Colimits in 2-dimensional slices

We generalize to dimension 2 the well-known fact that a colimit in a 1-dimensional slice is precisely the map from the colimit of the domains which is induced by the universal property. We show two different approaches to this; a more intuitive one, based on the reduction of the weighted 2-colimits to oplax normal conical ones, and a more abstract one, based on an original concept of colim-fibration and on an extension of the Grothendieck construction. We find the need to consider lax slices, and prove results of preservation, reflection and lifting of 2-colimits for the domain 2-functor from a lax slice. The preservation result is shown by proving a general theorem of \F-category theory, which states that a lax left adjoint preserves appropriate colimits if the adjunction is strict on one side and is suitably \F-categorical. Finally, we apply this theorem of preservation of 2-colimits to the 2-functor of change of base along a split Grothendieck opfibration between lax slices, after showing that it is such a left adjoint by laxifying the proof that Conduch\'{e} functors are exponentiable. We conclude extending the result of preservation of 2-colimits for the change of base 2-functor to any finitely complete 2-category with a dense generator

Aspects of 2-dimensional elementary topos theory

We contribute to expand 2-dimensional elementary topos theory. We focus on the concept of 2-classifier, which is a 2-categorical generalization of the notion of subobject classifier. The idea is that of a discrete opfibration classifier. Interestingly, a 2-classifier can also be thought of as a Grothendieck construction inside a 2-category. We introduce the notion of good 2-classifier, that captures well-behaved 2-classifiers and is closer to the point of view of logic. We substantially reduce the work needed to prove that something is a 2-classifier. We prove that both the conditions of 2-classifier and what gets classified by a 2-classifier can be checked just over the objects that form a dense generator. This technique allows us to produce a good 2-classifier in prestacks that classifies all discrete opfibrations with small fibres, and to restrict such good 2-classifier to one in stacks. This is the main part of a proof that Grothendieck 2-topoi are elementary 2-topoi. Our results also solve a problem posed by Hofmann and Streicher when attempting to lift Grothendieck universes to sheaves. To produce our good 2-classifier in prestacks, we present an indexed version of the Grothendieck construction. This gives a pseudonatural equivalence of categories between opfibrations over a fixed base in the 2-category of 2-copresheaves and 2-copresheaves on the Grothendieck construction of the fixed base. Our result can be interpreted as the result that every (op)fibrational slice of a Grothendieck 2-topos is a Grothendieck 2-topos. We thus generalize what is called the fundamental theorem of elementary topos theory to dimension 2, in the Grothendieck topoi case. In order to reach our theorems of reduction of the study of a 2-classifier to dense generators, we develop a calculus of colimits in 2-dimensional slices. We generalize to dimension 2 the well-known fact that a colimit in a 1-dimensional slice category is precisely the map from the colimit of the domains of the diagram which is induced by the universal property. We explain that we need to consider lax slices, and prove results of preservation, reflection and lifting of 2-colimits for the domain 2-functor from a lax slice. We then study the 2-functor of change of base between lax slices. Our calculus of colimits in 2-dimensional slices is based on an original concept of colim fibration and on the reduction of weighted 2-colimits to essentially conical ones, which is regulated by the 2-category of elements construction. The latter construction is a natural extension of the Grothendieck construction. We study it in detail from an abstract point of view and we conceive it as the 2-Set-enriched Grothendieck construction, via an original notion of pointwise Kan extension. Our work is relevant to higher dimensional elementary topos theory as well as to a generalization of the Grothendieck construction to the enriched setting

A comonad for Grothendieck fibrations

We study the 2-category theory of Grothendieck fibrations in the 2-category of functors \ct{Cat}^{\ct{2}}. After redrawing a few general results in that context, we show that fibrations over a given base are pseudo-coalgebras for a 2-comonad on \ct{Cat} / \ct{B}. We use that result to explain how an arbitrary fibration is equivalent to one with a splitting

parSMURF, a high-performance computing tool for the genome-wide detection of pathogenic variants.

BACKGROUND: Several prediction problems in computational biology and genomic medicine are characterized by both big data as well as a high imbalance between examples to be learned, whereby positive examples can represent a tiny minority with respect to negative examples. For instance, deleterious or pathogenic variants are overwhelmed by the sea of neutral variants in the non-coding regions of the genome: thus, the prediction of deleterious variants is a challenging, highly imbalanced classification problem, and classical prediction tools fail to detect the rare pathogenic examples among the huge amount of neutral variants or undergo severe restrictions in managing big genomic data. RESULTS: To overcome these limitations we propose parSMURF, a method that adopts a hyper-ensemble approach and oversampling and undersampling techniques to deal with imbalanced data, and parallel computational techniques to both manage big genomic data and substantially speed up the computation. The synergy between Bayesian optimization techniques and the parallel nature of parSMURF enables efficient and user-friendly automatic tuning of the hyper-parameters of the algorithm, and allows specific learning problems in genomic medicine to be easily fit. Moreover, by using MPI parallel and machine learning ensemble techniques, parSMURF can manage big data by partitioning them across the nodes of a high-performance computing cluster. Results with synthetic data and with single-nucleotide variants associated with Mendelian diseases and with genome-wide association study hits in the non-coding regions of the human genome, involhing millions of examples, show that parSMURF achieves state-of-the-art results and an 80-fold speed-up with respect to the sequential version. CONCLUSIONS: parSMURF is a parallel machine learning tool that can be trained to learn different genomic problems, and its multiple levels of parallelization and high scalability allow us to efficiently fit problems characterized by big and imbalanced genomic data. The C++ OpenMP multi-core version tailored to a single workstation and the C++ MPI/OpenMP hybrid multi-core and multi-node parSMURF version tailored to a High Performance Computing cluster are both available at https://github.com/AnacletoLAB/parSMURF

