Publications by authors named "Alessandro Giuliani"

200 Publications

Detecting the effects of predator-induced stress on the global metabolism of an ungulate prey using fecal metabolomic fingerprinting.

Sci Rep 2021 Mar 17;11(1):6129. Epub 2021 Mar 17.

School of the Environment, Washington State University, Pullman, WA, USA.

Few field tests have assessed the effects of predator-induced stress on prey fitness, particularly in large carnivore-ungulate systems. Because traditional measures of stress present limitations when applied to free-ranging animals, new strategies and systemic methodologies are needed. Recent studies have shown that stress and anxiety related behaviors can influence the metabolic activity of the gut microbiome in mammal hosts, and these metabolic alterations may aid in identification of stress. In this study, we used NMR-based fecal metabolomic fingerprinting to compare the fecal metabolome, a functional readout of the gut microbiome, of cattle herds grazing in low vs. high wolf-impacted areas within three wolf pack territories. Additionally, we evaluated if other factors (e.g., cattle nutritional state, climate, landscape) besides wolf presence were related to the variation in cattle metabolism. By collecting longitudinal fecal samples from GPS-collared cattle, we found relevant metabolic differences between cattle herds in areas where the probability of wolf pack interaction was higher. Moreover, cattle distance to GPS-collared wolves was the factor most correlated with this difference in cattle metabolism, potentially reflecting the variation in wolf predation risk. We further validated our results through a regression model that reconstructed cattle distances to GPS-collared wolves based on the metabolic difference between cattle herds. Although further research is needed to explore if similar patterns also hold at a finer scale, our results suggests that fecal metabolomic fingerprinting is a promising tool for assessing the physiological responses of prey to predation risk. This novel approach will help improve our knowledge of the consequences of predators beyond the direct effect of predation.
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http://dx.doi.org/10.1038/s41598-021-85600-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971053PMC
March 2021

Differentiating cancer cells reveal early large-scale genome regulation by pericentric domains.

Biophys J 2021 Feb 14;120(4):711-724. Epub 2021 Jan 14.

Latvian Biomedicine Research and Study Centre, Riga, Latvia. Electronic address:

Finding out how cells prepare for fate change during differentiation commitment was our task. To address whether the constitutive pericentromere-associated domains (PADs) may be involved, we used a model system with known transcriptome data, MCF-7 breast cancer cells treated with the ErbB3 ligand heregulin (HRG), which induces differentiation and is used in the therapy of cancer. PAD-repressive heterochromatin (H3K9me3), centromere-associated-protein-specific, and active euchromatin (H3K4me3) antibodies, real-time PCR, acridine orange DNA structural test (AOT), and microscopic image analysis were applied. We found a two-step DNA unfolding after 15-20 and 60 min of HRG treatment, respectively. This behavior was consistent with biphasic activation of the early response genes (c-fos - fosL1/myc) and the timing of two transcriptome avalanches reported in the literature. In control, the average number of PADs negatively correlated with their size by scale-free distribution, and centromere clustering in turn correlated with PAD size, both indicating that PADs may create and modulate a suprachromosomal network by fusing and splitting a constant proportion of the constitutive heterochromatin. By 15 min of HRG treatment, the bursting unraveling of PADs from the nucleolus boundary occurred, coinciding with the first step of H3K4me3 chromatin unfolding, confirmed by AOT. The second step after 60 min of HRG treatment was associated with transcription of long noncoding RNA from PADs and peaking of fosL1/c-myc response. We hypothesize that the bursting of PAD clusters under a critical silencing threshold pushes the first transcription avalanche, whereas the destruction of the PAD network enables genome rewiring needed for differentiation repatterning, mediated by early response bivalent genes.
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http://dx.doi.org/10.1016/j.bpj.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896032PMC
February 2021

Shaping therapeutic trajectories in mental health: Instructive vs. permissive causality.

Eur Neuropsychopharmacol 2021 Feb 29;43:1-9. Epub 2020 Dec 29.

Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy.

We are currently facing the challenge of improving treatments for psychiatric disorders such as major depression. Notably, antidepressants have an incomplete efficacy, mostly due to our limited knowledge of their action. Here we present a theoretical framework that considers the distinction between instructive and permissive causality, which allows formalizing and disentangling the effects exerted by different therapeutic strategies commonly used in psychiatry. Instructive causality implies that an action determines a specific effect while permissive causality allows an action to take effect or not. We posit that therapeutic strategies able to improve the quality of the living environment or the ability to face it, including changes in lifestyle and psychotherapeutic interventions, rely mainly on instructive causality and thus shape the individual's ability to face the psychopathology and build resilience. By contrast, pharmacological treatments, such as selective serotonin reuptake inhibitors, act primarily through a permissive causality: they boost neural plasticity, i.e. the ability of the brain to change itself, and therefore allow for instructive interventions to produce beneficial effects or not. The combination of an instructive and a permissive action represents the most promising approach since the quality of the living environment can shape the path leading to mental health while drug treatment can increase the likelihood of achieving such a goal.
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http://dx.doi.org/10.1016/j.euroneuro.2020.12.001DOI Listing
February 2021

New statistical RI index allow to better track the dynamics of COVID-19 outbreak in Italy.

