1,121 results on '"Cava Antonio"'
Search Results
2. CAR immunotherapy in autoimmune diseases: promises and challenges.
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Yu, Jingjing, Yang, Yiming, Gu, Zhanjing, Shi, Min, La Cava, Antonio, and Liu, Aijing
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CAR-T cells ,T regulatory cells ,autoimmune diseases ,double-negative T cells ,immunotherapy ,natural killer cells ,γδ T cells ,Humans ,Immunotherapy ,Adoptive ,Autoimmune Diseases ,Receptors ,Chimeric Antigen ,Animals ,T-Lymphocytes - Abstract
In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkins lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögrens syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed.
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- 2024
3. Low-dose interleukin-2 therapy in systemic lupus erythematosus.
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La Cava, Antonio
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T regulatory cells ,interleukin-2 ,low-dose IL-2 ,systemic lupus erythematosus - Abstract
In systemic lupus erythematosus (SLE), T regulatory cells (Tregs) contribute to the inhibition of autoimmune responses by suppressing self-reactive immune cells. Interleukin (IL)-2 plays an essential role in the generation, function and homeostasis of the Tregs and is reduced in SLE. Several clinical studies, including randomized trials, have shown that low-dose IL-2 therapy in SLE patients is safe and effective and can reduce disease manifestations. This review discusses the rationale for the use of low-dose IL-2 therapy in SLE, the clinical responses in patients, and the effects of this therapy on different types of T cells. Considerations are made on the current and future directions of use of low-dose IL-2 regimens in SLE.
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- 2023
4. The draft genomes of Crassostrea gasar and Crassostrea rhizophorae: key resources for leveraging oyster cultivation in the Southwest Atlantic
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Lima, Nicholas Costa Barroso, de Almeida, Luiz Gonzaga Paula, Bainy, Afonso Celso Dias, Gerber, Alexandra Lehmkuhl, de Campos Guimarães, Ana Paula, Solé-Cava, Antonio Mateo, de Melo, Claudio Manoel Rodrigues, Lazoski, Cristiano, Zacchi, Flávia Lucena, Henning, Frederico, Soares, Leticia Maria Monteiro, Soares, Rafaela Guilherme, and Ribeiro Vasconcelos, Ana Tereza
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- 2024
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5. Southern marsh deer (Blastocerus dichotomus) populations assessed using Amplicon Sequencing on fecal samples
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Wolfenson, Laura I., Pereira, Javier A., Ruzzante, Daniel E., Solé-Cava, Antonio M., McCracken, Gregory R., Gómez-Fernández, María J., Pereyra, María D., and Mirol, Patricia M.
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- 2024
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6. Mitochondrial genome structure and composition in 70 fishes: a key resource for fisheries management in the South Atlantic
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Alvarenga, Marcela, D’Elia, Ananda Krishna Pereira, Rocha, Graciane, Arantes, Clara Alvarez, Henning, Frederico, de Vasconcelos, Ana Tereza Ribeiro, and Solé-Cava, Antonio Mateo
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- 2024
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7. Equivalent width Measurements in Optical Spectra of Galaxies in Local Clusters: Hints On the Star Formation History in Clusters
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Fritz Jacopo, Poggianti Bianca M., Cava Antonio, and Moretti Alessia
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galaxies ,classification ,starburst ,clusters ,Astronomy ,QB1-991 - Abstract
Equivalent widths of spectral lines in the optical spectra of galaxies are commonly used to characterize their stellar populations and to get some insight on their evolution. Here we describe a new method to measure automatically equivalent widths of spectral lines with a good accuracy. This makes possible to classify galaxies according to the presence/absence and intensity of [O II] and Hδ lines. Based on these classification criteria, we give a description of the characteristics of the star-forming and post-starburst galaxies in local clusters, and their dependence on the cluster characteristics.
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- 2011
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8. Fifteen years of elasmobranchs trade unveiled by DNA tools: Lessons for enhanced monitoring and conservation actions
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Alvarenga, Marcela, Bunholi, Ingrid Vasconcellos, de Brito, Gustavo Reis, Siqueira, Marcos Vinícius Bohrer Monteiro, Domingues, Rodrigo Rodrigues, Charvet, Patricia, Foresti, Fausto, Solé-Cava, Antonio Mateo, and da Cruz, Vanessa Paes
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- 2024
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9. MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity.
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Gelzo, Monica, Castaldo, Alice, Giannattasio, Antonietta, Scalia, Giulia, Raia, Maddalena, Esposito, Maria, Maglione, Marco, Muzzica, Stefania, DAnna, Carolina, Grieco, Michela, Tipo, Vincenzo, La Cava, Antonio, and Castaldo, Giuseppe
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MIS-C ,autoimmune diseases ,autoinflammatory diseases ,cytokines ,flow cytometry ,Child ,Humans ,COVID-19 ,Interleukin-10 ,SARS-CoV-2 ,Interleukin-17 ,Interleukin-6 ,RNA ,Viral ,Cytokines ,Immunologic Deficiency Syndromes ,Autoimmune Diseases ,Biomarkers ,Autoantigens ,Guanine Nucleotide Exchange Factors - Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.
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- 2022
10. ALMA 1.3 mm Survey of Lensed Submillimeter Galaxies (SMGs) Selected by Herschel: Discovery of Spatially Extended SMGs and Implications
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Sun, Fengwu, Egami, Eiichi, Rawle, Timothy D., Walth, Gregory L., Smail, Ian, Dessauges-Zavadsky, Miroslava, Perez-Gonzalez, Pablo G., Richard, Johan, Combes, Francoise, Ebeling, H., Pello, Roser, van der Werf, Paul P., Altieri, B., Boone, Frederic, Cava, Antonio, Chapman, Scott C., Clement, Benjamin, Finoguenov, Alexis, Nakajima, Kimihiko, Rujopakarn, Wiphu, Schaerer, Daniel, and Valtchanov, Ivan
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Astrophysics - Astrophysics of Galaxies - Abstract
We present an ALMA 1.3 mm (Band 6) continuum survey of lensed submillimeter galaxies (SMGs) at $z=1.0\sim3.2$ with an angular resolution of $\sim0.2$". These galaxies were uncovered by the Herschel Lensing Survey (HLS), and feature exceptionally bright far-infrared continuum emission ($S_\mathrm{peak} \gtrsim 90$ mJy) owing to their lensing magnification. We detect 29 sources in 20 fields of massive galaxy clusters with ALMA. Using both the Spitzer/IRAC (3.6/4.5 $\mathrm{\mu m}$) and ALMA data, we have successfully modeled the surface brightness profiles of 26 sources in the rest-frame near- and far-infrared. Similar to previous studies, we find the median dust-to-stellar continuum size ratio to be small ($R_\mathrm{e,dust}/R_\mathrm{e,star} = 0.38\pm0.14$) for the observed SMGs, indicating that star formation is centrally concentrated. This is, however, not the case for two spatially extended main-sequence SMGs with a low surface brightness at 1.3 mm ($\lesssim 0.1$ mJy arcsec$^{-2}$), in which the star formation is distributed over the entire galaxy ($R_\mathrm{e,dust}/R_\mathrm{e,star}>1$). As a whole, our SMG sample shows a tight anti-correlation between ($R_\mathrm{e,dust}/R_\mathrm{e,star}$) and far-infrared surface brightness ($\Sigma_\mathrm{IR}$) over a factor of $\simeq$ 1000 in $\Sigma_\mathrm{IR}$. This indicates that SMGs with less vigorous star formation (i.e., lower $\Sigma_\mathrm{IR}$) lack central starburst and are likely to retain a broader spatial distribution of star formation over the whole galaxies (i.e., larger $R_\mathrm{e,dust}/R_\mathrm{e,star}$). The same trend can be reproduced with cosmological simulations as a result of central starburst and potentially subsequent "inside-out" quenching, which likely accounts for the emergence of compact quiescent galaxies at $z\sim2$., Comment: 32 pages, 18 figures, 4 tables. Accepted for publication in ApJ
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- 2021
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11. Nanoparticle-mediated Delivery of IL-2 To T Follicular Helper Cells Protects BDF1 Mice from Lupus-like Disease.
