Efficient pruning of large knowledge graphs

In this paper we present an efficient and highly accurate algorithm to prune noisy or over-ambiguous knowledge graphs given as input an extensional definition of a domain of interest, namely as a set of instances or concepts. Our method climbs the graph in a bottom-up fashion, iteratively layering the graph and pruning nodes and edges in each layer while not compromising the connectivity of the set of input nodes. Iterative layering and protection of pre-defined nodes allow to extract semantically coherent DAG structures from noisy or over-ambiguous cyclic graphs, without loss of information and without incurring in computational bottlenecks, which are the main problem of stateof- the-art methods for cleaning large, i.e., Webscale, knowledge graphs. We apply our algorithm to the tasks of pruning automatically acquired taxonomies using benchmarking data from a SemEval evaluation exercise, as well as the extraction of a domain-adapted taxonomy from theWikipedia category hierarchy. The results show the superiority of our approach over state-of-art algorithms in terms of both output quality and computational efficiency

Efficient pruning of large knowledge graphs

In this paper we present an efficient and highly accurate algorithm to prune noisy or over-ambiguous knowledge graphs given as input an extensional definition of a domain of interest, namely as a set of instances or concepts. Our method climbs the graph in a bottom-up fashion, iteratively layering the graph and pruning nodes and edges in each layer while not compromising the connectivity of the set of input nodes. Iterative layering and protection of pre-defined nodes allow to extract semantically coherent DAG structures from noisy or over-ambiguous cyclic graphs, without loss of information and without incurring in computational bottlenecks, which are the main problem of stateof- the-art methods for cleaning large, i.e., Webscale, knowledge graphs. We apply our algorithm to the tasks of pruning automatically acquired taxonomies using benchmarking data from a SemEval evaluation exercise, as well as the extraction of a domain-adapted taxonomy from theWikipedia category hierarchy. The results show the superiority of our approach over state-of-art algorithms in terms of both output quality and computational efficiency

Performance of the main technologies demonstrated in the ENVISION project

Within the context of ENVISION project, different technologies have been developed aiming to harvest energy being integrated into the building façade. These technologies have been tested in different demosites with a monitoring phase of around one year in order to assess their performances on-field. The technologies developed within ENVISION and reported in this article are solar façade collectors coupled with Heat Pumps and PV windows. The present paper reports the assessment of the performance of the ENVISION technologies in the different demos. This analysis is carried out through the calculation of normalized KPIs related to four different domains (energy, social, economic, and environmental) and the aggregation of these KPIs in domain scores to understand the strengths and weaknesses of each demo. In all the different demosites, the monitored data have been collected and processed to calculate the most valuable KPIs, which are compared with state-of-the-art values found in the literature to calculate a normalized KPI. Depending on the obtained value of the normalized KPIs a score from 0 (worst performance) to 5 (best performance) is assigned, considering that a score of 3/5 has been assigned to the State-Of-the-Art. Some KPIs are specific for the single demo (e.g. the SCOP of the heat pump), while others are common to all the demos and were used to carry on a direct comparison between the technologies. All the demos showed promising results in the social, energy, and environmental domains. For the last domain, in particular, the best results are obtained, as each technology leads to significant savings in GHG emissions. There is room for improvement on the economic side, which can be filled by progressively lowering the cost of technology over the years

Legal Status and the Criminal Activity of Immigrants

We exploit exogenous variation in legal status following the January 2007 European Union enlargement to estimate its effect on immigrant crime. We difference out unobserved time-varying factors by (i) comparing recidivism rates of immigrants from the “new” and “candidate” member countries; and (ii) using arrest data on for eign detainees released upon a mass clemency that occurred in Italy in August 2006. The timing of the two events allows us to setup a difference-in-differences strategy. Legal status leads to a 50 percent reduction in recidivism, and explains one-half to two-thirds of the observed differences in crime rates between legal and illegal immigrants

Partial T cell defects and expanded CD56bright NK cells in an SCID patient carrying hypomorphic mutation in the IL2RG gene

X-linked severe combined immunodeficiency (X-SCID) caused by full mutation of the IL2RG gene leads to T- B+ NK- phenotype and is usually associated with severe opportunistic infections, diarrhea, and failure to thrive. When IL2RG hypomorphic mutation occurs, diagnosis could be delayed and challenging since only moderate reduction of T and NK cells may be present. Here, we explored phenotypic insights and the impact of the p.R222C hypomorphic mutation (IL2RGR222C ) in distinct cell subsets in an 8-month-old patient with atypical X-SCID. We found reduced CD4+ T cell counts, a decreased frequency of naïve CD4+ and CD8+ T cells, and an expansion of B cells. Ex vivo STAT5 phosphorylation was impaired in CD4+ CD45RO+ T cells, yet compensated by supraphysiological doses of IL-2. Sanger sequencing on purified cell subsets showed a partial reversion of the mutation in total CD3+ cells, specifically in recent thymic emigrants (RTE), effector memory (EM), and CD45RA+ terminally differentiated EM (EMRA) CD4+ T cells. Of note, patient's NK cells had a normal frequency compared to age-matched healthy subjects, but displayed an expansion of CD56bright cells with higher perforin content and cytotoxic potential, associated with accumulation of NK-cell stimulatory cytokines (IL-2, IL-7, IL-15). Overall, this report highlights an alteration in the NK-cell compartment that, together with the high disease-phenotype variability, should be considered in the suspicion of X-SCID with hypomorphic IL2RG mutation

First Case of Patient With Two Homozygous Mutations in MYD88 and CARD9 Genes Presenting With Pyogenic Bacterial Infections, Elevated IgE, and Persistent EBV Viremia

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro. Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis

Radiosensitivity in patients affected by ARPC1B deficiency: a new disease trait?

Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions

The Inborn Errors of Immunity—Virtual Consultation System Platform in Service for the Italian Primary Immunodeficiency Network: Results from the Validation Phase

purposeInborn errors of immunity (IEI) represent a heterogeneous group of rare genetically determined diseases. In some cases, patients present with complex or atypical phenotypes, not fulfilling the accepted diagnostic criteria for IEI and, thus, at high risk of misdiagnosis or diagnostic delay. this study aimed to validate a platform that, through the opinion of immunologist experts, improves the diagnostic process and the level of care of patients with atypical/complex IEI.MethodsHere, we describe the functioning of the IEI-Virtual consultation system (VCS), an innovative platform created by the italian Immunodeficiency network (IPINet). resultsIn the validation phase, from January 2020 to June 2021, 68 cases were entered on the IEI-VCS platform. a final diagnosis was achieved in 35/68 cases (51%, 95% CI 38.7 to 64.2). In 22 out of 35 solved cases, the diagnosis was confirmed by genetic analysis. In 3/35 cases, a diagnosis of secondary immunodeficiency was made. In the remaining 10 cases, an unequivocal clinical and immunological diagnosis was obtained, even though not substantiated by genetic analysis. conclusionFrom our preliminary study, the VCS represents an innovative and useful system to improve the diagnostic process of patients with complex unsolved IEI disorders, with benefits both in terms of reduction of time of diagnosis and access to the required therapies. these results may help the functioning of other international platforms for the management of complex cases

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT034786