Sci Rep 2020 12 22;10(1):22365. Epub 2020 Dec 22.

NHAZCA Srl, SpinOff; Earth Science Department-Sapienza University, Rome, Italy.

COVID-19 pandemic in Italy displayed a spatial distribution that made the tracking of its time course quite difficult. The most relevant anomaly was the marked spatial heterogeneity of COVID-19 diffusion. Lombardia region accounted for around 60% of fatal cases (while hosting 15% of Italian population). Moreover, 86% of fatalities concentrated in four Northern Italy regions. The 'explosive' outbreak of COVID-19 in Lombardia at the very beginning of pandemic fatally biased the R-like statistics routinely used to control the disease dynamics. To (at least partially) overcome this bias, we propose a new index RI = dH/dI (daily derivative ratio of H and I, given H = Healed and I = Infected), corresponding to the ratio between healed and infected patients relative daily changes. The proposed index is less flawed than R by the uncertainty related to the estimated number of infected persons and allows to follow (and possibly forecast) epidemic dynamics in a largely model-independent way. To analyze the dynamics of the epidemic, starting from the beginning of the virus spreading-when data are insufficient to make an estimate by adopting SIR model-a "sigmoidal family with delay" logistic model was introduced. That approach allowed in estimating the epidemic peak using the few data gathered even before mid-March. Based on this analysis, the peak was correctly predicted to occur by end of April. Analytical methodology of the dynamics of the epidemic we are proposing herein aims to forecast the time and intensity of the epidemic peak (forward prediction), while allowing identifying the (more likely) beginning of the epidemic (backward prediction). In addition, we established a relationship between hospitalization in intensive care units (ICU) versus deaths daily rates by avoiding the necessity to rely on precise estimates of the infected fraction of the population The joint evolution of the above parameters over time allows for a trustworthy and unbiased estimation of the dynamics of the epidemic, allowing us to clearly detect the qualitatively different character of the 'so-called' second wave with respect to the previous epidemic peak.
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http://dx.doi.org/10.1038/s41598-020-79039-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755893PMC
December 2020

Disclosing Allostery Through Protein Contact Networks.

Methods Mol Biol 2021 ;2253:7-20

Environment and Health Department, Instituto Superiore di Sanità, Rome, Italy.

Proteins are located in the twilight zone between chemistry and biology, where a peculiar kind of complexity starts. Proteins are the smallest 'devices' showing a sensible adaptation to their environment by the production of appropriate behavior when facing a specific stimulus. This fact qualifies (from the 'effector' side) proteins as nanomachines working as catalysts, motors, or switches. However (from the sensor side), the need to single out the 'specific stimulus' out of thermal noise qualifies proteins as information processing devices. Allostery corresponds to the modification of the configuration (in a broad sense) of the protein molecule in response to a specific stimulus in a non-strictly local way, thereby connecting the sensor and effector sides of the nanomachine. This is why the 'disclosing' of allostery phenomenon is at the very heart of protein function; in this chapter, we will demonstrate how a network-based representation of protein structure in terms of nodes (aminoacid residues) and edges (effective contacts between residues) is the natural language for getting rid of allosteric phenomena and, more in general, of protein structure/function relationships.
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http://dx.doi.org/10.1007/978-1-0716-1154-8_2DOI Listing
March 2021

Complexity in Biological Organization: Deconstruction (and Subsequent Restating) of Key Concepts.

Entropy (Basel) 2020 Aug 12;22(8). Epub 2020 Aug 12.

National Health Institute, 00161 Rome, Italy.

The "magic" word complexity evokes a multitude of meanings that obscure its real sense. Here we try and generate a bottom-up reconstruction of the deep sense of complexity by looking at the convergence of different features shared by complex systems. We specifically focus on complexity in biology but stressing the similarities with analogous features encountered in inanimate and artefactual systems in order to track an integrative path toward a new "mainstream" of science overcoming the actual fragmentation of scientific culture.
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http://dx.doi.org/10.3390/e22080885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517488PMC
August 2020

Modelling and Recognition of Protein Contact Networks by Multiple Kernel Learning and Dissimilarity Representations.

Entropy (Basel) 2020 Jul 21;22(7). Epub 2020 Jul 21.

Department of Information Engineering, Electronics and Telecommunications, University of Rome "La Sapienza", Via Eudossiana 18, 00184 Rome, Italy.

