| 1. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 2. |
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| 3. |
- Alvarez, Alberto, et al.
(författare)
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Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines
- 2020
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Ingår i: Transgenic research. - : Springer Nature. - 0962-8819 .- 1573-9368. ; 29:1, s. 53-68
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Tidskriftsartikel (refereegranskat)abstract
- The CreER(T2)/loxP system is widely used to induce conditional gene deletion in mice. One of the main advantages of the system is that Cre-mediated recombination can be controlled in time through Tamoxifen administration. This has allowed researchers to study the function of embryonic lethal genes at later developmental timepoints. In addition, CreER(T2) mouse lines are commonly used in combination with reporter genes for lineage tracing and mosaic analysis. In order for these experiments to be reliable, it is crucial that the cell labeling approach only marks the desired cell population and their progeny, as unfaithful expression of reporter genes in other cell types or even unintended labeling of the correct cell population at an undesired time point could lead to wrong conclusions. Here we report that all CreER(T2) mouse lines that we have studied exhibit a certain degree of Tamoxifen-independent, basal, Cre activity. Using Ai14 and Ai3, two commonly used fluorescent reporter genes, we show that those basal Cre activity levels are sufficient to label a significant amount of cells in a variety of tissues during embryogenesis, postnatal development and adulthood. This unintended labelling of cells imposes a serious problem for lineage tracing and mosaic analysis experiments. Importantly, however, we find that reporter constructs differ greatly in their susceptibility to basal CreER(T2) activity. While Ai14 and Ai3 easily recombine under basal CreER(T2) activity levels, mTmG and R26R-EYFP rarely become activated under these conditions and are therefore better suited for cell tracking experiments.
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| 4. |
- Alvarez, Ines, et al.
(författare)
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Comparing Admission Control Architectures for Real-Time Ethernet
- 2020
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Ingår i: IEEE Access. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 2169-3536. ; 8, s. 136260-136260
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Tidskriftsartikel (refereegranskat)abstract
- Industry 4.0 and Autonomous Driving are emerging resource-intensive distributed application domains that deal with open and evolving environments. These systems are subject to stringent resource, timing, and other non-functional constraints, as well as frequent reconfiguration. Thus, real-time behavior must not preclude operational flexibility. This combination is motivating ongoing efforts within the Time Sensitive Networking (TSN) standardization committee to define admission control mechanisms for Ethernet. Existing mechanisms in TSN, like those of AVB, its predecessor, follow a distributed architecture that favors scalability. Conversely, the new mechanisms envisaged for TSN (IEEE 802.1Qcc) follow a (partially) centralized architecture, favoring short reconfiguration latency. This paper shows the first quantitative comparison between distributed and centralized admission control architectures concerning reconfiguration latency. Here, we compare AVB against a dynamic real-time reconfigurable Ethernet technology with centralized management, namely HaRTES. Our experiments show a significantly lower latency using the centralized architecture. We also observe the dependence of the distributed architecture in the end nodes & x2019; performance and the benefit of having a protected channel for the admission control transactions.
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| 5. |
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| 6. |
- Alvarez Vadillo, Ines, et al.
(författare)
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Centralised Architecture for the Automatic Self-Configuration of Industrial Networks
- 2023
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Ingår i: IEEE Int. Conf. Emerging Technol. Factory Autom., ETFA. - : Institute of Electrical and Electronics Engineers Inc.. - 9798350339918
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Konferensbidrag (refereegranskat)abstract
- Novel production paradigms aim at increasing the efficiency and flexibility of production systems. Nonetheless, traditional industrial infrastructures lack the mechanisms needed to support these new paradigms. One of the main limiting factors is the architecture, which follows the automation pyramid in which subsystems are divided in layers depending on their functionalities. This allowed to meet the timing and dependability requirements of the production subsystems, however at the cost of limiting the exchange of information required to provide increased flexibility to the system. For this reason, in this paper we propose a new industrial architecture with a single network infrastructure to connect all the devices that conform to the industrial systems. On top of that, we design an Automatic Network Configurator to support the automatic configuration of the system. To assess the feasibility of our design and evaluate its performance, we implement the first instance of the architecture capable of supporting changes in the traffic requirements during run-time, i.e., without stopping or disrupting the system's operation. Furthermore, we use the implemented instance to measure the time required for reconfigurations.
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| 7. |
- Alvarez Vadillo, Ines, et al.