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Ferretti, Concetta, Horwitz, David, Bickerton, Sean, and La Cava, Antonio
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T cells ,T follicular helper (TFH) cells ,autoimmunity ,systemic lupus erythematosus - Abstract
We recently reported that poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) loaded with interleukin (IL)-2 and targeted to T cells inhibited the development of lupus-like disease in BDF1 mice by inducing functional T regulatory cells (Tregs). Here we show that the protection from disease and the extended survival of BDF1 mice provided by IL-2-loaded NPs targeted to T cells is not only due to an induction of Tregs but also contributed by an inhibition of T follicular helper (TFH) cells. These results identify a dual protective activity of IL-2 in the control of lupus autoimmunity, namely the inhibition of effector TFH cells, in addition to the previously known induction of Tregs. This newly recognized activity of IL-2 delivered by NPs can help better explain the beneficial effects of low-dose IL-2 immunotherapy in systemic lupus erythematosus (SLE), and might be considered as a new strategy to slow disease progression and improve outcomes in lupus patients.
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- 2021
12. The pleiotropic roles of leptin in metabolism, immunity, and cancer.
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de Candia, Paola, Prattichizzo, Francesco, Garavelli, Silvia, Alviggi, Carlo, La Cava, Antonio, and Matarese, Giuseppe
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Animals ,Energy Metabolism ,Gene Expression Regulation ,Homeostasis ,Humans ,Inflammation ,Leptin ,Mutation ,Neoplasms ,Obesity - Abstract
The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.
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- 2021
13. Systemic Lupus Erythematosus and Coronavirus Disease 2019.
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Cava, Antonio
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coronavirus disease 2019 ,systemic lupus erythematosus - Abstract
Coronavirus disease 2019 (COVID-19) is a contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It manifests with variable clinical pictures ranging from asymptomatic to mild or uncomplicated illness to severe disease with possible multi-organ involvement, with respiratory and vascular systems being the most often affected. Since COVID-19 can affect patients with autoimmune rheumatic conditions, the concomitant presence of two diseases may have clinical characteristics whose knowledge may help facilitate clinical management. This review discusses the data available in the literature on COVID-19 in systemic lupus erythematosus (SLE) patients.
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- 2021
14. Nanoparticles Engineered as Artificial Antigen-Presenting Cells Induce Human CD4+ and CD8+ Tregs That Are Functional in Humanized Mice.
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Giang, Sophia, Horwitz, David, Bickerton, Sean, and La Cava, Antonio
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T cells ,T regulatory cells ,autoimmunity ,graft-versus-host disease ,humanized mice ,immune tolerance ,nanoparticles ,systemic lupus erythematosus ,Animals ,Antigen-Presenting Cells ,CD8-Positive T-Lymphocytes ,Cell Differentiation ,Cell Proliferation ,Cells ,Cultured ,Disease Models ,Animal ,Forkhead Transcription Factors ,Graft vs Host Disease ,Humans ,Interleukin-2 ,Leukocytes ,Mononuclear ,Mice ,Inbred NOD ,Mice ,SCID ,Nanoparticles ,Polylactic Acid-Polyglycolic Acid Copolymer ,Proof of Concept Study ,T-Lymphocytes ,Regulatory ,Transforming Growth Factor beta ,Mice - Abstract
Artificial antigen-presenting cells (aAPCs) are synthetic versions of naturally occurring antigen-presenting cells (APCs) that, similar to natural APCs, promote efficient T effector cell responses in vitro. This report describes a method to produce acellular tolerogenic aAPCs made of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and encapsulating IL-2 and TGF-β for a paracrine release to T cells. We document that these aAPCs can induce both human CD4+ and CD8+ T cells to become FoxP3+ T regulatory cells (Tregs). The aAPC NP-expanded human Tregs are functional in vitro and can modulate systemic autoimmunity in vivo in humanized NSG mice. These findings establish a proof-of-concept to use PLGA NPs as aAPCs for the induction of human Tregs in vitro and in vivo, highlighting the immunotherapeutic potential of this targeted approach to repair IL-2 and/or TGF-β defects documented in certain autoimmune diseases such as systemic lupus erythematosus.
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- 2021
15. DNA vaccine encoding heat shock protein 90 protects from murine lupus
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Liu, Aijing, Shi, Fu-Dong, Cohen, Irun R, Castaldo, Giuseppe, Matarese, Giuseppe, Quintana, Francisco J, and La Cava, Antonio
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Biomedical and Clinical Sciences ,Immunology ,Prevention ,Immunization ,Kidney Disease ,Biotechnology ,Vaccine Related ,Autoimmune Disease ,Clinical Research ,Lupus ,Prevention of disease and conditions ,and promotion of well-being ,3.4 Vaccines ,Inflammatory and immune system ,Animals ,Autoantibodies ,Disease Models ,Animal ,Heat-Shock Proteins ,Lupus Erythematosus ,Systemic ,Mice ,Mice ,Inbred NZB ,Vaccines ,DNA ,Systemic lupus erythematosus ,Heat shock proteins ,DNA vaccine ,Autoimmunity ,T regulatory cells ,Clinical Sciences ,Public Health and Health Services ,Arthritis & Rheumatology ,Clinical sciences - Abstract
BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice.Methods(NZB x NZW)F1 (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria.ResultsVaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs).ConclusionsThe beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.
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- 2020
16. Molecular clouds in the Cosmic Snake normal star-forming galaxy 8 billion years ago
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Dessauges-Zavadsky, Miroslava, Richard, Johan, Combes, Françoise, Schaerer, Daniel, Rujopakarn, Wiphu, Mayer, Lucio, Cava, Antonio, Boone, Frédéric, Egami, Eiichi, Kneib, Jean-Paul, Pérez-González, Pablo G., Pfenniger, Daniel, Rawle, Tim D., Teyssier, Romain, and van der Werf, Paul P.
