Comments on "nonlinear H-infinity output feedback control with integrator for polynomial discrete-time systems'

[EN] This note points out that controllers resulting from Corollaries 3.1 and 3.2 and Theorem 3.1 in Saat and Nguang (Int. J. Robust Nonlinear Control 2013; 10.1002/rnc.3130) do not improve over the open-loop performance.The research in this area has been supported by the Spanish Government (MINECO) under research project DPI2011-27845-C02-01.Sala, A.; Pitarch Pérez, JL. (2015). Comments on "nonlinear H-infinity output feedback control with integrator for polynomial discrete-time systems'. International Journal of Robust and Nonlinear Control. 25(15):2869-2870. https://doi.org/10.1002/rnc.3237S28692870251

Optimization Alternatives for Robust Model-based Design of Synthetic Biological Circuits

[EN] Synthetic biology is reaching the situation where tuning devices by hand is no longer possible due to the complexity of the biological circuits being designed. Thus, mathematical models need to be used in order, not only to predict the behavior of the designed synthetic devices; but to help on the selection of the biological parts, i.e., guidelines for the experimental implementation. However, since uncertainties are inherent to biology, the desired dynamics for the circuit usually requires a trade-off among several goals. Hence, a multi-objective optimization design (MOOD) naturally arises to get a suitable parametrization (or range) of the required kinetic parameters to build a biological device with some desired properties. Biologists have classically addressed this problem by evaluating a set of random Monte Carlo simulations with parameters between an operation range. In this paper, We propose solving the MOOD by means of dynamic programming using both a global multi-objective evolutionary algorithm (MOLA) and a local gradient-based nonlinear programming (NLP) solver. The performance of both alternatives is then checked in the design of a well-known biological circuit: a genetic incoherent feed-forward loop showing adaptive behavior. (C) 2016, IFAC (International Federation of Antomatic Control) Hosting by Elsevier Ltd. All rights reserved.The research leading to these results has received funding from the European Union (FP7/2007-2013 under grant agreement no604068), the Spanish Government (FEDER-CICYT DPI2011-524 28112-C04-01, DPI2014-55276-C5-1-R, DPI2015-70975-P) and the National Council of Scientific and Technologic Development of Brazil (BJT-304804/2014-2). Yadira Boada thanks also grant FPI/2013-3242 of the Universitat Politecnica de ValenciaBoada-Acosta, YF.; Pitarch Pérez, JL.; Vignoni, A.; Reynoso Meza, G.; Picó, J. (2016). Optimization Alternatives for Robust Model-based Design of Synthetic Biological Circuits. IFAC-PapersOnLine. 49(7):821-826. https://doi.org/10.1016/j.ifacol.2016.07.291S82182649

Dystrophinopathy Phenotypes and Modifying Factors in Exon 45-55 Deletion

Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-80

The outcome of boosting mitochondrial activity in alcohol-associated liver disease is organ-dependent.

BACKGROUND AND AIMS Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. APPROACH AND RESULTS C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD + /NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. CONCLUSIONS Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.This work was supported by grants from Ministerio de Ciencia e Innovación, Programa Retos-Colaboración RTC2019-007125-1 (for Jorge Simon and Maria Luz Martinez-Chantar); Ministerio de Economía, Industria y Competitividad, Retos a la Sociedad AGL2017- 86927R (for F.M.); Instituto de Salud Carlos III, Proyectos de Investigación en Salud DTS20/00138 and DTS21/00094 (for Jorge Simon and Maria Luz Martinez-Chantar, and Asis Palazon. respectively); Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias co-founded by European Regional Development Fund/European Social Fund, “Investing in your future” PI19/00819, “Una manera de hacer Europa” FIS PI20/00765, and PI21/01067 (for Jose J. G. Marin., Pau Sancho-Bru,. and Mario F. Fraga respectively); Departamento de Industria del Gobierno Vasco (for Maria Luz Martinez-Chantar); Asturias Government (PCTI) co-funding 2018-2023/ FEDER IDI/2021/000077 (for Mario F. Fraga.); Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00, CEX2021-001136-S PID2020-117941RB-I00, PID2020-11827RB-I00 and PID2019-107956RA-100 integrado en el Plan Estatal de Investigación Científica y Técnica y Innovación, cofinanciado con Fondos FEDER (for Maria Luz Martinez-Chantar, Francisco J Cubero., Yulia A Nevzorova and Asis Palazon); Ayudas Ramón y Cajal de la Agencia Estatal de Investigación RY2013-13666 and RYC2018- 024183-I (for Leticia Abecia and Asis Palazon); European Research Council Starting Grant 804236 NEXTGEN-IO (for Asis Palazon); The German Research Foundation SFB/TRR57/P04, SFB1382-403224013/ A02 and DFG NE 2128/2-1 (for Francisco J Cubero and Yulia A Nevzorova); National Institute of Health (NIH)/National Institute of Alcohol Abuse and Alcoholism (NIAAA) 1U01AA026972-01 (For Pau Sancho-Bru); Junta de Castilla y León SA074P20 (for Jose J. G. Marin); Junta de Andalucía, Grupo PAIDI BIO311 (for Franz Martin); CIBERER Acciones Cooperativas y Complementarias Intramurales ACCI20-35 (for Mario F. Fraga); Ministerio de Educación, Cultura y Deporte FPU17/04992 (for Silvia Ariño); Fundació Marato TV3 201916-31 (for Jose J. G. Marin.); Ainize Pena-Cearra is a fellow of the University of the Basque Country (UPV/ EHU); BIOEF (Basque Foundation for Innovation and Health Research); Asociación Española contra el Cáncer (Maria Luz Martinez-Chantar and Teresa C. Delgado.); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for Maria Luz Martinez-Chantar); La Caixa Foundation Program (for Maria Luz Martinez-Chantar); Proyecto Desarrollo Tecnologico CIBERehd (for Maria Luz Martinez-Chantar); Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.S

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Investigación en tecnologías de valoración funcional biomecánica para el seguimiento clínico objetivo y fiable de pacientes con prótesis de rodilla

Gomez Pellin, A.; Pedrero, J.; Pitarch Corresa, S.; Peydro De Moya, MF.; Martínez Pérez, M.; Tomás I Chenoll, J.; Caprara, G.... (2020). Investigación en tecnologías de valoración funcional biomecánica para el seguimiento clínico objetivo y fiable de pacientes con prótesis de rodilla. Innovación biomecánica en Europa. (9):1-6. http://hdl.handle.net/10251/169031S16