Theoretical and implementation aspects in the mechanization of the metatheory of programming languages

Interactive theorem provers are tools designed for the certification of formal proofs developed by means of man-machine collaboration. Formal proofs obtained in this way cover a large variety of logical theories, ranging from the branches of mainstream mathematics, to the field of software verification. The border between these two worlds is marked by results in theoretical computer science and proofs related to the metatheory of programming languages. This last field, which is an obvious application of interactive theorem proving, poses nonetheless a serious challenge to the users of such tools, due both to the particularly structured way in which these proofs are constructed, and to difficulties related to the management of notions typical of programming languages like variable binding. This thesis is composed of two parts, discussing our experience in the development of the Matita interactive theorem prover and its use in the mechanization of the metatheory of programming languages. More specifically, part I covers: - the results of our effort in providing a better framework for the development of tactics for Matita, in order to make their implementation and debugging easier, also resulting in a much clearer code; - a discussion of the implementation of two tactics, providing infrastructure for the unification of constructor forms and the inversion of inductive predicates; we point out interactions between induction and inversion and provide an advancement over the state of the art. In the second part of the thesis, we focus on aspects related to the formalization of programming languages. We describe two works of ours: - a discussion of basic issues we encountered in our formalizations of part 1A of the Poplmark challenge, where we apply the extended inversion principles we implemented for Matita; - a formalization of an algebraic logical framework, posing more complex challenges, including multiple binding and a form of hereditary substitution; this work adopts, for the encoding of binding, an extension of Masahiko Sato's canonical locally named representation we designed during our visit to the Laboratory for Foundations of Computer Science at the University of Edinburgh, under the supervision of Randy Pollack.

La traduzione automatica e i language service provider: il caso di CTI

La presente tesi nasce da un tirocinio avanzato svolto presso l’azienda CTI (Communication Trend Italia) di Milano. Gli obiettivi dello stage erano la verifica della possibilità di inserire gli strumenti automatici nel flusso di lavoro dell’azienda e l'individuazione delle tipologie testuali e delle combinazioni linguistiche a cui essi sono applicabili. Il presente elaborato si propone di partire da un’analisi teorica dei vari aspetti legati all’utilizzo della TA, per poi descriverne l’applicazione pratica nei procedimenti che hanno portato alla creazione dei sistemi custom. Il capitolo 1 offre una panoramica teorica sul mondo della machine translation, che porta a delineare la modalità di utilizzo della TA ad oggi più diffusa: quella in cui la traduzione fornita dal sistema viene modificata tramite post-editing oppure il testo di partenza viene ritoccato attraverso il pre-editing per eliminare gli elementi più ostici. Nel capitolo 2, partendo da una panoramica relativa ai principali software di traduzione automatica in uso, si arriva alla descrizione di Microsoft Translator Hub, lo strumento scelto per lo sviluppo dei sistemi custom di CTI. Nel successivo passaggio, l’attenzione si concentra sull’ottenimento di sistemi customizzati. Un ampio approfondimento è dedicato ai metodi per reperire ed utilizzare le risorse. In seguito viene descritto il percorso che ha portato alla creazione e allo sviluppo dei due sistemi Bilanci IT_EN e Atto Costitutivo IT_EN in Microsoft Translator Hub. Infine, nel quarto ed ultimo capitolo gli output che i due sistemi forniscono vengono rivisti per individuarne le caratteristiche e analizzati tramite alcuni tool di valutazione automatica. Grazie alle informazioni raccolte vengono poi formulate alcune previsioni sul futuro uso dei sistemi presso l’azienda CTI.

Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome

Marginal zone B-cell lymphomas (MZLs) have been divided into 3 distinct subtypes (extranodal MZLs of mucosa-associated lymphoid tissue [MALT] type, nodal MZLs, and splenic MZLs). Nevertheless, the relationship between the subtypes is still unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Samples from 218 MZL patients (25 nodal, 57 MALT, 134 splenic, and 2 not better specified MZLs) were analyzed with the Affymetrix Human Mapping 250K SNP arrays, and the data combined with matched gene expression in 33 of 218 cases. MALT lymphoma presented significantly more frequently gains at 3p, 6p, 18p, and del(6q23) (TNFAIP3/A20), whereas splenic MZLs was associated with del(7q31), del(8p). Nodal MZLs did not show statistically significant differences compared with MALT lymphoma while lacking the splenic MZLs-related 7q losses. Gains of 3q and 18q were common to all 3 subtypes. del(8p) was often present together with del(17p) (TP53). Although del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZLs.

Report from a consensus conference on antibody-mediated rejection in heart transplantation

The problem of AMR remains unsolved because standardized schemes for diagnosis and treatment remains contentious. Therefore, a consensus conference was organized to discuss the current status of antibody-mediated rejection (AMR) in heart transplantation.

Subcolumnar Dendritic and Axonal Organization of Spiny Stellate and Star Pyramid Neurons within a Barrel in Rat Somatosensory Cortex

Excitatory neurons at the level of cortical layer 4 in the rodent somatosensory barrel field often display a strong eccentricity in comparison with layer 4 neurons in other cortical regions. In rat, dendritic symmetry of the 2 main excitatory neuronal classes, spiny stellate and star pyramid neurons (SSNs and SPNs), was quantified by an asymmetry index, the dendrite-free angle. We carefully measured shrinkage and analyzed its influence on morphological parameters. SSNs had mostly eccentric morphology, whereas SPNs were nearly radially symmetric. Most asymmetric neurons were located near the barrel border. The axonal projections, analyzed at the level of layer 4, were mostly restricted to a single barrel except for those of 3 interbarrel projection neurons. Comparing voxel representations of dendrites and axon collaterals of the same neuron revealed a close overlap of dendritic and axonal fields, more pronounced in SSNs versus SPNs and considerably stronger in spiny L4 neurons versus extragranular pyramidal cells. These observations suggest that within a barrel dendrites and axons of individual excitatory cells are organized in subcolumns that may confer receptive field properties such as directional selectivity to higher layers, whereas the interbarrel projections challenge our view of barrels as completely independent processors of thalamic input.

Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system

PDZ-binding motifs are found in the C-terminal tails of numerous integral membrane proteins where they mediate specific protein-protein interactions by binding to PDZ-containing proteins. Conventional yeast two-hybrid screens have been used to probe protein-protein interactions of these soluble C termini. However, to date no in vivo technology has been available to study interactions between the full-length integral membrane proteins and their cognate PDZ-interacting partners. We previously developed a split-ubiquitin membrane yeast two-hybrid (MYTH) system to test interactions between such integral membrane proteins by using a transcriptional output based on cleavage of a transcription factor from the C terminus of membrane-inserted baits. Here we modified MYTH to permit detection of C-terminal PDZ domain interactions by redirecting the transcription factor moiety from the C to the N terminus of a given integral membrane protein thus liberating their native C termini. We successfully applied this "MYTH 2.0" system to five different mammalian full-length renal transporters and identified novel PDZ domain-containing partners of the phosphate (NaPi-IIa) and sulfate (NaS1) transporters that would have otherwise not been detectable. Furthermore this assay was applied to locate the PDZ-binding domain on the NaS1 protein. We showed that the PDZ-binding domain for PDZK1 on NaS1 is upstream of its C terminus, whereas the two interacting proteins, NHERF-1 and NHERF-2, bind at a location closer to the N terminus of NaS1. Moreover NHERF-1 and NHERF-2 increased functional sulfate uptake in Xenopus oocytes when co-expressed with NaS1. Finally we used MYTH 2.0 to demonstrate that the NaPi-IIa transporter homodimerizes via protein-protein interactions within the lipid bilayer. In summary, our study establishes the MYTH 2.0 system as a novel tool for interactive proteomics studies of membrane protein complexes.

A system for 3-D reconstruction of a patient-specific surface model from calibrated X-ray images

This paper presents a system for 3-D reconstruction of a patient-specific surface model from calibrated X-ray images. Our system requires two X-ray images of a patient with one acquired from the anterior-posterior direction and the other from the axial direction. A custom-designed cage is utilized in our system to calibrate both images. Starting from bone contours that are interactively identified from the X-ray images, our system constructs a patient-specific surface model of the proximal femur based on a statistical model based 2D/3D reconstruction algorithm. In this paper, we present the design and validation of the system with 25 bones. An average reconstruction error of 0.95 mm was observed.

