On Euclidean diagrams and geometrical knowledge

We argue against the claim that the employment of diagrams in Euclidean geometry gives rise to gaps in the proofs. First, we argue that it is a mistake to evaluate its merits through the lenses of Hilbert’s formal reconstruction. Second, we elucidate the abilities employed in diagram-based inferences in the Elements and show that diagrams are mathematically reputable tools. Finally, we complement our analysis with a review of recent experimental results purporting to show that, not only is the Euclidean diagram-based practice strictly regimented, it is rooted in cognitive abilities that are universally shared.; Argumentamos en contra de la afirmación de que el uso de diagramas en la geometría euclidiana da lugar a vacíos o lagunas en las pruebas. En primer lugar, mostramos que es un error evaluar sus méritos a través de las lentes de la reconstrucción formal de Hilbert. En segundo lugar, esclarecemos las habilidades empleadas en las inferencias basadas en los diagramas en los Elementos, y mostramos que los diagramas son herramientas matemáticas respetables. Finalmente, complementamos nuestro análisis con una revisión de resultados experimentales recientes que pretenden mostrar que la práctica diagramática euclidiana no solo está estrictamente regimentada, sino que también está enraizada en ciertas habilidades cognitivas universalmente compartidas

UPRmt activation improves pathological alterations in cellular models of mitochondrial diseases

Background: Mitochondrial diseases represent one of the most common groups of genetic diseases. With a prevalence greater than 1 in 5000 adults, such diseases still lack effective treatment. Current therapies are purely palliative and, in most cases, insufficient. Novel approaches to compensate and, if possible, revert mitochondrial dysfunction must be developed. Results: In this study, we tackled the issue using as a model fibroblasts from a patient bearing a mutation in the GFM1 gene, which is involved in mitochondrial protein synthesis. Mutant GFM1 fibroblasts could not survive in galactose restrictive medium for more than 3 days, making them the perfect screening platform to test several compounds. Tetracycline enabled mutant GFM1 fibroblasts survival under nutritional stress. Here we demonstrate that tetracycline upregulates the mitochondrial Unfolded Protein Response (UPR), a compensatory pathway regulating mitochondrial proteostasis. We additionally report that activation of UPR improves mutant GFM1 cellular bioenergetics and partially restores mitochondrial protein expression. Conclusions: Overall, we provide compelling evidence to propose the activation of intrinsic cellular compensatory mechanisms as promising therapeutic strategy for mitochondrial diseases.This work was supported by FIS PI16/00786 (2016) and FIS PI19/00377 (2019) grants, the Ministerio de Sanidad, Spain and the Fondo Europeo de Desarrollo Regional (FEDER Unión Europea), Spanish Ministry of Education, Culture and Sport. This activity has been co-financed by the European Regional Development Fund (ERDF) and by the Regional Ministry of Economic Transformation, Industry, Knowledge and Universities of the Junta de Andalucía, within the framework of the ERDF Andalusia operational program 2014–2020 Thematic objective "01—Reinforcement of research, technological development and innovation" through the reference research project CTS-5725 and PY18-850

Lack of replication of interactions between polymorphisms in rheumatoid arthritis susceptibility: case-control study

Introduction: Approximately 100 loci have been definitively associated with rheumatoid arthritis (RA) susceptibility. However, they explain only a fraction of RA heritability. Interactions between polymorphisms could explain part of the remaining heritability. Multiple interactions have been reported, but only the shared epitope (SE) × protein tyrosine phosphatase nonreceptor type 22 (PTPN22) interaction has been replicated convincingly. Two recent studies deserve attention because of their quality, including their replication in a second sample collection. In one of them, researchers identified interactions between PTPN22 and seven single-nucleotide polymorphisms (SNPs). The other showed interactions between the SE and the null genotype of glutathione S-transferase Mu 1 (GSTM1) in the anti-cyclic citrullinated peptide-positive (anti-CCP+) patients. In the present study, we aimed to replicate association with RA susceptibility of interactions described in these two high-quality studies. Methods: A total of 1,744 patients with RA and 1,650 healthy controls of Spanish ancestry were studied. Polymorphisms were genotyped by single-base extension. SE genotypes of 736 patients were available from previous studies. Interaction analysis was done using multiple methods, including those originally reported and the most powerful methods described. Results: Genotypes of one of the SNPs (rs4695888) failed quality control tests. The call rate for the other eight polymorphisms was 99.9%. The frequencies of the polymorphisms were similar in RA patients and controls, except for PTPN22 SNP. None of the interactions between PTPN22 SNPs and the six SNPs that met quality control tests was replicated as a significant interaction term the originally reported finding or with any of the other methods. Nor was the interaction between GSTM1 and the SE replicated as a departure from additivity in anti-CCP+ patients or with any of the other methods. Conclusions: None of the interactions tested were replicated in spite of sufficient power and assessment with different assays. These negative results indicate that whether interactions are significant contributors to RA susceptibility remains unknown and that strict standards need to be applied to claim that an interaction exists

Counteracting gradients of light and soil nutrients in the understorey of Mediterranean oak forests.

The forest canopy modifies the availability of resources (light, water, and soil nutrients) in the understorey. In this paper we analyze the relationships between woody canopy density, litter accumulation, and topsoil N and P availability in the understorey of two oak forests: one in southern Portugal and the other in southern Spain. Both forests persist on low-nutrient soils, particularly poor in P. We hypothesize that direct and indirect effects of the canopy overstorey cause opposite gradients in the availability of essential resources (light and key soil nutrients) in the understorey. In both studied forests we found significant relationships between the overall canopy density, light availability, topsoil litter accumulation, and the availability of N and P, which frequently limit plant growth. Path analysis (by Shipley’s d-sep method) showed that the available data were consistent with the proposed causal model. The average values of soil variables at the end quartiles of the light-availability gradient were compared. Results showed large differences in litter accumulation (~30×) and available-N and -P topsoil concentrations (~3×) in the Spanish forest (with the wider environmental gradient). Furthermore, P increased from the ‘very low’ range to the ‘low’ or even the ‘optimum’ range of availability (according to standard plant growth criteria), which suggests potential effects on the growth of the understorey plant species. We conclude that the counteracting gradients of the essential resources -light and nutrients- in the forest understorey resulted from direct and indirect effects of the canopy overstorey, respectively. We suggest that these counteracting effects of the woody canopy on essential resources of different nature must be considered when interpreting the patterns of understorey plant populations and communities.The spanish MEC (CGL2005-05830-C03-01-BOS, DINAMED project) and the Portuguese FCT(SFRH/BD/8322/2002 grant to SMM)supported the research.Peer reviewe

FUS-DDIT3 Prevents the Development of Adipocytic Precursors in Liposarcoma by Repressing PPARγ and C/EBPα and Activating eIF4E

FUS-DDIT3 is a chimeric protein generated by the most common chromosomal translocation t(12;16)(q13;p11) linked to liposarcomas, which are characterized by the accumulation of early adipocytic precursors. Current studies indicate that FUS-DDIT3- liposarcoma develops from uncommitted progenitors. However, the precise mechanism whereby FUS-DDIT3 contributes to the differentiation arrest remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Here we have characterized the adipocyte regulatory protein network in liposarcomas of FUS-DITT3 transgenic mice and showed that PPARgamma2 and C/EBPalpha expression was altered. Consistent with in vivo data, FUS-DDIT3 MEFs and human liposarcoma cell lines showed a similar downregulation of both PPARgamma2 and C/EBPalpha expression. Complementation studies with PPARgamma but not C/EBPalpha rescued the differentiation block in committed adipocytic precursors expressing FUS-DDIT3. Our results further show that FUS-DDIT3 interferes with the control of initiation of translation by upregulation of the eukaryotic translation initiation factors eIF2 and eIF4E both in FUS-DDIT3 mice and human liposarcomas cell lines, explaining the shift towards the truncated p30 isoform of C/EBPalpha in liposarcomas. Suppression of the FUS-DDIT3 transgene did rescue this adipocyte differentiation block. Moreover, eIF4E was also strongly upregulated in normal adipose tissue of FUS-DDIT3 transgenic mice, suggesting that overexpression of eIF4E may be a primary event in the initiation of liposarcomas. Reporter assays showed FUS-DDIT3 is involved in the upregulation of eIF4E in liposarcomas and that both domains of the fusion protein are required for affecting eIF4E expression. CONCLUSIONS/SIGNIFICANCE: Taken together, this study provides evidence of the molecular mechanisms involve in the disruption of normal adipocyte differentiation program in liposarcoma harbouring the chimeric gene FUS-DDIT3.Research in ISG group is supported partially by FEDER and by MEC (SAF2006-03726), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC Consolider-Ingenio 2010 (Ref. CSD2007-0017).Research in ISG group is supported partially by FEDER and by MEC (SAF2006-03726 and PETRI N° 95-0913.OP), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC Consolider-Ingenio 2010 (Ref. CSD2007-0017). MSM is supported by the Ramon y Cajal Scientific Spanish Program, Fondo Investigacion Sanitaria (FIS PI04-1271), Junta de Castilla y León (SA085A06) and Fundación Manuel Solorzano, University of Salamanca.Peer reviewe

Star formation in the local Universe from the CALIFA sample: I. Calibrating the SFR using integral field spectroscopy data

The star formation rate (SFR) is one of the main parameters used to analyze the evolution of galaxies through time. The need for recovering the light reprocessed by dust commonly requires the use of low spatial resolution far-infrared data. Recombination line luminosities provide an alternative, although uncertain dust-extinction corrections based on narrowband imaging or long-slit spectroscopy have traditionally posed a limit to their applicability. Integral field spectroscopy (IFS) is clearly the way to overcome this kind of limitation. Aims. We obtain integrated Hα, ultraviolet (UV) and infrared (IR)-based SFR measurements for 272 galaxies from the CALIFA survey at 0.005 <z< 0.03 using single-band and hybrid tracers. We aim to determine whether the extinction-corrected Hα luminosities provide a good measure of the SFR and to shed light on the origin of the discrepancies between tracers. Updated calibrations referred to Hα are provided. The well-defined selection criteria and large statistics allow us to carry out this analysis globally and split by properties, including stellar mass and morphological type. Methods. We derive integrated, extinction-corrected Hα fluxes from CALIFA, UV surface and asymptotic photometry from GALEX and integrated WISE 22 μm and IRAS fluxes. Results. We find that the extinction-corrected Hα luminosity agrees with the hybrid updated SFR estimators based on either UV or Hα plus IR luminosity over the full range of SFRs (0.03-20 M yr). The coefficient that weights the amount of energy produced by newly-born stars that is reprocessed by dust on the hybrid tracers, a, shows a large dispersion. However, this coefficient does not became increasingly small at high attenuations, as expected if significant highly-obscured Hα emission were missed, i.e., after a Balmer decrement-based attenuation correction is applied. Lenticulars, early-type spirals, and type-2 AGN host galaxies show smaller coefficients because of the contribution of optical photons and AGN to dust heating. Conclusions. In the local Universe, the Hα luminosity derived from IFS observations can be used to measure SFR, at least in statistically-significant, optically-selected galaxy samples, once stellar continuum absorption and dust attenuation effects are accounted for. The analysis of the SFR calibrations by galaxies properties could potentially be used by other works to study the impact of different selection criteria in the SFR values derived, and to disentangle selection effects from other physically motivated differences, such as environmental or evolutionary effects.The CALIFA collaboration also thanks the CAHA staff for the dedication to this project. C.C.-T. thanks the support of the Spanish Ministerio de Educacion, Cultura y Deporte by means of the FPU fellowship program. The authors also thank the support from the Plan Nacional de Investigacion y Desarrollo funding programs, AYA2012-30717 and AyA2013-46724P, of Spanish Ministerio de Economia y Competitividad (MINECO). P.G.P.-G. acknowledges support from the AYA2012-30717 and AYA2012-31277. J.I.P. acknowledges financial support from the Spanish MINECO under grant AYA2010-21887-C04-01 and from Junta de Andalucia Excellence Project PEX2011-FQM7058. R.A.M. is funded by the Spanish program of International Campus of Excellence Moncloa (CEI). M.A.P.T. acknowledges support from the Spanish MINECO through grant AYA2012-38491-C02-02. A.d.O. acknowledge financial support from the Spanish grant AYA2013-42227-P. Support for L.G. is provided by the Ministry of Economy, Development, and Tourism's Millennium Science Initiative through grant IC120009, awarded to The Millennium Institute of Astrophysics, MAS. L.G. acknowledges support by CONICYT through FONDECYT grant 3140566. J.M.G. acknowledges support from the Fundacao para a Ciencia e a Tecnologia (FCT) through the Fellowship SFRH/BPD/66958/2009 from FCT (Portugal) and POPH/FSE (EC) by FEDER funding through the program Programa Operacional de Factores de Competitividade (COMPETE). J.M.G. also acknowledges support by FCT under project FCOMP-01-0124-FEDER- 029170 (Reference FCT PTDC/FIS-AST/3214/2012), funded by FCT-MEC (PIDDAC) and FEDER (COMPETE).Peer Reviewe

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Introduction: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. Methods: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. Results: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. Conclusion: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes

Validation Study Of Genetic Biomarkers Of Response To Tnf Inhibitors In Rheumatoid Arthritis

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi

Quantum Gravity in 2+1 Dimensions: The Case of a Closed Universe

In three spacetime dimensions, general relativity drastically simplifies, becoming a ``topological'' theory with no propagating local degrees of freedom. Nevertheless, many of the difficult conceptual problems of quantizing gravity are still present. In this review, I summarize the rather large body of work that has gone towards quantizing (2+1)-dimensional vacuum gravity in the setting of a spatially closed universe.Comment: 61 pages, draft of review for Living Reviews; comments, criticisms, additions, missing references welcome; v2: minor changes, added reference