Multiple kernel learning is a paradigm which employs a properly constructed chain of kernel functions able to simultaneously analyse different data or different representations of the same data. In this paper, we propose an hybrid classification system based on a linear combination of multiple kernels defined over multiple dissimilarity spaces. The core of the training procedure is the joint optimisation of kernel weights and representatives selection in the dissimilarity spaces. This equips the system with a two-fold knowledge discovery phase: by analysing the weights, it is possible to check which representations are more suitable for solving the classification problem, whereas the pivotal patterns selected as representatives can give further insights on the modelled system, possibly with the help of field-experts. The proposed classification system is tested on real proteomic data in order to predict proteins' functional role starting from their folded structure: specifically, a set of eight representations are drawn from the graph-based protein folded description. The proposed multiple kernel-based system has also been benchmarked against a clustering-based classification system also able to exploit multiple dissimilarities simultaneously. Computational results show remarkable classification capabilities and the knowledge discovery analysis is in line with current biological knowledge, suggesting the reliability of the proposed system.
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http://dx.doi.org/10.3390/e22070794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517365PMC
July 2020

Phylostratic Shift of Whole-Genome Duplications in Normal Mammalian Tissues towards Unicellularity Is Driven by Developmental Bivalent Genes and Reveals a Link to Cancer.

Int J Mol Sci 2020 Nov 19;21(22). Epub 2020 Nov 19.

Department of Oncology, Latvian Biomedical Research and Study Centre, Cancer Research Division, LV-1067 Riga, Latvia.

Tumours were recently revealed to undergo a phylostratic and phenotypic shift to unicellularity. As well, aggressive tumours are characterized by an increased proportion of polyploid cells. In order to investigate a possible shared causation of these two features, we performed a comparative phylostratigraphic analysis of ploidy-related genes, obtained from transcriptomic data for polyploid and diploid human and mouse tissues using pairwise cross-species transcriptome comparison and principal component analysis. Our results indicate that polyploidy shifts the evolutionary age balance of the expressed genes from the late metazoan phylostrata towards the upregulation of unicellular and early metazoan phylostrata. The up-regulation of unicellular metabolic and drug-resistance pathways and the downregulation of pathways related to circadian clock were identified. This evolutionary shift was associated with the enrichment of ploidy with bivalent genes ( < 10). The protein interactome of activated bivalent genes revealed the increase of the connectivity of unicellulars and (early) multicellulars, while circadian regulators were depressed. The mutual polyploidy--bivalent genes-associated protein network was organized by gene-hubs engaged in both embryonic development and metastatic cancer including driver (proto)-oncogenes of viral origin. Our data suggest that, in cancer, the atavistic shift goes hand-in-hand with polyploidy and is driven by epigenetic mechanisms impinging on development-related bivalent genes.
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http://dx.doi.org/10.3390/ijms21228759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699474PMC
November 2020

Minimally invasive video-assisted thyroidectomy and transoral video-assisted thyroidectomy: A comparison of two systematic reviews.

J Minim Access Surg 2020 Oct-Dec;16(4):315-322

Department of Surgical Sciences, 'Sapienza' University of Rome, Rome, Italy.

Background: We compared two systematic reviews, one focusing on transoral video-assisted thyroidectomy (TOVAT) and the other on minimally invasive video-assisted thyroidectomy (MIVAT), to highlight the pros and cons that can determine the choice of one or the other procedure.

Materials And Methods: PubMed, Scopus and ISI Web of Science databases were searched for relevant articles published from 2000 to June 2018. Both searches were performed using the same keywords. All articles describing human surgical case series of any size were included, while the following were excluded: articles published in languages other than English, case reports, reviews, early cadaver and animal studies and old reports of cases now included in more recent works. Application of the above selection criteria yielded 151 articles on TOVAT and 246 on MIVAT. Of these, 34 articles were selected for inclusion in the present study: 17 for the TOVAT group and 17 for the MIVAT group. The comparison was made considering the most common variables used in evaluating thyroid surgery procedures. The statistical methods used were Cohen's delta, Student's t-test and the non-parametric Mann-Whitney U-test.

Results: The variable 'operative time' was found to show a very large effect size, and 'hospital stay' also differed significantly between the MIVAT and TOVAT groups.

Conclusions: TOVAT and MIVAT should not be considered in competition with each other, but seen simply as alternative choices. Both appear to be safe methods, comparable in terms of post-operative complications, although the main reason for using TOVAT seems to be purely aesthetic.
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http://dx.doi.org/10.4103/jmas.JMAS_123_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597888PMC
September 2020

Biodynamic Interfaces Are Essential for Human-Environment Interactions.

Bioessays 2020 11 26;42(11):e2000017. Epub 2020 Aug 26.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.

The environment impacts human health in profound ways, yet few theories define the form of the relationship between human physiology and the environment. It is conjectured that such complex systems cannot interact directly, but rather their interaction requires the formation of an intermediary "interface." This position contrasts with current epidemiological constructs of causation, which implicitly assume that two complex systems transfer information directly while remaining separate entities. Further, it is contended that dynamic, process-based interfaces incorporate components from all the interacting systems but exhibit operational independence. This property has many consequences, the foremost being that characteristics of the interface cannot be fully resolved by only studying the systems involved in the interaction. The interface itself must be the subject of inquiry. Without refocusing the attention on biodynamic interfaces, how the environment impacts health cannot be discerned. Also see the video abstract here https://youtu.be/XeyjeZeyo4o.
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http://dx.doi.org/10.1002/bies.202000017DOI Listing
November 2020

Quantization of the Interacting Hall Conductivity in the Critical Regime.

