Reverse Engineering of Modified Genes by Bayesian Network Analysis Defines Molecular Determinants Critical to the Development of Glioblastoma

In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I–IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96–100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential ‘hubs of activity’. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several ‘key genes’ may be required for the development of glioblastoma. Further studies are needed to validate these ‘key genes’ as useful tools for early detection and novel therapeutic options for these tumors.

Iniciação docente na educação infantil: cenários de uma cultura profissional

This paper focalizes the initial teacher socialization in the Infantile Education from the acknowledgement about that as a phase of a professional life cycle on distinguish of other steps in the teachers’ carrier. It is based on the studies of sociological and anthropological mark with the comprehension that the professional reality is equally constructed by daily practices of social interactions in the work environment. It aims understanding how the initial process of professional culture building of beginners in the infantile education occurs under a view toward to the organizational and dynamics aspects of the teacher activity (events, interactions, practices, wisdoms, tensions and dilemmas). This investigation assuming the orientations of an ethnographic type approach has been developed in a Municipal Center of Infantile Education (Centro Municipal de Educação Infantil) in the city of Natal, with daycare and pre-school. The participant subjects are four female teachers with less than five years in Infantile Education career. It has used a participant observation and a semi-structured interview in the data building that had interpreted through a content analysis and sources triangulation. It delineates three dimensions to the professional culture scenarios: the personal and formative profile of the subjects, the school daily and the teacher work management. The multiform character of the finds evidences that the professional culture of the novice teachers has been constituted from the confrontation with different situations of unpredictably in their emotions, routines and pedagogical and administrative difficulties, simultaneously to the dilemmas of child care and educate. The solitude feeling has been generating from the institutional and scholar organization, which offers no material and pedagogical conditions to the peers collaboration and discussion. Finally it means that teaching in the Infantile Education must been based on an expanding network relations, been indispensable to the beginners the support and orientation related to doubts, wistfulness and expectations as means of socializing and redefining their teaching practice

Computer assisted synthesis and in-vitro cytotoxic evaluation of new pyrazole-fused isoquinolinoquinones derivatives as PI3K receptor antagonist with promising antitumoral activity

The importance of pyrazole and isoquinoline-5,8-dione scaffolds in medical chemistry is underlined by the high number of drugs currently on trading that contains these active ingredients. Due to their cytotoxic capability, the interest of medicinal chemists in these heterocyclic rings has grown exponentially especially, for cancer therapy. In this project, the first synthesis of pyrazole-fused isoquinoline-5,8-diones has been developed. 1,3-Dipolar cycloaddition followed by oxidative aromatization, established by our research group, has been employed. Screening of reaction conditions and characterization studies about the regioselectivity have been successfully performed. A remote control of regioselectivity, to achieve the two possible regioisomers has been accomplished. Through Molecular Docking studies, Structure-Activity relationship of differently substituted scaffolds containing our central core proved that a family of PI3K inhibitors have been discovered. Finally, in order to verify the promising antitumor activity, a first test of cell viability in vitro on T98G cell line of a solid brain tumor, the Glioblastoma Multiforme, showed cytotoxic inhibition comparable to currently trade anticancer drugs.

Une éthique de responsabilité en quête de fondement - Réflexion à partir d'un contexte africain de crise

Sur quoi fonder une éthique de responsabilité et quelle place accorder aux cultures et aux traditions dans un contexte nouveau caractérisé par la mondialisation? Pour répondre à cette question, posée à partir de l’Afrique, nous avons pris un long chemin de réflexion. À partir de l’évaluation faite par Fabien Eboussi de la crise multiforme actuelle qui frappe l’Afrique, où l’auteur cherche et désigne les coupables et les responsables que sont, selon lui, les cultures africaines, la colonisation européenne et le christianisme, nous nous sommes concentré sur le sujet humain comme tel. La responsabilité est d’abord, à nos yeux, une question de conscience morale. Les approches anthropologiques utilisées dans leurs théories éthiques par Xavier Thévenot, Paul Ricoeur et Emmanuel Levinas nous ont permis de bâtir une définition du sujet comme une « liberté précédée ». L’antécédence est à la fois un principe anthropologique et éthique dans la relation et dans l’existence. Nous avons appliqué ce principe de précédence à la notion africaine d’ancestralité conçue comme le temps éthique hiérarchisé et orienté. Pour échapper à l’étroitesse tribale ou ethnique dans laquelle se vit cette ancestralité africaine, nous l’avons étendue aux dimensions de l’humanité, comme le fondement d’une éthique de responsabilité universelle. On est ancêtre de l’humanité. Sous le néologisme d’ancestrogenèse, nous avons proposé une éthique fondée sur le recrutement de ces ancêtres ou bienfaiteurs de l’humanité. L’ancestrogenèse est donc la construction d’une communauté humaine où chaque membre soit responsable de ses actes devant sa communauté locale – naturelle ou historique – en lien avec toute la communauté humaine dont la facilité de la communication accélère la convergence. À la suite de Bénezet Bujo, et pour fonder cette communauté sur le roc et la faire survivre aux fluctuations de l’esprit humain, nous avons placé le Christ à la tête des ancêtres, comme proto-ancêtre. En lui, nous avons le Verbe créateur unique, le sauveur unique et le rassembleur unique de l’humanité de tous lieux et de tous temps. Voilà qui suscite une multitude de questions d’ordre pédagogique, biblique, christologique, ecclésiologique, éthique, anthropologique, politique et sociologique, questions relatives à la formation morale du sujet-ancêtre telle qu’ébauchée dans le cadre limité de cette recherche.

