A FRET-based cGMP biosensor in Drosophila

CUTie2 is a FRET-based cGMP biosensor tested so far only in cells. To expand its use to multicellular organisms we generated two transgenic Drosophila melanogaster strains that express the biosensor in a tissue-dependent manner. CUTie2 expression and subcellular localization was verified by confocal microscopy. The performance of CUTie2 was analyzed on dissected larval brains by hyperspectral microscopy and flow cytometry. Both approaches confirmed its responsivity, and the latter showed a rapid and reversible change in the fluorescence of the FRET acceptor upon cGMP treatment. This validated reporter system may prove valuable for studying cGMP signaling at organismal level.Agencia Nacional de Investigación e InnovaciónDirección Nacional de Innovación, Ciencia y Tecnologí

Efficacy and Safety of Anakinra Plus Standard of Care for Patients With Severe COVID-19: A Randomized Phase 2/3 Clinical Trial

Efficacy; Safety; COVID-19Eficacia; Seguridad; COVID-19Eficàcia; Seguretat; COVID-19Importance COVID-19 pneumonia is often associated with hyperinflammation. The efficacy and safety of anakinra in treating patients with severe COVID-19 pneumonia and hyperinflammation are still unclear. Objective To assess the efficacy and safety of anakinra vs standard of care alone for patients with severe COVID-19 pneumonia and hyperinflammation. Design, Setting, and Participants The Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to COVID-19 (ANA-COVID-GEAS) was a multicenter, randomized, open-label, 2-group, phase 2/3 clinical trial conducted at 12 hospitals in Spain between May 8, 2020, and March 1, 2021, with a follow-up of 1 month. Participants were adult patients with severe COVID-19 pneumonia and hyperinflammation. Hyperinflammation was defined as interleukin-6 greater than 40 pg/mL, ferritin greater than 500 ng/mL, C-reactive protein greater than 3 mg/dL (rationale, ≥5 upper normal limit), and/or lactate dehydrogenase greater than 300 U/L. Severe pneumonia was considered if at least 1 of the following conditions was met: ambient air oxygen saturation 94% or less measured with a pulse oximeter, ratio of partial pressure O2 to fraction of inspired O2 of 300 or less, and/or a ratio of O2 saturation measured with pulse oximeter to fraction of inspired O2 of 350 or less. Data analysis was performed from April to October 2021. Interventions Usual standard of care plus anakinra (anakinra group) or usual standard of care alone (SoC group). Anakinra was given at a dose of 100 mg 4 times a day intravenously. Main Outcomes and Measures The primary outcome was the proportion of patients not requiring mechanical ventilation up to 15 days after treatment initiation, assessed on an intention-to-treat basis. Results A total of 179 patients (123 men [69.9%]; mean [SD] age, 60.5 [11.5] years) were randomly assigned to the anakinra group (92 patients) or to the SoC group (87 patients). The proportion of patients not requiring mechanical ventilation up to day 15 was not significantly different between groups (64 of 83 patients [77.1%] in the anakinra group vs 67 of 78 patients [85.9%] in the SoC group; risk ratio [RR], 0.90; 95% CI, 0.77-1.04; P = .16). Anakinra did not result in any difference in time to mechanical ventilation (hazard ratio, 1.72; 95% CI, 0.82-3.62; P = .14). There was no significant difference between groups in the proportion of patients not requiring invasive mechanical ventilation up to day 15 (RR, 0.99; 95% CI, 0.88-1.11; P > .99). Conclusions and Relevance In this randomized clinical trial, anakinra did not prevent the need for mechanical ventilation or reduce mortality risk compared with standard of care alone among hospitalized patients with severe COVID-19 pneumonia.Funding for this study was received from the Regional Government of Navarra, Spain (project 0011-3597-2020-000028 to Dr Fanlo), and drugs were provided by the company Swedish Orphan Biovitrum (Sobi)

Exploring the Interplay between Cellular Senescence, Immunity, and Fibrosing Interstitial Lung Diseases: Challenges and Opportunities

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs

The fast declining Type Ia supernova 2003gs, and evidence for a significant dispersion in near-infrared absolute magnitudes of fast decliners at maximum light

We obtained optical photometry of SN 2003gs on 49 nights, from 2 to 494 days after T(B_max). We also obtained near-IR photometry on 21 nights. SN 2003gs was the first fast declining Type Ia SN that has been well observed since SN 1999by. While it was subluminous in optical bands compared to more slowly declining Type Ia SNe, it was not subluminous at maximum light in the near-IR bands. There appears to be a bimodal distribution in the near-IR absolute magnitudes of Type Ia SNe at maximum light. Those that peak in the near-IR after T(B_max) are subluminous in the all bands. Those that peak in the near-IR prior to T(B_max), such as SN 2003gs, have effectively the same near-IR absolute magnitudes at maximum light regardless of the decline rate Delta m_15(B). Near-IR spectral evidence suggests that opacities in the outer layers of SN 2003gs are reduced much earlier than for normal Type Ia SNe. That may allow gamma rays that power the luminosity to escape more rapidly and accelerate the decline rate. This conclusion is consistent with the photometric behavior of SN 2003gs in the IR, which indicates a faster than normal decline from approximately normal peak brightness.Comment: 41 pages, 13 figures, to be published in the December, 2009, issue of the Astronomical Journa

Controlled Magnetic Anisotropy in Single Domain Mn-doped Biosynthesized Nanoparticles

Magnetotactic bacteria Magnetospirillum gryphiswaldense synthesize cubo-octahedral shaped magnetite nanoparticles, called magnetosomes, with a mean diameter of 40 nm. The high quality of the biosynthesized nanoparticles makes them suitable for numerous applications in fields like cancer therapy, among others. The magnetic properties of magnetite magnetosomes can be tailored by doping them with transition metal elements, increasing their potential applications. In this work, we address the effect of Mn doping on the main properties of magnetosomes by the combination of structural and magnetic characterization techniques. Energy-dispersive X-ray spectroscopy, X-ray absorption nearedge structure, and X-ray magnetic circular dichroism results reveal a Mn dopant percentage of utmost 2.3%, where Mn cations are incorporated as a combination of Mn2+ and Mn3+, preferably occupying tetrahedral and octahedral sites, respectively. Fe substitution by Mn notably alters the magnetic behavior of the doped magnetosomes. Theoretical modeling of the experimental hysteresis loops taken between 5 and 300 K with a modified Stoner-Wohlfarth approach highlights the different anisotropy contributions of the doped magnetosomes as a function of temperature. In comparison with the undoped magnetosomes, Mn incorporation alters the magnetocrystalline anisotropy introducing a negative and larger cubic anisotropy down to the Verwey transition, which appears shifted to lower temperature values as a consequence of Mn doping. On the other hand, Mn-doped magnetosomes show a decrease in the uniaxial anisotropy in the whole temperature range, most likely associated with a morphological modification of the Mn-doped magnetosomes.The Spanish and Basque Governments are acknowledged for funding under project numbers MAT2017- 83631-C3-R and IT-1245-19, respectively

Methylation and Transcriptome Signatures of Monocytes Reveal Novel Pathways Involved in Giant Cell Arteritis Pathogenesis.

Congresos y Conferencias: Comunicación de Congreso - Oral

Transcriptomic and methylomic profiling of CD4+ T-cells in giant cell arteritis with different disease activity.

Comunicación, Congreso, Póster

LOS PERFILES DE METILACIÓN Y EXPRESIÓN GÉNICA DE MONOCITOS REVELAN NUEVAS VÍAS IMPLICADAS EN LA PATOGÉNESIS DE LA ARTERITIS DE CÉLULAS.

Congresos y Conferencias: Comunicación de Congreso - Póster

Vertebral fracture risk in glucocorticoid-induced osteoporosis: the role of hypogonadism and corticosteroid boluses

Objective: The aim of this study was to identify the risk factors associated with fragility fracture (FF) development in glucocorticoid (GC)-treated patients. Methods: 127 patients (aged 62±18 years, 63% women) on GC-treatment (mean dose 14.5±14.1 mg/day and duration 47.7±69 months) were included. The clinical data collected included bone metabolism study (including gonadal axis), GC-treatment, disease activity, dual-energy X-ray absorptiometry analysis (evaluating densitometric osteoporosis (OP) and trabecular bone score (TBS) degraded microarchitecture values (DMA)), X-ray (assessing vertebral fractures (VF)), FRAX risk (GC-adjusted) and previous FF. Results: 17% of the patients had VF, 28% FF (VF and/or non-VF), 29% OP and 52% DMA. Patients with VF received more GC boluses (57.1% vs 29.5%, p=0.03), were older (68±13 vs 60±19 years, p=0.02), postmenopausal (100% vs 67%, p=0.02), had low testosterone levels (57% vs 11%, p=0.02), lower TBS values (1.119±0.03 vs 1.237±0.013, p100, p=0.01) and having received GC boluses (OR 3.45; 95% CI 1.04 to 12.15, p=0.01) were the main factors related to VF. Hypogonadism (OR 7.03; 95% CI 1.47 to 38.37, p=0.01) and FRAX >20 (OR 7.08; 95% CI 1.28 to 53.71, p=0.02) were factors related to FF. Conclusion: Hypogonadism is the principal risk factor for developing fractures in GC-treated men and women, whereas receiving GC boluses is a major factor for VF. These results indicate the importance of evaluating the gonadal axis in these patients

BSA-capped gold nanoclusters as potential theragnostic for skin diseases: Photoactivation, skin penetration, in vitro, and in vivo toxicity

BSA-capped gold nanoclusters are promising theragnostic systems that can be excited to render both fluorescence emission and reactive oxygen species. Although their synthesis and photoluminescence properties are already well described, more accurate information about their use as photosensitizers is required in order to advance towards health applications. In this work, we have obtained BSA-capped gold nanoclusters and characterized their photophysics by different techniques. Singlet oxygen production was detected upon irradiation, which was enough to produce toxicity on two cell lines. Remarkably, an internal energy transfer, probably due to the presence of smaller nanoclusters and the contribution of oxidized residues of BSA in the system, caused fluorescence emission near 640 nm after excitation in the UV range. Additionally, the system was capable of penetrating human skin beyond the stratum corneum, which enhances the potential of these nanoclusters as bifunctional photodynamic therapy effectors and biomarkers with application in a diversity of skin diseases. In the absence of radiation, BSA-capped gold nanoclusters did not cause toxicity in vitro, while their toxic effect on an in vivo model as zebrafish was determined.Fil: Lillo, Rolando Cristian Rodrigo. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Calienni, Maria Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Rivas Aiello, Maria Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Prieto, Maria Jimena. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Rodriguez, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Tuninetti, Jimena Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Toledo, Pamela Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Alonso, Silvia del Valle. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Moya, Sergio Enrique. Centro de Investigación Cooperativa en Biomateriales; España. Centro de Investigación Cooperativa en Biomateriales; EspañaFil: Gonzalez, Monica Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; ArgentinaFil: Martinetti Montanari, Jorge Anibal. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB | Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular. Grupo Vinculado al IMBICE - Grupo de Biología Estructural y Biotecnología - Universidad Nacional de Quilmes - GBEyB; ArgentinaFil: Soler Illia, Galo Juan de Avila Arturo. Universidad Nacional de San Martin. Instituto de Nanosistemas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin