in solid cancers. Therefore, to investigate the microbiota-immunity axis in CRC patients is crucial to well understand the cancer development with positive relapses in prevention and treatment. AimThe cellular and molecular characterization of the immune response and the evaluation of GM composition in healthy and tumor mucosa, focusing on the correlation between cytokines profile and GM signature. MethodsWe collected tumoral (CRC) and healthy (CRC-S) mucosa samples of 45 CRC patients. For each sample, we characterized the Tissue Infiltrating Lymphocytes (TIL)s subset profile and the GM composition. In addition, in 14 CRC patients, we evaluated the CRC and CRC-S molecular inflammatory response (26 cytokines/chemokines) and we correlated this profile with GM composition using the Dirichlet Multinomial Regression. ResultsThe analysis of T cells subsets distribution showed that CRC samples displayed higher percentages of Th17, Th2, Tregs, Tc17, Tc1/Tc17, and Tcreg, compared to CRC-S. Notably, also the number of Th9 was higher, even if not significantly, in CRC tissue compared to healthy one. In addition, we found that MIP-1, IL-1{beta}, IL-2, IP-10, IL-6, IL-8, IL-17A, IFN-{gamma}, TNF-, MCP-1, IL-1, P-selectin and IL-9 were significantly increased in CRC compared to CRC-S. Moreover, the GM analysis revealed that CRC samples had significantly higher levels of Fusobacteria, Proteobacteria, Fusobacterium, Ruminococcus2 (Lachnospiraceae family) and Ruminococcus (Ruminococcaceae family) than CRC-S. Finally, we found that the abundance of Prevotella spp in CRC samples was negatively correlated with IL-17A and positively with IL-9. In addition, the abundance of Bacteroides and Escherichia/Shigella species in CRC samples showed a negative association with IL-9 and IP-10 respectively. ConclusionsOur data show a clear dissimilarity of inflammatory profile and GM composition between the tumor and the adjacent healthy tissue, displaying the generation of a peculiar CRC microenvironment. Interestingly, relating the tissue cytokine profile with the GM composition, we confirmed the presence of a bidirectional crosstalk between the immune response and the hosts commensal microorganisms; in detail, we documented for the first time that Prevotella spp. and Bacteroides spp. are correlated (positively and negatively, respectively) with the IL-9, whose role in CRC development is still debated.

immunology↗

bioRxiv2020

Coordinated prefrontal state transition leads extinction of reward-seeking behaviors

Extinction learning suppresses conditioned reward responses and is thus fundamental to adapt to changing environmental demands and to control excessive reward seeking. The medial prefrontal cortex (mPFC) monitors and controls conditioned reward responses. Using in vivo multiple single-unit recordings of mPFC we studied the relationship between single-unit and population dynamics during different phases of an operant conditioning task. To examine the fine temporal relation between neural activity and behavior, we developed a model-based statistical analysis that captured behavioral idiosyncrasies. We found that single-unit responses to conditioned stimuli changed throughout the course of a session even under stable experimental conditions and consistent behavior. However, when behavioral responses to task contingencies had to be updated during the extinction phase, unit-specific modulations became coordinated across the whole population, pushing the network into a new stable attractor state. These results show that extinction learning is not associated with suppressed mPFC responses to conditioned stimuli, but is driven by single-unit coordination into population-wide transitions of the animals internal state.

neuroscience↗

bioRxiv2019

Phasic dopamine enhances the distinct decoding and perceived salience of stimuli

Subjects learn to assign value to stimuli that predict outcomes. Novelty, rewards or punishment evoke reinforcing phasic dopamine release from midbrain neurons to ventral striatum that mediates expected value and salience of stimuli in humans and animals. It is however not clear whether phasic dopamine release is sufficient to form distinct engrams that encode salient stimuli within these circuits. We addressed this question in awake mice. Evoked phasic dopamine induced plasticity selectively to the population encoding of coincidently presented stimuli and increased their distinctness from other stimuli. Phasic dopamine thereby enhanced the decoding of previously paired stimuli and increased their perceived salience. This dopamine-induced plasticity mimicked population coding dynamics of conditioned stimuli during reinforcement learning. These findings provide a network coding mechanism of how dopaminergic learning signals promote value assignment to stimulus representations.

neuroscience↗