Biology subjects

Benedetti, F.

Publications and source records attributed to Benedetti, F..

16 recordsLinked to original sources

bioRxiv2026

Actionable spatial prostanoid barriers constrain BiTE-driven adoptive T cell immunity in intact human tumors

Adoptive cell therapy (ACT) in solid tumors is limited by tumor microenvironment (TME)-imposed resistance mechanisms that are inadequately addressed by conventional systems. We developed tissue-preserving patient-derived explants (PDEs) from lung and ovarian cancer to interrogate redirected T cell immunity in intact human tissue. Using mesothelin-targeting bispecific T cell engager (BiTE(R), Amgen trademark)-secreting T cells, we observed antigen-dependent but heterogeneous responses across lesions. An integrated ex vivo response score stratified responder and non-responder TMEs, revealing that resistance associates with reduced antigen density, stromal dominance, and limited myeloid licensing rather than baseline lymphocyte abundance. Elevated prostaglandin E2 (PGE2) inversely correlated with BiTE-induced T cell activation, identifying the COX/PGE2 axis as a tissue-imposed constraint. COX inhibition amplified interferon-driven immune programs enhanced intratumoral CD8 infiltration, and increased tumor-restricted apoptosis. Spatial transcriptomics localized these effects to tumor-proximal immune hubs in responders, whereas non-responders remained stromally insulated. These findings position PDEs as human-based new approach methodologies enabling combinatorial ACT pharmacodynamics and stratification. Statement of significancePatient-derived explants provide a human-based new approach methodology to interrogate adoptive immunotherapy pharmacodynamics within intact tumor microenvironments in NSCLC and HGSOC. We uncover a COX/PGE2-mediated tissue ceiling that limits BiTE-driven T cell function and demonstrate that COX inhibition reactivates tumor-proximal immune hubs to enhance intratumoral CD8 infiltration and tumor-restricted apoptosis, informing patient stratification and rational combinations.

systems biology↗

bioRxiv2026

Disrupted Higher-Order Topology in OCD Brain Networks Revealed by Hodge Laplacian - an ENIGMA Study

Brain disorders are increasingly understood as disorders of distributed brain circuits, yet functional connectivity (FC), the dominant framework for mapping them, treats the brain as a collection of pairwise relationships between regions and cannot represent pathology distributed across coordinated sets of connections. We introduce a Hodge-Laplacian topological framework that localizes higher-order "loop" (1-cycle) organization within functional connectome, maps each loop to specific edges and networks, and yields a subject-level measure of loop expression. Applied to resting-state fMRI from the ENIGMA-OCD consortium (1,024 patients and 1,028 controls across 28 sites), the framework identified 93 loop-level abnormalities in obsessive-compulsive disorder (OCD), concentrated in frontoparietal and somatomotor systems. The edges forming these loops largely showed no significant differences between groups, indicating that the abnormalities were invisible to conventional FC analysis. The frontoparietal and somatomotor loop clusters recurred across the clinical subgroups, suggesting convergence on a shared higher-order phenotype. Robustness analyses showed the loop signal reflected higher-order organization rather than an artifact of individual edges, the network backbone, or any single site. These results indicate that coordinated, multi-edge pathology exists and can be localized even when pairwise analyses fail to detect it, positioning higher-order topology as a generalizable axis for mapping circuit pathology across psychiatric and neurological disorders.

neuroscience↗

bioRxiv2026

Phytoplankton performance in the lab predicts occurrence in the field across a global temperature gradient