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Astrophysics - Astrophysics of Galaxies - Abstract
The cold molecular gas in contemporary galaxies is structured in discrete cloud complexes. These giant molecular clouds (GMCs), with $10^4$-$10^7$ solar masses and radii of 5-100 parsecs, are the seeds of star formation. Highlighting the molecular gas structure at such small scales in distant galaxies is observationally challenging. Only a handful of molecular clouds were reported in two extreme submillimetre galaxies at high redshift. Here we search for GMCs in a typical Milky Way progenitor at z = 1.036. Using the Atacama Large Millimeter/submillimeter Array (ALMA), we mapped the CO(4-3) emission of this gravitationally lensed galaxy at high resolution, reading down to 30 parsecs, which is comparable to the resolution of CO observations of nearby galaxies. We identify 17 molecular clouds, characterized by masses, surface densities and supersonic turbulence all of which are 10-100 times higher than present-day analogues. These properties question the universality of GMCs and suggest that GMCs inherit their properties from ambient interstellar medium. The measured cloud gas masses are similar to the masses of stellar clumps seen in the galaxy in comparable numbers. This corroborates the formation of molecular clouds by fragmentation of distant turbulent galactic gas disks, which then turn into stellar clumps ubiquitously observed in galaxies at cosmic noon., Comment: 1 pages, 4 figures, Supplementary information containing 8 figures and 1 table, published in Nature Astronomy
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- 2019
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17. The CANDELS/SHARDS multi-wavelength catalog in GOODS-N: Photometry, Photometric Redshifts, Stellar Masses, Emission line fluxes and Star Formation Rates
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Barro, Guillermo, Perez-Gonzalez, Pablo G., Cava, Antonio, Brammer, Gabriel, Pandya, Viraj, Moral, Carmen Eliche, Esquej, Pilar, Dominguez-Sanchez, Helena, Pampliega, Belen Alcalde, Guo, Yicheng, Koekemoer, Anton M., Trump, Jonathan R., Ashby, Matthew L. N., Cardiel, Nicolas, Castellano, Marco, Conselice, Christopher J., Dickinson, Mark E., Dolch, Timothy, Donley, Jennifer L., Briones, Nestor Espino, Faber, Sandra M., Fazio, Giovanni G., Ferguson, Henry, Finkelstein, Steve, Fontana, Adriano, Galametz, Audrey, Gardner, Jonathan P., Gawiser, Eric, Giavalisco, Mauro, Grazian, Andrea, Grogin, Norman A., Hathi, Nimish P., Hemmati, Shoubaneh, Hernan-Caballero, Antonio, Kocevski, Dale, Koo, David C., Kodra, Dritan, Lee, Kyoung-Soo, Lin, Lihwai, Lucas, Ray A., Mobasher, Bahram, McGrath, Elizabeth J., Nandra, Kirpal, Nayyeri, Hooshang, Newman, Jeffrey A., Pforr, Janine, Peth, Michael, Rafelski, Marc, Rodriguez-Munoz, Lucia, Salvato, Mara, Stefanon, Mauro, van der Wel, Arjen, Willner, Steven P., Wiklind, Tommy, and Wuyts, Stijn
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Astrophysics - Astrophysics of Galaxies - Abstract
We present a WFC3 F160W ($H$-band) selected catalog in the CANDELS/GOODS-N field containing photometry from the ultraviolet (UV) to the far-infrared (IR), photometric redshifts and stellar parameters derived from the analysis of the multi-wavelength data. The catalog contains 35,445 sources over the 171 arcmin$^{2}$ of the CANDELS F160W mosaic. The 5$\sigma$ detection limits (within an aperture of radius 0\farcs17) of the mosaic range between $H=27.8$, 28.2 and 28.7 in the wide, intermediate and deep regions, that span approximately 50\%, 15\% and 35\% of the total area. The multi-wavelength photometry includes broad-band data from UV (U band from KPNO and LBC), optical (HST/ACS F435W, F606W, F775W, F814W, and F850LP), near-to-mid IR (HST/WFC3 F105W, F125W, F140W and F160W, Subaru/MOIRCS Ks, CFHT/Megacam K, and \spitzer/IRAC 3.6, 4.5, 5.8, 8.0 $\mu$m) and far IR (\spitzer/MIPS 24$\mu$m, HERSCHEL/PACS 100 and 160$\mu$m, SPIRE 250, 350 and 500$\mu$m) observations. In addition, the catalog also includes optical medium-band data (R$\sim50$) in 25 consecutive bands, $\lambda=500$ to 950~nm, from the SHARDS survey and WFC3 IR spectroscopic observations with the G102 and G141 grisms (R$\sim210$ and 130). The use of higher spectral resolution data to estimate photometric redshifts provides very high, and nearly uniform, precision from $z=0-2.5$. The comparison to 1,485 good quality spectroscopic redshifts up to $z\sim3$ yields $\Delta z$/(1+$z_{\rm spec}$)$=$0.0032 and an outlier fraction of $\eta=$4.3\%. In addition to the multi-band photometry, we release added-value catalogs with emission line fluxes, stellar masses, dust attenuations, UV- and IR- based star formation rates and rest-frame colors., Comment: The catalogs, images and spectra are available in Rainbow-slicer (https://bit.ly/2OxKKx1 ), navigator (https://bit.ly/2GDS180 ) and MAST (https://bit.ly/2YtoBQ4 ). In addition to the photometry and other added-value catalogs we release UV+IR star formation rates based on Spitzer (MIPS) and Herschel (PACS and SPIRE) in the 5 CANDELS fields
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- 2019
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18. Anti-CD2 Antibody-Coated Nanoparticles Containing IL-2 Induce NK Cells That Protect Lupus Mice via a TGF-β-Dependent Mechanism.
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Horwitz, David, Liu, Aijing, Bickerton, Sean, Castaldo, Giuseppe, Matarese, Giuseppe, Fahmy, Tarek, and La Cava, Antonio
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NK cells ,autoimmunity ,cytokines ,immune regulation ,immunotherapy ,nanoparticles ,systemic lupus erythematosus ,Animals ,CD2 Antigens ,Interleukin-2 ,Killer Cells ,Natural ,Lupus Erythematosus ,Systemic ,Mice ,Mice ,Inbred C57BL ,Mice ,Inbred DBA ,Nanoparticles ,Transforming Growth Factor beta - Abstract
We recently reported that the treatment with nanoparticles (NPs) loaded with tolerogenic cytokines suppressed the manifestations of lupus-like disease induced by the transfer of donor CD4+ T cells from DBA/2 mice into (C57BL/6 × DBA/2)F1 (BDF1) mice. Although the protective effects were ascribed to the induction of adaptive CD4+ and CD8+ T regulatory cells, the results suggested that another population of immune cells could be involved. Here we report that NK cells critically contribute to the protection from lupus-like disease conferred by NPs to BDF1 mice, and that this effect is TGF-β-dependent.
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- 2020
19. Serafino Zappacosta: An Enlightened Mentor and Educator
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Carbone, Ennio, De Felice, Mario, Di Rosa, Francesca, D'Oro, Ugo, Fontana, Silvia, La Cava, Antonio, Maio, Michele, Matarese, Giuseppe, Racioppi, Luigi, Ruggiero, Giuseppina, and Terrazzano, Giuseppe
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Immunology ,Quality Education ,Allergy and Immunology ,History ,20th Century ,History ,21st Century ,Humans ,Immunity ,Cellular ,Major Histocompatibility Complex ,Male ,Mentors ,Research ,T-Lymphocytes ,education ,MHC ,T cells ,NK cells ,immune response ,Medical Microbiology ,Biochemistry and cell biology - Abstract
With this article, the authors aim to honor the memory of Serafino Zappacosta, who had been their mentor during the early years of their career in science. The authors discuss how the combination of Serafino Zappacosta's extraordinary commitment to teaching and passion for science created a fostering educational environment that led to the creation of the "Ruggero Ceppellini Advanced School of Immunology." The review also illustrates how the research on the MHC and the inspirational scientific context in the Zappacosta's laboratory influenced the authors' early scientific interests, and subsequent professional work as immunologists.
- Published
- 2020
20. Molecular testing of the São Francisco River as an ecological filter for the Brazilian large-eyed stingray Hypanus marianae (Dasyatidae, Myliobatiformes)
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Costa, Tiego L. A., Petean, Flávia F., Berbel-Filho, Waldir M., Solé-Cava, Antonio M., Mendes, Liana F., and Lima, Sergio M. Q.
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- 2022
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21. Evolution of the anti-truncated stellar profiles of S0 galaxies since $z=0.6$ in the SHARDS survey: II - Structural and photometric evolution
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Borlaff, Alejandro, Eliche-Moral, M. Carmen, Beckman, John E., Vazdekis, Alexandre, Lumbreras-Calle, Alejandro, Ciambur, Bogdan C., Pérez-González, Pablo G., Cardiel, Nicolás, Barro, Guillermo, and Cava, Antonio
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Astrophysics - Astrophysics of Galaxies - Abstract
Type-III S0 galaxies present tight scaling relations between their surface brightness photometric and structural parameters. Several evolutionary models have been proposed for the formation of Type-III S0 galaxies but the observations of are usually limited to the local Universe. We study the evolution of the photometric and structural scaling relations found between the parameters of the surface brightness profiles in the rest-frame R-band of Type-III S0 galaxies with z and the possible differences between the rest-frame (B-R) colours of the inner and outer disc profiles. We make use of a sample of 14 Type-III E/S0--S0 galaxies at 0.2
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- 2018
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22. Rebalancing Immune Homeostasis to Treat Autoimmune Diseases
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Horwitz, David A, Fahmy, Tarek M, Piccirillo, Ciriaco A, and La Cava, Antonio
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Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Vaccine Related ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Inflammatory and immune system ,Animals ,Autoimmune Diseases ,Autoimmunity ,Dendritic Cells ,Homeostasis ,Humans ,Inflammation ,T-Lymphocytes ,autoimmune diseases ,immune regulation ,immunotherapy ,nanoparticles ,Biochemistry and cell biology - Abstract
During homeostasis, interactions between tolerogenic dendritic cells (DCs), self-reactive T cells, and T regulatory cells (Tregs) contribute to maintaining mammalian immune tolerance. In response to infection, immunogenic DCs promote the generation of proinflammatory effector T cell subsets. When complex homeostatic mechanisms maintaining the balance between regulatory and effector functions become impaired, autoimmune diseases can develop. We discuss some of the newest advances on the mechanisms of physiopathologic homeostasis that can be employed to develop strategies to restore a dysregulated immune equilibrium. Some of these designs are based on selectively activating regulators of immunity and inflammation instead of broadly suppressing these processes. Promising approaches include the use of nanoparticles (NPs) to restore Treg control over self-reactive cells, aiming to achieve long-term disease remission, and potentially to prevent autoimmunity in susceptible individuals.
