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Esposito, G.

Publications and source records attributed to Esposito, G..

At least 19 recordsLinked to original sources
bioRxiv2026

Left Temporoparietal Neural Synchrony Tracks Cooperative Performance Across Adult Dyads

Cooperation requires interacting individuals to coordinate their actions toward shared goals, and interpersonal neural synchrony (INS) has been proposed as a neural correlate of this coordination. However, the relationship between INS and cooperative performance remains heterogeneous, and relatively little is known about how it varies across social relationships. The present study examined INS and behavioral performance during a naturalistic cooperative tabletop Jenga task in close-friend, romantic-partner, and mother--child dyads (N = 284 participants). Brain activity was simultaneously recorded using functional near-infrared spectroscopy (fNIRS) hyperscanning, and INS was quantified using wavelet transform coherence across the bilateral inferior frontal gyrus (IFG) and temporoparietal junction (TPJ). Cooperative performance was assessed using tower collapse and the number of valid turns completed during the game. True interacting dyads exhibited significantly greater neural synchrony than surrogate dyads across all examined regional pairings (d range = 0.35-0.55), indicating robust interaction-related inter-brain synchrony. Behavioral performance was not associated with INS at the whole-network level. Region-specific analyses, however, showed that tower collapse was associated with reduced synchrony in the left TPJ-left TPJ (p Bonf = 0.009) and left TPJ-right TPJ (p Bonf = 0.017) pairings, whereas the number of valid turns was unrelated to INS. Follow-up analyses further indicated that the association between tower collapse and left TPJ--left TPJ synchrony was present in close-friend (p Bonf = 0.020) and romantic-partner (p Bonf = 0.026) dyads but not in mother-child dyads. These findings suggest that the behavioral relevance of interpersonal neural synchrony is not uniform, but depends on the neural systems involved, the specific index of cooperative performance, and the relational and developmental context in which interaction unfolds.

neuroscience↗
bioRxiv2026

Wavelet Transform Coherence Under Controlled Temporal Correspondence and Social Co-Presence: Implications for fNIRS Hyperscanning

Interpersonal neural synchrony research using functional near-infrared spectroscopy (fNIRS) frequently relies on wavelet transform coherence (WTC) to quantify temporal correspondence between cortical signals. Yet, whether WTC reliably recovers experimentally defined differences in signal correspondence remains insufficiently established. Here, we evaluated WTC using an auditory-guided finger-tapping paradigm in which matching and non-matching temporal structures were compared within participants and between dyad members during individual and joint performance. Task-evoked analyses confirmed reliable recruitment of contralateral motor and premotor regions across both contexts, whereas the ipsilateral motor cortex was significantly recruited only during joint performance and was the only region differing between sessions. WTC sensitivity was strongly modulated by social co-presence. Within participants, WTC failed to discriminate matching from non-matching temporal structures during individual performance, whereas robust matching-related increases emerged during joint performance, particularly in contralateral motor and premotor regions. Between participants, WTC showed limited and region-specific discrimination when participants were tested separately, but higher coherence for matching temporal structures emerged during joint performance, particularly in motor regions. These findings show that WTC can recover experimentally defined temporal correspondence between fNIRS signals, but that this sensitivity is not context-independent. The within-participant results further suggest that social co-presence may alter the temporal dynamics of the individual neural signals themselves. WTC should therefore be interpreted as a context-sensitive measure whose meaning depends on the functional and social processes generating the signals being compared.

neuroscience↗
bioRxiv2026

Avocado-derived compounds alter lipid homeostasis and lipid droplets profile in Caenorhabditis elegans

