Genetics of Primary Immunodeficiency in Finland

Primary Immunodeficiency (PIDs) categorize a broad and heterogeneous group of inborn immunity errors. Despite being generally quite rare, PIDs collectively account for consistent morbidity and mortality. Currently, more than 350 monogenic PIDs have been recognised to embody clinical phenotypes ranging from life-threatening infections to autoimmune/inflammatory diseases, allergies and/or malignancy. Many PIDs display genetic and allelic heterogeneity with an overlap of symptoms among different syndromes, often making diagnoses challenging. In the past few years, advancements in genomic technologies have revolutionised the world of genetic testing, and currently, next-generation sequencing (NGS)-based approaches are widely applied to routine genetic diagnostics of human disorders. Among the different methods, whole-exome sequencing (WES) proved highly efficient in revealing the genetic variants behind rare disorders. To further depict the genetics of PIDs, a WES-based approach was carried out, targeting the possible disease-causing variants in Finnish subjects lacking a clinical diagnosis. The cohort included patients with a clinical suspicion of immune or/and haematological disorders (n= 212). In the first study, a Finnish founder mutation in the AICDA gene was identified in patients affected by hyper-IgM syndrome type 2 (HIGM2). The disease is a primary antibody deficiency characterised by early-onset recurrent infections, autoimmunity and an absence/low levels of IgG, IgA and IgE but elevated/normal levels of IgM. The retrieved ancestral founder allele is significantly enriched in Finns compared to other European populations (38.56-fold) and has accounted for all HIGM2 cases diagnosed in Finns thus far. In the second study, biallelic ADA2 mutations that cause a deficiency of adenosine deaminase 2 (DADA2) were identified in seven PID patients, all sharing one of the causal variants, which were significantly enriched in Finns (3.31-fold). DADA2 was originally associated with systemic autoinflammation, polyarteritis nodosa-type vasculitis and mild immunodeficiency. Only a fraction of the identified DADA2 patients presented with vasculopathies. In addition, recurrent haematological manifestations are noted, and for the first time, the occurrence of lymphoproliferation is described for some of the patients, expanding the phenotypic spectrum of DADA2. Finally, novel causal variants in telomere biology disorders (TBDs)-associated genes were identified in three families with heterogeneous phenotypes that lacked the classic clinical pathognomonic signs of telomeropathies. The phenotypes ranged from mild signs of Dyskeratosis congenita (DKC) to SCID. The genetic diagnosis was confirmed by an assessment of shortened telomere lengths in patients. In addition, the spectrum of TBD-associated phenotypes was enlarged, showing variable degrees of cytopenia in some patients. This work attests to the validity of clinical WES testing to identify rare disease-causing variants despite the heterogeneous and/or atypical clinical presentations of PIDs. The achievement of a genetic diagnosis allowed for updating the spectrum of reported phenotypes as well as including atypical clinical presentations that might have otherwise remained undiagnosed. In addition, the enrichment of some rare PID-causing mutations in Finland has been depicted, highlighting the correlation of the population history with the distribution of rare deleterious variants of clinical relevance.Primary Immunodeficiency (PIDs) categorize a broad and heterogeneous group of inborn immunity errors. Despite being generally quite rare, PIDs collectively account for consistent morbidity and mortality. Currently, more than 350 monogenic PIDs have been recognised to embody clinical phenotypes ranging from life-threatening infections to autoimmune/inflammatory diseases, allergies and/or malignancy. Many PIDs display genetic and allelic heterogeneity with an overlap of symptoms among different syndromes, often making diagnoses challenging. In the past few years, advancements in genomic technologies have revolutionised the world of genetic testing, and currently, next-generation sequencing (NGS)-based approaches are widely applied to routine genetic diagnostics of human disorders. Among the different methods, whole-exome sequencing (WES) proved highly efficient in revealing the genetic variants behind rare disorders. To further depict the genetics of PIDs, a WES-based approach was carried out, targeting the possible disease-causing variants in Finnish subjects lacking a clinical diagnosis. The cohort included patients with a clinical suspicion of immune or/and haematological disorders (n= 212). In the first study, a Finnish founder mutation in the AICDA gene was identified in patients affected by hyper-IgM syndrome type 2 (HIGM2). The disease is a primary antibody deficiency characterised by early-onset recurrent infections, autoimmunity and an absence/low levels of IgG, IgA and IgE but elevated/normal levels of IgM. The retrieved ancestral founder allele is significantly enriched in Finns compared to other European populations (38.56-fold) and has accounted for all HIGM2 cases diagnosed in Finns thus far. In the second study, biallelic ADA2 mutations that cause a deficiency of adenosine deaminase 2 (DADA2) were identified in seven PID patients, all sharing one of the causal variants, which were significantly enriched in Finns (3.31-fold). DADA2 was originally associated with systemic autoinflammation, polyarteritis nodosa-type vasculitis and mild immunodeficiency. Only a fraction of the identified DADA2 patients presented with vasculopathies. In addition, recurrent haematological manifestations are noted, and for the first time, the occurrence of lymphoproliferation is described for some of the patients, expanding the phenotypic spectrum of DADA2. Finally, novel causal variants in telomere biology disorders (TBDs)-associated genes were identified in three families with heterogeneous phenotypes that lacked the classic clinical pathognomonic signs of telomeropathies. The phenotypes ranged from mild signs of Dyskeratosis congenita (DKC) to SCID. The genetic diagnosis was confirmed by an assessment of shortened telomere lengths in patients. In addition, the spectrum of TBD-associated phenotypes was enlarged, showing variable degrees of cytopenia in some patients. This work attests to the validity of clinical WES testing to identify rare disease-causing variants despite the heterogeneous and/or atypical clinical presentations of PIDs. The achievement of a genetic diagnosis allowed for updating the spectrum of reported phenotypes as well as including atypical clinical presentations that might have otherwise remained undiagnosed. In addition, the enrichment of some rare PID-causing mutations in Finland has been depicted, highlighting the correlation of the population history with the distribution of rare deleterious variants of clinical relevance

