Biology subjects

Bello, E.

Publications and source records attributed to Bello, E..

5 recordsLinked to original sources

bioRxiv2024

DNA methylation status classifies pleural mesothelioma cells according to their immune profile: implication for precision epigenetic therapy

Backgroundco-targeting of immune checkpoint inhibitors (ICI) CTLA-4 and PD-1 has recently become the new first-line standard of care therapy of pleural mesothelioma (PM) patients, with a significant improvement of overall survival over conventional chemotherapy. The analysis by tumor histotype demonstrated a greater efficacy of ICI therapy in non-epithelioid (non-E) vs epithelioid (E) PM; although some E PM patients also benefit from treatment. This evidence suggests that molecular tumor features, beyond histotype, could be relevant to improve the efficacy of ICI therapy in PM. Among these, tumor DNA methylation emerges as a promising factor to explore, due to its potential role in driving the immune phenotype of cancer cells. Thus, we utilized a panel of cultured PM cells of different histotype, to provide preclinical evidence supporting the role of the tumor methylation landscape and of its pharmacologic modulation, to prospectively improve the efficacy of ICI therapy of PM patients. Methodsthe methylome profile (EPIC array) of distinct E (#5) and non-E (#9) PM cell lines was analyzed, followed by integrated analysis with their associated transcriptomic profile (Clariom S array), before and after in vitro treatment with the DNA hypomethylating agent (DHA) guadecitabine. The most variable methylated probes were selected to calculate the methylation score (CIMP index) for each cell line at baseline. Genes that were differentially expressed and methylated were then selected for gene ontology analysis. Resultsthe CIMP index stratified PM cell lines in two distinct classes, CIMP (hyper-methylated; #7) and LOW (hypo-methylated; #7), regardless of their E or non-E histotype. Integrated analyses of methylome and transcriptome data revealed that CIMP PM cells had a substantial number of hyper-methylated, silenced genes, which negatively impacted their immune phenotype compared to LOW PM cells. Treatment with DHA reverted the methylation-driven immune-compromised profile of CIMP PM cells and enhanced the constitutive immune-favorable profile of LOW PM cells. Conclusionthe study highlighted the relevance of DNA methylation in shaping the constitutive immune classification of PM cells, that is independent from their histological subtypes. The identified role of DHA in shifting the phenotype of PM cells towards an immune-favorable state supports its role in clinical trials of precision epigenetic therapy combined with ICI.

cancer biology↗

bioRxiv2024

Predator cues and environmental enrichment during development drive intraspecific variation in the behaviour and life-history of juvenile lobsters

Intraspecific variation in ecologically relevant traits is critical for animal populations to survive in our rapidly changing world. This is especially true for species that suffer from intense harvesting regimes, whereby populations density is often low. Standard hatchery procedures can assist some management and conservation programs by producing large numbers of juveniles to be released into the wild. Yet we know surprisingly little on the impact that such standard, minimalistic settings have on the development of intraspecific variation in important phenotypes of the individuals, including among-individual variation in behavioural (individuality) and life-history traits, and in the plasticity of those traits in response to varying environmental conditions. Here, we fill this gap by testing whether early-life exposure to different environmental conditions alters the development of individuality and plasticity in ecologically relevant behaviours and life-history traits of the European lobster (Homarus gammarus)--one the most harvested species in the Mediterranean, which has been subjected to conservation programs for decades. By accessing one of the largest lobsters hatcheries in Italy, we used the progeny of wild-caught females and manipulated--in a full factorial design--the environmental complexity of the individual enclosures (i.e. presence/absence of substrate and/or shelter) and the level of exposure to cues from their natural predators. We repeatedly quantified behaviours (i.e. activity, refuge use, and aggressiveness) and life-history traits (i.e. carapace length and intermoult period) of the individuals throughout their early development, capturing both mean and individual-level variation across treatments. Our results offer solid evidence that effects of standard hatchery settings extend far beyond mean changes in the behaviour and life history of the animals, compromising the development of individual plasticity in those traits that are essentials for populations to survive in the wild--likely reducing the effectiveness of conservation programs.