Background: Natural compounds from avocado fruit (avocadene, avocadyne, and acetate derivatives) exhibit notable biological activity, although their molecular mechanisms remain unclear. The avocado-derived lipids exert potent nematocidal activity against several parasitic nematodes. In Caenorhabditis elegans (C. elegans), those compounds caused concentration-dependent toxicity, impairing first stage larval growth, egg hatching, and adult survival. Treated worms exhibited impaired mitochondrial respiration, reduced oxygen consumption, and elevated reactive oxygen species. These effects suggest that avocado lipids disrupt mitochondrial function and lipid metabolism, in part by inhibiting acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis. Methods: We investigated the effects of these compounds on the lipid profile of C. elegans and their association with endogenous lipid pools using NMR spectroscopy, click-chemistry-based fluorescence labeling, thin-layer chromatography (TLC), and microscopy. Results: Lipidomic analysis of stage 4 larvae (L4) and embryos treated with avocadene acetate revealed increased lipid NMR signals. Fluorescence-assisted TLC and NMR further suggested that avocadyne preferentially associates with triglyceride-linked fatty acids, particularly monounsaturated and flexible polyunsaturated chains, without detectable interactions with conformationally-constrained polyunsaturated species. Fluorescent avocadyne derivatives were efficiently internalized with distinct localization patterns in L4 larvae and embryonic cells. Conclusions: Overall, the lipid homeostasis remodeling of L4 larvae in response to lipotoxic shock was associated with phospholipid increase and remarkable lipid droplets onset, whereas embryos showed accumulation of lipids in enlarged droplets and developmental arrest.

cell biology↗
bioRxiv2026

Structural and Stereochemical Elucidation of Cyanochelin C, a Siderophore Associated with Novel Class of Cyanobacterial Acyl Hydrolases

Iron is a key micronutrient that constrains microbial growth and productivity in many aquatic and terrestrial environments due to its limited bioavailability. Microorganisms evolved sophisticated acquisition strategies, including the production of siderophores, high-affinity iron-chelating molecules that facilitate iron solubilisation and uptake. Cyanobacteria, photosynthetic prokaryotes and major contributors to global primary production, also depend on iron as a cofactor to their core metabolic enzymes. However, very few cyanobacterial siderophores were described so far, and cyanobacteria remain an underxplored source of possibly novel siderophores. Here we report a novel cyanobacterial siderophore, cyanochelin C, that employs two {beta}-hydroxyaspartate residues for iron chelation. We provide extensive nuclear magnetic resonance (NMR) and mass spectrometry (MS) evidence on the molecular structure and identify the corresponding biosynthetic gene cluster (BGC). Bioinformatic analysis of the BGC further revealed the presence of an acylase CcsQ clustering with a broader cyanobacteria-specific family of acylases associated with predicted siderophore-encoding BGCs. Discovery of cyanochelin C and its deacylation by CcsQ expands the known structural diversity of cyanobacterial siderophores and improves the understanding of important enzymatic reactions.

microbiology↗
bioRxiv2026

Over-Synchrony: Higher Maternal Neuroticism Associates with Stronger Interpersonal Neural Synchrony with Child During Passive and Free Interactions

Interpersonal neural synchrony (INS) in mother-child dyads is often interpreted as a neural marker of relational quality and sensitive caregiving, yet findings on its predictors remain heterogeneous. One possible source of this variability is the diversity of interactional paradigms used in hyperscanning research. This study examined how maternal personality, child temperament, and affective states relate to INS across interaction contexts varying in social interactivity. Thirty-three mother-child dyads (n = 20 female children) participated in a functional near-infrared spectroscopy hyperscanning experiment involving passive video co-exposure, a structured cooperative task, and free interaction. Fronto-temporal activity was recorded simultaneously, and INS was computed using wavelet transform coherence. Above-chance levels of INS emerged in inter-brain region combinations primarily involving the mothers left inferior frontal gyrus (IFG) and the childs right IFG (adjusted ps < 0.030, Cohens d range = 0.14-0.31). Maternal neuroticism was the only significant predictor of INS, with higher levels associated with increased synchrony during passive video co-exposure (adjusted p = 0.012) and free interaction (adjusted p = 0.021), but not during the structured game. These findings indicate that maternal dispositional traits shape INS in a context-dependent manner. Notably, the positive association between neuroticism and INS suggests that heightened neural synchrony may reflect over-attunement in more anxious caregivers, rather than optimal coordination. Excessive synchrony may therefore index tightly coupled, over-monitoring interaction dynamics, consistent with models of affiliative vigilance in anxious parenting. Overall, INS may follow a non-linear pattern in which moderate levels are most adaptive, highlighting its flexible, dynamic, and context-sensitive nature.

neuroscience↗
bioRxiv2025

Membrane Sensing Peptides -Enhanced SiMoA Platform for the Detection of HER2 on Extracellular Vesicles in Metastatic Breast Cancer Patients

Extracellular vesicles (EVs) offer a promising avenue for non-invasive, real-time monitoring of metastatic breast cancer (mBC), but clinical application as a liquid biopsy is hindered by their heterogeneity and low abundance. Here we present a Single Molecule Array (SiMoA) platform enhanced by membrane sensing peptides (MSP) for the highly sensitive detection of HER2 on EV membranes (EVs-HER2) and general EVs population (CD9+) directly from plasma samples of mBC patients. The MSP-based SiMoA assay demonstrated superior sensitivity and specificity compared to conventional antibody-based assays, allowing the detection of lower amounts of EVs and discriminating EVs derived from breast cancer patient-derived organoids (BC-PDO) from healthy control-derived organoids (HC-PDO). Concerning the analysis of EVs in plasma samples (n=49 mBC patients, n=30 healthy controls), we observed significantly lower CD9+ EVs levels in mBC patients relative to healthy controls, a trend consistently confirmed across assays. Notably, EVs-HER2 levels were significantly enriched in HER2-positive patients and correlated with clinical HER2 status assessed by immunohistochemistry. Besides, lower CD9+ EVs levels were associated with poorer clinical outcomes, highlighting the potential prognostic utility of EV quantification. Our findings underscore the potential of MSP-enhanced SiMoA platforms for accurate, minimally invasive monitoring of EVs-HER2 in mBC and for monitoring CD9+ EVs levels to assess disease progression.

biochemistry↗
bioRxiv2025

Emotional and Linguistic Features Predict Prefrontal Functional Connectivity during Ongoing Dialogues: An fNIRS Investigation

Identifying the neural bases of language has been a central focus in neuro-science since the pioneering case studies by Broca and Wernicke. Contemporary research has moved beyond classical modular models to conceptualize language as supported by a distributed network of anatomically and functionally interconnected brain regions. Yet, few studies have explored how these networks operate during spontaneous, real-life speech, limiting our understanding of language in natural contexts. In this study, we collected data from 84 individuals engaged in live conversations. Participants prefrontal brain activity was recorded using functional near-infrared spectroscopy hyperscanning, and functional connectivity was quantified via wavelet transform coherence. Dialogues were manually transcribed, and computational methods were applied to extract emotional and semantic/syntactic features from the speech data. Using linear mixed-effects models, we found that emotional content significantly predicted prefrontal functional connectivity [Formula] Among all emotional predictors, expressed anger was the most robust: higher anger levels were associated with reduced connectivity between the left middle frontal gyrus and the right inferior frontal gyrus [Formula]. While other semantic and syntactic features did not predict overall connectivity, degree assortativity--an index of linguistic structure--was negatively associated with connectivity between the superior frontal gyri and the left inferior frontal gyrus [Formula]. These findings highlight how both affective and structural properties of speech modulate prefrontal connectivity during real-life interaction. More broadly, this work demonstrates the potential of integrating computational linguistics with social neuroscience to uncover the neural mechanisms of real-life social interactions.

neuroscience↗
bioRxiv2025

Interpersonal Neural Synchrony Across Levels of Interpersonal Closeness and Social Interactivity