Biologists aim to predict where species will survive and thrive as the planet warms. To do so, we often rely on data-hungry species distribution models (SDMs) that use associations between species occurrences and environmental predictors to capture the realised niche. An alternative basis for predictions is to experimentally quantify the effect of environmental drivers on performance, which captures the fundamental niche. We presently do not know which of these approaches represents a better path towards accurate forecasts. SDMs may depend too strongly on present-day environmental covariation, which will change in the future. In contrast, a major shortcoming of experiments is that they ignore most environmental drivers to focus on one or two. Quantifying how well fundamental and realised niches agree today would help establish how useful both SDMs and experiments are likely to be. We therefore compared both niches in 39 relatively common marine phytoplankton species. The temperature-dependence of population growth rate was characterised with a thermal performance curve model applied to lab experimental data, and the temperature-dependence of species occurrence probability estimated with SDMs applied to a global compilation of marine presence records. We found a fairly strong, near 1:1 relationship between measures of thermal niche centre: the median growth temperature in the lab and the median occurrence temperature in the field (R2 = 0.49). We also found a modest positive relationship between measures of thermal niche width, the growth niche width and the occurrence niche width (R2 = 0.24). This agreement should increase our confidence in environmental preferences inferred with SDMs. It also suggests that simple experiments can reliably constrain species ranges and help forecast range shifts. This has important implications for forecasting community composition and ecosystem processes, as we ought to be able to predict range shifts in biogeochemically-important taxa such as diatoms and nitrogen-fixing cyanobacteria.

ecology↗

bioRxiv2025

Executive control in Obsessive-Compulsive Disorder: A worldwide mega-analysis of task-based functional neuroimaging data of the ENIGMA-OCD consortium

ObjectiveObsessive-compulsive disorder (OCD) is associated with impaired executive function and altered activity in associated neural circuits, contributing to reduced goal-directed behavior. To investigate neural activation during executive control, we conducted a mega-analysis in the ENIGMA-OCD consortium pooling individual participant data from 475 individuals with OCD and 345 healthy controls across 15 fMRI tasks collected worldwide. MethodsIndividual participant data was uniformly processed using HALFpipe to construct voxelwise statistical images of executive control and task load contrasts. Parameter estimates extracted from regions of interest were entered into multilevel Bayesian models to examine regional and whole-brain effects of diagnosis, and, within OCD, the influence of medication status, symptom severity, and age of onset on task activation. ResultsWe observed a robust task activation pattern across individuals with OCD and control participants in executive control regions across tasks. Relative to controls, individuals with OCD showed moderate to very strong evidence of weaker activation of the dorsolateral prefrontal cortex, precuneus, frontal eye fields, and inferior parietal lobule during executive control (all positive posterior probabilities [P+]<0.1). Individuals with OCD also showed stronger activation in regions of the default mode network during executive function relative to controls. We found little evidence for differential activation during executive control in task- positive regions related to disease onset, severity and medication status. ConclusionIn the first mega-analysis of fMRI studies of executive function in OCD, we found strong evidence of weaker frontoparietal activation during executive control tasks. Our findings also suggest a failure of default mode network regions to appropriately disengage during task performance in OCD.

neuroscience↗

bioRxiv2025

Dissecting heterogeneity in cortical thickness abnormalities in major depressive disorder: a large-scale ENIGMA MDD normative modelling study