Hordéolo ou algo mais?

Criança do sexo feminino, caucasiana, 15 anos, com história de hordéolo da pálpebra inferior do olho esquerdo, medicada com antibiótico e corticóide tópico associado a limpeza palpebral, desde há cerca de 4 semanas. Por ausência de melhoria e com crescimento progressivo da lesão, recorreu ao serviço de urgência. Negava outras queixas oftalmológicas ou sistémicas associadas. Ao exame objectivo observou-se tumefação da pálpebra inferior do olho esquerdo, com eritema mas sem dor ou calor à palpação, sem blefarite. Acuidade visual de 10/10 em ambos os olhos, com movimentos oculares mantidos e sem proptose. Reflexo pupilar mantido. Segmento anterior e fundoscopia sem alterações de relevo. As 2 principais hipóteses de diagnósticas foram celulite pré-septal ou rabdomiossarcoma. A TC de órbita revelou lesão infero-medial da órbita esquerda, com componente pré-septal envolvendo a pálpebra inferior e pós-septal, de densidade identifica à dos músculos extra-oculares, sem aparente envolvimento do recto medial e inferior. Foi realizada biópsia excisional e estabeleceu-se o diagnóstico de rabdomiossarcoma do tipo embrionário (T1N0M0). Iniciou tratamento com quimioterapia (ifosfamida, vincristina, doxorubicina) e radioterapia local (40Gy). Após 1 ano, apresenta –se clinicamente estável, sem recidiva local nem complicações oculares, mantendo uma AV de 10/10. Conclusão: O diagnóstico de rabdomiossarcoma deve ser lembrado, pois apesar de raro, é o tumor maligno primário da órbita mais frequente na criança. Na presença de uma massa palpebral de rápido crescimento geralmente indolor e/ou proptose, a hipótese de rabdomiossarcoma orbitário deve ser equacionada. Para se obterem bons resultados terapêuticos do ponto de vista de sobrevida e funcional é essencial um diagnóstico e tratamento precoce.

Toward an effective strategy in glioblastoma treatment. Part II: RNA interference as a promising way to sensitize glioblastomas to temozolomide.

International audience

Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide.

International audience

Análise do transcriptoma das glândulas venenosas do escorpião Tityus stigmurus

In Brazil, accidents with scorpions are considered of medical importance, not only by the high incidence, but also for the potentiality of the venom from some species in determining severe clinical conditions. Tityus stigmurus is a widely distributed scorpion species in Northeastern Brazil and known to cause severe human envenomations, inducing pain, hyposthesia, edema, erythema, paresthesia, headaches and vomiting. The present study uses a transcriptomic approach to characterize the molecular repertoire from the non-stimulated venom gland of Tityus stigmurus scorpion. A cDNA library was constructed and 540 clones were sequenced and grouped into 37 clusters, with more than one EST (expressed sequence tag) and 116 singlets. Forty-one percent of ESTs belong to recognized toxin-coding sequences, with antimicrobial toxins (AMP-like) the most abundant transcripts, followed by alfa KTx- like, beta KTx-like, beta NaTx-like and alfa NaTx-like. Our analysis indicated that 34% include other possible venom molecules , whose transcripts correspond to anionic peptides, hypothetical secreted peptides, metalloproteinases, cystein-rich peptides and lectins. Fifteen percent of ESTs are similar to cellular transcripts. Sequences without good matches corresponded to 11%. This investigation provides the first global view of cDNAs from Tityus stigmurus. This approach enables characterization of a large number of venom gland component molecules, which belong either to known or atypical types of venom peptides and proteins from the Buthidae family

RARβ gene methylation is a candidate for primary glioblastoma treatment planning.