J Stat Phys 2020 6;180(1):332-365. Epub 2019 Nov 6.

Department of Mathematics, University of Tübingen, Auf der Morgenstelle 10, 72076 Tübingen, Germany.

The Haldane model is a paradigmatic 2 lattice model exhibiting the integer quantum Hall effect. We consider an interacting version of the model, and prove that for short-range interactions, smaller than the bandwidth, the Hall conductivity is quantized, for all the values of the parameters outside two critical curves, across which the model undergoes a 'topological' phase transition: the Hall coefficient remains integer and constant as long as we continuously deform the parameters without crossing the curves; when this happens, the Hall coefficient jumps abruptly to a different integer. Previous works were limited to the perturbative regime, in which the interaction is much smaller than the bare gap, so they were restricted to regions far from the critical lines. The non-renormalization of the Hall conductivity arises as a consequence of lattice conservation laws and of the regularity properties of the current-current correlations. Our method provides a full construction of the critical curves, which are modified ('dressed') by the electron-electron interaction. The shift of the transition curves manifests itself via apparent infrared divergences in the naive perturbative series, which we resolve via renormalization group methods.
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http://dx.doi.org/10.1007/s10955-019-02405-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405942PMC
November 2019

Plate-Nematic Phase in Three Dimensions.

Commun Math Phys 2020 5;373(1):327-356. Epub 2019 Dec 5.

Department of Physics, Princeton University, Princeton, USA.

We consider a system of anisotropic plates in the three-dimensional continuum, interacting via purely hard core interactions. We assume that the particles have a finite number of allowed orientations. In a suitable range of densities, we prove the existence of a uni-axial nematic phase, characterized by long range orientational order (the minor axes are aligned parallel to each other, while the major axes are not) and no translational order. The proof is based on a coarse graining procedure, which allows us to map the plate model into a contour model, and in a rigorous control of the resulting contour theory, via Pirogov-Sinai methods.
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http://dx.doi.org/10.1007/s00220-019-03543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336247PMC
December 2019

Cell-Fate Determination from Embryo to Cancer Development: Genomic Mechanism Elucidated.

Int J Mol Sci 2020 Jun 27;21(13). Epub 2020 Jun 27.

Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0394, Japan.

Elucidation of the genomic mechanism that guides the cell-fate change is one of the fundamental issues of biology. We previously demonstrated that whole genome expression is coordinated by the emergence of a critical point at both the cell-population and single-cell levels through the physical principle of self-organized criticality. In this paper, we further examine the genomic mechanism that determines the cell-fate changes from embryo to cancer development. The state of the critical point, acting as the organizing center of the cell fate, determines whether the genome resides in a super- or sub-critical state. In the super-critical state, a specific stochastic perturbation can spread over the entire system through the "genome engine", an autonomous critical-control genomic system, whereas in the sub-critical state, the perturbation remains at a local level. The cell-fate changes when the genome becomes super-critical. We provide a consistent framework to develop a time-evolutional transition theory for the biological regulation of the cell-fate change.
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http://dx.doi.org/10.3390/ijms21134581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369777PMC
June 2020

The Discovery of a Putative Allosteric Site in the SARS-CoV-2 Spike Protein Using an Integrated Structural/Dynamic Approach.

J Proteome Res 2020 11 1;19(11):4576-4586. Epub 2020 Jul 1.

Environmental and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy.

SARS-CoV-2 has caused the largest pandemic of the twenty-first century (COVID-19), threatening the life and economy of all countries in the world. The identification of novel therapies and vaccines that can mitigate or control this global health threat is among the most important challenges facing biomedical sciences. To construct a long-term strategy to fight both SARS-CoV-2 and other possible future threats from coronaviruses, it is critical to understand the molecular mechanisms underlying the virus action. The viral entry and associated infectivity stems from the formation of the SARS-CoV-2 spike protein complex with angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein molecule can be used to elucidate the molecular pathways that can be targeted with allosteric drugs to weaken the spike-ACE2 interaction and, thus, reduce viral infectivity. In this study, we present the results of the application of different computational methods aimed at detecting allosteric sites on the SARS-CoV-2 spike protein. The adopted tools consisted of the protein contact networks (PCNs), SEPAS (Affinity by Flexibility), and perturbation response scanning (PRS) based on elastic network modes. All of these methods were applied to the ACE2 complex with both the SARS-CoV2 and SARS-CoV spike proteins. All of the adopted analyses converged toward a specific region (allosteric modulation region [AMR]), present in both complexes and predicted to act as an allosteric site modulating the binding of the spike protein with ACE2. Preliminary results on hepcidin (a molecule with strong structural and sequence with AMR) indicated an inhibitory effect on the binding affinity of the spike protein toward the ACE2 protein.
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http://dx.doi.org/10.1021/acs.jproteome.0c00273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331933PMC
November 2020

What Differentiates Poor- and Good-Outcome Psychotherapy? A Statistical-Mechanics-Inspired Approach to Psychotherapy Research, Part Two: Network Analyses.

Front Psychol 2020 20;11:788. Epub 2020 May 20.