Interpersonal neural synchrony is a fundamental aspect of social interactions, offering insights into the neural mechanisms underlying human connection and developmental outcomes. So far, hyperscanning studies have examined synchrony across different dyads and tasks, leading to inconsistencies in experimental findings and limiting cross-study comparability. This variability has posed challenges for building a unified theoretical framework for neural synchrony. This study investigated the effects of interpersonal closeness and social interactivity on neural synchrony using functional near-infrared spectroscopy hyperscanning. We recorded brain activity from 142 dyads (70 close-friend, 39 romantic-partner, and 33 mother-child dyads) across three interaction conditions: video co-exposure (passive), a cooperative game (structured active), and free interaction (unstructured active). Neural synchrony was computed between participants bilateral inferior frontal gyrus (IFG) and temporoparietal junction (TPJ) using wavelet transform coherence. Results showed that true dyads exhibited significantly higher synchrony than noninteracting surrogate dyads (qs <.001, Cohens d range: 0.17-0.32), particularly in combinations involving the right IFG. Mother-child dyads displayed lower synchrony than adult-adult dyads at the network (p <.001) and local level of analysis, pointing to possible developmental and maturational influences on neural synchrony. At the network level, synchrony was highest during video co-exposure, followed by the cooperative game and free interaction (p <.001). However, left IFG-left IFG and left IFG-right TPJ synchrony peaked during the cooperative game. Although these effects were statistically significant, the overall impact of social interactivity on interpersonal neural synchrony was small, suggesting that the complexity and richness of social exchanges alone may only modestly influence neural synchrony in naturalistic contexts. By comparing different types of dyads and interaction contexts, this study highlights factors that may guide future hypothesis-driven hyperscanning research and contribute incremental evidence to ongoing efforts to understand the neural mechanisms underlying human social interactions.

neuroscience↗
bioRxiv2025

Cyanochelin B: A siderophore produced by cyanobacterium Leptolyngbya sp. NIES-3755 with photolytic properties that negate iron monopolization in the UV-light

Siderophores are low-molecular-weight compounds excreted by microorganisms to facilitate iron uptake in times of its unavailability. Microbes may produce siderophores to monopolize iron and achieve competitive exclusion of other strains. Alternatively, siderophores may be exchanged for other substrates in mutualistic relationships. Siderophores that employ {beta}-hydroxy-aspartate ({beta}-OH-Asp) for iron chelation were shown to undergo UV-mediated photolytic cleavage with simultaneous reduction of Fe3+ to Fe2+. Photolytic siderophores can mediate algal-bacterial mutualism, where the bacteria provide iron in exchange for dissolved organic carbon. We use an interdisciplinary strategy to provide a complex characterization of cyanochelin B, a photolytic {beta}-OH-Asp-containing siderophore produced by filamentous cyanobacterium Leptolyngbya sp. NIES-3755. A combination of nuclear magnetic resonance, high resolution mass spectrometry and bioinformatic analyses complemented with Marfeys and Muratas methods yielded the structure of cyanochelin B with the configuration of its stereocenters. Cyanochelin B-iron complexes exposed to UV- light photolyze within minutes (t1/2 = 8.9 min; [~]3.5 uE UV-A) and release reduced Fe2+. We have co-cultured Leptolyngbya together with Synechocystis PCC6803 as a reporter strain lacking siderophore production. The cultivation setup was based on membrane-separated compartments accommodating individual strains and employed alginate-embedded FeCl3 to simulate poorly accessible precipitated iron. Our results demonstrate that in the absence of UV-light cyanochelin B can monopolize iron in favor of Leptolyngbya. However, UV-light eliminates any monopolization of iron and makes it available to competing organisms. Finally, we report the isolation of novel cyanochelin B-producing strains of Phormidesmis from field material and discuss the phenomenon of photolytic siderophores in a broader context. ImportanceIron is an essential micronutrient that is required by all living organisms as a cofactor of indispensable enzymes. Due to its specific properties it is mostly precipitated and biologically unavailable. To facilitate iron uptake, microbes produce siderophores - low-molecular-weight compounds that bind iron. Siderophores are mediators of microbial interactions and facilitate competitive exclusion of non-compatible strains or foster mutualistic partners and cheater strains. We report a full structural elucidation of cyanochelin B, a photolytic cyanobacterial siderophore that contains {beta}-OH-Asp. Our co-culture experiments show that cyanochelin B may monopolize iron to its producer or make it accessible to other strains depending on the presence of UV light. Moreover, our data suggest that the benefits from production of photolytic siderophores are not restricted to symbiotic partners of the producer but rather available to the whole irradiated community. Of known siderophores, 17.5% contain the photoreactive {beta}-OH-Asp and can function in a similar way.