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- 2019
23. Human T cell repertoire: what happens in thymus does not stay in thymus
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La Cava, Antonio
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Immunology ,Underpinning research ,1.1 Normal biological development and functioning ,Inflammatory and immune system ,Animals ,Complementarity Determining Regions ,Cross Reactions ,Humans ,Mice ,Receptors ,Antigen ,T-Cell ,alpha-beta ,T-Lymphocytes ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The T cell receptor (TCR) repertoire is diverse, thus allowing recognition of a wide range of pathogens by T cells. In humans, the study of the formation of TCR repertoires is problematic because of the difficulty in performing investigations in vivo. In this issue of the JCI, Khosravi-Maharlooei and colleagues describe a new humanized mouse model that allows direct investigations on this topic. Using high-throughput and single-cell TCR-complementarity-determining region 3 β (TCR-CDR3β) sequencing, the authors were able to demonstrate that human thymic selection is a major driver of TCR sequence sharing, also implicating a preferential selection of shared cross-reactive CDR3βs during repertoire formation.
- Published
- 2019
24. The Influence of Diet and Obesity on Gene Expression in SLE.
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La Cava, Antonio
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Humans ,Lupus Erythematosus ,Systemic ,Obesity ,Disease Progression ,Inflammation ,Diet ,Gene Expression Regulation ,Nutrients ,diet ,obesity ,systemic lupus erythematosus ,Lupus Erythematosus ,Systemic ,Genetics - Abstract
This review provides an overview of the known effects of diet, obesity, and the intake of different nutrients on systemic lupus erythematosus (SLE). It summarizes and discusses the studies in rodents that identified how different diets can regulate gene expression in the disease, together with a description of the effects of diet on lupus patients' inflammatory state and disease severity. The identification of selected dietary candidates that can modulate SLE onset and progression is analyzed in relation to possible targeted approaches that could ultimately ameliorate the management and prognosis of this disease.
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- 2019
25. Suppression of Murine Lupus by CD4+ and CD8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β
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Horwitz, David A, Bickerton, Sean, Koss, Michael, Fahmy, Tarek M, and La Cava, Antonio
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Autoimmune Disease ,Kidney Disease ,Lupus ,Bioengineering ,Nanotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,CD8-Positive T-Lymphocytes ,Disease Models ,Animal ,Dose-Response Relationship ,Drug ,Interleukin-2 ,Lupus Erythematosus ,Systemic ,Mice ,Mice ,Inbred C57BL ,Nanoparticles ,T-Lymphocytes ,Regulatory ,Transforming Growth Factor beta ,Clinical Sciences ,Immunology ,Public Health and Health Services ,Arthritis & Rheumatology - Abstract
ObjectiveTo develop a nanoparticle (NP) platform that can expand both CD4+ and CD8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE).MethodsPoly(lactic-co-glycolic acid) (PLGA) NPs encapsulating interleukin-2 (IL-2) and transforming growth factor β (TGFβ) were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 × DBA/2)F1 (BDF1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-double-stranded DNA antibody levels by enzyme-linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features.ResultsAnti-CD2/CD4 antibody-coated, but not noncoated, NPs encapsulating IL-2 and TGFβ induced CD4+ and CD8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF1 mice with lupus. The administration of anti-CD2/CD4 antibody-coated NPs encapsulating IL-2 and TGFβ resulted in the expansion of CD4+ and CD8+ Treg cells, a marked suppression of anti-DNA antibody production, and reduced renal disease.ConclusionThis study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGFβ can expand both CD4+ and CD8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE, could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL-2 deficiency.
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- 2019
26. The nature of giant clumps in distant galaxies probed by the anatomy of the Cosmic Snake
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Cava, Antonio, Schaerer, Daniel, Richard, Johan, Pérez-González, Pablo G., Dessauges-Zavadsky, Miroslava, Mayer, Lucio, and Tamburello, Valentina
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Astrophysics - Astrophysics of Galaxies - Abstract
Giant stellar clumps are ubiquitous in high-redshift galaxies. They are thought to play an important role in the build-up of galactic bulges and as diagnostics of star formation feedback in galactic discs. Hubble Space Telescope (HST) blank field imaging surveys have estimated that these clumps have masses up to 10$^{9.5}$ M$_{\odot}$ and linear sizes larger than ~1 kpc. Recently, gravitational lensing has also been used to get higher spatial resolution. However, both recent lensed observations and models suggest that the clumps properties may be overestimated by the limited resolution of standard imaging techniques. A definitive proof of this observational bias is nevertheless still missing. Here we investigate directly the effect of resolution on clump properties by analysing multiple gravitationally-lensed images of the same galaxy at different spatial resolutions, down to 30 pc. We show that the typical mass and size of giant clumps, generally observed at $\sim$1 kpc resolution in high-redshift galaxies, are systematically overestimated. The high spatial resolution data, only enabled by strong gravitational lensing using currently available facilities, support smaller scales of clump formation by fragmentation of the galactic gas disk via gravitational instabilities., Comment: Nature Astronomy, published online on 13th of November 2017 (see https://www.nature.com/natastron/). Authors' version including Letter+Methods+Supplementary Info: 12 pages, 3 figures (main); 20 pages (Methods); 18 pages, 10 figures, 5 tables (Supplementary Info)
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- 2017
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27. SHARDS Frontier Fields: Physical properties of a low mass Lyman-alpha emitter at z=5.75
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Hernán-Caballero, Antonio, Pérez-González, Pablo G., Diego, José M., Lagattuta, David, Richard, Johan, Schaerer, Daniel, Alonso-Herrero, Almudena, Marino, Raffaella Anna, Sklias, Panos, Alcalde-Pampliega, Belén, Cava, Antonio, Conselice, Christopher J., Dannerbauer, Helmut, Domínguez-Sánchez, Helena, Eliche-Moral, Carmen, Esquej, Pilar, Huertas-Company, Marc, Marques-Chaves, Rui, Pérez-Fournon, Ismael, Rawle, Tim, Espinosa, José Miguel Rodríguez, González, Daniel Rosa, and Rujopakarn, Wiphu
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Astrophysics - Astrophysics of Galaxies - Abstract
We analyze the properties of a multiply-imaged Lyman-alpha (Lya) emitter at z=5.75 identified through SHARDS Frontier Fields intermediate-band imaging of the Hubble Frontier Fields (HFF) cluster Abell 370. The source, A370-L57, has low intrinsic luminosity (M_UV~-16.5), steep UV spectral index (\beta=-2.4+/-0.1), and extreme rest-frame equivalent width of Lya (EW(Lya)=420+180-120 \AA). Two different gravitational lens models predict high magnification (\mu~10--16) for the two detected counter-images, separated by 7", while a predicted third counter-image (\mu~3--4) is undetected. We find differences of ~50% in magnification between the two lens models, quantifying our current systematic uncertainties. Integral field spectroscopy of A370-L57 with MUSE shows a narrow (FWHM=204+/-10 km/s) and asymmetric Lya profile with an integrated luminosity L(Lya)~10^42 erg/s. The morphology in the HST bands comprises a compact clump (r_e<100 pc) that dominates the Lya and continuum emission and several fainter clumps at projected distances <1 kpc that coincide with an extension of the Lya emission in the SHARDS F823W17 and MUSE observations. The latter could be part of the same galaxy or an interacting companion. We find no evidence of contribution from AGN to the Lya emission. Fitting of the spectral energy distribution with stellar population models favors a very young (t<10 Myr), low mass (M*~10^6.5 Msun), and metal poor (Z<4x10^-3) stellar population. Its modest star formation rate (SFR~1.0 Msun/yr) implies high specific SFR (sSFR~2.5x10^-7 yr^-1) and SFR density (Sigma_SFR ~ 7-35 Msun/yr/kpc^2). The properties of A370-L57 make it a good representative of the population of galaxies responsible for cosmic reionization., Comment: 14 pages, 8 figures, 4 tables. Accepted for publication in ApJ
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- 2017
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28. Morphological Segregation in the Surroundings of Cosmic Voids
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Ricciardelli, Elena, Cava, Antonio, Varela, Jesus, and Tamone, Amelie
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Astrophysics - Astrophysics of Galaxies - Abstract