Department of Psychology, NCIUL University, London, United Kingdom.

Statistical mechanics is the field of physics focusing on the prediction of the behavior of a given system by means of statistical properties of ensembles of its microscopic elements. The authors examined the possibility of applying such an approach to psychotherapy research with the aim of investigating (a) the possibility of predicting good and poor outcomes of psychotherapy on the sole basis of the correlation pattern among their descriptors and (b) the analogies and differences between the processes of good- and poor-outcome cases. This work extends the results reported in a previous paper and is based on higher-order statistics stemming from a complex network approach. Four good-outcome and four poor-outcome brief psychotherapies were recorded, and transcripts of the sessions were coded according to Mergenthaler's Therapeutic Cycle Model (TCM), i.e., in terms of abstract language, positive emotional language, and negative emotional language. The relative frequencies of the three vocabularies in each word-block of 150 words were investigated and compared in order to understand similarities and peculiarities between poor-outcome and good-outcome cases. Network analyses were performed by means of a cluster analysis over the sequence of TCM categories. The network analyses revealed that the linguistic patterns of the four good-outcome and four poor-outcome cases were grounded on a very similar dynamic process substantially dependent on the relative frequency of the states in which the transition started and ended ("random-walk-like behavior", adjusted = 0.729, < 0.001). Furthermore, the psychotherapy processes revealed statistically significant changes in the relative occurrence of visited states between the beginning and the end of therapy, thus pointing to the non-stationarity of the analyzed processes. The present study showed not only how to quantitatively describe psychotherapy as a network, but also found out the main principles on which its evolution is based. The mind, from a linguistic perspective, seems to work-through psychotherapy sessions by passing from the most adjacent states and the most occurring ones. This finding can represent a fertile ground to rethink pivotal clinical concepts such as the timing of an interpretation or a comment, the clinical issue to address within a given session, and the general task of a psychotherapist: from someone who delivers a given technique toward a consultant promoting the flexibility of the clinical field and, thus, of the patient's mind.
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http://dx.doi.org/10.3389/fpsyg.2020.00788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251305PMC
May 2020

Deregulated expression of the imprinted DLK1-DIO3 region in glioblastoma stemlike cells: tumor suppressor role of lncRNA MEG3.

Neuro Oncol 2020 12;22(12):1771-1784

Department of Oncology and Molecular Medicine Rome, Italy.

Background: Glioblastoma (GBM) stemlike cells (GSCs) are thought to be responsible for the maintenance and aggressiveness of GBM, the most common primary brain tumor in adults. This study aims at elucidating the involvement of deregulations within the imprinted delta-like homolog 1 gene‒type III iodothyronine deiodinase gene (DLK-DIO3) region on chromosome 14q32 in GBM pathogenesis.

Methods: Real-time PCR analyses were performed on GSCs and GBM tissues. Methylation analyses, gene expression, and reverse-phase protein array profiles were used to investigate the tumor suppressor function of the maternally expressed 3 gene (MEG3).

Results: Loss of expression of genes and noncoding RNAs within the DLK1-DIO3 region was observed in GSCs and GBM tissues compared with normal brain. This downregulation is mainly mediated by epigenetic silencing. Kaplan-Meier analysis indicated that low expression of MEG3 and MEG8 long noncoding (lnc)RNAs significantly correlated with short survival in GBM patients. MEG3 restoration impairs tumorigenic abilities of GSCs in vitro by inhibiting cell growth, migration, and colony formation and decreases in vivo tumor growth, reducing infiltrative growth. These effects were associated with modulation of genes involved in cell adhesion and epithelial-to-mesenchymal transition (EMT).

Conclusion: In GBM, MEG3 acts as a tumor suppressor mainly regulating cell adhesion, EMT, and cell proliferation, thus providing a potential candidate for novel GBM therapies.
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http://dx.doi.org/10.1093/neuonc/noaa127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746944PMC
December 2020

Evaluation of the applicability of existing (Q)SAR models for predicting the genotoxicity of pesticides and similarity analysis related with genotoxicity of pesticides for facilitating of grouping and read across: An EFSA funded project.

Regul Toxicol Pharmacol 2020 Jul 22;114:104658. Epub 2020 Apr 22.

Istituto Superiore di Sanità (ISS), Environmental and Health Department, Rome, Italy.

To facilitate the practical implementation of the guidance on the residue definition for dietary risk assessment, EFSA has organized an evaluation of applicability of existing in silico models for predicting the genotoxicity of pesticides and their metabolites, including literature survey, application of QSARs and development of Read Across methodologies. This paper summarizes the main results. For the Ames test, all (Q)SAR models generated statistically significant predictions, comparable with the experimental variability of the test. The reliability of the models for other assays/endpoints appears to be still far from optimality. Two new Read Across approaches were evaluated: Read Across was largely successful for predicting the Ames test results, but less for in vitro Chromosomal Aberrations. The worse results for non-Ames endpoints may be attributable to the several revisions of experimental protocols and evaluation criteria of results, that have made the databases qualitatively non-homogeneous and poorly suitable for modeling. Last, Parent/Metabolite structural differences (besides known Structural Alerts) that may, or may not cause changes in the Ames mutagenicity were identified and catalogued. The findings from this work are suitable for being integrated into Weight-of-Evidence and Tiered evaluation schemes. Areas needing further developments are pointed out.
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http://dx.doi.org/10.1016/j.yrtph.2020.104658DOI Listing
July 2020

Phenotypic suppression caused by resonance with light-dark cycles indicates the presence of a 24-hours oscillator in yeast and suggests a new role of intrinsically disordered protein regions as internal mediators.

J Biomol Struct Dyn 2021 Apr 13;39(7):2490-2501. Epub 2020 Apr 13.

Department of Biology and Biotechnology 'Charles Darwin', Sapienza Università di Roma, Roma, Italy.

The mutual interaction between environment and life is a main topic of biological sciences. An interesting aspect of this interaction is the existence of biological rhythms spanning all the levels of organisms from bacteria to humans. On the other hand, the existence of a coupling between external oscillatory stimuli and adaptation and evolution rate of biological systems is a still unexplored issue. Here we give the demonstration of a substantial increase of heritable phenotypic changes in yeast, an organism lacking a photoreception system, when growing at 12 h light/dark cycles, with respect to both stable dark (or light) or non-12 + 12 h cycling. The model system was a yeast strain lacking a gene whose product is at the crossroad of many different physiological regulations, so ruling out any simple explanation in terms of increase in reverse gene mutations. The abundance of intrinsically disordered protein regions (IDPRs) in both deleted gene product and in its vast ensemble of interactors supports the hypothesis that resonance with the environmental cycle might be mediated by intrinsic disorder-driven interactions of protein molecules. This result opens to the speculation of the effect of environment/biological resonance phenomena in evolution and of the role of protein intrinsically disordered regions as internal mediators.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1749133DOI Listing
April 2021

Improved Functional Recovery in Rat Spinal Cord Injury Induced by a Drug Combination Administered with an Implantable Polymeric Delivery System.

J Neurotrauma 2020 08 14;37(15):1708-1719. Epub 2020 May 14.

Health Sciences and Technologies (HST) CIRI-SDV, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

Spinal cord injury (SCI) is an incurable condition, in which a cascade of cellular and molecular events triggered by inflammation and excitotoxicity impairs endogenous regeneration, namely remyelination and axonal outgrowth. We designed a treatment solution based on an implantable biomaterial (electrospun poly (l-lactic acid) [PLLA]) loaded with ibuprofen and triiodothyronine (T3) to counteract inflammation, thus improving endogenous regeneration. efficacy was tested by implanting the drug-loaded PLLA in the rat model of T8 contusion SCI. We observed the expected recovery of locomotion beginning on day 7. In PLLA-implanted rats (i.e., controls), the recovery stabilized at 21 days post-lesion (DPL), after which no further improvement was observed. On the contrary, in PLLA + ibuprofen (Ibu) + T3 (PLLA-Ibu-T3) rats a further recovery and a significant treatment effect were observed, also confirmed by the gait analysis on 49 DPL. Glutamate release at 24 h and 8 DPL was reduced in PLLA-Ibu-T3- compared to PLLA-implanted rats, such as the estimated lesion volume at 60 DPL. The myelin- and 200-neurofilament-positive area fraction was higher in PLLA-Ibu-T3-implanted rats, where the percentage of astrocytes was significantly reduced. The implant of a PLLA electrospun scaffold loaded with Ibu and T3 significantly improves the endogenous regeneration, leading to an improvement of functional locomotion outcome in the SCI.
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http://dx.doi.org/10.1089/neu.2019.6949DOI Listing
August 2020

Rediscovery of natural compounds acting via multitarget recognition and noncanonical pharmacodynamical actions.

Drug Discov Today 2020 05 7;25(5):920-927. Epub 2020 Mar 7.

Department of Surgery 'Pietro Valdoni', Sapienza University of Rome, 00161 Rome, Italy; Azienda Policlinico Umberto I, 00161 Rome, Italy.

Most drugs have a natural compound 'ancestor' acting as the lead molecule. Classic pharmacology does not explicitly take into consideration the peculiarities of natural origin compounds, the mechanism of action of which is interpreted by the same target-specific mode of action used for synthetic molecules. Over the past few decades, this approach has entered a crisis of efficacy, requiring general reconsideration of the nature of chemobiological interactions. Taking both the unique properties of natural compounds and their original presence in complex mixtures into account pushes researchers to enlarge the range of mechanisms of action well beyond the drug-receptor interaction and has the potential to overcome the current drug discovery crisis.
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http://dx.doi.org/10.1016/j.drudis.2020.02.010DOI Listing
May 2020

Constraints Shape Cell Function and Morphology by Canalizing the Developmental Path along the Waddington's Landscape.

Bioessays 2020 04 27;42(4):e1900108. Epub 2020 Feb 27.

Department of Surgery "Pietro Valdoni,", Sapienza University of Rome, 00161, Rome, Italy.

Studies performed in absence of gravitational constraint show that a living system is unable to choose between two different phenotypes, thus leading cells to segregate into different, alternative stable states. This finding demonstrates that the genotype does not determine by itself the phenotype but requires additional, physical constraints to finalize cell differentiation. Constraints belong to two classes: holonomic (independent of the system's dynamical states, as being established by the space-time geometry of the field) and non-holonomic (modified during those biological processes to which they contribute in shaping). This latter kind of "constraints", in which dynamics works on the constraint to recreate them, have emerged as critical determinants of self-organizing systems, by manifesting a "closure of constraints." Overall, the constraints act by harnessing the "randomness" represented by the simultaneous presence of equiprobable events restraining the system within one attractor. These results cast doubt on the mainstream scientific concept and call for a better understanding of causation in cell biology.
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http://dx.doi.org/10.1002/bies.201900108DOI Listing
April 2020

Redifferentiation therapeutic strategies in cancer.

Drug Discov Today 2020 04 3;25(4):731-738. Epub 2020 Feb 3.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy; Department of Surgery 'Pietro Valdoni', Sapienza University of Rome, 00161 Rome, Italy.

The widely recognized problems of pharmacological strategies based on killing cancer cells demand a rethink of therapeutic approaches. Tumor reversion strategies that aim to shift cancer cells to a healthy differentiated state are a promising alternative. Although many studies have firmly demonstrated the possibility of reverting cancer to a normal differentiated state, we are still unable (with the exception of retinoic acid in a form of leukemia) to revert cancer cells to a stable differentiated healthy state. Here, we review the main biological bases of redifferentiation strategies and provide a description of the most promising research avenues.
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http://dx.doi.org/10.1016/j.drudis.2020.01.021DOI Listing
April 2020

Non-symmetrical structural behavior of a symmetric protein: the case of homo-trimeric TRAF2 (tumor necrosis factor-receptor associated factor 2).

J Biomol Struct Dyn 2021 Jan 13;39(1):319-329. Epub 2020 Feb 13.

Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy.

The oligomeric state of TRAF2 (tumor necrosis factor-receptor associated factor 2), a TNF (tumor necrosis factor) receptor-associated factor, is crucial for membrane binding and probably plays a fundamental role in regulating the protein function in vivo. In this study we have combined molecular dynamics with the protein contact network approach to characterize the interaction of the three identical subunits of TRAF2. The average structure obtained after a 225 ns simulation reveals that two clusters of different size are formed, one of which includes almost completely two subunits, while the third monomer appears to be more independent. This picture is also confirmed by the estimated average number of inter-subunit contacts and by the comparison of side chains mobility in each monomer. The analysis of equilibrium pressure-induced dissociation measurements supports such findings, indicating that the dimeric-monomeric (2 + 1) might be prevalent with respect to the trimeric configuration, especially in the case of more diluted samples. These findings suggest that the formation of monomeric species, which is crucial for the formation of intra-luminal vesicles, might depend on preferential asymmetric interactions among the three subunits.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1719202DOI Listing
January 2021

White Matter and Neuroprotection in Alzheimer's Dementia.

Molecules 2020 Jan 23;25(3). Epub 2020 Jan 23.

Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano Emilia (BO), Italy.

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer's dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.
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http://dx.doi.org/10.3390/molecules25030503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038211PMC
January 2020

Metabolic networks classification and knowledge discovery by information granulation.

Comput Biol Chem 2020 Feb 19;84:107187. Epub 2019 Dec 19.

Department of Information Engineering, Electronics and Telecommunications, University of Rome "La Sapienza" - Via Eudossiana 18, 00184 Rome, Italy. Electronic address:

Graphs are powerful structures able to capture topological and semantic information from data, hence suitable for modelling a plethora of real-world (complex) systems. For this reason, graph-based pattern recognition gained a lot of attention in recent years. In this paper, a general-purpose classification system in the graphs domain is presented. When most of the information of the available patterns can be encoded in edge labels, an information granulation-based approach is highly discriminant and allows for the identification of semantically meaningful edges. The proposed classification system has been tested on the entire set of organisms (5299) for which metabolic networks are known, allowing for both a perfect mirroring of the underlying taxonomy and the identification of most discriminant metabolic reactions and pathways. The widespread diffusion of graph (network) structures in biology makes the proposed pattern recognition approach potentially very useful in many different fields of application. More specifically, the possibility to have a reliable metric to compare different metabolic systems is instrumental in emerging fields like microbiome analysis and, more in general, for proposing metabolic networks as a universal phenotype spanning the entire tree of life and in direct contact with environmental cues.
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http://dx.doi.org/10.1016/j.compbiolchem.2019.107187DOI Listing
February 2020

A pre-existing population of ZEB2 quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer.

J Exp Clin Cancer Res 2020 Jan 8;39(1). Epub 2020 Jan 8.

Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.

Background: Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown.

Methods: A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets.

Results: Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes.

Conclusions: These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.
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http://dx.doi.org/10.1186/s13046-019-1505-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947904PMC
January 2020

Sex Disparity in Response to Hepatitis B Vaccine Related to the Age of Vaccination.

