Biology subjects

Nicolau, D. V.

Publications and source records attributed to Nicolau, D. V..

3 recordsLinked to original sources

bioRxiv2024

A Rose by any Other Name: Towards a quantitative theory of neuroimmune interactions

Humanity has known about - and been fascinated by - the connection between mind and body since time immemorial, yet we have only been able to begin to quantitatively explore their interactions in recent years. Even so, the field of neuroimmunology is categorically in its infancy. Despite myriad and diverse experimental reports, no coherent theoretical approach to the neuroimmune system has been even attempted, which makes it difficult to make sense of the emerging body of empirical findings. Here, we take the first steps towards this goal by introducing a mathematical framework that describes the triggering and control of neurological memories (engrams) of immune challenges. Using peanut allergies as a model system, we show how a simple differential equation model of coupled immune-engram responses can explain a number of key observations regarding putative neurological control of focal inflammatory responses and failures thereof. Simulations of our model identify four areas of the parameter regime corresponding to distinct consequences of fake immune stimulation: a) resolution b) finite oscillations of inflammation, followed by resolution c) sustained, self-amplifying oscillations (cytokine storm-like phenomena) and d) resolution followed by the permanent establishment of a chronic higher-baseline inflammatory state. Importantly, we then show how our model recapitulates the key qualitative features of a recent experimental description of immune engram encoding and re-activation (respectively, suppression) in a mouse model of colitis. We conclude with remarks around clinical implications as well as directions for future work in theoretical neuroimmunology. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/605114v3_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@89ea55org.highwire.dtl.DTLVardef@778323org.highwire.dtl.DTLVardef@428edforg.highwire.dtl.DTLVardef@1b1deea_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Epigenome erosion drives neural crest-like phenotypic mimicry in triple-negative breast cancer and other SOX10+ malignancies

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSIntratumoural heterogeneity is a poor prognostic feature in triple-negative breast cancer (TNBC) and other high-grade malignancies. It is caused by genomic instability and phenotypic plasticity, but how these features co-evolve during tumour development remains unclear. SOX10 is a transcription factor, neural crest stem cell (NCSC) specifier and candidate mediator of cancer-associated phenotypic plasticity. MethodsUsing immunophenotyping, we investigated the expression of SOX10 in normal human breast tissue and breast cancer (n=21 cosmetic breast reduction and 1,860 tumour samples with clinical annotation). We then defined the context and evolution of its expression in TNBC compared to 21 other malignancies using systems-level transcriptomics. ResultsSOX10 was detected in nuclei of normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In breast cancer, nuclear SOX10 predicted poor outcome amongst cross-sectional (log-rank p=0.0015, hazard ratio 2.02, n=224) and metaplastic (log-rank p=0.04, n=66) TNBCs. Systems-level transcriptional network analysis identified a core module in SOX10s normal mammary epithelial transcription program that is rewired to NCSC genes in TNBC. Reprogramming was proportional to DNA damage and genome-wide promoter hypomethylation, particularly at CpG island shores. Using a novel network analysis pipeline, we found that NCSC-like transcriptional reprogramming is also strongly associated with promoter hypomethylation in other SOX10+ malignancies: glioma and melanoma. ConclusionsWe propose that cancer-associated genome hypomethylation simulates the open chromatin landscape of more primitive cell states, and that on this relatively unrestricted background, SOX10 recreates its ancestral gene regulatory circuits by default. These findings provide new insights about the basis of intratumoural heterogeneity and resurrection of developmental phenotypes in cancer; and highlight the potential for therapeutics that limit chromatin remodelling.

cancer biology↗

bioRxiv2018

Intracellular mechanisms of fungal space searching in microenvironments

The underlying intracellular mechanisms involved in the fungal growth received considerable attention, but the experimental and theoretical work did not take into account the modulation of these processes by constraining microenvironments similar to many natural fungal habitats. To fill this gap in the scientific knowledge, we used time-lapse live-cell imaging of Neurospora crassa growth in custom-built confining microfluidics environments. We show that the position and dynamics of the Spitzenkorper-microtubules system in constraining environments differs markedly from that associated with unconstrained growth. First, when hyphae encounter an obstacle at shallow angles, the Spitzenkorper moves from its central position in the apical dome off-axis towards a contact with the obstacle, thus functioning as a compass preserving the directional memory of the initial growth. The trajectory of Spitzenkorper is also followed by microtubules, resulting in a cutting corners pattern of the cytoskeleton in constrained geometries. Second, when an obstacle blocks a hypha at nearnormal incidence, the Spitzenkorper-microtubule system temporarily disintegrates, followed by the formation of two equivalent systems in the proto-hyphae - the basis of obstacle-induced branching. Third, a hypha, passing a lateral opening along a wall, continues to grow largely unperturbed while a lateral proto-hypha gradually branches into the opening, which starts forming its own Spitzenkorper-microtubule system. These observations suggest that the Spitzenkorper-microtubules system conserves the directional memory of the hyphae when they navigate around obstacles, but in the absence of the Spitzenkorper-microtubule system during constrainment-induced apical splitting and lateral branching, the probable driving force of obstacle-induced branching is the isotropic turgor pressure.

cell biology↗