Background: We screened RARβ methylation in primary glioblastoma multiforme (GBM) and the results were evaluated based on the clinical data and treatment type. Objective: The objective of this study was to find new areas for the usage of MS-HRM applications in the determination of methylation levels in primary GBM samples and it shows the association of RARβ methylation with the clinical outcome. Methods: In our study, tumor samples were collected during surgical resection by the Department of Neurosurgery. The clinical and radiologic data was carefully reviewed, compared, and evaluated with the histological results. The methylation status of RARβ was determined by using MS-HRM. Results: RARβ gene methylation was detected in 24 out of 40 cases (60%), with different quantitative methylation levels. The mean survival time was 19 months form ethylated cases and 15 months for the non-methylated cases. The survival time of the patients who received treatment was 25 months and the survival time of the patients who received radiotherapy alone or where no treatment protocol applied was 15-20 months. Therefore, a significant difference in survival rates has been observed (P<0.05). This study indicates a potential prognostic value for GBM treatment planning. Conclusion: Our study is the first study to investigate RARβ methylation in primary GBMs. We conclude that the RARβ gene could be a new prognostic and predictive candidate marker to designate the treatment protocol for primary GBMs. Keywords:

Microfluidics-based single-cell functional proteomics microchip for portraying protein signal transduction networks within the framework of physicochemical principles, with applications in fundamental and translational cancer research

Single-cell functional proteomics assays can connect genomic information to biological function through quantitative and multiplex protein measurements. Tools for single-cell proteomics have developed rapidly over the past 5 years and are providing unique opportunities. This thesis describes an emerging microfluidics-based toolkit for single cell functional proteomics, focusing on the development of the single cell barcode chips (SCBCs) with applications in fundamental and translational cancer research.

The microchip designed to simultaneously quantify a panel of secreted, cytoplasmic and membrane proteins from single cells will be discussed at the beginning, which is the prototype for subsequent proteomic microchips with more sophisticated design in preclinical cancer research or clinical applications. The SCBCs are a highly versatile and information rich tool for single-cell functional proteomics. They are based upon isolating individual cells, or defined number of cells, within microchambers, each of which is equipped with a large antibody microarray (the barcode), with between a few hundred to ten thousand microchambers included within a single microchip. Functional proteomics assays at single-cell resolution yield unique pieces of information that significantly shape the way of thinking on cancer research. An in-depth discussion about analysis and interpretation of the unique information such as functional protein fluctuations and protein-protein correlative interactions will follow.

The SCBC is a powerful tool to resolve the functional heterogeneity of cancer cells. It has the capacity to extract a comprehensive picture of the signal transduction network from single tumor cells and thus provides insight into the effect of targeted therapies on protein signaling networks. We will demonstrate this point through applying the SCBCs to investigate three isogenic cell lines of glioblastoma multiforme (GBM).

The cancer cell population is highly heterogeneous with high-amplitude fluctuation at the single cell level, which in turn grants the robustness of the entire population. The concept that a stable population existing in the presence of random fluctuations is reminiscent of many physical systems that are successfully understood using statistical physics. Thus, tools derived from that field can probably be applied to using fluctuations to determine the nature of signaling networks. In the second part of the thesis, we will focus on such a case to use thermodynamics-motivated principles to understand cancer cell hypoxia, where single cell proteomics assays coupled with a quantitative version of Le Chatelier's principle derived from statistical mechanics yield detailed and surprising predictions, which were found to be correct in both cell line and primary tumor model.

The third part of the thesis demonstrates the application of this technology in the preclinical cancer research to study the GBM cancer cell resistance to molecular targeted therapy. Physical approaches to anticipate therapy resistance and to identify effective therapy combinations will be discussed in detail. Our approach is based upon elucidating the signaling coordination within the phosphoprotein signaling pathways that are hyperactivated in human GBMs, and interrogating how that coordination responds to the perturbation of targeted inhibitor. Strongly coupled protein-protein interactions constitute most signaling cascades. A physical analogy of such a system is the strongly coupled atom-atom interactions in a crystal lattice. Similar to decomposing the atomic interactions into a series of independent normal vibrational modes, a simplified picture of signaling network coordination can also be achieved by diagonalizing protein-protein correlation or covariance matrices to decompose the pairwise correlative interactions into a set of distinct linear combinations of signaling proteins (i.e. independent signaling modes). By doing so, two independent signaling modes – one associated with mTOR signaling and a second associated with ERK/Src signaling have been resolved, which in turn allow us to anticipate resistance, and to design combination therapies that are effective, as well as identify those therapies and therapy combinations that will be ineffective. We validated our predictions in mouse tumor models and all predictions were borne out.