ImportanceMajor depressive disorder (MDD) is highly heterogeneous, with marked individual differences in clinical presentation and neurobiology, which may obscure identification of structural brain abnormalities in MDD. To explore this, we used normative modeling to index regional patterns of variability in cortical thickness (CT) across individual patients. ObjectiveTo use normative modeling in a large dataset from the ENIGMA MDD consortium to obtain individualised CT deviations from the norm (relative to age, sex and site) and examine the relationship between these deviations and clinical characteristics. Design, setting, and participantsA normative model adjusting for age, sex and site effects was trained on 35 CT measures from FreeSurfer parcellation of 3,181 healthy controls (HC) from 34 sites (40 scanners). Individualised z-score deviations from this norm for each CT measure were calculated for a test set of 2,119 HC and 3,645 individuals with MDD. For each individual, each CT z-score was classified as being within the normal range (95% of individuals) or within the extreme range (2.5% of individuals with the thinnest or thickest cortices). Main outcome measuresZ-score deviations of CT measures of MDD individuals as estimated from a normative model based on HC. ResultsZ-score distributions of CT measures were largely overlapping between MDD and HC (minimum 92%, range 92-98%), with overall thinner cortices in MDD. 34.5% of MDD individuals, and 30% of HC individuals, showed an extreme deviation in at least one region, and these deviations were widely distributed across the brain. There was high heterogeneity in the spatial location of CT deviations across individuals with MDD: a maximum of 12% of individuals with MDD showed an extreme deviation in the same location. Extreme negative CT deviations were associated with having an earlier onset of depression and more severe depressive symptoms in the MDD group, and with higher BMI across MDD and HC groups. Extreme positive deviations were associated with being remitted, of not taking antidepressants and less severe symptoms. Conclusions and relevanceOur study illustrates a large heterogeneity in the spatial location of CT abnormalities across patients with MDD and confirms a substantial overlap of CT measures with HC. We also demonstrate that individualised extreme deviations can identify protective factors and individuals with a more severe clinical picture. Key points QuestionCan z-scores derived from normative modelling shed light on the heterogeneous group-level findings of cortical thickness abnormalities in major depression and what characterises individuals at the extreme ends of cortical thickness abnormalities? FindingWe confirmed a large overlap in z-score distributions between depressed individuals and healthy controls and a heterogeneous spatial distribution of extreme z-deviations across brain regions across individual patients. Lower z-scores for cortical thickness were related to more severe clinical characteristics. MeaningOur findings confirm the heterogeneity in individual variation in the location and extent of CT abnormalities across patients with MDD and stress the importance of individualised predictions when examining cortical thickness abnormalities.

neuroscience↗

bioRxiv2024

A generalizable normative deep autoencoder for brain morphological anomaly detection: application to the multi-site StratiBip dataset on bipolar disorder in an external validation framework.

The heterogeneity of psychiatric disorders makes researching disorder-specific neurobiological markers an ill-posed problem. Here, we face the need for disease stratification models by presenting a generalizable multivariate normative modelling framework for characterizing brain morphology, applied to bipolar disorder (BD). We employed deep autoencoders in an anomaly detection framework, combined with a confounder removal step integrating training and external validation. The model was trained with healthy control (HC) data from the human connectome project and applied to multi-site external data of HC and BD individuals. We found that brain deviating scores were greater, more heterogeneous, and with increased extreme values in the BD group, with volumes prominently from the basal ganglia, hippocampus and adjacent regions emerging as significantly deviating. Similarly, individual brain deviating maps based on modified z scores expressed higher abnormalities occurrences, but their overall spatial overlap was lower compared to HCs. Our generalizable framework enabled the identification of subject- and group-level brain normative-deviating patterns, a step forward towards the development of more effective and personalized clinical decision support systems and patient stratification in psychiatry.

neuroscience↗

bioRxiv2024

Standardizing marine habitat modelling practices to enhance inter-comparability across biological observations

In recent years, the volume of accessible marine pelagic observations has increased exponentially and now incorporates a wealth of new data types, including information derived from metagenomics and quantitative imaging. This calls for standardized modelling protocol across taxonomically harmonized observations, to better predict biogeographic patterns in space and time, and thus investigate marine ecosystem structure and functioning on a macroecological scale. In this context, we introduce CEPHALOPOD (Comprehensive Ensemble Pipeline for Habitat modelling Across Large-scale Ocean Pelagic Observation Datasets), a standardized and flexible framework to perform multi-species marine habitat modelling across data types and data sources. We built this new framework on observational data from federating initiatives such as AtlantECO, OBIS, GBIF, associated with already existing statistical and machine learning methods that enable to extract and model information from heterogeneous, scarce, and biased field observations. Here, we first document our statistical ensemble modelling approach and then assess its strength and limitations with a virtual ecologist approach. We show how our framework performs in reproducing a range of distributions from biased field samples. Then, we illustrate its performance and comparability across data types by investigating the global diversity patterns of coccolithophores from both abundance and metagenomic data. Our modelling framework serves as a foundation for the consistent generation of Essential Biodiversity and Ocean Variables (EBVs and EOVs) and carries the potential to significantly advance our comprehension of biodiversity and marine ecosystems functioning. Finally, it provides an unprecedented opportunity to foster collaborations in the field of marine science, sustainable ecological practices, and, ultimately, contribute to the preservation of global marine biodiversity.

