The Cretan Mesolithic in context: new data from Livari Skiadi (SE Crete)

Investigations at Livari (south-eastern Crete) produced a small Mesolithic chipped stone assemblage, whose techno-typological characteristics situate it within an ‘early Holocene Aegean island lithic tradition’ (9000–7000 cal BC). The material provides antecedent characteristics for the lithics of Crete’s founder Neolithic population at Knossos (c. 7000–6500/6400 cal BC). The idiosyncrasies of the Knossian material can be viewed as a hybrid lithic tradition that emerged from interaction between migrant Anatolian farmers and indigenous hunter-gatherers. Small quantities of Melian obsidian at Livari attest to early Holocene maritime insular networks, knowledge of which likely enabled the first farmers’ successful voyage to Crete.Raziskave na najdišču Livari (na jugovzhodnu Krete) so pokazale navzočnost drobnega mezolitskega kamnitega inventarja, katerega tehnološke in tipološke značilnosti ga postavljajo v okvir ‘zgodnje holocenske egejske tradicije kamnitih artefaktov’ (9000–7000 cal BC). Ta material predstavlja predhodnike tipov kamnitih orodij, ki so značilna za kretsko ustanoviteljsko neolitsko populacijo v Knossosu (ok. 7000–6500/6400 cal BC). Značilnosti materiala iz Knossosa kažejo na hibridne tradicije v tipologiji kamnitih artefaktov, ki so se pojavile kot posledica interakcije med migranti – poljedelci iz Anatolije in domorodnimi lovci in nabiralci. Manjša količina obsidiana iz Melosa na najdišču Livari pa kaže na zgodnje holocensko morsko omrežje, ki je potekalo med otoki, kar je omogočalo prvim poljedelcem, da so pridobili znanje za uspešno plovbo do Krete