In the last part, some preliminary results about the clinical translation of single-cell proteomics chips will be presented. The successful demonstration of our work on human-derived xenografts provides the rationale to extend our current work into the clinic. It will enable us to interrogate GBM tumor samples in a way that could potentially yield a straightforward, rapid interpretation so that we can give therapeutic guidance to the attending physicians within a clinical relevant time scale. The technical challenges of the clinical translation will be presented and our solutions to address the challenges will be discussed as well. A clinical case study will then follow, where some preliminary data collected from a pediatric GBM patient bearing an EGFR amplified tumor will be presented to demonstrate the general protocol and the workflow of the proposed clinical studies.

Alterations of the epigenome in brain cancer: loss of 5-hydroxymethylcytosine

Abstract : 5-Methylcytosine is an epigenetic mark, which can be oxidized to 5-hydroxymethylcytosine (5hmC) in DNA by ten-eleven translocation (TET) oxygenases. It is an initial step in the demethylation of 5mC. Levels of 5hmC is relatively high in the brain compared to other organs, but these levels are known to be significantly reduced during the development of a brain tumor, especially in glioblastoma multiforme (GBM). However, no known mechanisms may fully explain this abnormality. The objectives of my project were to (1) understand the implications of the demethylation pathway mediated by TET, and (2) gain a deeper insight in the epigenetic make-up of brain tumors. (1) U87 cells were incubated with 5mC, 5hmC, 5-formylcytosine (5fC) or co-incubated of 5hmC with 3,4,5,6-tetrahydro-2’-deoxyuridine (dTHU) over a timeline of 0, 24, 48 and 96 hours. (2) 130 brain tumors (GBM= 79; grade II/III= 51) were obtained directly from surgery and immediately suspended in DNA extraction buffer. Both cell samples and tumor tissues underwent DNA extraction and DNA digestion protocols. The percent per cytosine (%/C) was obtained by quantification of 5mC, 5hmC, 5fC, 5-hydroxymethyluracil (5hmU) and 5formyluracil (5fU) using LC-MS/MS. (1) Cellular incubations showed that it is possible to increase levels of 5hmC in DNA, but also a slight increase in 5mC levels throughout the experiment. 5HmC levels dramatically increased by 1.9-fold after 96h. On the other hand, no increase was observed in 5fC levels. Both 5hmC and 5fC incubations were accompanied by high increases in 5hmU and 5fU levels respectively. The addition of dTHU to the 5hmC incubation decreased 5hmU incorporation by 65%. (2) The average levels of 5mC, 5hmC and 5fC, in brain tumors, were 4.0, 0.15 and 0.021 %/C respectively. 5HmU and 5fU levels were present at comparable levels of 5hmC and 5fC. Levels of 5hmC, 5hmU and 5fU were significantly lower in the DNA of GBM specimens. There was a strong correlation between 5mC with 5hmC and 5fC in GBM, but this was absent in low grade tumors. The presence of 5hmU and 5fU in brain tumor and the increase in their levels during cell incubations indicate a deamination activity in these cancerous cells, which may impinge on the cellular levels of 5hmC, in particular. Furthermore, upon the incubations with 5hmC, downstream levels of 5fC did not increase suggesting a TET malfunction. TET activity is maintained in GBMs, but impaired in low grade tumors due to isocitrate dehydrogenase-1 (IDH1) mutations. Therefore, in brain tumors, a strong deamination activity and TET impairment may lead to epigenetic reduction of 5hmC.