microbiology↗
bioRxiv2024

A new class of natural anthelmintics targeting lipid metabolism

Parasitic helminths are a major global health threat, infecting nearly one-fifth of the human population and causing significant losses in livestock and crops. Resistance to the few anthelmintic drugs is increasing. Here, we report a set of avocado fatty alcohols/acetates (AFAs) that exhibit nematocidal activity against four veterinary parasitic nematode species: Brugia pahangi, Teladorsagia circumcincta and Heligmosomoides polygyrus, as well as a multidrug resistant strain (UGA) of Haemonchus contortus. AFA shows significant efficacy in H. polygyrus infected mice. In C. elegans, AFA exposure affects all developmental stages, causing paralysis, impaired mitochondrial respiration, increased reactive oxygen species production and mitochondrial damage. In embryos, AFAs penetrate the eggshell and induce rapid developmental arrest. Genetic and biochemical tests reveal that AFAs inhibit POD-2, encoding an acetyl CoA carboxylase, the rate-limiting enzyme in lipid biosynthesis. These results uncover a new anthelmintic class affecting lipid metabolism.

cell biology↗
bioRxiv2024

Translating human drug use patterns into rat models: exploring spontaneous interindividual differences via refined drug self-administration procedures

Heroin and cocaine users tailor their dosage and frequency of use, as well as their method of administration, to maximize the drugs pleasurable effects and prevent withdrawal symptoms. On the other hand, many preclinical self-administration and choice experiments employ fixed unit doses and mandatory timeouts after doses (known as discrete dimension procedures). These restrictions fail to consider the distinct pharmacokinetic properties of heroin and cocaine, leading to uniform and comparable behaviors (including drug-taking patterns). This uniformity contrasts sharply with the significantly different ways humans use heroin and cocaine, which are characterized by highly individualized drug use behaviors. Here, we introduce a no-timeout procedure that overcomes this limitation (continuous dimension procedure). We analyzed the heroin and cocaine taking- and seeking-patterns and estimated drug-brain levels in the presence or absence of timeout between drug injections. We further assessed how absence of timeout and the availability of drug or social peer (access time to the two rewards) affect drug preference. Removing the timeout had a profound effect on pattern of heroin taking and seeking, promoting the emergence of burst-like drug intake and social withdrawal as revealed by a discrete choice procedure. On the other hand, timeout removal had a lesser impact on cocaine taking and seeking and did not impact social preference. By removing timeout during self-administration and increasing the access time during choice resulted in a self-administration procedure that more closely mimic human heroin intake, offering a platform to identify novel medications.

neuroscience↗
bioRxiv2024

Emotional Content and Semantic Structure of Dialogues Predict Interpersonal Neural Synchrony in the Prefrontal Cortex: a Hyperscanning Studywith Functional Near-Infrared Spectroscopy

A fundamental characteristic of social exchanges is the synchronization of individuals behaviors, physiological responses, and neural activity. However, the association between how individuals communicate in terms of emotional content and expressed associative knowledge and interpersonal synchrony has been scarcely investigated so far. This study addresses this research gap by bridging recent advances in cognitive neuroscience data, affective computing, and cognitive data science frameworks. Using functional near-infrared spectroscopy (fNIRS) hyperscanning, prefrontal neural data were collected during social interactions involving 84 participants (i.e., 42 dyads) aged 18-35 years. Wavelet transform coherence was used to assess interpersonal neural synchrony between participants. We used manual transcription of dialogues and automated methods to codify transcriptions as emotional levels and syntactic/semantic networks. Our quantitative findings reveal higher than random expectations levels of interpersonal neural synchrony in the superior frontal gyrus (q = .038) and the bilateral middle frontal gyri (q < .001, q < .001). Linear mixed models based on dialogues emotional content only significantly predicted interpersonal neural synchrony across the prefrontal cortex[Formula] . Conversely, models relying on syntactic/semantic features were more effective at the local level, for predicting brain synchrony in the right middle frontal gyrus [Formula] Generally, models based on the emotional content of dialogues were not effective when limited to data from one region of interest at a time, whereas models based on syntactic/semantic features show the opposite trend, losing predictive power when incorporating data from all regions of interest. Moreover, we found an interplay between emotions and associative knowledge in predicting brain synchrony, providing quantitative support to the major role played by these linguistic components in social interactions and in prefrontal processes. Our study identifies a mind-brain duality in emotions and associative knowledge reflecting neural synchrony levels, opening new ways for investigating human interactions.