ecology↗

bioRxiv2024

Myeloid cell networks determine reinstatement of original immune environments in recurrent ovarian cancer

Immunotherapy has produced disappointing results in recurrent ovarian cancer (OC). However, the prognostic value of tumour-infiltrating lymphocytes (TILs) is largely based on the analysis of treatment-naive tumours. To understand the immunobiology of recurrent cancers, and their evolution, we profiled 170 patient-matched primary-recurrent OC samples from 69 patients of two independent cohorts. By capturing heterogeneous TIL distributions, we identified four immune phenotypes associated with differential prognosis, TILs states and TILs:myeloid networks, which dictate malignant evolution after chemotherapy and recurrence. Notably, recurrent tumours recapitulate the immunogenic patterns of original cancers. Mirroring inflamed human OC, preclinical recurrent Brca1mut tumours maintained activated TILs:dendritic cells (DCs) niches and immunostimulatory tumour-associated macrophages (TAMs). Conversely, recurrent Brca1wt tumours displayed loss of TILs:DCs niches and accumulated immunosuppressive myeloid networks featuring Trem2/ApoEhigh TAMs and Nduf4l2high/Galectin3high malignant states. Our study highlights that persistent immunogenicity in recurrent OC is governed by the crosstalk between dissimilar myeloid cells and TILs, which is BRCA-dependent.

immunology↗

bioRxiv2023

Tumor-reactive clonotype dynamics underlying clinical response to TIL therapy in melanoma

The profiles, specificity and dynamics of tumor-specific clonotypes that are associated with clinical response to adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) remain unclear. Using single-cell RNA/TCR-sequencing, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients treated with TIL-ACT. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, which were more effectively mobilized upon in vitro expansion, yielding products with higher numbers of tumor-specific CD8+ cells, which also preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes, and with cell products mostly composed of blood-borne clonotypes mainly persisting in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost the specific signatures of states originally exhibited in tumors, including exhaustion, and in responders acquired an intermediate exhausted effector state after tumor engraftment, revealing important functional cell reinvigoration.

cancer biology↗

bioRxiv2023

Global gradients in species richness of marine plankton functional groups

The patterns of species diversity of plankton functional groups (PFGs) remain poorly understood although they matter for marine ecosystem functioning. Here, we use an ensemble of empirical species distribution models for 845 plankton species to estimate the mean annual global species richness of three phytoplankton and eleven zooplankton functional groups as a function of objectively selected environmental predictors. The species richness of all PFGs decreases from the low to the high latitudes, but the steepness and the shape of this decrease varies significantly across PFGs. Pteropods, small copepods (Oithonids and Poecilostomatoids) and Salps show the steepest latitudinal gradients, whereas Amphipods and the three phytoplankton groups show the weakest ones. While the position of such peaks and troughs in richness is modulated by the presence of upwelling systems, boundary currents and oxygen minimum zones, the gradients of temperature, irradiance, and nutrient concentration are the first-order control on the main latitudinal richness patterns. The species richness of all PFGs increases with net primary production but decreases with particles size and the efficiency of the biological carbon pump. Our study puts forward emergent Biodiversity-Ecosystem Functioning relationships and hypotheses about their underlying drivers for future field-based and modelling research.

ecology↗

bioRxiv2022

Tumor Microenvironment Cellular Crosstalk Predicts Response to Adoptive TIL Therapy in Melanoma