Reibung – ein unterschätztes Phänomen in der Verpackungslogistik

„Geiz ist geil!“ ist das Motto eines Handelshauses. Aber diese Philosophie erweist sich immer häufiger als ungeeignet, längerfristigen Erfolg zu sichern. Oftmals wird gerade aus diesem Grund wieder verstärkt auf Qualität geachtet, auf die Qualität von Produkten, auf die Qualität von Herstellungsprozessen, auf die Qualität von Logistikprozessen etc. Dieser Sinneswandel beeinflusst auch alle Verpackungsprozesse, da diese untrennbar mit der Sicherung der Produktqualität und der sicheren Abwicklung aller logistischen Prozesse verbunden ist. Neben der Forderung nach einem wirtschaftlichen Produktschutz als Kernaufgabe der Verpackung müssen jedoch auch zwingende Vorgaben – beispielsweise seitens des Gesetzgebers (z. B. im Lebensmittelbereich, in der Gefahrgutlogistik, im Straßenverkehrsrecht) – beachtet werden. Das führt u. a. dazu, dass alle verpackten Güter so geschützt sein sollten, dass sie den Belastungen im Transportprozess, aber auch den Belastungen aufgrund von Ladungs- und Ladeeinheitensicherungsmaßnahmen standhalten können. Da sich jedoch nicht alle Ladegüter oder Packstücke beliebig für form- oder kraftschlüssige Sicherungsmaßnahmen eignen, sollte bei der Auslegung von Verpackungsmaßnahmen insbesondere der hilfreichen Wirkung von Reibungskräften zur Reduzierung zusätzlicher Sicherungsmaßnahmen Aufmerksamkeit gewidmet werden.

Reibung – ein unterschätztes Phänomen in der Verpackungslogistik

„Geiz ist geil!“ ist das Motto eines Handelshauses. Aber diese Philosophie erweist sich immer häufiger als ungeeignet, längerfristigen Erfolg zu sichern. Oftmals wird gerade aus diesem Grund wieder verstärkt auf Qualität geachtet, auf die Qualität von Produkten, auf die Qualität von Herstellungsprozessen, auf die Qualität von Logistikprozessen etc. Dieser Sinneswandel beeinflusst auch alle Verpackungsprozesse, da diese untrennbar mit der Sicherung der Produktqualität und der sicheren Abwicklung aller logistischen Prozesse verbunden ist. Neben der Forderung nach einem wirtschaftlichen Produktschutz als Kernaufgabe der Verpackung müssen jedoch auch zwingende Vorgaben – beispielsweise seitens des Gesetzgebers (z. B. im Lebensmittelbereich, in der Gefahrgutlogistik, im Straßenverkehrsrecht) – beachtet werden. Das führt u. a. dazu, dass alle verpackten Güter so geschützt sein sollten, dass sie den Belastungen im Transportprozess, aber auch den Belastungen aufgrund von Ladungs- und Ladeeinheitensicherungsmaßnahmen standhalten können. Da sich jedoch nicht alle Ladegüter oder Packstücke beliebig für form- oder kraftschlüssige Sicherungsmaßnahmen eignen, sollte bei der Auslegung von Verpackungsmaßnahmen insbesondere der hilfreichen Wirkung von Reibungskräften zur Reduzierung zusätzlicher Sicherungsmaßnahmen Aufmerksamkeit gewidmet werden.

Standard methods for maintaining adult Apis mellifera in cages under in vitro laboratory conditions

Adult honey bees are maintained in vitro in laboratory cages for a variety of purposes. For example, researchers may wish to perform experiments on honey bees caged individually or in groups to study aspects of parasitology, toxicology, or physiology under highly controlled conditions, or they may cage whole frames to obtain newly emerged workers of known age cohorts. Regardless of purpose, researchers must manage a number of variables, ranging from selection of study subjects (e.g. honey bee subspecies) to experimental environment (e.g. temperature and relative humidity). Although decisions made by researchers may not necessarily jeopardize the scientific rigour of an experiment, they may profoundly affect results, and may make comparisons with similar, but independent, studies difficult. Focusing primarily on workers, we provide recommendations for maintaining adults under in vitro laboratory conditions, whilst acknowledging gaps in our understanding that require further attention. We specifically describe how to properly obtain honey bees, and how to choose appropriate cages, incubator conditions, and food to obtain biologically relevant and comparable experimental results. Additionally, we provide broad recommendations for experimental design and statistical analyses of data that arises from experiments using caged honey bees. The ultimate goal of this, and of all COLOSS BEEBOOK papers, is not to stifle science with restrictions, but rather to provide researchers with the appropriate tools to generate comparable data that will build upon our current understanding of honey bees.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis.

BACKGROUND Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC. METHODS AND FINDINGS Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship. CONCLUSIONS This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Bayesian inference and its application to meta-analysis of epidemiologic data

In Part One, the foundations of Bayesian inference are reviewed, and the technicalities of the Bayesian method are illustrated. Part Two applies the Bayesian meta-analysis program, the Confidence Profile Method (CPM), to clinical trial data and evaluates the merits of using Bayesian meta-analysis for overviews of clinical trials.^ The Bayesian method of meta-analysis produced similar results to the classical results because of the large sample size, along with the input of a non-preferential prior probability distribution. These results were anticipated through explanations in Part One of the mechanics of the Bayesian approach. ^