neuroscience↗
bioRxiv2023

Assessing nanobody interaction with SARS-CoV-2 Nsp9

The interaction between SARS-CoV-2 non-structural protein Nsp9 and the nanobody 2NSP90 was investigated by NMR spectroscopy using the paramagnetic perturbation methodology PENELOP (Paramagnetic Equilibrium vs Nonequilibrium magnetization Enhancement or LOss Perturbation). The Nsp9 monomer is an essential component of the replication and transcription complex (RTC) that reproduces the viral gRNA for subsequent propagation. Therefore preventing Nsp9 recruitment in RTC would represent an efficient antiviral strategy that could be applied to different coronaviruses, given the Nsp9 relative invariance. The NMR results were consistent with a previous characterization suggesting a 4:4 Nsp9-to-nanobody stoichiometry with the occurrence of two epitope pairs on each of the Nsp9 units that establish the inter-dimer contacts of Nsp9 tetramer. The oligomerization state of Nsp9 was also analyzed by molecular dynamics simulations and both dimers and tetramers resulted plausible. However a different distribution of the mapped epitopes on the tetramer surface with respect to the former 4:4 complex could also be possible, as well as different stoichiometries of the Nsp9-nanobody assemblies such as the 2:2 stoichiometry suggested by the recent crystal structure of the Nsp9 complex with 2NSP23 (PDB ID: 8dqu), a nanobody exhibiting essentially the same affinity as 2NSP90. The experimental NMR evidence, however, ruled out the occurrence in liquid state of the relevant Nsp9 conformational change observed in the same crystal structure.

biophysics↗
bioRxiv2023

Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity

Nanobodies are emerging as critical tools for drug design. Several have been recently created to serve as inhibitors of SARS-Cov-2 entry in the host cell by targeting surface-exposed Spike protein. However, due to the high frequency of mutations that affect Spike, these nanobodies may not target it to their full potential and as a consequence, inhibition of viral entry may not be efficient. Here we have established a pipeline that instead targets highly conserved viral proteins that are made only after viral entry into the host cell when the SARS-Cov-2 RNA-based genome is translated. As proof of principle, we designed nanobodies against the SARS-CoV-2 non-structural protein Nsp9, required for viral genome replication. To find out if this strategy efficiently blocks viral replication, one of these anti-Nsp9 nanobodies, 2NSP23, previously characterized using immunoassays and NMR spectroscopy for epitope mapping, was encapsulated into lipid nanoparticles (LNP) as mRNA. We show that this nanobody, hereby referred to as LNP-mRNA- 2NSP23, is internalized and translated in HEK293 cells. We next infected HEK293-ACE2 cells with multiple SARS-CoV-2 variants and subjected them to LNP-mRNA-2NSP23 treatment. Analysis of total RNA isolated from infected cells treated or untreated with LNP-mRNA-2NSP23 using qPCR and RNA deep sequencing shows that the LNP-mRNA-2NSP23 nanobody protects HEK293-ACE2 cells and suppresses replication of several SARS-CoV-2 variants. These observations indicate that following translation, the nanobody 2NSP23 inhibits viral replication by targeting Nsp9 in living cells. We speculate that LNP-mRNA-2NSP23 may be translated into an innovative technology to generate novel antiviral drugs highly efficient across coronaviruses.

cell biology↗
bioRxiv2023

Infant attachment behaviors reflect the parenting style of individual caregiver in common marmosets