Adoptive cell therapy (ACT) using ex vivo expanded tumor-infiltrating T lymphocytes (TILs) can mediate responses in metastatic melanoma, but long-term efficacy remains limited to a fraction of patients. Here we interrogated tumor-microenvironment (TME) cellular states and interactions of longitudinal samples from 13 metastatic melanoma patients treated with TIL-ACT in our clinical study (NCT03475134). We performed single-cell RNA-seq and spatial proteomic analyses in pre- and post-ACT tumor tissues and showed that responders exhibited higher tumor cell-intrinsic immunogenicity. Also, endogenous CD8+ TILs and myeloid cells of responders were characterized by increased cytotoxicity, exhaustion and costimulation and type-I IFN signaling, respectively. Cell-cell interaction prediction analyses corroborated by spatial neighborhood analyses revealed that responders have rich baseline intratumoral and stromal tumor-reactive T-cell networks with activated myeloid populations. Successful TIL-ACT therapy further reprogrammed the myeloid compartment and increased TIL-myeloid networks. Our systematic target discovery study reveals CD8+ T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials. One-Sentence SummaryResponse to adoptive TIL therapy in melanoma is determined by CD8+ TIL-myeloid cell networks

immunology↗

bioRxiv2022

Copepod functional traits and groups show contrasting biogeographies in the global ocean

AimThe distribution of zooplankton functional traits is a key factor for regulating food web dynamics and carbon cycling in the oceans. Yet, we lack a clear understanding of how many functional groups (FGs) exist in the zooplankton and how their traits are distributed on a global scale. Here, we model and map the environmental habitats of copepod (i.e. the main component of marine zooplankton) FGs to identify regions sharing similar functional trait expression, at the community level. TaxonMarine planktonic Neocopepoda. LocationGlobal ocean. MethodsFactor analysis on mixed data and hierarchical clustering were used to identify copepod FGs based on five species-level functional traits. An ensemble of species distribution models was used to estimate the environmental niches of the species modelled and the community weighted mean values of the traits studied. Ocean regions were defined based on their community-level mean trait expression using a principal component analysis and hierarchical clustering. ResultsEleven global copepod FGs were identified. They displayed contrasting latitudinal patterns in mean annual habitat suitability that could be explained by differences in environmental niche preferences: two FGs were associated with polar conditions, one followed the global temperature gradient, five were associated with tropical oligotrophic gyres, and the remaining three with boundary currents and counter currents. Four main regions of varying community weighted mean trait values emerged: the Southern Ocean, the northern and southern high latitudes, the tropical gyres, and the boundary currents and upwelling systems. ConclusionsThe present FGs will improve the representation of copepods in global marine ecosystem models. This study improves the understanding of the patterns and drivers of copepods trait biogeography and will serve as a basis for studying links between zooplankton biodiversity and ecosystem functioning in a context of climate change.

ecology↗

bioRxiv2021

SARS-CoV-2 B.1.617 Indian variants: are electrostatic potential changes responsible for a higher transmission rate?

Lineage B.1.617+, also known as G/452R.V3, is a recently described SARS-CoV-2 variant under investigation (VUI) firstly identified in October 2020 in India. As of May 2021, three sublineages labelled as B.1.617.1, B.1.617.2 and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R and P681R. Here we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the Receptor Binding Domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 sublineage, which shows multiple replacements of neutral or negatively-charged amino acids with positively-charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+RBD and the negatively-charged ACE2 thus conferring a potential increase in the virus transmission.

bioinformatics↗

bioRxiv2021

Identification and characterization of human CD34+ and CD34dim/- neutrophil committed progenitors

We report the identification of human CD66b-CD64dimCD115- neutrophil-committed progenitors within SSClowCD45dimCD34+ and CD34dim/- bone marrow cells, that we named neutrophil myeloblast (NMs). CD34+ and CD34dim/-NMs resulted as either CD45RA+ or CD45RA-, with CD34+CD45RA-NMs found as selectively expanded in chronic-phase chronic myeloid leukemia patients. By scRNA-seq experiments, CD34+ and CD34dim/-NMs were found to consist of combinations of four cell clusters, characterized by different maturation stages and distributed along two differentiation routes. Cell clusters were identified by neutrophil-specific gene profiles, one of them associated to an interferon-stimulated gene (ISG) signature, hence supporting recently identified expansions of mature neutrophil subsets expressing ISGs in blood of diseased individuals. Altogether, our data shed light on the very early phases of neutrophil ontogeny.

