pinecone/core-2020-05-10-deduplication huggingface dataset:
The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis and bone remodeling

The IL-23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL-23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL-23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL-23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation-mediated joint erosion, IL-23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL-23 in autoimmune arthritis in patients and murine models, and provide an overview of IL-23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL-23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation-mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis
Absence of DCIR1 reduces the mortality rate of endotoxemic hepatitis in mice

Dendritic cell immunoreceptor (DCIR) is a C‐type lectin with an immunoreceptor tyrosine‐based inhibitory motif (ITIM). Mice lacking DCIR1 (Dcir1−/− mice) show higher susceptibility to chronic arthritis with increasing age, suggesting that DCIR1 is involved in immune modulation via its ITIM. However, the role of DCIR1 in acute immune responses is not clear. In this study, we explored its role in acute experimental hepatitis. Upon injection of d‐galactosamine and lipopolysaccharide, Dcir1−/− mice showed decreased mortality rates and serum levels of alanine aminotransferase. In early onset hepatitis, serum levels of TNF‐α, which primarily cause inflammation and hepatocyte apoptosis, were significantly lower in Dcir1−/− mice than in WT mice. In the liver of Dcir1−/− mice, influx of neutrophils and other leukocytes decreased. Consistently, the levels of neutrophil‐chemoattractant chemokine CXCL1/KC, but not CXCL2/MIP‐2, were lower in Dcir1−/− mice than in WT mice. However, chemotaxis of Dcir1−/− neutrophils to CXCL1/KC appeared normal. Pervanadate treatment induced binding of DCIR1 and Src homology region 2 domain‐containing phosphatase (SHP)‐2, possibly leading to CXCL1/KC expression. These results suggest that DCIR1 is involved in exacerbation of endotoxemic hepatitis, providing a new therapeutic target for lethal hepatitis
A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells.

The TNF family cytokines B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) support plasma cell survival. It is known that inhibitors of BAFF only (BAFFR-Fc) or BAFF and APRIL (TACI-Fc) administered early enough in an NZB/NZW F1 mouse model of systemic lupus erythematosus (SLE) ameliorate clinical outcomes, pointing to a pathogenic role of BAFF. In the present study, TACI-Fc administrated at a later stage of disease, after onset of autoimmunity, decreased the number of bone marrow plasma cells and slowed down further formation of autoantibodies. TACI-Fc prevented renal damage during a 12-week treatment period regardless of autoantibody levels, while BAFFR-Fc did not despite a similar BAFF-blocking activity in vivo. TACI-Fc also decreased established plasma cells in a T-dependent hapten/carrier immunization system better than single inhibitors of BAFF or APRIL, and sometimes better than combined single inhibitors with at least equivalent BAFF and APRIL inhibitory activities. These results indicate that TACI-Fc can prevent symptoms of renal damage in a mouse model of SLE when BAFFR-Fc cannot, and point to a plasticity of plasma cells for survival factors. Targeting plasma cells with TACI-Fc might be beneficial to prevent autoantibody-mediated damages in SLE
Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells.

Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN-iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-β when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-β-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders
TCR signalling network organization at the immunological synapses of murine regulatory T cells.

Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCθ, PLCγ1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells
T cell receptor alpha variable 12-2 bias in the immunodominant response to Yellow fever virus.

The repertoire of human αβ T-cell receptors (TCRs) is generated via somatic recombination of germline gene segments. Despite this enormous variation, certain epitopes can be immunodominant, associated with high frequencies of antigen-specific T cells and/or exhibit bias toward a TCR gene segment. Here, we studied the TCR repertoire of the HLA-A*0201-restricted epitope LLWNGPMAV (hereafter, A2/LLW) from Yellow Fever virus, which generates an immunodominant CD8 &lt;sup&gt;+&lt;/sup&gt;  T cell response to the highly effective YF-17D vaccine. We discover that these A2/LLW-specific CD8 &lt;sup&gt;+&lt;/sup&gt;  T cells are highly biased for the TCR α chain TRAV12-2. This bias is already present in A2/LLW-specific naïve T cells before vaccination with YF-17D. Using CD8 &lt;sup&gt;+&lt;/sup&gt;  T cell clones, we show that TRAV12-2 does not confer a functional advantage on a per cell basis. Molecular modeling indicated that the germline-encoded complementarity determining region (CDR) 1α loop of TRAV12-2 critically contributes to A2/LLW binding, in contrast to the conventional dominant dependence on somatically rearranged CDR3 loops. This germline component of antigen recognition may explain the unusually high precursor frequency, prevalence and immunodominance of T-cell responses specific for the A2/LLW epitope
Siglec-1 inhibits RSV-induced interferon gamma production by adult T cells in contrast to newborn T cells

Interferon gamma (IFN-γ) plays an important role in the antiviral immune response during respiratory syncytial virus (RSV) infections. Monocytes and T cells are recruited to the site of RSV infection, but it is unclear whether cell-cell interactions between monocytes and T cells regulate IFN-γ production. In this study, micro-array data identified the upregulation of sialic acid-binding immunoglobulin-type lectin 1 (Siglec-1) in human RSV-infected infants. In vitro, RSV increased expression of Siglec-1 on healthy newborn and adult monocytes. RSV-induced Siglec-1 on monocytes inhibited IFN-γ production by adult CD4+ T cells. In contrast, IFN-γ production by RSV in newborns was not affected by Siglec-1. The ligand for Siglec-1, CD43, is highly expressed on adult CD4+ T cells compared to newborns. Our data show that Siglec-1 reduces IFN-γ release by adult T cells possibly by binding to the highly expressed CD43. The Siglec-1-dependent inhibition of IFN-γ in adults and the low expression of CD43 on newborn T cells provides a better understanding of the immune response against RSV in early life and adulthood
Expression of Plet1 controls interstitial migration of murine small intestinal dendritic cells.

Under homeostatic conditions, dendritic cells (DCs) continuously patrol the intestinal lamina propria. Upon antigen encounter, DCs initiate C-C motif chemokine receptor 7 (CCR7) expression and migrate into lymph nodes to direct T cell activation and differentiation. The mechanistic underpinnings of DC migration from the tissues to lymph nodes have been largely elucidated, contributing greatly to our understanding of DC functionality and intestinal immunity. In contrast, the molecular mechanisms allowing DCs to efficiently migrate through the complex extracellular matrix of the intestinal lamina propria prior to antigen encounter are still incompletely understood. Here we show that small intestinal murine CD11b &lt;sup&gt;+&lt;/sup&gt;  CD103 &lt;sup&gt;+&lt;/sup&gt;  DCs express Placenta-expressed transcript 1 (Plet1), a glycophoshatidylinositol (GPI)-anchored surface protein involved in migration of keratinocytes during wound healing. In the absence of Plet1, CD11b &lt;sup&gt;+&lt;/sup&gt;  CD103 &lt;sup&gt;+&lt;/sup&gt;  DCs display aberrant migratory behavior, and accumulate in the small intestine, independent of CCR7 responsiveness. RNA-sequencing indicated involvement of Plet1 in extracellular matrix-interactiveness, and subsequent in-vitro migration assays revealed that Plet1 augments the ability of DCs to migrate through extracellular matrix containing environments. In conclusion, our findings reveal that expression of Plet1 facilitates homeostatic interstitial migration of small intestinal DCs
Neutral and Cationic [Bis(η1-amidosilyl)-η5-cyclopentadienyl]titanium and -zirconium complexes: synthesis, X-ray molecular structures and DFT calculations

