Biology subjects

Mariani, M.

Publications and source records attributed to Mariani, M..

10 recordsLinked to original sources

bioRxiv2026

Parvalbumin interneuron maturation reorganizes cortical population activity structure during development

During brain development, spontaneous cortical activity undergoes a dramatic transformation from highly synchronous network events to less correlated and sparse neuronal firing that is thought to underlie more flexible neural coding. However, how the structure of population activity changes across this transition, what circuit mechanisms drive this reorganization, and the implications for information encoding have not been fully established. Using longitudinal in vivo calcium imaging in early postnatal mice, we demonstrate that cortical network desynchronization during the second postnatal week is accompanied by a redistribution of fractional variance from dominant, low-dimensional modes into many weaker dimensions, and a growing influence of GABAergic interneurons (INs) on the network. All-optical circuit interrogation revealed that parvalbumin (PV) INs, but not somatostatin (SST) INs, are sufficient to desynchronize the network and shift the distribution of population variance. Through targeted ablation of a fraction of PV INs, we show dimensionality is highly correlated with stimulus decoding accuracy. Furthermore, PV INs undergo a sharp increase in transcriptional maturation between postnatal day (P) 8 and 11, during which they preferentially enrich for synaptic genes. Lastly, a novel, biologically plausible, multi-cell-type computational model reproduced the developmental desynchronization and rise in dimensionality. Strikingly, without being constrained by perturbation data, the model accurately predicted the effects of each IN class on the network that we observed empirically.

neuroscience↗

bioRxiv2026

Distillation enables scalable high-fidelity virtual screening across ultra-large chemical libraries

Accurate virtual screening of ultra-large chemical libraries remains challenging. Existing approaches rely on lower-fidelity scoring functions or sampling-based strategies that can limit predictive accuracy and bias the exploration of chemical space. Here, we present FastBindRank, a distillation-based framework that transfers the predictive power of the structure-based model Boltz-2 into an efficient sequence-based surrogate. Trained on [~]1% of the 122-million-compound PubChem library, FastBindRank enables high-fidelity screening at scale. Applied to histone deacetylase 11 (HDAC11), FastBindRank substantially enriched high-confidence binders relative to the background chemical space. The lightweight model captured structural patterns associated with predicted binding, revealing structural determinants of binding. Under a comparable computational budget, FastBindRank achieved a 74-fold increase in hit rate and over a 30-fold increase in discovery yield over direct subset-based screening. Experimental validation confirmed the activity of two novel compounds. These results establish distillation as a practical strategy for scalable, high-fidelity virtual screening of ultra-large chemical libraries.

bioinformatics↗

bioRxiv2026

Scalable genotyping in fixed transcriptomes resolves clonal heterogeneity via single-cell sequencing

Despite the promise of single-cell transcriptomics for understanding cell states in heterogeneous populations, widely used platforms have limited ability to link transcriptional states to somatic mutations within the same cells. Here, we introduce Genotyping in Fixed Transcriptomes (GIFT) for the simultaneous detection of large numbers of targeted genetic variants with whole transcriptome profiles in single cells. The core innovation of GIFT is a rationally designed gapfilling reaction between adjacent single-stranded DNA (ssDNA) probes that barcodes native transcript sequence to enable highly-specific targeted mutation detection. GIFT achieves greater than 99% genotyping accuracy and flexible capture of hundreds of mutations per cell, including in formalin-fixed, paraffin-embedded (FFPE) tissue, enabling clonal lineage tracing in heterogeneous settings. We demonstrate the unique scalability of GIFT by profiling more than 700,000 cells from 35 donors with myeloproliferative neoplasms (MPN), revealing mutation-dependent hematopoietic responses to systemic inflammation associated with the characteristic JAK2V617 mutation, including an allelic dose gradient of interferon-associated transcriptional programs and priming of hematopoietic stem cells that develop into divergent disease states. The technical advantages of GIFT enable direct resolution of genotype-to-phenotype relationships via clonal tracing with comprehensive cell-state measurements at single-cell resolution.

genomics↗

bioRxiv2025

Multiple long-range cis interactions generate CTCF insulator-dependent viral chromatin domains in quiescent HSV-1 genomes