SWEET - User manual (version 2.0)

SWEET (Shallow Water Equations Evolving in Time) is a code for the solution of the 2D de Saint Venant equations, written in their conservative form. The code adopts a Finite Differences scheme to advance in time, with a fractional step procedure. The space discretization is realized through Finite Elements, with a linear representation of the water elevation and a quadratic representation of the unit- width discharge. In this document, the physical model and the numerical schemes used for solving the resulting equations are extensively described. The accuracy of the scheme is verified in different test cases. The sequential algorithm has been ported in the parallel computing framework by using the domain decomposition approach. The Schwarz algorithm has been added to the scheme for preconditioning the iterative solution of the elliptic equation modeling the dynamics of the elevation of the water level. The performance of the parallel code are evaluated on a large size computational test case. The structure of the code is explained by a description of the role of each sub- routine and by a flowchart of the program. The input and output files are described in detail, as they constitute the user interface of the code. Both input and output files have a simple structure, and any effort has been made to simplify the procedure of the input setup for the parallel code, and to manage the output results. The PVM message passing library has been used to perform the communications in the parallel version of SWEET. A short introduction to PVM is added at the end of the present report. The SWEET package is the results of a joint work between CRS4 and Enel - Polo Idraulico e Strutturale. The authors of this document kindly acknowledge the valuable contributions of Vincenzo Pennati, from Enel - Polo Idraulico e Strutturale, and of Luca Formaggia, Alfio Quarteroni and Alan Scheinine, from CRS4. This manual is an extension and revision of the SWEET User Manual Version 1.0, 1996. The author of the former document, as well as of the largest part of the SWEET code, is Davide Ambrosi, currently at Politecnico di Torino. To him, not only our sincere thank is due, but mainly the recognizance that SWEET is and will remain a work of his

Robustness to systematics for future dark energy probes

We extend the Figure of Merit formalism usually adopted to quantify the statistical performance of future dark energy probes to assess the robustness of a future mission to plausible systematic bias. We introduce a new robustness Figure of Merit which can be computed in the Fisher Matrix formalism given arbitrary systematic biases in the observable quantities. We argue that robustness to systematics is an important new quantity that should be taken into account when optimizing future surveys. We illustrate our formalism with toy examples, and apply it to future type Ia supernova (SNIa) and baryonic acoustic oscillation (BAO) surveys. For the simplified systematic biases that we consider, we find that SNIa are a somewhat more robust probe of dark energy parameters than the BAO. We trace this back to a geometrical alignement of systematic bias direction with statistical degeneracy directions in the dark energy parameter space.Comment: Added clarifications following referee report, main results unchanged. Matched version accepted by MNRA

High-yield fabrication of entangled photon emitters for hybrid quantum networking using high-temperature droplet epitaxy

Several semiconductor quantum dot techniques have been investigated for the generation of entangled photon pairs. Among the other techniques, droplet epitaxy enables the control of the shape, size, density, and emission wavelength of the quantum emitters. However, the fraction of the entanglement-ready quantum dots that can be fabricated with this method is still limited to around 5%, and matching the energy of the entangled photons to atomic transitions (a promising route towards quantum networking) remains an outstanding challenge. Here, we overcome these obstacles by introducing a modified approach to droplet epitaxy on a high symmetry (111)A substrate, where the fundamental crystallization step is performed at a significantly higher temperature as compared to previous reports. Our method drastically improves the yield of entanglement-ready photon sources near the emission wavelength of interest, which can be as high as 95% due to the low values of fine structure splitting and radiative lifetime, together with the reduced exciton dephasing offered by the choice of GaAs/AlGaAs materials. The quantum dots are designed to emit in the operating spectral region of Rb-based slow-light media, providing a viable technology for quantum repeater stations.Comment: 14 pages, 3 figure

Effects of Dielectric Stoichiometry on the Photoluminescence Properties of Encapsulated WSe2 Monolayers