(författare)
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Implementing a First CNC for Scheduling and Configuring TSN Networks
- 2022
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Ingår i: IEEE International Conference on Emerging Technologies and Factory Automation, ETFA. - : Institute of Electrical and Electronics Engineers Inc.. - 9781665499965
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Konferensbidrag (refereegranskat)abstract
- Novel industrial applications are leading to important changes in industrial systems. One of the most important changes is the need for systems that are capable to adapt to changes in the environment or the system itself. Because of their nature many of these applications are distributed, and their network infrastructure is key to guarantee the correct operation of the overall system. Furthermore, in order for a distributed system to be able to adapt, its network must be flexible enough to support changes in the traffic during runtime. The Time-Sensitive Networking (TSN) Task Group has proposed a series of standards that aim at providing deterministic real-time communications over Ethernet. TSN also provides centralised online configuration and control architectures which enable the online configuration of the network. A key part in TSN's centralised architectures is the Centralised Network Configuration element (CNC). In this work we present a first implementation of a CNC capable of scheduling time-triggered traffic and deploying such configuration in the network using the Network Configuration (NETCONF) protocol. We also assess the correctness of our implementation using an industrial use case provided by Volvo Construction Equipment.
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| 8. |
- Barry, Antonia, et al.
(författare)
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Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system
- 2023
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Ingår i: Lab on a Chip. - 1473-0197 .- 1473-0189. ; 23:11, s. 2664-2682
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Tidskriftsartikel (refereegranskat)abstract
- Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (PRMTs). Inhibitors of PRMTs have recently entered clinical trials to target several types of cancer, including gliomas (NCT04089449). People with glioblastoma (GBM), the most aggressive form of brain tumour, are among those with the poorest quality of life and likelihood of survival of anyone diagnosed with cancer. There is currently a lack of (pre)clinical research on the possible application of PRMT inhibitors to target brain tumours. Here, we set out to investigate the effects of clinically-relevant PRMT inhibitors on GBM biopsies. We present a new, low-cost, easy to fabricate perfusion device that can maintain GBM tissue in a viable condition for at least eight days post-surgical resection. The miniaturised perfusion device enables the treatment of GBM tissue with PRMT inhibitors ex vivo, and we observed a two-fold increase in apoptosis in treated samples compared to parallel control experiments. Mechanistically, we show thousands of differentially expressed genes after treatment, and changes in the type of arginine methylation of the RNA binding protein FUS that are consistent with hundreds of differential gene splicing events. This is the first time that cross-talk between different types of arginine methylation has been observed in clinical samples after treatment with PRMT inhibitors.
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| 9. |
- Bujosa Mateu, Daniel, et al.
(författare)
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CSRP : An Enhanced Protocol for Consistent Reservation of Resources for AVB/TSN
- 2021
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Ingår i: IEEE Transactions on Industrial Informatics. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 1551-3203 .- 1941-0050. ; 17:5, s. 3640-3650
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Tidskriftsartikel (refereegranskat)abstract
- The IEEE Audio Video Bridging (AVB) Task Group (TG) was created to provide Ethernet with soft real-time guarantees. Later on, the TG was renamed to Time-Sensitive Networking (TSN) and its scope broadened to support hard real-time and critical applications. The Stream Reservation Protocol (SRP) is a key work of the TGs as it allows reserving resources in the network, guaranteeing the required quality of service. AVB's SRP is based on a distributed architecture, whereas TSN's is based on centralized ones. The distributed version of SRP is supported and used in TSN. Nevertheless, it was not designed to provide properties that are important for critical applications. In this article, we model SRP using UPPAAL and we study the termination and consistency. We verify that SRP does not provide such properties. Furthermore, we propose an improved protocol called Consistent Stream Reservation Protocol (CSRP) and we formally verify its correctness using UPPAAL.
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| 10. |
- Dominguez, Mev, et al.
(författare)
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Mutation spectrum in South American Lynch syndrome families
- 2013
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Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1897-4287. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic counselling and testing for Lynch syndrome have recently been introduced in several South American countries, though yet not available in the public health care system. Methods: We compiled data from publications and hereditary cancer registries to characterize the Lynch syndrome mutation spectrum in South America. In total, data from 267 families that fulfilled the Amsterdam criteria and/or the Bethesda guidelines from Argentina, Brazil, Chile, Colombia and Uruguay were included. Results: Disease-predisposing mutations were identified in 37% of the families and affected MLH1 in 60% and MSH2 in 40%. Half of the mutations have not previously been reported and potential founder effects were identified in Brazil and in Colombia. Conclusion: The South American Lynch syndrome mutation spectrum includes multiple new mutations, identifies potential founder effects and is useful for future development of genetic testing in this continent.
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