immunology↗

bioRxiv2019

White Matter Microstructure and its Relation to Clinical Features of Obsessive-Compulsive Disorder: Findings from the ENIGMA OCD Working Group

ImportanceMicrostructural alterations in cortico-subcortical connections are thought to be present in Obsessive-Compulsive Disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. ObjectiveTo investigate microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. Design, Setting, and ParticipantsIn this cross-sectional case-control magnetic resonance study, we investigated diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA-OCD Working Group. Main Outcomes and MeasuresWe extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohens d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. ResultsAdult OCD patients showed significant FA reduction in the sagittal stratum (d=-0.21, z=-3.21, p=0.001) and posterior thalamic radiation (d=-0.26, z=-4.57, p<0.0001). In the sagittal stratum only, lower FA was associated with a younger age of onset (z=2.71, p=0.006), longer duration of illness (z=-2.086, p=0.036) and a higher percentage of medicated patients in the cohorts studied (z=-1.98, p=0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to matched controls. Conclusions and RelevanceMicrostructural alterations in projection and association fibers to posterior brain regions were found in adult OCD, and related to disease course and medication status. Such results are relevant to models positing deficits in connectivity as a crucial mechanism in OCD. KEY POINTSO_ST_ABSQuestionC_ST_ABSDo patients with Obsessive-Compulsive Disorder (OCD) show white matter microstructural alterations, and are these alterations related to clinical features? FindingsData from 19 sites of the ENIGMA-OCD Consortium were included, involving 700 adult patients and 645 adult controls, 174 pediatric patients and 144 pediatric controls. Diffusion tensor imaging data were meta-analyzed using a harmonized data processing and analysis protocol. Adult, but not pediatric, patients showed alterations in the sagittal stratum and posterior thalamic radiation; sagittal stratum differences were associated with clinical features. MeaningMicrostructural abnormalities found in adult but not in the pediatric cohort, are related to illness duration and medication status.

neuroscience↗

bioRxiv2018

Chromatin-loop extrusion and chromatin unknotting

It has been a puzzle how decondensed interphase chromosomes remain essentially unknotted. The natural expectation is that in the presence of type II DNA topoisomerases that permit passages of double-stranded DNA regions through each other, all chromosomes should reach the state of topological equilibrium. The topological equilibrium in highly crowded interphase chromosomes forming chromosome territories would result in formation of highly knotted chromatin fibres. However, Chromosome Conformation Capture (3C) methods revealed that the decay of contacts with the genomic distance in interphase chromosomes is practically the same as in the crumpled globule state that is formed when long polymers condense without formation of any knots. To remove knots from highly crowded chromatin, one would need an active process that should not only provide the energy to move the system from the state of topological equilibrium but also guide topoisomerase-mediated passages in such a way that knots would be efficiently unknotted instead of making the knots even more complex. We show here that the process of chromatin-loop extrusion is ideally suited to actively unknot chromatin fibres in interphase chromosomes.\n\nSIGNIFICANCE STATEMENTSimilar to earphone cables crammed into a pocket, long and crowded chromatin fibres that form chromosomes in living cells have the natural tendency to get knotted. This is exacerbated by the action of DNA topoisomerases that transiently cut some chromatin fibres and let other to pass through. Yet, the knotting frequency of chromatin fibres is very low and it has been a puzzle how this is achieved. Recently a novel active mechanism known as chromatin loop extrusion has been proposed to be involved in shaping chromosomes by forming sequential arrays of ca 1 Mb large chromatin loops. Using numerical simulations, we show here that chromatin loop extrusion is ideally suited to remove knots from chromatin fibres.

biophysics↗