Two-dimensional transition-metal-dichalcogenide semiconductors have emerged as promising candidates for optoelectronic devices with unprecedented properties and ultra-compact performances. However atomically thin materials are highly sensitive to surrounding dielectric media, which imposes severe limitations to their practical applicability. Hence for their suitable integration into devices, the development of reliable encapsulation procedures that preserve their physical properties are required. Here, the excitonic photoluminescence of WSe2 monolayer flakes is assessed, at room temperature and 10 K, on mechanically exfoliated flakes encapsulated with SiOx and AlxOy layers employing chemical and physical deposition techniques. Conformal flakes coating on untreated - non-functionalized - flakes is successfully demonstrated by all the techniques except for atomic layer deposition, where a cluster-like oxide coating is observed. No significant compositional or strain state changes in the flakes are detected upon encapsulation by any of the techniques. Remarkably, our results evidence that the flakes' optical emission is strongly influenced by the quality of the encapsulating oxide - stoichiometry -. When the encapsulation is carried out with slightly sub-stoichiometric oxides two remarkable phenomena are observed. First, there is a clear electrical doping of the monolayers that is revealed through a dominant trion - charged exciton - room-temperature photoluminescence. Second, a strong decrease of the monolayers optical emission is measured attributed to non-radiative recombination processes and/or carriers transfer from the flake to the oxide. Power- and temperature-dependent photoluminescence measurements further confirm that stoichiometric oxides obtained by physical deposition lead to a successful encapsulation.Comment: 30 pages, 6 figure

Relativistic Digital Twin: Bringing the IoT to the Future

Complex IoT ecosystems often require the usage of Digital Twins (DTs) of their physical assets in order to perform predictive analytics and simulate what-if scenarios. DTs are able to replicate IoT devices and adapt over time to their behavioral changes. However, DTs in IoT are typically tailored to a specific use case, without the possibility to seamlessly adapt to different scenarios. Further, the fragmentation of IoT poses additional challenges on how to deploy DTs in heterogeneous scenarios characterized by the usage of multiple data formats and IoT network protocols. In this paper, we propose the Relativistic Digital Twin (RDT) framework, through which we automatically generate general-purpose DTs of IoT entities and tune their behavioral models over time by constantly observing their real counterparts. The framework relies on the object representation via the Web of Things (WoT), to offer a standardized interface to each of the IoT devices as well as to their DTs. To this purpose, we extended the W3C WoT standard in order to encompass the concept of behavioral model and define it in the Thing Description (TD) through a new vocabulary. Finally, we evaluated the RDT framework over two disjoint use cases to assess its correctness and learning performance, i.e., the DT of a simulated smart home scenario with the capability of forecasting the indoor temperature, and the DT of a real-world drone with the capability of forecasting its trajectory in an outdoor scenario.Comment: 17 pages, 10 figures, 4 tables, 6 listing

Dual-mode wake-up nodes for IoT monitoring applications: Measurements and algorithms

Internet of Things (IoTs)-based monitoring applications usually involve large-scale deployments of battery-enabled sensor nodes providing measurements at regular intervals. In order to guarantee the service continuity over time, the energy-efficiency of the networked system should be maximized. In this paper, we address such issue via a combination of novel hardware/software solutions including new classes of Wake-up radio IoT Nodes (WuNs) and novel data- and hardware-driven network management algorithms. Three main contributions are provided. First, we present the design and prototype implementation of WuN nodes able to support two different energy-saving modes; such modes can be configured via software, and hence dynamically tuned. Second, we show by experimental measurements that the optimal policy strictly depends on the application requirements. Third, we move from the node design to the network design, and we devise proper orchestration algorithms which select both the optimal set of WuN to wake-up and the proper energy-saving mode for each WuN, so that the application lifetime is maximized, while the redundancy of correlated measurements is minimized. The proposed solutions are extensively evaluated via OMNeT++ simulations under different IoT scenarios and requirements of the monitoring applications

Information needs on precision medicine: a survey of Italian health care professionals.

BACKGROUND: Despite advances in technology development for precision medicine, obstacles remain as barriers to progress and change. In this context simple questions arise: what is the level of understanding of precision medicine among healthcare professionals? We tried to address this question with a survey whose objective was to explore the perception and understanding of precision medicine. METHODS: A questionnaire was administered to a sample made of oncologists, clinical and hospital pharmacists, pharmacologists and infectiologists in the context of five different Italian national congresses. Participation in the survey was voluntary and anonymous. RESULTS: The questionnaire was filled-in by a total number of 1,113 professionals out of 3,670 registered participants in the congresses. About half of respondents stated they were not sufficiently informed about precision medicine, and infectiologists were the ones who felt less informed. Most respondents agreed with the basic principles and definitions of precision medicine and believed this new approach is going to require deep changes in healthcare. CONCLUSIONS: Our findings show that healthcare professionals have partial knowledge on this topic and that there is a significant association between respondents’ knowledge and their clinical specialty. However, despite some misconceptions about precision medicine, a genuine interest and familiarity with its basic principles seems to emerge.