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Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel—the MYC pathway and the cyclin D–cyclin-dependent kinase (CDK)–retinoblastoma protein (RB) pathway1,2. Both MYC and the cyclin D–CDK–RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1–cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis. AMBRA1-mediated degradation of cyclin D through CRL4–DDB1 regulates cell proliferation and prevents replication stress in neurodevelopment and cancer.

Il presente contributo prende in considerazione le attestazioni di manufatti in ambra della necropoli peuceta di Strada Santo Stefano a Gravina in Puglia (BA). Dopo una panoramica generale, si è scelto di analizzare una sepoltura, la numero 28, che conserva un pendaglio a goccia particolarmente interessante rispetto al contesto di rinvenimento. La tomba presenta inoltre un notevole corredo, composto di diversi ornamenti personali e oggetti ceramici, anche figurati, che offre lo spunto per una ipotesi di lettura complessiva della deposizione., This paper analyzes the presence of amber artifacts in the Peucetian necropolis of Strada Santo Stefano in Gravina in Puglia (BA). It has been chosen to focus on one single tomb, number 28, which includes an outstanding pendant with teardrop shape. In the grave were also found some remarkable ornamental objects and vases, some figured, which allow to give a possible interpretation of the burial.

The selective removal of undesired or damaged mitochondria by autophagy, known as mitophagy, is crucial for cellular homoeostasis, and prevents tumour diffusion, neurodegeneration and ageing. The pro-autophagic molecule AMBRA1 (autophagy/beclin-1 regulator-1) has been defined as a novel regulator of mitophagy in both PINK1/PARKIN-dependent and -independent systems. Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors. Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014. This modification is mediated by the IKKα kinase and induces structural changes in AMBRA1, thus promoting its interaction with LC3/GABARAP (mATG8) proteins and its mitophagic activity. Altogether, these results demonstrate that AMBRA1 regulates mitophagy through a novel pathway, in which HUWE1 and IKKα are key factors, shedding new lights on the regulation of mitochondrial quality control and homoeostasis in mammalian cells.

Background: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting. Methods: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies). Results: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35–82) for the EVA and 57.8 years (range 35.0–82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1–48) and 12.4 months (range 2.9–70.0) in the two data sets, respectively. Conclusion: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

La grande crisi del popolamento che ha colpito l’area delle Terramare nel XII sec. a.C. ha investito in pieno anche la Romagna. A seguito di tale crisi la pianura romagnola rimane sostanzialmente spopolata per tutto il Bronzo finale, mentre nell’area della collina e della bassa montagna si è precocemente ricostituito un sistema di abitati su altura, molto ben attestato nel Montefeltro-valle del Marecchia. In quest’area sono noti diversi centri, situati ad alcuni chilometri di distanza, tra cui spicca quello ubicato sull’ampio pianoro (26 ha) di Verucchio, la cui esistenza è stata accertata da uno scavo stratigrafico. Agli inizi della prima età del Ferro si manifesta una rilevante riorganizzazione: alcuni abitati d’altura preesistenti vengono abbandonati o molto ridimensionati, mentre Verucchio diviene sede di un importante centro afferente alla c.d. cultura villanoviana, che si impianta con un rapporto di discontinuità nella cultura materiale rispetto a quanto documentato per le fasi precedenti, ma tenendo conto evidentemente di un ruolo territoriale del sito già emerso nel Bronzo finale. Si ritiene che tale riorganizzazione, in cui coesistono – come altrove – caratteri locali e processi globali, possa trovare una spiegazione ipotizzando la formazione di un vasto sistema di alleanze sociopolitiche, volto al controllo permanente delle risorse e dei traffici. Attorno al centro di Verucchio si forma, soprattutto nel corso della seconda fase della prima età del Ferro, un tessuto di centri minori – segno di un sistema capillare di controllo e sfruttamento del territorio – che si estende entro un raggio di alcune decine di chilometri fino all’Adriatico e verso nord-ovest fino al torrente Pisciatello. Mentre nella prima fase Verucchio presenta una cultura materiale e rituale simile a quella di Bologna, nell’VIII e nei primi decenni del VII sec. a.C. costruisce una propria cultura peculiare, e si struttura come comunità fortemente gerarchizzata e caratterizzata da fortissime concentrazioni di ricchezza e prestigio nei corredi funerari. Molto rilevanti sono anche le locali produzioni artigianali specializzate. Come già noto, una delle fonti di tale crescita economica consiste nel controllo del flusso dell’ambra proveniente dall’Europa del Nord, che viene lavorata in loco producendo una gamma molto vasta di manufatti, a volte frutto di tecniche alquanto elaborate e raffinate. Nell’ambito di un vasto progetto pluridecennale le testimonianze della prima età del Ferro di Verucchio sono state oggetto sia di nuovi scavi che di studi dettagliati. Dalla seriazione cronologica proposta nell’ambito di tali studi è emersa una distinzione in cinque fasi, mediante le quali si può cogliere l’evoluzione della comunità, dalla crescita economica e demografica evidente durante l’VIII sec. a.C., all’apogeo raggiunto tra ultimo quarto dell’VIII e inizi VII, fino all’ultima fase di prima metà VII e all’abbandono finale. Tale abbandono, databile intorno al 650 a.C. o poco dopo, è probabilmente dovuto a una crisi interna legata a una mancata evoluzione verso una più complessa struttura di tipo urbano, e forse anche all’inizio della pressione di gruppi italici di ceppo umbro, che tra la fine del VII e gli inizi del VI sec. a.C. occupano gran parte della Romagna.