In cellular genomes, CTCF insulators impact transcription over small distances in a one-dimensional manner and over much longer distances in a three-dimensional manner by maintaining chromatin loops. We have previously shown that the latent HSV-1 genome contains CTCF insulators that function to regulate lytic transcription of adjacent genes in a one-dimensional manner. Here, we test the hypothesis that HSV-1 CTCF insulators nucleate chromatin loops to regulate the expression of distance separated gene regions through three-dimensional organization of viral genomes. We used 4C-seq methods to identify multiple long-range cis interactions in HSV-1 genomes that generate viral chromatin domains, including those nucleated by the viral CTCF insulator CTRL2. Deletion of the CTRL2 insulator disrupted these viral chromatin domains. Loop-nucleating interactions were quantitated with a novel approach (UMI-4C-seq) that utilizes unique molecular identifiers to label and count chromatin interactions associated with specific viewpoint primers. Cis-interaction peaks across four different viewpoints were quantified. Viral genomes lacking CTRL2 displayed more cis-interaction peaks and wider ranges of interaction lengths compared to wt virus, suggesting altered chromatin organization. Furthermore, differential looping analysis showed viral genomes lacking CTRL2 displayed a more transcriptionally permissive chromatin environment. Thus, the CTRL2 insulator functions as a critical regulator of long-range chromatin interactions and its deletion reshapes the viral chromatin landscape, leading to a more accessible and dynamic regulatory environment that may influence HSV-1 transcriptional programs and latency-associated chromatin states.

microbiology↗

bioRxiv2025

A universal power law optimizes energy and representation fidelity in visual adaptation

Sensory systems continuously adapt their responses based on the probability of encountering a given stimulus. In the mouse primary visual cortex (V1), the population response magnitude is a power law of the stimulus probability in the environment. For a given stimulus type (e.g., oriented gratings), the power law's exponent is invariant to changes in statistical environments, enabling predictions of population responses to new environments. Here, we aim to provide a normative explanation for the power law behavior. We develop an efficient coding model where neurons adjust their firing rates through optimization of a weighted objective, hypothesizing that the neural population adapts to enhance stimulus detection and discrimination while reducing overall neural activity. We show that a model balancing representational fidelity and energy efficiency matches the power law observed experimentally for a wide range of parameters, while models of adaptation with alternative coding objectives and resource constraints are unable to reproduce this empirical observation. Furthermore, we account for the invariance of the power law's exponent across environmental changes by linking it to the dependence of tuning curve modulation on stimulus probability. Finally, we explain how variations in the exponent with different stimulus types (e.g., natural stimuli) result from changes in the minimal distances between neural representations, in agreement with experimental findings. We conclude that a universal power law of adaptation can be explained as a trade-off between representation fidelity and energy cost.

neuroscience↗

bioRxiv2024

Loss of function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

PurposeEpigenetic dysregulation has been associated with many inherited disorders. RBBP5 encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. MethodsWe identify five unrelated individuals with de novo heterozygous pathogenic variants in RBBP5. Three truncating and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. ResultsBoth missense p.T232I and p.E296D variants affect evolutionarily conserved amino acids and are expected to interfere with the interface between RBBP5 and the histones. In Drosophila, ubiquitous overexpression of human RBBP5 is lethal in the larval developmental stage. Loss of Rbbp5 leads to a reduction in brain size, and the human reference, p.T232I, or p.E296D variant transgenes fail to rescue loss of Rbbp5. Expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both p.T232I and p.E296D variants are loss-of-function alleles. ConclusionDe novo heterozygous variants in RBBP5 are associated with a syndromic neurodevelopmental disorder. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/578086v1_ufig1.gif" ALT="Figure 1"> O_LINKSMALLFIG WIDTH=200 HEIGHT=24 SRC="FIGDIR/small/578086v1_ufig1a.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@11337daorg.highwire.dtl.DTLVardef@b7f4d8org.highwire.dtl.DTLVardef@12bc283org.highwire.dtl.DTLVardef@1ef4e09_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2020

Lipidome profiles of plasma microvesicles differ in experimental cerebral malaria, compared to malaria without neurological complications

Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms, which include an excessive release of microvesicles (MV). Plasma MV levels have been found elevated in CM patients and in the experimental mouse model. We compared lipid profiles in circulating MV purified from CBA mice infected with P. berghei ANKA (PbA), which causes CM, to those from P. yoelii (Py), which does not. Here we show that plasma MV produced at the time of CM differed dramatically from those from non-CM mice, in spite of identical levels of parasitaemia. Using high-resolution LCMS, we identified over 300 lipid species within 12 lipid classes. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to uninfected mice, while they were unchanged in Py MV, and lysophosphatidylcholine (LPC) was more significantly reduced in PbA mice compared to the other two groups. These results suggest, for the time, that experimental CM is characterised by specific changes in lipid composition of circulating MV, pointing towards triglycerides (TG) especially docosahexaenoic acid (DHA 22:6) containing species, phosphatidylethanolamine (PE), LPC, LPE, and diacylglycerol (DG) as potential important players in CM pathogenesis.

pathology↗

bioRxiv2020

Lithium ameliorates Cornelia de Lange syndrome associated phenotypes in experimental models

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

genetics↗

bioRxiv2018

High throughput droplet single-cell Genotyping of Transcriptomes (GoT) reveals the cell identity dependency of the impact of somatic mutations

Defining the transcriptomic identity of clonally related malignant cells is challenging in the absence of cell surface markers that distinguish cancer clones from one another or from admixed non-neoplastic cells. While single-cell methods have been devised to capture both the transcriptome and genotype, these methods are not compatible with droplet-based single-cell transcriptomics, limiting their throughput. To overcome this limitation, we present single-cell Genotyping of Transcriptomes (GoT), which integrates cDNA genotyping with high-throughput droplet-based single-cell RNA-seq. We further demonstrate that multiplexed GoT can interrogate multiple genotypes for distinguishing subclonal transcriptomic identity. We apply GoT to 26,039 CD34+ cells across six patients with myeloid neoplasms, in which the complex process of hematopoiesis is corrupted by CALR-mutated stem and progenitor cells. We define high-resolution maps of malignant versus normal hematopoietic progenitors, and show that while mutant cells are comingled with wildtype cells throughout the hematopoietic progenitor landscape, their frequency increases with differentiation. We identify the unfolded protein response as a predominant outcome of CALR mutations, with significant cell identity dependency. Furthermore, we identify that CALR mutations lead to NF-{kappa}B pathway upregulation specifically in uncommitted early stem cells. Collectively, GoT provides high-throughput linkage of single-cell genotypes with transcriptomes and reveals that the transcriptional output of somatic mutations is heavily dependent on the native cell identity.

cancer biology↗

bioRxiv2018

RNASeq analysis identifies non-canonical role of STAT2 and IRF9 in the regulation of a STAT1-independent antiviral and immunoregulatory transcriptional program induced by IFNβ and TNFα

IFN{beta} typically induces an antiviral and immunoregulatory transcriptional program through the activation of ISGF3 (STAT1, STAT2 and IRF9) transcriptional complexes. The response to IFN{beta} is context-dependent and is prone to crosstalk with other cytokines, such as TNF IFN{beta} and TNF synergize to drive a specific delayed transcriptional program. Previous observation led to the hypothesis that an alternative STAT1-independent pathway involving STAT2 and IRF9 might be involved in gene induction by the combination of IFN{beta} and TNF. Using genome wide transcriptional profiling by RNASeq, we found that the costimulation with IFN{beta} and TNF induces a broad antiviral and immunoregulatory transcriptional program independently of STAT1. Additionally, STAT2 and IRF9 are involved in the regulation of only a subset of these STAT1-independent genes. Consistent with the growing literature, STAT2 and IRF9 act in concert to regulate a subgroup of these genes. Unexpectedly, STAT2 and IRF9 were also engaged in specific independent pathways to regulate distinct sets of IFN{beta} and TNF-induced genes. Altogether these observations highlight the existence of distinct previously unrecognized non-canonical STAT1-independent, but STAT2 and/or IRF9-dependent pathways in the establishment of a delayed antiviral and immunoregulatory transcriptional program in conditions where elevated levels of both IFN{beta} and TNF are present.

immunology↗