Childrens physical, cognitive, and emotional maturation require adequate interactions and secure attachment with their primary caregivers. However, the causal relationships between parenting components and infant attachment behaviors remain unclear. New World monkey common marmosets provide an ideal model of human parent-infant relations because, like humans, infant attachment is shared among family caregivers, including parents and older siblings using intricate vocal communications. Combining the natural variations in parenting styles and subsecond-scale microanalyses of dyadic vocal and physical interactions, we demonstrate that marmoset infants signal their need by context-dependent call use and selectively maintain proximity with familiar caregivers. The infant attachment behaviors are individually tuned according to the caregivers parenting style; infants keep producing isolation calls when they are carried by rejecting caregivers and exhibit avoidance toward neglectful and rejecting caregivers. Family-deprived infants failed to develop such adaptive uses of attachment behaviors or age-appropriate autonomy and exhibited disorganized attachment behaviors. Thus, marmoset infants shape their ability to modulate their intricate attachment system depending on the caregivers attitude through early social interactions with their family caregivers. Demonstrating the significant similarity of the infant attachment system between marmosets and humans, these findings will pave a path to elucidating the neural mechanisms of the infant attachment system.

animal behavior and cognition↗
bioRxiv2023

signifinder enables the identification of tumor cell states and cancer expression signatures in bulk, single-cell and spatial transcriptomic data

Over the last decade, many studies and some clinical trials have proposed gene expression signatures as a valuable tool for understanding cancer mechanisms, defining subtypes, monitoring patient prognosis, and therapy efficacy. However, technical and biological concerns about reproducibility have been raised. Technical reproducibility is a major concern: we currently lack a computational implementation of the proposed signatures, which would provide detailed signature definition and assure reproducibility, dissemination, and usability of the classifier. Another concern regards intratumor heterogeneity, which has never been addressed when studying these types of biomarkers using bulk transcriptomics. With the aim of providing a tool able to improve the reproducibility and usability of gene expression signatures, we propose signifinder, an R package that provides the infrastructure to collect, implement, and compare expression-based signatures from cancer literature. The included signatures cover a wide range of biological processes from metabolism and programmed cell death, to morphological changes, such as quantification of epithelial or mesenchymal-like status. Collected signatures can score tumor cell characteristics, such as the predicted response to therapy or the survival association, and can quantify microenvironmental information, including hypoxia and immune response activity. signifinder has been used to characterize tumor samples and to investigate intra-tumor heterogeneity, extending its application to single-cell and spatial transcriptomic data. Through these higher-resolution technologies, it has become increasingly apparent that the single-sample score assessment obtained by transcriptional signatures is conditioned by the phenotypic and genetic intratumor heterogeneity of tumor masses. Since the characteristics of the most abundant cell type or clone might not necessarily predict the properties of mixed populations, signature prediction efficacy is lowered, thus impeding effective clinical diagnostics. Through signifinder, we offer general principles for interpreting and comparing transcriptional signatures, as well as suggestions for additional signatures that would allow for more complete and robust data inferences. We consider signifinder a useful tool to pave the way for reproducibility and comparison of transcriptional signatures in oncology.

bioinformatics↗
bioRxiv2021

Low dose/dose rate γ irradiation protects Drosophila melanogaster chromosomes from double strand breaks and telomere fusions by modulating the expression of Loquacious.

It is still continuously debated whether the low-dose/dose-rate (LDR) of ionizing radiation represents a hazard for humans. Model organisms, such as fruit flies, are considered valuable systems to reveal insights into this issue. We found that, in wild-type Drosophila melanogaster larval neuroblasts, the frequency of Chromosome Breaks (CBs), induced by acute {gamma}-irradiation, is significantly reduced when flies are previously exposed to a protracted dose of 0.4Gy delivered at a dose rate of 2.5mGy/h. This indicates that this exposure, which is associated with an increased expression of DNA damage response proteins, induces a radioadaptive response (RAR) that protects Drosophila from extensive DNA damage. Interestingly, the same exposure reduces the frequency of telomere fusions (TFs) from Drosophila telomere capping mutants suggesting that the LDR can generally promote a protective response on chromatin sites that are recognized as DNA breaks. Deep RNA sequencing revealed that RAR is associated with a reduced expression of Loquacious D (Loqs-RD) gene that encodes a well-conserved dsRNA binding protein required for esiRNAs biogenesis. Remarkably, loss of Loqs mimics the LDR-mediated chromosome protection as it decreases the IR-induced CBs and TF frequency. Thus, our molecular characterization of RAR identifies Loqs as a key factor in the cellular response to LDR and unveils unprecedented epigenetic routes involved in radioresistance.

genetics↗