We explore the morphology of galaxies living in the proximity of cosmic voids, using a sample of voids identified in the Sloan Digital Sky Survey Data Release 7. At all stellar masses, void galaxies exhibit morphologies of a later type than galaxies in a control sample, which represent galaxies in an average density environment. We interpret this trend as a pure environmental effect, independent of the mass bias, due to a slower galaxy build-up in the rarefied regions of voids. We confirm previous findings about a clear segregation in galaxy morphology, with galaxies of a later type being found at smaller void-centric distances with respect to the early-type galaxies. We also show, for the first time, that the radius of the void has an impact on the evolutionary history of the galaxies that live within it or in its surroundings. In fact, an enhanced fraction of late-type galaxies is found in the proximity of voids larger than the median void radius. Likewise, an excess of early-type galaxies is observed within or around voids of a smaller size. A significant difference in galaxy properties in voids of different sizes is observed up to 2 Rvoid, which we define as the region of influence of voids. The significance of this difference is greater than 3sigma for all the volume-complete samples considered here. The fraction of star-forming galaxies shows the same behavior as the late-type galaxies, but no significant difference in stellar mass is observed in the proximity of voids of different sizes., Comment: Published in ApJL
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- 2017
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29. Structural and dynamical modeling of WINGS clusters. I. The distribution of cluster galaxies of different morphological classes within regular and irregular clusters
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Cava, Antonio, Biviano, Andrea, Mamon, Gary A., Varela, Jesus, Bettoni, Daniela, D'Onofrio, Mauro, Fasano, Giovanni, Fritz, Jacopo, Moles, Mariano, Moretti, Alessia, and Poggianti, Bianca
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Astrophysics - Astrophysics of Galaxies - Abstract
[Abridged] We use the WINGS database to select a sample of 67 nearby galaxy clusters with at least 30 spectroscopic members each. 53 of these clusters do not show evidence of substructures in phase-space, while 14 do. We estimate the virial radii and circular velocities of the 67 clusters by a variety of proxies (velocity dispersion, X-ray temperature, and richness) and use these estimates to build stack samples from these 53 and 14 clusters ('Reg' and 'Irr' stacks, respectively). We determine the number-density and velocity-dispersion profiles (VDPs) of E, S0, and Sp+Irr (S) galaxies in the Reg and Irr samples, separately, and fit models to these profiles. The number density profiles of E, S0, and S galaxies are adequately described by either a NFW or a cored King model, both for the Reg and Irr samples, with a slight preference for the NFW model. The spatial distribution concentration increases from the S to the S0 and to the E populations, both in the Reg and the Irr stacks, reflecting the well-known morphology-radius relation. Reg clusters have a more concentrated spatial distribution of E and S0 galaxies than Irr clusters, while the spatial distributions of S galaxies in Reg and Irr clusters are similar. We propose a new phenomenological model that provides acceptable fits to the VDP of all our galaxy samples. The VDPs become steeper and with a higher normalization from E to S0 to S galaxies. The S0 VDP is close to that of E galaxies in Reg clusters, and intermediate between those of E and S galaxies in Irr clusters. Our results suggest that S galaxies are a recently accreted cluster population, that take less than 3 Gyr to evolve into S0 galaxies after accretion, and in doing so modify their phase-space distribution, approaching that of cluster ellipticals. While in Reg clusters this evolutionary process is mostly completed, it is still ongoing in Irr clusters., Comment: A&A, in press - 11 pages, 9 figures, 4 tables
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- 2017
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30. Extreme magnification of a star at redshift 1.5 by a galaxy-cluster lens
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Kelly, Patrick L., Diego, Jose M., Rodney, Steven, Kaiser, Nick, Broadhurst, Tom, Zitrin, Adi, Treu, Tommaso, Perez-Gonzalez, Pablo G., Morishita, Takahiro, Jauzac, Mathilde, Selsing, Jonatan, Oguri, Masamune, Pueyo, Laurent, Ross, Timothy W., Filippenko, Alexei V., Smith, Nathan, Hjorth, Jens, Cenko, S. Bradley, Wang, Xin, Howell, D. Andrew, Richard, Johan, Frye, Brenda L., Jha, Saurabh W., Foley, Ryan J., Norman, Colin, Bradac, Marusa, Zheng, Weikang, Brammer, Gabriel, Benito, Alberto Molino, Cava, Antonio, Christensen, Lise, de Mink, Selma E., Graur, Or, Grillo, Claudio, Kawamata, Ryota, Kneib, Jean-Paul, Matheson, Thomas, McCully, Curtis, Nonino, Mario, Perez-Fournon, Ismael, Riess, Adam G., Rosati, Piero, Schmidt, Kasper Borello, Sharon, Keren, and Weiner, Benjamin J.
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Astrophysics - Astrophysics of Galaxies ,Astrophysics - Cosmology and Nongalactic Astrophysics - Abstract
Galaxy-cluster gravitational lenses can magnify background galaxies by a total factor of up to ~50. Here we report an image of an individual star at redshift z=1.49 (dubbed "MACS J1149 Lensed Star 1 (LS1)") magnified by >2000. A separate image, detected briefly 0.26 arcseconds from LS1, is likely a counterimage of the first star demagnified for multiple years by a >~3 solar-mass object in the cluster. For reasonable assumptions about the lensing system, microlensing fluctuations in the stars' light curves can yield evidence about the mass function of intracluster stars and compact objects, including binary fractions and specific stellar evolution and supernova models. Dark-matter subhalos or massive compact objects may help to account for the two images' long-term brightness ratio., Comment: Accepted by Nature Astronomy on February 23, 2018
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- 2017
31. Evolution of the anti-truncated stellar profiles of S0 galaxies since $z=0.6$ in the SHARDS survey: I - Sample and Methods
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Borlaff, Alejandro, Eliche-Moral, M. Carmen, Beckman, John E., Ciambur, Bogdan C., Pérez-González, Pablo G., Barro, Guillermo, Cava, Antonio, and Cardiel, Nicolás
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Astrophysics - Astrophysics of Galaxies - Abstract
The controversy about the origin of the structure of S0--E/S0 galaxies may be due to the difficulty of comparing surface brightness profiles with different depths, photometric corrections and PSF effects (almost always ignored). We aim to quantify the properties of Type-III (anti-truncated) discs in a sample of S0 galaxies at 0.2
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- 2017
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32. GASP I: Gas stripping phenomena in galaxies with MUSE
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Poggianti, Bianca M., Moretti, Alessia, Gullieuszik, Marco, Fritz, Jacopo, Jaffe, Yara, Bettoni, Daniela, Fasano, Giovanni, Bellhouse, Callum, Hau, George, Vulcani, Benedetta, Biviano, Andrea, Omizzolo, Alessandro, Paccagnella, Angela, D'Onofrio, Mauro, Cava, Antonio, Sheen, Y. -K., Couch, Warrick, and Owers, Matt
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Astrophysics - Astrophysics of Galaxies - Abstract
GASP (GAs Stripping Phenomena in galaxies with MUSE) is a new integral-field spectroscopic survey with MUSE at the VLT aiming at studying gas removal processes in galaxies. We present an overview of the survey and show a first example of a galaxy undergoing strong gas stripping. GASP is obtaining deep MUSE data for 114 galaxies at z=0.04-0.07 with stellar masses in the range 10^9.2-10^11.5 M_sun in different environments (galaxy clusters and groups, over more than four orders of magnitude in halo mass). GASP targets galaxies with optical signatures of unilateral debris or tails reminiscent of gas stripping processes ("jellyfish galaxies"), as well as a control sample of disk galaxies with no morphological anomalies. GASP is the only existing Integral Field Unit (IFU) survey covering both the main galaxy body and the outskirts and surroundings, where the IFU data can reveal the presence and the origin of the outer gas. To demonstrate GASP's ability to probe the physics of gas and stars, we show the complete analysis of a textbook case of a "jellyfish" galaxy, JO206. This is a massive galaxy (9 x 10^10 M_sun in a low-mass cluster (sigma ~500 km/s), at a small projected clustercentric radius and a high relative velocity, with >=90kpc-long tentacles of ionized gas stripped away by ram pressure. We present the spatially resolved kinematics and physical properties of gas and stars, and depict the evolutionary history of this galaxy., Comment: accepted for publication in ApJ
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- 2017
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33. On the stellar masses of giant clumps in distant star-forming galaxies
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Dessauges-Zavadsky, Miroslava, Schaerer, Daniel, Cava, Antonio, Mayer, Lucio, and Tamburello, Valentina
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Astrophysics - Astrophysics of Galaxies - Abstract
We analyse stellar masses of clumps drawn from a compilation of star-forming galaxies at 1.1
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- 2017
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34. CAR immunotherapy in autoimmune diseases: promises and challenges.
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Jingjing Yu, Yiming Yang, Zhanjing Gu, Min Shi, Cava, Antonio La, and Aijing Liu
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REGULATORY T cells ,KILLER cells ,SYSTEMIC lupus erythematosus ,CYTOKINE release syndrome ,T cells ,AUTOIMMUNE diseases - Abstract
In recent years, the use of chimeric antigen receptor (CAR)-T cells has emerged as a promising immunotherapy in multiple diseases. CAR-T cells are T cells genetically modified to express a surface receptor, known as CAR, for the targeting of cognate antigens on specific cells. The effectiveness of CAR-T cell therapy in hematologic malignancies including leukemia, myeloma, and non-Hodgkin’s lymphoma has led to consider its use as a potential avenue of treatment for autoimmune diseases. However, broadening the use of CAR-T cell therapy to a large spectrum of autoimmune conditions is challenging particularly because of the possible development of side effects including cytokine release syndrome and neurotoxicity. The design of CAR therapy that include additional immune cells such as double-negative T cells, γδ T cells, T regulatory cells and natural killer cells has shown promising results in preclinical studies and clinical trials in oncology, suggesting a similar potential utility in the treatment of autoimmune diseases. This review examines the mechanisms, efficacy, and safety of CAR approaches with a focus on their use in autoimmune diseases including systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, multiple sclerosis, myasthenia gravis, lupus nephritis and other autoimmune diseases. Advantages and disadvantages as compared to CAR-T cell therapy will also be discussed. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Deep genetic divergence among bluefish (Pomatomus saltatrix) of the Southwestern Atlantic.
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Villela, Livia Bonetti, Carvalho, Pedro Hollanda, de Vilasboa, Anderson, Rodríguez‐Rey, Ghennie Tatiana, Henning, Frederico, Grothues, Thomas, and Solé‐Cava, Antonio Mateo
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FISH populations ,POPULATION genetics ,FISHERY resources ,SYMPATRIC speciation ,HAPLOGROUPS - Abstract
Neglected cryptic diversity can lead to the permanent loss of locally adapted alleles, which can reduce resilience to rapid environmental change. It can also result in overestimation of fisheries stock sizes that can result from treating different species as if they belonged to one. Bluefish (Pomatomus saltatrix) is considered a circumtropical and subtropical species and an important fishery resource all over the world. Differences in ecologically relevant traits are observed among isolated populations. Also, in the Southwestern Atlantic, molecular data suggest multiple populations, but these are treated as a single fish stock by regulatory agencies due to a lack of definitive information. We used whole mitogenome sequences, nuclear (rho) and mitochondrial (coxI and cytb) genes, as well as microsatellites to investigate historical and current genetic population structure and parameters of bluefish in the Western Atlantic. A total of 263 samples were collected along the Brazilian coast and in the USA (New Jersey, Northwest Atlantic). Data revealed the existence of two evolutionarily significant units (ESU) of bluefish along the South American coast, later confirmed by whole mitogenome sequencing of both haplogroups. These two ESUs have a mostly parapatric distribution, with some areas of overlap, which vary along the year. We also conducted seasonal sampling in Brazil to investigate migration patterns. ESUs occur mostly north and south of parallel 23° 40′ S, with an overlap area that varied seasonally. The level of differentiation between those two ESUs in the SW Atlantic, even in sympatry, is as high as that found between them and those from the NW Atlantic and Europe. Parapatric distribution and restricted gene flow suggest the existence of ecological barriers and local adaptation. The splitting of an ancient population from the Southwestern Atlantic into two putative species is important to understand bluefish evolutionary diversification and has implications for fishery regulatory measures in Brazil. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Brain Ischemia Induces Diversified Neuroantigen-Specific T-Cell Responses That Exacerbate Brain Injury
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Jin, Wei-Na, Gonzales, Rayna, Feng, Yan, Wood, Kristofer, Chai, Zhi, Dong, Jing-Fei, La Cava, Antonio, Shi, Fu-Dong, and Liu, Qiang
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Brain Disorders ,Neurosciences ,Autoimmune Disease ,Stroke ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,Neurological ,Adoptive Transfer ,Animals ,Brain ,Brain Injuries ,Brain Ischemia ,Central Nervous System ,Humans ,Infarction ,Middle Cerebral Artery ,Mice ,Inbred C57BL ,Myelin-Oligodendrocyte Glycoprotein ,T-Lymphocytes ,adaptive immunity ,antigen presentation ,brain injury ,brain ischemia ,T-cells ,Cardiorespiratory Medicine and Haematology ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Background and purposeAutoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury.MethodsUsing a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients.ResultsBy coupling transfer of labeled MOG35-55-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG91-108 and MOG103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke.ConclusionsOur findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury.
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- 2018
37. Inteligência artificial em sala de aula: amiga ou inimiga? Estudantes ajudam ChatGPT a fazer músicas sobre Evolução
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Solé-Cava, Antonio Mateo, primary and Silva, Marcelo Cortes, additional
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- 2024
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38. Clumpy galaxies seen in H-alpha: inflated observed clump properties due to limited spatial resolution and sensitivity
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Tamburello, Valentina, Rahmati, Alireza, Mayer, Lucio, Cava, Antonio, Dessauges-Zavadsky, Miroslava, and Schaerer, Daniel
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Astrophysics - Astrophysics of Galaxies - Abstract
High-resolution simulations of star-forming massive galactic discs have shown that clumps form with a characteristic baryonic mass in the range $10^7-10^8~M_{\odot}$, with a small tail exceeding $10^9~M_{\odot}$ produced by clump-clump mergers. This is in contrast with the observed kpc-size clumps with masses up to $10^{10}~M_{\odot}$ in high-redshift star-forming galaxies. In this paper we show that the comparison between simulated and observed star-forming clumps is hindered by limited observational spatial resolution and sensitivity. We post-process high-resolution hydrodynamical simulations of clumpy discs using accurate radiative transfer to model the effect of ionizing radiation from young stars and to compute H$\alpha$ emission maps. By comparing the intrinsic clump size and mass distributions with those inferred from convolving the H$\alpha$ maps with different gaussian apertures, we mimick the typical resolution used in observations. We found that with 100 pc resolution, mock observations can recover the intrinsic clump radii and stellar masses, in agreement with those found by lensing observations. Instead, using a 1 kpc resolution smears out individual clumps, resulting in their apparent merging. This causes significant overestimations of the clump radii and, therefore, masses derived using methods that use their observed sizes. We show that limited sensitivity can also force observations to significantly overestimate the clump masses. We conclude that a significant fraction of giant clumps detected in the observations may result from artificially inflated radii and masses, and that $\approx 100$ pc spatial resolution is required to capture correctly the physical characteristics of star-forming clumps if they are coherent structures produced by disc fragmentation., Comment: submitted to MNRAS on 07.10.2016. New reference to Dessauges et al. 2016 added post submission. Comments are welcome
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- 2016
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39. Slow quenching of star formation in OMEGAWINGS clusters: galaxies in transition in the local universe
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Paccagnella, Angela, Vulcani, Benedetta, Poggianti, Bianca Maria, Moretti, Alessia, Fritz, Jacopo, Gullieuszik, Marco, Couch, Warrick, Bettoni, Daniela, Cava, Antonio, Fasano, Giovanni, and D'Onofrio, Mauro
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Astrophysics - Astrophysics of Galaxies - Abstract
The star formation quenching depends on environment, but a full understanding of what mechanisms drive it is still missing. Exploiting a sample of galaxies with masses $M_\ast>10^{9.8}M_\odot$, drawn from the WIde-field Nearby Galaxy-cluster Survey (WINGS) and its recent extension OMEGAWINGS, we investigate the star formation rate (SFR) as a function of stellar mass (M$_*$) in galaxy clusters at $0.04
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- 2015
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40. Leptin in inflammation and autoimmunity
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La Cava, Antonio
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Autoimmune Disease ,Emerging Infectious Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Adaptive Immunity ,Animals ,Autoimmunity ,Humans ,Immunity ,Innate ,Inflammation ,Leptin ,Mice ,Obesity ,Biochemistry and Cell Biology ,Genetics ,Immunology - Abstract
After its discovery as a key controller of metabolic function, leptin has been later extensively implicated in additional functions including important modulatory activities on the innate and adaptive immune response. This review analyzes the known implications of leptin in multiple inflammatory conditions, including autoimmune diseases, and how this knowledge could be instrumental in the design of leptin-based manipulation strategies to help restoration of abnormal immune responses.