The impact of phosphoinositide metabolic enzymes in glioblastoma: a tale of phosphoinositide-specific phospholipase C PLCβ1 and 5-phosphatase SKIP

Background: Glioblastoma multiforme (GBM) is one of the deadliest and most aggressive form of primary brain tumor. Unfortunately, current GBM treatment therapies are not effective in treating GBM patients. They usually experience very poor prognosis with a median survival of approximately 12 months. Only 3-5% survive up to 3 years or more. A large-scale gene profile study revealed that several genes involved in essential cellular processes are altered in GBM, thus, explaining why existing therapies are not effective. The survival of GBM patients depends on understanding the molecular and key signaling events associated with these altered physiological processes in GBM. Phosphoinositides (PI) form just a tiny fraction of the total lipid content in humans, however they are implicated in almost all essential biological processes, such as acting as second messengers in spatio-temporal regulation of cell signaling, cytoskeletal reorganization, cell adhesion, migration, apoptosis, vesicular trafficking, differentiation, cell cycle and post-translational modifications. Interestingly, these essential processes are altered in GBM. More importantly, incoming reports have associated PI metabolism, which is mediated by several PI phosphatases such as SKIP, lipases such as PLCβ1, and other kinases, to regulate GBM associated cellular processes. Even as PLCβ1 and SKIP are involved in regulating aberrant cellular processes in several other cancers, very few studies, of which majority are in-silico-based, have focused on the impact of PLCβ1 and SKIP in GBM. Hence, it is important to employ clinical, in vitro, and in vivo GBM models to define the actual impact of PLCβ1 and SKIP in GBM. AIM: Since studies of PLCβ1 and SKIP in GBM are limited, this study aimed at determining the pathological impact of PI metabolic enzymes, PLCB1 and SKIP, in GBM patient samples, GBM cell line models, and xenograft models for SKIP. Results: For the first time, this study confirmed through qPCR that PLCβ1 gene expression is lower in human GBM patient samples. Moreover, PLCβ1 gene expression inversely correlates with pathological grades of glioma; it decreases as glioma grades increases or worsens. Silencing PLCβ1 in U87MG GBM cells produces a dual impact in GBM by participating in both pro-tumoral and anti-tumoral roles. PLCβ1 knockdown cells were observed to have more migratory abilities, increased cell to extracellular matrix (ECM) adhesion, transition from epithelial phenotype to mesenchymal phenotype through the upregulation of EMT transcription factors Twist1 and Slug, and mesenchymal marker, vimentin. On the other hand, p-Akt and p-mTOR protein expression were downregulated in PLCβ1 knockdown cells. Thus, the oncogenic pathway PI3K/Akt/mTOR pathway is inhibited during PLCβ1 knockdown. Consistently, cell viability in PLCβ1 knockdown cells were significantly decreased compared to controls. As for SKIP, this study demonstrated that about 48% of SKIP colocalizes with nuclear PtdIns(4,5)P2 to nuclear speckles and that SKIP knockdown alters nuclear PtdIns(4,5)P2 in a cell-type dependent manner. In addition, SKIP silencing increased tumor volume and weight in xenografts than controls by reducing apoptosis and increasing viability. All in all, these data confirm that PLCβ1 and SKIP are involved in GBM pathology and a complete understanding of their roles in GBM may be beneficial.

Evaluation of the theranostic use of miRNAs in correlation to the radiopharmaceutical 64CuCl2 in glioblastoma

B:Glioblastoma multiforme(GBM) is one of the most prevalent and aggressive malignant primary brain tumors in adult patients. 64CuCl2 is an innovative radiopharmaceutical investigated as theranostic agent in GBM patients. The therapeutic scheme is still under evaluation, therefore the research focused on the possibility of radioresistance development. The actors responsible for modulating radioresistance could be miRNAs, thus their potential use was investigated both in radioresistant cell lines and in GBM patients plasma samples. M:Radioresistant cell lines were generated by exposing U87MG, U373MG lines to increasing doses of radiation for 32 weeks. Cell membrane permeability alterations and DNA damage were assessed to characterize the lines. Moreover, 64Cu cell incorporation and subcellular distribution were investigated measuring gamma-radiation emission. miRNA expression was evaluated: in parental and radioresistant cell lines, both in cell pellet and media exosomes; in plasma samples of GBM patients using TaqMan Array MicroRNA Cards. R:Radioresistant lines exhibited reduction in membrane permeability and in DNA DSBs indicating the capability to skip the drug killing effect. Cell uptake assays showed internalization of 64Cu both in the sensitive and radioresistant lines. Radioresistant lines showed a different miRNA expression profile compared to the parental lines. 5 miRNAs were selected as possible biomarkers of response to treatment (miR-339-3p, miR-133b, miR-103a-3p, miR-32-5p, miR-335-5p) and 6 miRNAs as possible predictive biomarkers of response to treatment (let-7e-5p, miR-15a-5p, miR-29c-3p, miR-495, miR-146b-5p, miR-199a-5p). miR-32-5p was selected as possible molecule to be used to restore 64CuCl2 responsiveness in the radioresistant cell lines. C: This is the first study describing the development and characterization of 64CuCl2 radioresistant cell lines useful to implement the approach for dosimetric analysis to avoid radioresistance uprising. miRNAs could bring to a better understanding of 64CuCl2 treatment, becoming a useful tool both in detection of treatment response and both as molecule that could restore responsiveness to 64CuCl2 treatment.

«Norma a' piu famosi compositori di sonate a solo». Le sonate per violino di Carlo Ambrogio Lonati

Sempre più spesso negli ultimi decenni la figura e la musica di Carlo Ambrogio Lonati (c.1645-post 1701) hanno destato l’interesse degli studiosi e degli esecutori, i quali hanno preso in considerazione singoli aspetti della sua biografia e della sua produzione. Tuttavia, il processo di riscoperta e di recupero è stato ostacolato dalla mancanza di un’investigazione complessiva e integrata, capace tanto di dar conto della poliedricità di Lonati – violinista, compositore, cantante, didatta – quanto di riesaminare e ricontestualizzare le sue composizioni. Questa dissertazione tenta di colmare tale lacuna e propone una riconsiderazione di Lonati alla luce della sua produzione per violino. L’impiego di un approccio circolare fa in modo che mentre le composizioni violinistiche offrono un canale privilegiato allo studio del percorso artistico e dell’opera di questo compositore, la riconsiderazione critica della biografia permette di calare la musica per violino in un contesto ampio, oltre le distinzioni tra generi. L’integrazione di approcci metodologici differenti ha permesso di proporre una visione completamente nuova del compositore e di riformulare lo studio delle sonate violinistiche. Uno scrupoloso studio codicologico e filologico ha investito quattro testimoni a stampa e diciannove manoscritti e ha permesso di riconsiderare profondamente alcune composizioni già individuate. Suddivise in certe, attribuibili e dubbie, le trentuno sonate sono state poste sotto la lente di diverse prospettive interpretative e analitiche e appaiono differenti per tradizione e statuto testuale, stile, forma e scrittura. Il quadro multiforme che esse descrivono permette un approccio trasversale al repertorio violinistico e strumentale europeo del tardo Sei e del primo Settecento e introduce questioni relative all’autorialità, all’attribuzionismo e ai concetti di opus, creatività e stile. L’edizione critica delle diciannove sonate per violino inedite offre un primo confronto con questo repertorio; l’inventario di tutte le composizioni oggi note attribuite a Lonati fornisce invece le basi per i prossimi studi.

Integración de sistemas para la documentación, gestión y puesta en valor del patrimonio arquitectónico: el parque arqueológico de las tumbas de la Vía Latina en Roma

En la civilización de la antigua Roma, tres de los aspectos más importantes de la vida cotidiana estaban vinculados a la arquitectura: las termas, los acueductos y las tumbas. Esta investigación propone el estudio de la integración de sistemas avanzados para la documentación, gestión y valorización del patrimonio arquitectónico funerario de la Vie Latina y la Appia Antica, en estrecha relación con el tema del Paisaje Cultural. De hecho, el Parque de las Tumbas Latinas alberga uno de los complejos funerarios más importantes, que en la actualidad conserva el aspecto tradicional del antiguo paisaje romano. A lo largo de una vía empedrada, como todas las vías consulares, la Vía Latina (al igual que la Vía Appia Antica), que, como recordaba Tito Livio, conectaba en su día las ciudades de Roma con Capua, sigue manteniendo "congelado" el antiguo trazado urbano/paisajístico. El sistema multiforme del Ager Romanus y del sitio cultural Via Latina/Appia Antica estudiado en esta investigación es, por tanto, comparable a una estructura viva y dinámica y, como tal, debe ser analizada. Por lo tanto, para diseñar una herramienta de protección y gestión tan "potente" y adecuada para un sitio histórico de enorme importancia, fue necesario utilizar las técnicas de levantamiento arquitectónico más avanzadas que se utilizan actualmente (como el escaneo láser y la fotogrametría, junto con un software de análisis específico), acompañadas de un estudio en profundidad de las técnicas de construcción antiguas. El último aspecto clave que pretende abordar la investigación es la catalogación. De hecho, los sitios y monumentos históricos no se pueden mantener sólo mediante su uso y utilización pasiva, sino activando todas las operaciones de protección y conservación mediante intervenciones directas (mantenimiento/restauración) e indirectas, como la catalogación constante de las obras históricas y la consiguiente "catalogación dinámica".