DIGITAL APPLICATIONS IN ARCHAEOLOGICAL EDUCATION AND EXCAVATION TRAINING: THE DELTA COURSE

Despite the fact that over the last two decades there has been a considerable increase in the adoption of digital applications in archaeological excavations, the application of digital educational tools in the excavation training of Archaeology, students has not made commensurate progress. As a consequence, it is still difficult to integrate in Archaeology curricula the physical space of an archaeological excavation with that of the university classroom. The impact of the limited use of digital educational tools became even more apparent during the recent COVID-19 pandemic, which created serious problems in conducting face-to-face excavation training in both the classroom and the excavation site. Within this context, the integration of these two physical spaces through the digital “space” of online training is the main objective of project DELTA (Digital Excavation through Learning and Training in Archaeology), a transnational project funded in the context of Erasmus+/KA2 EU programme. Through the DELTA project, students of Archaeology will be able to improve their subject knowledge and develop digital and 21st century skills. This paper presents the results of the first phase of the DELTA project, during which we conducted extensive desk and field research aiming at recording the existing situation in the three countries regarding: (1) the use of digital applications in archaeological excavations, (2) current courses on excavation practices, methods and techniques and (3) the use of digital educational tools in such courses. By analysing the results from Internet search and a survey using online questionnaires, we present (a) the most recent trends in the university curricula of Archaeology, (b) the current level of digital skills and expertise of students and professionals and (c) the needs and expectations of students and professors regarding the use of digital applications in excavation and Archaeology education. The results of this research were particularly revealing, especially when comparing the situation between the three countries, but also when contrasting the existing digital skills and the aspirations of the various categories of responders (e.g. educational level, current position etc.). This research provided us with the necessary evidence for the design and development of a blended training course that combines the use of an online platform with face to face and on-site learning in a joint excavation; the ADDIE model was adapted in the course design. In addition, the online piloting of the course allowed participating Universities to discuss the level of integration of digital applications in Archaeology education and make suggestions for future actions, particularly within the context of the recent pandemic and the problems it created in students’ excavation training.Nonostante il fatto che negli ultimi due decenni ci sia stato un notevole aumento nell'adozione di applicazioni digitali negli scavi archeologici, l'applicazione di strumenti didattici digitali nella formazione degli studenti di Archeologia non ha fatto progressi commisurati. Di conseguenza, è ancora difficile integrare nei curricula di Archeologia lo spazio fisico di uno scavo archeologico con quello dell'aula universitaria. L'impatto dell'uso limitato degli strumenti didattici digitali è diventato ancora più evidente durante la recente pandemia COVID-19, che ha creato seri problemi nel condurre la formazione di scavo faccia a faccia sia in aula che sul sito di scavo. In questo contesto, l'integrazione di questi due spazi fisici attraverso lo "spazio" digitale della formazione online è l'obiettivo principale del progetto DELTA (Digital Excavation through Learning and Training in Archaeology), un progetto transnazionale finanziato nel contesto del programma europeo Erasmus+/KA2. Attraverso il progetto DELTA, gli studenti di Archeologia saranno in grado di migliorare la loro conoscenza della materia e sviluppare competenze digitali e del 21° secolo. Questo documento presenta i risultati della prima fase del progetto DELTA, durante la quale abbiamo condotto un'ampia ricerca a tavolino e sul campo con l'obiettivo di registrare la situazione esistente nei tre paesi per quanto riguarda: (1) l'uso di applicazioni digitali negli scavi archeologici, (2) i corsi attuali su pratiche, metodi e tecniche di scavo e (3) l'uso di strumenti didattici digitali in tali corsi. Analizzando i risultati di una ricerca su Internet e di un'indagine tramite questionari online, presentiamo (a) le tendenze più recenti nei curricula universitari di Archeologia, (b) l'attuale livello di abilità e competenze digitali di studenti e professionisti e (c) le esigenze e le aspettative di studenti e professori riguardo all'uso di applicazioni digitali nello scavo e nella formazione in Archeologia. I risultati di questa ricerca sono stati particolarmente rivelatori, soprattutto quando si confronta la situazione tra i tre paesi, ma anche quando si contrappongono le competenze digitali esistenti e le aspirazioni delle varie categorie di intervistati (ad esempio il livello di istruzione, la posizione attuale ecc.) Questa ricerca ci ha fornito le prove necessarie per la progettazione e lo sviluppo di un corso di formazione misto che combina l'uso di una piattaforma online con l'apprendimento faccia a faccia e sul posto in uno scavo congiunto; il modello ADDIE è stato adattato nella progettazione del corso. Inoltre, il pilotaggio online del corso ha permesso alle Università partecipanti di discutere il livello di integrazione delle applicazioni digitali nella formazione in Archeologia e di dare suggerimenti per azioni future, in particolare nel contesto della recente pandemia e dei problemi che ha creato nella formazione degli studenti allo scavo

Linear Estimation of Location and Scale Parameters Using Partial Maxima

Consider an i.i.d. sample X^*_1,X^*_2,...,X^*_n from a location-scale family, and assume that the only available observations consist of the partial maxima (or minima)sequence, X^*_{1:1},X^*_{2:2},...,X^*_{n:n}, where X^*_{j:j}=max{X^*_1,...,X^*_j}. This kind of truncation appears in several circumstances, including best performances in athletics events. In the case of partial maxima, the form of the BLUEs (best linear unbiased estimators) is quite similar to the form of the well-known Lloyd's (1952, Least-squares estimation of location and scale parameters using order statistics, Biometrika, vol. 39, pp. 88-95) BLUEs, based on (the sufficient sample of) order statistics, but, in contrast to the classical case, their consistency is no longer obvious. The present paper is mainly concerned with the scale parameter, showing that the variance of the partial maxima BLUE is at most of order O(1/log n), for a wide class of distributions.Comment: This article is devoted to the memory of my six-years-old, little daughter, Dionyssia, who leaved us on August 25, 2010, at Cephalonia isl. (26 pages, to appear in Metrika

Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer

OBJECTIVES: There is an increasing number of driver fusions in NSCLC which are amenable to targeted therapy. Panel testing for fusions is increasingly appropriate but can be costly and requires adequate good quality biopsy material. In light of the typical mutual exclusivity of driver events in NSCLC, the objective of this study was to trial a novel testing pathway, supported by industrial collaboration, in which only patients negative for driver mutations on DNA-NGS were submitted for fusion panel analysis. MATERIALS AND METHODS: Over 18 months, all patients from a single centre with non-squamous NSCLC were submitted for DNA-NGS, plus ALK and ROS1 immunohistochemistry +/− FISH. Those which were negative for a driver mutation were then recalled for RNA panel testing. RESULTS: 307 samples were referred for DNA-NGS mutation analysis, of which, 10% of cases were unsuitable for or failed DNA-NGS analysis. Driver mutations were detected in 61% (167/275) of all those successfully tested. Of those without a driver mutation and with some remaining tissue available, 28% had insufficient tissue/extracted RNA or failed RNA-NGS. Of those successfully tested, 24% (17/72) had a fusion gene detected involving either ALK, ROS, MET, RET, FGFR or EGFR. Overall, 66% (184/277) of patients had a driver event detected through the combination of DNA and RNA panels. CONCLUSION: Sequential DNA and RNA based molecular profiling increased the efficacy of detecting fusion driven NSCLCs. Continued optimisation of tissue procurement, handling and the diagnostic pathways for gene fusion analysis is necessary to reduce analysis failure rates and improve detection rate for treatment with the next generation of small molecule inhibitors

Target identification of Mycobacterium tuberculosis phenotypic\textit{Mycobacterium tuberculosis phenotypic} hits using a concerted chemogenomic, biophysical and structural approach

Mycobacterium phenotypic hits are a good reservoir for new chemotypes for the treatment of tuberculosis. However, the absence of defined molecular targets and modes of action could lead to failure in drug development. Therefore, a combination of ligand-based and structure-based chemogenomic approaches followed by biophysical and biochemical validation have been used to identify targets for Mycobacterium tuberculosis phenotypic hits. Our approach identified EthR and InhA as targets for several hits, with some showing dual activity against these proteins. From the 35 predicted EthR inhibitors, eight exhibited an IC50 below 50 μM against M. tuberculosis EthR and three were confirmed to be also simultaneously active against InhA. Further hit validation was performed using X-ray crystallography yielding eight new crystal structures of EthR inhibitors. Although the EthR inhibitors attain their activity against M. tuberculosis by hitting yet undefined targets, these results provide new lead compounds that could be further developed to be used to potentiate the effect of EthA activated pro-drugs, such as ethionamide, thus enhancing their bactericidal effect.GM is grateful to the European Molecular Biology Laboratory and Marie Sklodowska-Curie Actions for funding this work. VM and MB acknowledge Bill & Melinda Gates Foundation [subcontract by the Foundation for the National Institutes of Health (NIH)] (OPP1024021). VM and MS acknowledge the European Community’s Seventh Framework Programme [grant number 260872]. GP would like to acknowledge the Wellcome Trust and the European Molecular Biology Laboratory for funding. JPO was funded by the member nation states of the European Molecular Biology Laboratory. TLB acknowledges The Wellcome Trust for funding and support (grant number 200814/Z/16/Z)

Evaluation of machine-learning methods for ligand-based virtual screening

Machine-learning methods can be used for virtual screening by analysing the structural characteristics of molecules of known (in)activity, and we here discuss the use of kernel discrimination and naive Bayesian classifier (NBC) methods for this purpose. We report a kernel method that allows the processing of molecules represented by binary, integer and real-valued descriptors, and show that it is little different in screening performance from a previously described kernel that had been developed specifically for the analysis of binary fingerprint representations of molecular structure. We then evaluate the performance of an NBC when the training-set contains only a very few active molecules. In such cases, a simpler approach based on group fusion would appear to provide superior screening performance, especially when structurally heterogeneous datasets are to be processed

ChEMBL: a large-scale bioactivity database for drug discovery

ChEMBL is an Open Data database containing binding, functional and ADMET information for a large number of drug-like bioactive compounds. These data are manually abstracted from the primary published literature on a regular basis, then further curated and standardized to maximize their quality and utility across a wide range of chemical biology and drug-discovery research problems. Currently, the database contains 5.4 million bioactivity measurements for more than 1 million compounds and 5200 protein targets. Access is available through a web-based interface, data downloads and web services at: https://www.ebi.ac.uk/chembldb

Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients

Purpose Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London. Methods We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity. Results Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar–plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity. Conclusions Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino