Resultados de investigación

Many-body interactions in water are known to be important but difficult to treat in atomistic models and often are included only as a correction. Polarizable models treat them explicitly, with long-range many-body potentials, within their classical approximation. However, their calculation is computationally expensive. Here, we evaluate how relevant the contributions to the many-body interaction associated with different coordination shells are. We calculate the global energy minimum, and the corresponding configuration, for nanoclusters of up to 20 water molecules. We find that including the first coordination shell, i.e., the five-body term of the central molecule, is enough to approximate within 5% the global energy minimum and its structure. We show that this result is valid for three different polarizable models, the Dang–Chang, the MB-pol, and the Kozack–Jordan potentials. This result suggests a strategy to develop many-body potentials for water that are reliable and, at the same time, computationally efficient., Peer reviewed

Supplemental Figure S1. Characterization of 35S:FBN6-RFP lines.-- Supplemental Table S1. Primers used in this work.-- Supplemental Table S2. Phytoene levels in control and NFZ-treated N. benthamiana leaves agroinfiltrated with FBN6 and/or PSY constructs.-- Supplemental Table S3. Photosynthetic pigment levels in N. benthamiana leaves agroinfiltrated with FBN6, PSY, and/or crtB constructs.-- Supplemental Table S4. Photosynthetic pigment levels in etiolated and de-etiolating WT and fbn6 Arabidopsis seedlings.-- Supplemental Table S5. Photosynthetic pigment levels in WT and fbn6 Arabidopsis seedlings exposed to HL., Carotenoids are health-promoting plastidial isoprenoids with essential functions in plants as photoprotectants and photosynthetic pigments in chloroplasts. They also accumulate in specialized plastids named chromoplasts, providing color to non-photosynthetic tissues such as flower petals and ripe fruit. Carotenoid accumulation in chromoplasts requires specialized structures and proteins such as fibrillins (FBNs). The FBN family includes structural components of carotenoid sequestering structures in chromoplasts and members with metabolic roles in chloroplasts and other plastid types. However, the association of FBNs with carotenoids in plastids other than chromoplasts has remained unexplored. Here, we show that Arabidopsis (Arabidopsis thaliana) FBN6 interacts with phytoene synthase (PSY), the first enzyme of the carotenoid pathway. FBN6, but not FBN4 (a FBN that does not interact with PSY), enhances the activity of plant PSY (but not of the bacterial PSY crtB) in Escherichia coli cells. Overexpression of FBN6 in Nicotiana benthamiana leaves results in a higher production of phytoene, the product of PSY activity, whereas loss of FBN6 activity in Arabidopsis mutants dramatically reduces the production of carotenoids during seedling de-etiolation and after exposure to high light. Our work hence demonstrates that FBNs promote not only the accumulation of carotenoids in chromoplasts but also their biosynthesis in chloroplasts., This work was funded by grants from Spanish MCIN/AEI/10.13039/501100011033 and European NextGeneration EU/PRTR and PRIMA programs to M.R.-C. (PID2020-115810GB-I00 and UToPIQ-PCI2021-121941). M.R.-C. is also supported by Generalitat Valenciana (PROMETEU/2021/056 and AGROALNEXT/2022/067). Our group is a member of CaRed (Spanish Carotenoid Network) funded by MCIN/AEI (RED2022-134577-T). A.I.-S. and J.N.-C. received predoctoral fellowships from MCIN/AEI (PRE2018-083610 and PRE2021-098681, respectively)., Peer reviewed

This dataset presents the decapod species and abundance, along with the habitat (detached seagrass leaves, fine fraction of detritus, detrital macroalgae, organic matter in sediments, seagrass shoot density and height of unburried rhizomes), landscape (landscape configuration) and geographical attributes (inlet aperture and confinement) in Posidonia oceanica seagrass meadows in 5 localities accross the NW Mediterranean sea. We found that geographical level attributes (i.e., inlet aperture, confinement) affected the most the decapod assemblages, while we only found a modest contribution from habitat (e.g., detritus biomass, sediment organic matter) and landscape attributes (e.g. fragmentation). We suggest that decapod assemblages are driven by the interaction of multiple processes occurring at different scales and other highly stochastic phenomena such as larval dispersion and recruitment, This study was supported financially by the Spanish government (projects CTM2010-22273-C02-01 and CTM2013-48027-C3-1-R). The Spanish government also supported AMR (scholarship BES-2011-046849), Table 1. Decapod species and number of total individuals of 5 randomly selected quadrat (40 cm x 40 cm) found in Aiguablava (Ag), Rustella (Ru), Giverola (Gi, Cativa (Ca) and Portlligat (Po) in continuous seagrass meadows of Posidonia oceanica (CO), patches in sand matrix (PS) and patches in rock matrix (PR). Table 2. Habitat attributes and geographical attributes of 5 randomly selected quadrat (40 cm x 40 cm) found in Aiguablava (Ag), Rustella (Ru), Giverola (Gi, Cativa (Ca) and Portlligat (Po) in continuous seagrass meadows of Posidonia oceanica (CO), patches in sand matrix (PS) and patches in rock matrix (PR), Peer reviewed

S1 Previous Results on Coordination Games.-- S2 Defrost of Frozen Configurations.-- S3 Probability Distributions: Size and Number of Fragments.-- S4 Fragmentation Transition in a General Coordination Game.-- S5 Evolution of the Transition Line (UI rule).-- S6 Cases ⟨k⟩ = 10, 20.--, Peer reviewed

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)., MOMAST® is a patented natural phenolic complex, rich in tyrosol (9.0 g/kg, Tyr), hydroxityrosol (43,5 g/kg, OH-Tyr), and verbascoside (5.0 g/Kg), which is obtained from the OVW by-product of the Coratina cultivar with potent direct antioxidant activity (measured by DPPH and FRAP assays, respectively). Indeed, MOMAST® represents an innovative sustainable bioactive ingredient which has been obtained with ethical and empowering behavior by applying the principles of a circular economy. In the framework of research aimed at fostering its health-promoting activity, in this study it was clearly demonstrated that MOMAST® treatment reduced the oxidative stress and levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, and increased the HDL levels, without changes in the triglyceride (TG) levels in Western diet (WD)-fed mice. The modulation of the plasmatic lipid profile is similar to red yeast rice (RYR) containing Monacolin K (3%). In addition, at the molecular level in liver homogenates, similarly to RYR, MOMAST® exerts cholesterol-lowering activity through the activation of LDL receptor, whereas, unlike RYR, MOMAST® reduces proprotein convertase subtilisin/kexin type 9 (PCSK9) protein levels via hepatic nuclear factor 1 (HNF1)-α activation. Hence, this study provides the proof of concept regarding the hypocholesterolemic activity of MOMAST, which could be successfully exploited as an active ingredient for the development of innovative and sustainable dietary supplements and functional foods., This research was funded by Bioenutra S.R.L. (Ginosa (TA) Italy) and Fundación de Investigación de la Universidad de Sevilla-FIUS (4588/0401). G.S.-S. was supported by a FPU grant from the Spanish Ministerio de Educación, Cultura y Deporte (FPU16/02339). E.P.-E. was supported by the VI Program of Inner Initiative for Research and Transfer of University of Seville (VI PPIT-US). I.C.-C. was supported by a postdoctoral fellowship from the Andalusian Government Ministry of Economy, Knowledge, Business, and University (DOC_00587/2020)., Peer reviewed

Peer reviewed

Supplementary Figures: Supplementary Figure 1. Evaluation of the specificity of the detection reagents for the identification of academic CAR-T cells by flow cytometry.-- Supplementary figure 2. Evaluation of the specificity of the detection reagents for the identification of commercial CAR-T cells by flow cytometry.-- Supplementary Figure 3. Commercial CD19 CAR-T cell expansion in the blood of patients with lymphoma.-- Supplementary Figure 4. Comparison of the expansion dynamics of different commercial CD19 CAR-T cell products.-- Supplementary Figure 5. Immunophenotype characterization of non-modified T cells and CAR-T cells at the time of peak expansion in blood of patients with lymphoma.-- Supplementary Figure 6. Immunophenotype characterization of non-modified T cells and CAR-T cells at the time of peak expansion in blood of patients infused with Tisa-cel vs Axi-cel.-- Supplementary Figure 7. Comparison of T cell subsets between leukapheresis and non-modified T and CAR-T cells at the time of peak expansion.-- Supplementary Figure 8. Quantitative determination of the TCR Vβ repertoire of human T lymphocytes by flow cytometry.-- Supplementary Figure 9. Correlation between CAR-T cell expansion in blood of patients with lymphoma and toxicity or response.-- Supplementary Figure 10. Comparison of the toxicity and efficacy of Tisa-cel and Axi-cel products. // Supplementary Table 1. Flow cytometry reagents for the validation of the detection and immune-phenotype characterization of academic and commercial CD19 CAR-T cells, Purpose: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes., Experimental design: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed., Results: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control., Conclusions: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy., This work has been supported by the Instituto de Salud Carlos III (ISCIII), Project RD21/0017/0021, Red Española de Terapias Avanzadas TERAV funded by European Union-NextGenerationEU. “Plan de Recuperación Transformación y Resiliencia” and Consejería de Salud y Familia, Junta de Andalucía PECART-0185-2020-7, PECART-0185-2020 CSYF 2021 – Proyectos Fondos FEDER. Proyectos estratégicos en Investigación en CAR-T. “Monitorización inmune tras tratamiento con células CAR-T: búsqueda de biomarcadores y medición de la actividadmetabólica como predictores de respuesta”., Peer reviewed

Supplementary_File_1_HP1_peaks Supplementary_File_2_HP1_gene_tissues Supplementary_File_3_Overlapping between HP1 bound genes with tissue-specific genes Supplementary_File_4_Overlapping between tissue-specific genes bound by HP1 proteins Supplemental Figures and Tables, Peer reviewed

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data., Additional figures (S1-S7) and tables (S1-S2)., Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V–VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD., This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI18/01556 and PI21/00914 (to JV) and PI18/01557 and PI21/00915 (to AG); by Junta de Andalucia Consejería de Economía y Conocimiento through grants US-1262734 and P20-00843 (to JV), UMA18-FEDERJA-211 (to AG) and PI18-RT-2233 (to AG) co-financed by Programa Operativo FEDER 2014-2020; by Spanish Minister of Science and Innovation grant PID2019-108911RA-100 (to DBV), Beatriz Galindo Program BAGAL18/00052 (to DBV), grant PID2019-107090RA-I00 (to IMG) and Ramon y Cajal Program RYC-2017-21879 (to IMG); and by Malaga University grant B-2019_06 (to ESM)., Peer reviewed

Table 1: Examples of feedback from clinicians in relation to dominant themes from analysis of model evaluation., Background: Post-infarct ventricular septal defect (PIVSD) is a serious complication of myocardial infarction. We evaluated 3D-printing models in PIVSD clinical assessment and the feasibility of statistical shape modeling for morphological analysis of the defects. Methods: Models (n = 15) reconstructed from computed tomography data were evaluated by clinicians (n = 8). Statistical shape modeling was performed on 3D meshes to calculate the mean morphological configuration of the defects. Results: Clinicians’ evaluation highlighted the models’ utility in displaying defects for interventional/surgical planning, education/training and device development. However, models lack dynamic representation. Morphological analysis was feasible and revealed oval-shaped (n = 12) and complex channel-like (n = 3) defects. Conclusion: 3D-PIVSD models can complement imaging data for teaching and procedural planning. Statistical shape modeling is feasible in this scenario., The authors gratefully acknowledge the support of the British Heart Foundation (CH/17/1/32804), the Bristol BHF Accelerator Award (AA/18/1/34219), The Grand Appeal (Bristol Children’s Hospital Charity), and the Bristol National Institute for Health Research (NIHR) Biomedical Research Centre (BRC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., Peer reviewed