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- 2017
41. SHARDS: A global view of the star formation activity at z~0.84 and z~1.23
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Cava, Antonio, Pérez-González, Pablo G., Eliche-Moral, M. Carmen, Ricciardelli, Elena, Vidal-García, Alba, Pampliega, Belen Alcalde, Alonso-Herrero, Almudena, Barro, Guillermo, Cardiel, Nicolas, Cenarro, A. Javier, Charlot, Stephane, Daddi, Emanuele, Dessauges-Zavadsky, Miroslava, Sánchez, Helena Domínguez, Espino-Briones, Nestor, Esquej, Pilar, Gallego, Jesus, Hernán-Caballero, Antonio, Huertas-Company, Marc, Koekemoer, Anton M., Muñoz-Tunon, Casiana, Rodriguez-Espinosa, Jose M., Rodríguez-Muñoz, Lucia, Tresse, Laurence, and Villar, Victor
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Astrophysics - Astrophysics of Galaxies - Abstract
In this paper, we present a comprehensive analysis of star-forming galaxies (SFGs) at intermediate redshifts (z~1). We combine the ultra-deep optical spectro-photometric data from the Survey for High-z Absorption Red and Dead Sources (SHARDS) with deep UV-to-FIR observations in the GOODS-N field. Exploiting two of the 25 SHARDS medium-band filters, F687W17 and F823W17, we select [OII] emission line galaxies at z~0.84 and z~1.23 and characterize their physical properties. Their rest-frame equivalent widths (EW$_{\mathrm{rf}}$([OII])), line fluxes, luminosities, star formation rates (SFRs) and dust attenuation properties are investigated. The evolution of the EW$_{\mathrm{rf}}$([OII]) closely follows the SFR density evolution of the universe, with a trend of EW$_{\mathrm{rf}}$([OII])$\propto$(1+z)$^3$ up to redshift z~1, followed by a possible flattening. The SF properties of the galaxies selected on the basis of their [OII] emission are compared with complementary samples of SFGs selected by their MIR and FIR emission, and also with a general mass-selected sample of galaxies at the same redshifts. We demonstrate observationally that the UVJ diagram (or, similarly, a cut in the specific SFR) is only partially able to distinguish the quiescent galaxies from the SFGs. The SFR-M$_*$ relation is investigated for the different samples, yelding a logarithmic slope ~1, in good agreement with previous results. The dust attenuations derived from different SFR indicators (UV(1600), UV(2800), [OII], IR) are compared and show clear trends with respect to both the stellar mass and total SFR, with more massive and highly star-forming galaxies being affected by stronger dust attenuation., Comment: Replaced to match the accepted version (24 pages, 1 table, 17 figures). Published in ApJ, 812, 155 (2015): http://stacks.iop.org/0004-637X/812/155
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- 2015
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42. Pathways to quiescence: SHARDS view on the Star Formation Histories of massive quiescent galaxies at 1.0 < z < 1.5
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Sánchez, Helena Domínguez, Pérez-González, Pablo G., Esquej, Pilar, Eliche-Moral, M. Carmen, Barro, Guillermo, Cava, Antonio, Koekemoer, Anton M., Pampliega, Belén Alcalde, Herrero, Almudena Alonso, Bruzual, Gustavo, Cardiel, Nicolás, Cenarro, Javier, Ceverino, Daniel, Charlot, Stéphane, and Caballero, Antonio Hernán
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Astrophysics - Astrophysics of Galaxies - Abstract
We present Star Formation Histories (SFHs) for a sample of 104 massive (stellar mass M > 10$^{10}$ M$_{\odot}$) quiescent galaxies (MQGs) at $z$=1.0-1.5 from the analysis of spectro-photometric data from the SHARDS and HST/WFC3 G102 and G141 surveys of the GOODS-N field, jointly with broad-band observations from ultraviolet (UV) to far-infrared (Far-IR). The sample is constructed on the basis of rest-frame UVJ colours and specific star formation rates (sSFR=SFR/Mass). The Spectral Energy Distributions (SEDs) of each galaxy are compared to models assuming a delayed exponentially declining SFH. A Monte Carlo algorithm characterizes the degeneracies, which we are able to break taking advantage of the SHARDS data resolution, by measuring indices such as MgUV and D4000. The population of MQGs shows a duality in their properties. The sample is dominated (85%) by galaxies with young mass-weighted ages, tM $<$ 2 Gyr, short star formation timescales, $\langle \tau \rangle$ $\sim$ 60-200 Myr, and masses log(M/M$_{\odot}$) $\sim$ 10.5. There is an older population (15%) with tM$=$2 - 4 Gyr, longer star formation timescales, $\langle \tau \rangle$$\sim$ 400 Myr, and larger masses, log(M/M$_{\odot}$) $\sim$ 10.7. The SFHs of our MQGs are consistent with the slope and the location of the Main Sequence (MS) of star-forming galaxies at $z$ $>$ 1.0, when our galaxies were 0.5-1.0 Gyr old. According to these SFHs, all the MQGs experienced a Luminous Infrared Galaxy (LIRG) phase that lasts for $\sim$ 500 Myr, and half of them an Ultra Luminous Infrared Galaxy (ULIRG) phase for $\sim$ 100 Myr. We find that the MQG population is almost assembled at $z$ $\sim$ 1, and continues evolving passively with few additions to the population., Comment: 26 pages, 18 figures. Accepted for publication in MNRAS
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- 2015
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43. Nanoparticles loaded with IL-2 and TGF-β promote transplantation tolerance to alloantigen.
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Horwitz, David A., Ju Hua Wang, Dongin Kim, Chang Kang, Brion, Katja, Bickerton, Sean, and La Cava, Antonio
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REGULATORY T cells ,T cells ,IMMUNOSUPPRESSION ,GRAFT versus host disease ,GRAFT rejection - Abstract
We have previously reported that nanoparticles (NPs) loaded with IL-2 and TGF-β and targeted to T cells induced polyclonal T regulatory cells (Tregs) that protected mice from graft-versus-host disease (GvHD). Here, we evaluated whether administration of these NPs during alloantigen immunization could prevent allograft rejection by converting immunogenic responses to tolerogenic ones. Using C57BL/6 mice and BALB/c mice as either donors or recipients of allogeneic splenocytes, we found that treatment with the tolerogenic NPs in both strains of mice resulted in a marked inhibition of mixed lymphocyte reaction (MLR) to donor cell alloantigen but not to third-party control mouse cells after transfer of the allogeneic cells. The decreased alloreactivity associated with a four- to fivefold increase in the number of CD4
+ and CD8+ T regulatory cells (Tregs) and the acquisition of a tolerogenic phenotype by recipient dendritic cells (DCs) in NP-treated mice. As allogeneic cells persisted in NP-treated mice, these findings suggest that tolerogenic NPs can induce alloantigen-specific Tregs and tolerogenic DCs promoting tolerogenic responses to alloantigen. By inhibiting reactivity to allotransplant, this approach could help reduce the need for immune suppression for the maintenance of allografts. [ABSTRACT FROM AUTHOR]- Published
- 2024
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44. Adeno‐Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis
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Moroncini, Gianluca, primary, Svegliati, Silvia, additional, Grieco, Antonella, additional, Cuccioloni, Massimiliano, additional, Mozzicafreddo, Matteo, additional, Paolini, Chiara, additional, Agarbati, Silvia, additional, Spadoni, Tatiana, additional, Amoresano, Angela, additional, Pinto, Gabriella, additional, Chen, Qingxin, additional, Benfaremo, Devis, additional, Tonnini, Cecilia, additional, Senzacqua, Martina, additional, Alizzi, Silvia, additional, Nieto, Karen, additional, Finke, Doreen, additional, Viola, Nadia, additional, Amico, Donatella, additional, Galgani, Mario, additional, Gasparini, Stefano, additional, Zuccatosta, Lina, additional, Menzo, Stefano, additional, Müller, Martin, additional, Kleinschmidt, Jürgen, additional, Funaro, Ada, additional, Giordano, Antonio, additional, La Cava, Antonio, additional, Dorfmüller, Peter, additional, Amoroso, Antonio, additional, Pucci, Piero, additional, Pezone, Antonio, additional, Avvedimento, Enrico V., additional, and Gabrielli, Armando, additional
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- 2024
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45. Role of Metabolism in the Immunobiology of Regulatory T Cells
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Galgani, Mario, De Rosa, Veronica, La Cava, Antonio, and Matarese, Giuseppe
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Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Animals ,Forkhead Transcription Factors ,Humans ,T-Lymphocytes ,Regulatory ,Immunology - Abstract
Intracellular metabolism is central to cell activity and function. CD4(+)CD25(+) regulatory T cells (Tregs) that express the transcription factor FOXP3 play a pivotal role in the maintenance of immune tolerance to self. Recent studies showed that the metabolism and function of Tregs are influenced significantly by local environmental conditions and the availability of certain metabolites. It also was reported that defined metabolic programs associate with Treg differentiation, expression of FOXP3, and phenotype stabilization. This article reviews how metabolism modulates FOXP3 expression and Treg function, what environmental factors are involved, and how metabolic manipulation could alter Treg frequency and function in physiopathologic conditions.
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- 2016
46. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation
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Lourenço, Elaine V, Liu, Aijing, Matarese, Giuseppe, and La Cava, Antonio
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Clinical Research ,Autoimmune Disease ,Lupus ,Kidney Disease ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Animals ,Autoantibodies ,Autoimmunity ,Disease Models ,Animal ,Humans ,Immunity ,Innate ,Inflammation ,Leptin ,Lupus Erythematosus ,Systemic ,Mice ,Mice ,Inbred NZB ,T-Lymphocytes ,Regulatory ,Terpenes ,systemic lupus erythematosus ,leptin ,autoimmunity ,immune regulation ,animal models - Abstract
Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.
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- 2016
47. Neural stem cells sustain natural killer cells that dictate recovery from brain inflammation
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Liu, Qiang, Sanai, Nader, Jin, Wei-Na, La Cava, Antonio, Van Kaer, Luc, and Shi, Fu-Dong
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Biomedical and Clinical Sciences ,Immunology ,Neurosciences ,Stem Cell Research - Nonembryonic - Non-Human ,Transplantation ,Regenerative Medicine ,Brain Disorders ,Stem Cell Research ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Aged ,80 and over ,Animals ,Brain ,Brain Chemistry ,Cell Proliferation ,Cerebral Ventricles ,Cytokines ,Encephalitis ,Encephalomyelitis ,Autoimmune ,Experimental ,Female ,Humans ,Immune Tolerance ,Interleukin-15 ,Killer Cells ,Natural ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Multiple Sclerosis ,Neural Stem Cells ,Recovery of Function ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery ,Biological psychology - Abstract
Recovery from organ-specific autoimmune diseases largely relies on the mobilization of endogenous repair mechanisms and local factors that control them. Natural killer (NK) cells are swiftly mobilized to organs targeted by autoimmunity and typically undergo numerical contraction when inflammation wanes. We report the unexpected finding that NK cells are retained in the brain subventricular zone (SVZ) during the chronic phase of multiple sclerosis in humans and its animal model in mice. These NK cells were found preferentially in close proximity to SVZ neural stem cells (NSCs) that produce interleukin-15 and sustain functionally competent NK cells. Moreover, NK cells limited the reparative capacity of NSCs following brain inflammation. These findings reveal that reciprocal interactions between NSCs and NK cells regulate neurorepair.
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- 2016
48. Considerations on COVID-19 vaccination
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La Cava, Antonio, primary
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- 2023
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49. Surface photometry of WINGS galaxies with GASPHOT
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D'Onofrio, Mauro, Bindoni, Daniele, Fasano, Gianni, Bettoni, Daniela, Cava, Antonio, Fritz, Jacopo, Gullieuszik, Marco, Kjaergaard, Per, Moretti, Alessia, Moles, Mariano, Omizzolo, Alessandro, Poggianti, Bianca, Valentinuzzi, Tiziano, and Varela, Jesus
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Astrophysics - Astrophysics of Galaxies - Abstract
Aims. We present the B-, V- and K-band surface photometry catalogs obtained running the automatic software GASPHOT on galaxies from the WINGS cluster survey having isophotal area larger than 200 pixels. The catalogs can be downloaded at the Centre de Donnees Astronomiques de Strasbourg (CDS). Methods. We outline the GASPHOT performances and compare our surface photometry with that obtained by SExtractor, GALFIT and GIM2D. This analysis is aimed at providing statistical information about the accuracy generally achieved by the softwares for automatic surface photometry of galaxies. Results. For each galaxy and for each photometric band the GASPHOT catalogs provide the parameters of the Sersic law best-fitting the luminosity profiles. They are: the sky coordinates of the galaxy center (R:A:; DEC:), the total magnitude (m), the semi-major axis of the effective isophote (Re), the Sersic index (n), the axis ratio (b=a) and a flag parameter (QFLAG) giving a global indication of the fit quality. The WINGS-GASPHOT database includes 41,463 galaxies in the B-band, 42,275 in the V-band, and 71,687 in the K-band. We find that the bright early-type galaxies have larger Sersic indices and effective radii, as well as redder colors in their center. In general the effective radii increase systematically from the K- to the V- and B-band. Conclusions. The GASPHOT photometry turns out to be in fairly good agreement with the surface photometry obtained by GALFIT and GIM2D, as well as with the aperture photometry provided by SExtractor. The main advantages of GASPHOT with respect to other tools are: (i) the automatic finding of the local PSF; (ii) the short CPU time of execution; (iii) the remarkable stability against the choice of the initial guess parameters. All these characteristics make GASPHOT an ideal tool for blind surface photometry of large galaxy samples in wide-field CCD mosaics., Comment: 14 pages, 9 figures
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- 2014
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50. The star formation activity in cosmic voids
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Ricciardelli, Elena, Cava, Antonio, Varela, Jesus, and Quilis, Vicent
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Astrophysics - Astrophysics of Galaxies - Abstract
Using a sample of cosmic voids identified in the Sloan Digital Sky Survey Data Release 7, we study the star formation activity of void galaxies. The properties of galaxies living in voids are compared with those of galaxies living in the void shells and with a control sample, representing the general galaxy population. Void galaxies appear to form stars more efficiently than shell galaxies and the control sample. This result can not be interpreted as a consequence of the bias towards low masses in underdense regions, as void galaxy subsamples with the same mass distribution as the control sample also show statistically different specific star formation rates. This highlights the fact that galaxy evolution in voids is slower with respect to the evolution of the general population. Nevertheless, when only the star forming galaxies are considered, we find that the star formation rate is insensitive to the environment, as the main sequence is remarkably constant in the three samples under consideration. This fact implies that environmental effects manifest themselves as fast quenching mechanisms, while leaving the non-quenched galaxies almost unaffected, as their star formation activity is largely regulated by the mass of their halo. We also analyse galaxy properties as a function of void-centric distance and find that the enhancement in the star formation activity with respect to the control sample is observable up to a radial distance 1.5 Rvoid. This result can be used as a suitable definition of void shells. Finally, we find that larger voids show an enhanced star formation activity in the shells with respect to their smaller counterparts, that could be related to the different dynamical evolution experienced by voids of different sizes., Comment: 11 pages, 10 figures, 1 table. Accepted for publication in MNRAS
- Published
- 2014
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