Treatment of LiNHtBu with THF solutions of C5H4(SiMe2Cl)2 gave C5H4(SiMe2NHtBu)2 (1). Deprotonation of 1 with M(NMe2)4 (M = Ti, Zr) under different conditions provided the monocyclopentadienyl complexes [M{η5-C5H3- [SiMe2(NHtBu)]2}(NMe2)3] [M = Ti (2), Zr (3)] and the single (η-amidosilyl)cyclopentadienyl compounds [M{η5-C5H3[SiMe2(NHtBu)][SiMe2(η1-NtBu)]}(NMe2)2] [M = Ti (4), Zr (5)]. The related dibenzyl compounds [M{η5-C5H3[SiMe2- (NHtBu)][SiMe2(η1-NtBu)]}(CH2Ph)2] [M = Ti (6), Zr (7)] resulted from treatment of 1 with M(CH2C6H5)4 (M = Ti, Zr). Further deprotonation of the amido complexes 4 and 5 and the benzyl complexes 6 and 7 by heating in toluene solution gave the bis(η-amidosilyl)cyclopentadienyl complexes [M{η5-C5H3[SiMe2(η1-NtBu)]2}(NMe2)] [M = Ti (8), Zr (9)] and [M{η5-C5H3[SiMe2(η1-NtBu)]2}(CH2Ph)] [M = Ti (10), Zr (11)], respectively. Treatment of the monobenzyl complexes 10 and 11 with B(C6F5)3 yielded the cationic compounds [M{η5-C5H3[SiMe2(η1-NtBu)]2}]+ as [(CH2Ph)B(C6F5)3] − [M = Ti (12), Zr (13)] salts. All new compounds were characterized by NMR spectroscopy, and the crystal structures of 10 and 13 were studied by diffraction methods. DFT calculations for the neutral and cationic species are described and provide an explanation for the unusual η1 coordination of a phenyl ring to a group-4 metal cationThe authors acknowledge the MCyT (project MAT2001-1309) for\ud
financial support and the EC (project COST-D12/0016/98). J. C.\ud
acknowledges CAM for a fellowship
Kinetic studies of the oxidative addition and transmetallation steps involved in the cross-coupling of alkynyl stannanes with aryl iodides catalysed by eta(2)-(dimethyl fumarate)(iminophosphane)palladium(0) complexes

The complexes [Pd(eta(2)-dmfu)(P-N)] {dmfu = dimethyl fumarate; P-N = 2-(PPh2)C6H4-1-CH=NR, R = C6H4OMe-4 (1a), CHMe2 (2a), C6H3Me2-2,6 (3a), C6H3(CHMe2)(2)-2,6 (4a)} undergo dynamic processes in solution which consist of a P-N ligand site exchange through initial rupture of the Pd-N bond at lower energy and an olefin dissociation-association at higher energy. According to equilibrium constant values for olefin replacement, the complex [Pd(eta(2)-fn)(P-N)] (fn = fumaronitrile, 1b) has a greater thermodynamic stability than its dmfu analogue 1a. The kinetics of the oxidative addition of ArI (Ar = C6H4CF3-4) to 1a and 2a lead to the products [PdI(Ar)(P-N)] (1c, 2c) and obey the rate law, k(obs) = k(1A) + k(2A)[ArI]. The k(1A) step involves oxidative addition to a reactive species [Pd(solvent)(P-N)] formed from dmfu dissociation. The k2A step is better interpreted in terms of oxidative addition to a species [Pd(eta(2) -dmfu) (solvent) (kappa(1)-P-N)] formed in a pre-equilibrium step from Pd-N bond breaking. The complexes 1c and 2c react with PhCequivalent toCSnBu(3) in the presence of an activated olefin (ol = dmfu, fn) to yield the palladium(0) derivatives [Pd(eta(2)-ol)(P-N)] along with lSnBu(3) and PhCequivalent toCAr. The kinetics of the transmetallation step, which is rate-determining for the overall reaction, obey the rate law: k(obs) = k(2T)[PhCequivalent toCSnBu(3)]. The k(2T) values are markedly enhanced in more polar solvents such as CH3CN and DMF. The solvent effect and the activation parameters suggest an associative S(E)2 mechanism with substantial charge separation in the transition state. The kinetic data of the above reactions in various solvents indicate that, for the cross-coupling of PhCequivalent toCSnBu(3) with ArI catalysed by 1a or 2a, the rate-determining step is represented by the oxidative addition and that CH3CN is the solvent in which the highest rates are observed. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004
Peripherally metallated porphyrins: the first examples of meso-η1-palladio(II) and -platinio(II) complexes with chelating diamine ligands

The oxidative addition of bis(dibenzylideneacetone)platinum(0) to meso-bromo-5,15-diarylporphyrins in the presence of PPh3 has been shown to be an effective way of synthesising η1-organoplatinum porphyrins in high yields. This methodology has been extended to synthesise various palladio- and platinioporphyrins that utilise bidentate nitrogen donor ligands [N,N,N’,N’-tetramethylethylenediamine (tmeda) and 2,2’-bipyridyl (bpy)] in order to enforce a cis configuration at the metal centre. The products were characterised by multinuclear NMR and UV-visible spectroscopies as well as fast atom bombardment and high-resolution electrospray ionisation mass spectrometries
Direct synthesis of tricarbonyl(cyclopentadienyl)rhenium and tricarbonyl(cyclopentadienyl)technetium units from ferrocenyl moieties - Preparation of 17 alpha-ethynylestradiol derivatives bearing a tricarbonyl(cyclopentadienyl)technetium group

The preparation of new tricarbonyl(cyclopentadienyl)rhenium and tricarbonyl(cyclopentadienyl)technetium derivatives is described. The approach used was applied to a cold target model, 17alpha-ethynylestradiol substituted at the 17alpha position by a ketotricarbonyl(cyclopentadienyl)rhenium group. The novel organometallic reaction applied here, when extended to potential radiopharmaceuticals, consists of a cyclopentadienyl-ligand transfer between ketoferrocenes and fac-Tc-99m(H2O)(3)(CO)(3)](+) in a water/DMSO 1:1 mixture. This reaction lead to the synthesis of a new estradiol derivative, labeled with Tc-99m. The synthesis of another product was performed by using (TcCl3)-Tc-99(CO)(3)](2-) as the Tc precursor and its X-ray crystal structure was determined. In each case high yields were obtained. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004
Studies related to the chloro titanium and zirconium complexes with [η5-Cyclopentadienyldi(silylamido)] Ligands

Trichloro complexes [M{η5-C5H3[SiMe2(NHtBu)]2}Cl3] [M = Zr (2), Ti (3)] have been synthesized by reaction of the corresponding chlorides MCl4 with the lithium salt LiC5H3[SiMe2(NHtBu)]2 (1). Complexes 2 and 3 react with 2 equiv. of TiCl4 in toluene at 110°C to afford the di(chlorosilyl) derivatives [M{η5-C5H3(SiMe2Cl)2}Cl3] [M = Ti (5), Zr (8)]. Intermediate formation of [Ti{η5-C5H3[SiMe2(NHtBu)](SiMe2Cl)}Cl3] (4) has been proven by NMR spectroscopy. Reaction of 1 with TiCl4 (2 equiv.) in toluene at 110 °C in the presence of excess NEt3 has yielded the chloro-silyl complex [Ti{η5-C5H3(SiMe2Cl)(SiMe2-η1-NtBu)}Cl2] (7) through the intermediate formation of the amino-silyl derivative [Ti{η5-C5H3[SiMe2(NHtBu)] (SiMe2-η1-NtBu)}Cl2] (6). Reactions of di-ansa-[M{η5-C5H3(SiMe2-η1-NtBu)2}R] and ansa-[M{η5-C5H3[SiMe2(NHtBu)] (SiMe2-η1-NtBu)}R2] (M = Ti, Zr; R = NMe2, CH2Ph) complexes with NEt3·HCl have afforded the dichloro derivatives [M{η5-C5H3[SiMe2(NHtBu)] (SiMe2-η1-NtBu)}Cl2] [M = Ti (6), Zr (12)], the amine-coordinated zirconium compound [Zr{η5-C5H3 [SiMe2(NHtBu)](SiMe2-η1-NtBu)} Cl2(NMe2H)] (9) and the chloro-benzyl titanium complex [Ti{η5-C5H3[SiMe2(NHtBu)](SiMe2-η1-NtBu)}Cl(CH2Ph)] (11). Formation of the mono-substituted chloroamido zirconium complex [Zr{η5-C5H3[SiMe2 (NHtBu)](SiMe2-η1-NtBu)}Cl(NMe2)] (10) by the reaction of [Zr{η5-C5H3[SiMe2(NHtBu)] (SiMe2-η1-NtBu)}(NMe2)2] with SiClMe3 has been monitored in C6D6 by NMR spectroscopy. All of the new chloro complexes have been characterized by elemental analyses and NMR spectroscopy and the X-ray crystal structure of [Ti(η5-C5H3{SiMe2(NHtBu)}2)Cl3] (3) has been studied by diffraction methods.Ministerio de Educación, Cultura y DeporteComunidad de Madri
Diastereoselective insertion of isocyanide into the alkyl metal bond of methylbenz[e]indenyl ansa-zirconocene complexes

Alkylation of ansa-zirconocene [Zr{(η5-C5H5)SiMe2(MBI)}Cl2] (MBI = η5-2-Me−C13H7) with MgRCl gave the dimethyl complex [Zr{(η5-C5H5)SiMe2(MBI)}Me2], but unresolvable mixtures containing mono-alkylated compounds were obtained when bulkier alkyls were used. However pure dialkyl complexes [Zr{(η5-C5H5)SiMe2(MBI)}R2] (R = CH2Ph, CH2SiMe3) were easily obtained using K(CH2Ph) and Li(CH2SiMe3) as alkylating agents. Diastereoselective insertion into the MBI-unprotected Zr−R bond was observed when all of these dialkyl complexes were treated with 2,6-xylyl isocyanide to give the iminoacyl compounds [Zr{(η5-C5H5)SiMe2(MBI)}R{CR[η2-N-(2,6-xylyl)]}] (R = Me, CH2Ph, CH2SiMe3). All of the new complexes were characterized by NMR spectroscopy and the X-ray molecular structures of the dibenzyl and the imino-benzyl compounds were determined. The catalytic activity for ethene polymerization and ethene/1-hexene copolymerization of the dichloro zirconocenes [Zr{(η5-C5H5)EMe2(MBI)}Cl2] (E = C, Si), activated with methylalumoxane (MAO), was measured.Repsol-YP
NMR T1-Relaxation Measurements on Paramagnetic Organolanthanides: An Alternative Tool for Structure Determination in Solution

1H NMR investigations were conducted on four paramagnetic organolanthanides all bearing the tetraisopropylcyclopentadienyl Cp4i ligand (Cp4i = HC5iPr4) in order to verify whether or not interactions observed in the solid state were maintained in solution. In some cases, variable temperature experiments were necessary to enhance the resolution and determine the best conditions of study. 1D NMR spectrum could be interpreted in every case. Complementary 2D COSY experiments allowed the full attribution of the signals. T1 (1H) relaxation measurements were determined for all the paramagnetic complexes at the most suitable temperature, and compared to those of the diamagnetic KCp4i. The same tendency was observed, with particular features concerning the isopropyl groups. Among the four methyl groups, one exhibits a much higher T1 value, one a much lower and the two others are intermediate. This was interpreted as the result of a privilegied conformation of the Cp4i ligand: the two a-isopropyl groups take a spatial orientation with one methyl in exo position, opposite to the metal, whereas the methyl groups of the two b-isopropyl are quite equidistant from the metal. Whatever the nature of the metal (Nd, Sm), the oxidation state (SmII, SmIII), or the temperature (298, 363 K), this conformation is retained. The structure in solution seems to be different from that previously determined in the solid state
Stereoisomerism in pentaerythritol-bridged cyclotriphosphazene tri-spiranes: spiro and ansa 1,3-propanediyldioxy disubstituted derivatives

Four isomeric products were isolated and purified from the reaction of 1,3-propanediol with the tetra-spirane cyclophosphazene-organophosphate compound (1): viz. the di-monospiro (2a), di-monoansa (2b) and two monospiro-monoansa derivatives (2c) and (2d).  It is shown by 31P NMR spectroscopy on addition of a chiral solvating agent (CSA) that both the di-monospiro (2a) and di-monoansa (2b) derivatives are racemates, as expected, whereas no splitting of NMR signals occurred on addition of CSA to solutions of (2c) and (2d).  It is found by X-ray crystallography that the two monospiro-monoansa spirane derivatives, (2c) and (2d), are meso diastereoisomers, which represent a new case of the stereochemistry of bis di-substituted cyclophosphazene derivatives of (1). It is also observed from the 31P NMR spectrum of the reaction mixture, supported by the yields of pure compounds, that formation of a spiro group is about 4.5 times more likely than that of an ansa moiety under the conditions of the reaction
Synthesis, electrochemical and spectroscopic properties of molybdenum  complexes bearing 5-alkoxy-thiophenic or- bithiophenic groups

Trans-[FMo{NN=CH(5´-R-thienyl)}(dppe)2][BF4]  (R  =  OMe  and  OEt)  and  trans[FMo{NN=CH(5’-R-2,2’-bithienyl)}(dppe)2][BF4] (R = OMe, OEt and O(iPr)) were synthesised  in  good  yields  by  reacting  2-formyl-5-alkoxylthiophenes  and    5-formyl-5’-alkoxy-2,2-’bithiophenes  respectively,  with  hydrazido(2-)  complex,  trans-[MoF(NNH2)(dppe)2][BF4].  The  electrochemical, spectroscopic and solvatochromic properties of these compounds were studied.  These results suggest that efficient π conjugated systems were obtained due to the low energy  charge transfer between the metal and the heterocyclic moieties.Fundação para a Ciência e a Tecnologia (FCT