Int J Environ Res Public Health 2020 01 2;17(1). Epub 2020 Jan 2.

Istituto Superiore di Sanità, Center for Gender Specific Medicine, 00161 Rome, Italy.

Hepatitis B virus (HBV) infection is one of the major infectious hazards for health-care workers (HCWs) because of the frequency of percutaneous exposures to blood or body fluids. For this reason, all HCWs should be vaccinated, including students in medicine and health professional degree programs. The aim of this study was to assess the immune coverage to anti-HBV vaccine and long-lasting protective titres of anti-HBs antibodies in female and male students to evaluate gender-related differences in response to HBV vaccination. Data relative to anti-HBs antibody titre, sex, age, and age at vaccination were collected and analyzed from 5291 Italian students (1812 males and 3479 females) of the graduate courses at the School of Medicine, who underwent the mandatory health surveillance of workers exposed to biological risk. The results indicated that gender affects the immune response to HBV vaccine, particularly evident in the case of females vaccinated after one year of age who exhibited a statistically significant ( = 0.0023) 1.21-fold increase in median antibody titre with respect to males. Our findings could contribute to the optimization of HBV vaccination schedules in health surveillance of HCWs.
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http://dx.doi.org/10.3390/ijerph17010327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981715PMC
January 2020

Resolution of Complex Issues in Genome Regulation and Cancer Requires Non-Linear and Network-Based Thermodynamics.

Int J Mol Sci 2019 Dec 29;21(1). Epub 2019 Dec 29.

Environmental and Health Department, Istituto Superiore di Sanità, 00161 Rome, Italy.

The apparent lack of success in curing cancer that was evidenced in the last four decades of molecular medicine indicates the need for a global re-thinking both its nature and the biological approaches that we are taking in its solution. The reductionist, one gene/one protein method that has served us well until now, and that still dominates in biomedicine, requires complementation with a more systemic/holistic approach, to address the huge problem of cross-talk between more than 20,000 protein-coding genes, about 100,000 protein types, and the multiple layers of biological organization. In this perspective, the relationship between the chromatin network organization and gene expression regulation plays a fundamental role. The elucidation of such a relationship requires a non-linear thermodynamics approach to these biological systems. This change of perspective is a necessary step for developing successful 'tumour-reversion' therapeutic strategies.
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http://dx.doi.org/10.3390/ijms21010240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981914PMC
December 2019

Fecal Metabolomics as a Novel Noninvasive Method for Short-Term Stress Monitoring in Beef Cattle.

J Proteome Res 2020 02 9;19(2):845-853. Epub 2020 Jan 9.

School of the Environment , Washington State University , Pullman , Washington 99164 , United States.

Traditional measures of short-term stress response such as fecal glucocorticoid metabolites (FGM) are widely used in controlled settings to quantify the intensity of stimulation to which cattle are exposed. However, FGMs present several methodological and interpretation pitfalls when applied on animals in free-ranging conditions. In this study, we proposed an NMR-based fecal metabolomics strategy for noninvasive stress detection in beef cattle. Using a longitudinal sample collection, we monitored the changes in the fecal metabolome and FGM concentrations before and after an acute stressful event. Our results showed that while the fecal metabolome changed as a function of stress ( < 0.001), the mean concentrations of FGM did not change (Levene's test: -ratio: 0.87, -value: 0.44). Furthermore, we showed that the interanimal variability observed in the stress response was correlated with the individual fecal microbiota. This result was in line with recent findings, indicating the gut microbiome as a crucial mediator of stress response. We conclude that NMR-based fecal metabolomics proved to be a reliable methodology to assess stress response and that its future applicability to studies for stress monitoring in range animals may be more appropriate than FGM analysis.
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http://dx.doi.org/10.1021/acs.jproteome.9b00655DOI Listing
February 2020

Phenotypic transitions enacted by simulated microgravity do not alter coherence in gene transcription profile.

NPJ Microgravity 2019 21;5:27. Epub 2019 Nov 21.

7Department of Experimental Medicine, Sapienza University, Rome, Italy.

Cells in simulated microgravity undergo a reversible morphology switch, causing the appearance of two distinct phenotypes. Despite the dramatic splitting into an adherent-fusiform and a floating-spherical population, when looking at the gene-expression phase space, cell transition ends up in a largely invariant gene transcription profile characterized by only mild modifications in the respective Pearson's correlation coefficients. Functional changes among the different phenotypes emerging in simulated microgravity using random positioning machine are adaptive modifications-as cells promptly recover their native phenotype when placed again into normal gravity-and do not alter the internal gene coherence. However, biophysical constraints are required to drive phenotypic commitment in an appropriate way, compatible with physiological requirements, given that absence of gravity foster cells to oscillate between different attractor states, thus preventing them to acquire a exclusive phenotype. This is a proof-of-concept of the adaptive properties of gene-expression networks supporting very different phenotypes by coordinated 'profile preserving' modifications.
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http://dx.doi.org/10.1038/s41526-019-0088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872750PMC
November 2019