animal behavior and cognition↗

bioRxiv2023

Model-Based Closed-Loop Control of Thalamic Deep Brain Stimulation

Closed-loop control of deep brain stimulation (DBS) is crucial for effective and automatic treatments of various neurological disorders like Parkinsons disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists expertise and patients experience. The continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system utilizes a feedback biomarker/signal to track worsening (or improving) patients symptoms and offers several advantages compared to open-loop DBS. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying the DBS or symptoms, for example how DBS modulates dynamics of synaptic plasticity. In this work, we proposed a computational framework for development of a model-based DBS controller where a biophysically-reasonable model can describe the relationship between DBS and neural activity, and a polynomial-based approximation can estimate the relationship between the neural and behavioral activity. A controller is utilized in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. These DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given EMG recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed a biophysically-reasonable simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By utilizing a PID controller, we showed that a closed-loop system can track EMG signals and adjusts the stimulation frequency of Vim-DBS so that the power of EMG in [2, 200] Hz reaches a desired target. We demonstrated that our model-based closed-loop control system of Vim-DBS finds an appropriate DBS frequency that aligns well with clinical studies. Our model-based closed-loop system is adaptable to different control targets, highlighting its potential usability for different diseases and personalized systems.

neuroscience↗

bioRxiv2023

Uncovering network mechanism underlying thalamic Deep Brain Stimulation using a novel firing rate model

Thalamic ventral intermediate nucleus (Vim) is the primary surgical target of deep brain stimulation (DBS) for reducing symptoms of essential tremor. High-frequency Vim-DBS ([≥]100Hz) has been clinically effective, generating two experimentally-observed features in Vim spiking activity: 1) a large transient excitatory response (lasting <1s), followed by 2) a suppressed steady-state consisting of oscillations. Yet, mechanisms underlying these observations have not been fully understood by previous studies. In this work, we developed a network rate model and a novel parameter optimization method that accurately fit in-vivo single-unit recordings of Vim in human patients with essential tremor receiving a wide range of DBS frequencies (5[~]200Hz). Our model incorporates both the DBS-induced synaptic plasticity of Vim neurons, and the recurrent connections among excitatory and inhibitory neurons in Vim-network. We hypothesized that besides inducing synaptic depression, the therapeutic mechanism of high-frequency Vim-DBS could be to engage more inhibitory neurons in stabilizing the underlying circuits. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=86 SRC="FIGDIR/small/570924v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1e78cbcorg.highwire.dtl.DTLVardef@c8bde1org.highwire.dtl.DTLVardef@12a3bb3org.highwire.dtl.DTLVardef@1b5a0dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

An Alzheimer's disease-associated common regulatory variant in PTK2B has causal effects on microglial function

Genome-wide association studies (GWAS) are revealing an ever-growing number of genetic associations with disease, but identifying and functionally validating the causal variants underlying these associations is very challenging and has only been done for a vanishingly small number of variants. Here we validate a single nucleotide polymorphism (SNP) associated with an increased risk of Alzheimers disease (AD) in an intronic enhancer of the PTK2B gene, by engineering it into human induced pluripotent stem cells (hiPSCs). Upon differentiation to macrophages and microglia, this variant shows effects on chromatin accessibility of the enhancer and increased binding of the transcription factor CEBPB but only subtle effects on PTK2B or CLU expression. Nevertheless, this variant results in global changes to the transcriptome and phenotype of these cells. Expression of interferon gamma responsive genes including chemokine transcripts and their protein products are altered, and chemotaxis of the resulting microglial cells is affected. This variant thus causes disease-relevant transcriptomic and phenotypic changes, and we propose that it acts by altering microglia reactivity, consistent with the role of these cells in progression of AD.

neuroscience↗