studio di una gemma in ambra di età ellenistica destinata al castone di un pendaglio e di un pendente di pasta vitrea (VI-IV sec.a.C.) dal santuario di Narce

The first part of this master thesis is focused on the personality of Lorenzo deʼ Medici and his inclusion in the period and cultural contexts. The literary background of Italy in the 15th century is introduced, as well as the Lorenzo's life, the summary of his literary output and his contribution as a patron of the Florentine culture and arts. The second part analyzes four of the Lorenzoʼs works related to mythological themes going back until the ancient writers. Lorenzoʼs evident influence by these authors is illustrated with the specific quotations but at the same time his own innovations in texts and stories are referred to. The conclusion compares an extend of this influence on him and the contribution of his own invention to the particular works. It points out the uniqueness of the personality of Lorenzo deʼ Medici both in the cultural and literary spheres as well.

An analysis of related sources like the medico-pharmaceutical requests in van Dam's and Herbert de Jager's memoranda showed, that Engelbert Kaempfer's plan to conduct research on Japan was not the result of a long term vision. It was born in Batavia after other plans to settle down had failed. His application for the post at Dejima was supported by old and new friends in the Dutch East India Company. Many of them were motivated to help him out of this impasse not only through friendship. They also saw in Kaempfer a scholar capable of conducting extensive research on problems in which they had an interest. As in many other aspects of Kaempfer's Japan project, his investigations concerning Japanese plants and drugs were strongly influenced by questions that had circulated among curious men in Batavia and their counterparts in Europe. Kaempfer, who before his arrival in Batavia knew virtually nothing about Japan, obviously established a link into this circle. His descriptions of plants and drugs in the "Amoenitates Exoticae" (1712) and his manuscript "Heutiges Japan", as well as his notes, clearly indicate that he was fully aware of the current state of knowledge. As three examples of plants and drugs considered by his partners to be of special importance show, Kaempfer was not a lone pioneer on uncharted paths. His research and his writings fit neatly into the context of previous publications and questions. On the basis of the information that he collected in Japan, he attempts to arrange, to clarify and, as far as possible, to add new details. Even when he does not explicitly refer to specific persons, he nevertheless reacts to their opinions.

Schede di catalogo monili in ambra

This paper aims to investigate the archaeological context and the chronology of the amber items in Minoan Crete. Following the discovery of an EM Tholos Tomb at Porti, Mesara Plain, in 1909 the Italian scholar Angelo Mosso identified some elements made of a resinous yellow brittle material, postulating that the Minoans knew real amber since a pre-Palatial period. However, chemical analysis has shown that the earliest evidence of amber artefacts in Minoan Crete is closely connected to the Mycenaean presence in LM II - III. The cemeteries around Knossos (Sellopoulo, Isopata, Gypsades) give evidence of the circulation of imported amber items among the burials of high-status individuals. The study focuses on the most recent chemical investigation in order to reconstruct the «Amber Routes» from Western Mediterranean, Northern Europe and Aegean. Finally, a specific part is about the possible significance of these objects, their symbolic value as rank- or status-markers. Studi in

Scheda sintetica relativa ad una sepoltura isolata rinvenuta nel corso di lavori pubblici a poca distanza dal sepolcreto della Galassina di Castelvetro (MO).

Amber artefacts found in prehistoric Sicily have been the subject of several studies in the last decade, the most systematic ones by C.W. Beck in 1993 and P. Szacki in 1999. These offer a most significant contribution to the problem of the identification of Sicilian amber or simetite, and to establishing the spectroscopic characteristics of the fossil resins, but little attention has been given to the archaeological context of these artefacts. There is a need for a comprehensive and systematic study of archaeological amber finds in Sicily, whether reported in the literature or stored in Museums and in private collections. Moreover, many artefacts in literature labelled as amber need to be correctly identified. Finally, the identification of Sicilian amber implies an accurate inventory of natural occurrences and related fossil resins deposited in Mineralogical Museums and classified as genuine simetite. An attempt to illuminate the evidence of the amber artefacts in the Sicily of the 2nd millennium BC imposes an interpretative process based on successive levels of investigation, starting from the status of the research.

I VAGHI Dl AMBRA DEL TIPOTIRINTO NELLA PROTOSTORIAITALlANA: NUOVI DATI DALL'AREA EGEO-BALCANICA. -Vengono presentati i risultati preliminari sulla classificazione, circolazione e inquadrarnento cronologico dei vaghi del tipo Tirinto rinvenuti nella Grecia micenea e nel mondo balcanico. Lo studio permette di attribuire questa classe di manufatti ad una fase iniziale del Tardo ElladicoIIIC e di stabilire una stretta relazione con le note "tombe dei guerrieri" attestate in Acaia e in Elide.