Spheres Derived from Lung Adenocarcinoma Pleural Effusions: Molecular Characterization and Tumor Engraftment

Malignant pleural effusions (MPEs) could represent an excellent source to culture a wide variety of cancer cells from different donors. In this study, we set up culture conditions for cancer cells deriving from MPEs of several patients affected by the most frequent form of lung cancer, namely the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases. AdenoCa malignant pleural effusions gave rise to in vitro cultures both in adherent and/or in spheroid conditions in almost all cases analyzed. We characterized in greater detail two samples which showed the most efficient propagation in vitro. In these samples we also compared gene profiles of spheroid vs adherent cultures and identified a set of differentially expressed genes. Finally we achieved efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells

A comonad for Grothendieck fibrations

We prove that cloven Grothendieck fibrations over a fixed base B are the pseudo-coalgebras for a lax idempotent 2-comonad on Cat/B. We show this via an original observation that the known colax idempotent 2-monad for fibrations over a fixed base has a right 2-adjoint. As an important consequence, we obtain an original cofree construction of a fibration on a functor. We also give a new, conceptual proof of the fact that the forgetful 2-functor from split fibrations to cloven fibrations over a fixed base has both a left 2-adjoint and a right 2-adjoint, in terms of coherence phenomena of strictification of pseudo-(co)algebras. The 2-monad for fibrations yields the left splitting and the 2-comonad yields the right splitting. Moreover, we show that the constructions induced by these coherence theorems recover Giraud's explicit constructions of the left and the right splittings

Long-term liver histology improvement in patients with chronic hepatitis B and sustained response to interferon

A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long-term liver histological changes induced by interferon (IFN). A total of 112 patients (mean age 46.4 years) were studied. All patients had received a 6-12-month IFN-α course (6-18 MU/week) and had successively undergone clinical, biochemical and virological follow-up for at least 36 months (range: 36-76). In each patient, two liver biopsies had been performed: 1-6 months before treatment and, 12-76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post-treatment liver necroinflammation and fibrosis mean(±SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 ± 2.2 vs 6.8 ± 2.9 and 0.8 ± 1.0 vs 1.2 ± 1.1, respectively; P 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12-23 months (n = 34), 24-35 months (n = 26) or more than 36 months (n = 27) after treatment, a progressive decrease of mean necroinflammatory score was observed (-2.6 ± 2.1, -4.1 ± 3.4 and -5.2 ± 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (-0.3 ± 0.6, -0.3 ± 0.7 and -0.7 ± 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12-month sustained response, unlike those who relapse, have a long-term progressive reduction and, in some cases, a complete regression of liver histological damage

An open source knowledge graph ecosystem for the life sciences

Translational research requires data at multiple scales of biological organization. Advancements in sequencing and multi-omics technologies have increased the availability of these data, but researchers face significant integration challenges. Knowledge graphs (KGs) are used to model complex phenomena, and methods exist to construct them automatically. However, tackling complex biomedical integration problems requires flexibility in the way knowledge is modeled. Moreover, existing KG construction methods provide robust tooling at the cost of fixed or limited choices among knowledge representation models. PheKnowLator (Phenotype Knowledge Translator) is a semantic ecosystem for automating the FAIR (Findable, Accessible, Interoperable, and Reusable) construction of ontologically grounded KGs with fully customizable knowledge representation. The ecosystem includes KG construction resources (e.g., data preparation APIs), analysis tools (e.g., SPARQL endpoint resources and abstraction algorithms), and benchmarks (e.g., prebuilt KGs). We evaluated the ecosystem by systematically comparing it to existing open-source KG construction methods and by analyzing its computational performance when used to construct 12 different large-scale KGs. With flexible knowledge representation, PheKnowLator enables fully customizable KGs without compromising performance or usability

Re-treatment of patients with chronic hepatitis C in clinical practice: Results of a multicenter retrospective survey [Ritrattamento dei pazienti con epatite cronica da HCV nella pratica clinica: Risultati di uno studio multicentrico retrospettivo]

Aims. To evaluate in a multicentric retrospective study, carried out at 35 Italian hospitals, the retreatment with interferon (IFN) or interferon-ribavirin (RBV) association in patients with chronic hepatitis C that were non-responder (NR) or responder-relapser (RR) at a previous IFN treatment. Methods. Complete descriptive data of 531 patients were collected from all participant centers by a centralized database (HEPANET). The evaluation of retreatments was done on 256 patients that had completed it on 31 December, 1999. Individuals with no viral genotype data, and those lost for adverse reactions and drop-outs, were excluded from the analysis. Univariate and multivariate statistical analyses were done to evaluate biochemical and virological response, to determine the presence of independent factors of response, and to compare different retreatment strategies. Results. A sustained biochemical response (SBR) was achieved in 30.1% of cases, and a sustained virological response (SVR) in 22.8%. Previous treatment outcome (RR instead of NR), RBV association, and duration of retreatment were independent factors of response. A better efficacy of a 12 months retreatment with IFN alone was confirmed. With the latter, high SVR rates, comparable to IFN+RBV 6 months course, were obtained, both in RR and NR patients. Conclusions. Retrospective multicentric study, as our is, could be a more reliable representation of results obtained in common clinical practice. They may give useful information, together with meta-analyses and randomized studies, for a better cost/benefit evaluation of retreatments in patients with hepatitis C (RR and NR)