Aim
To evaluate the impact of a psychoeducational, mobile health intervention based on cognitive behavioural therapy and mindfulness‐based approaches on the mental health of healthcare workers at the ...frontline against COVID‐19 in Spain.
Design
We will carry out a two‐week, individually randomized, parallel group, controlled trial. Participants will be individually randomized to receive the PsyCovidApp intervention or control App intervention.
Methods
The PsyCovidApp intervention will include five modules: emotional skills, lifestyle behaviour, work stress and burnout, social support, and practical tools. Healthcare workers having attended patients with COVID‐19 will be randomized to receive the PsyCovidApp intervention (intervention group) or a control App intervention (control group). A total of 440 healthcare workers will be necessary to assure statistical power. Measures will be collected telephonically by a team of psychologists at baseline and immediately after the 2 weeks intervention period. Measures will include stress, depression and anxiety (DASS‐21 questionnaire—primary endpoint), insomnia (ISI), burnout (MBI‐HSS), post‐traumatic stress disorder (DTS), and self‐efficacy (GSE). The study was funded in May 2020, and was ethically approved in June 2020. Trial participants, outcome assessors and data analysts will be blinded to group allocation.
Discussion
Despite the increasing use of mobile health interventions to deliver mental health care, this area of research is still on its infancy. This study will help increase the scientific evidence about the effectiveness of this type of intervention on this specific population and context.
Impact
Despite the lack of solid evidence about their effectiveness, mobile‐based health interventions are already being widely implemented because of their low cost and high scalability. The findings from this study will help health services and organizations to make informed decisions in relation to the development and implementation of this type of interventions, allowing them pondering not only their attractive implementability features, but also empirical data about its benefits.
Clinical trial registration
NCT04393818 (ClinicalTrials.gov identifier).
Approved funding
May 2020.
Reactions of the heterometallic MoRe complex MoReCp(μ-PR*)(CO)6 and its MoMn analogue with some small molecules having N–N multiple bonds, such as diazoalkanes and organic azides, were investigated ...(R* = 2,4,6-C6H2 t Bu3). Reactions with excess ethyl diazoacetate proceeded slowly and with concomitant denitrogenation to give complexes MoMCp(μ-η2 P,C:κ2 P,O-PR*CHCO2Et)(CO)5, which display a bridging phosphaalkene ligand in a novel μ-η2:κ2 coordination mode, while reactions with other diazoalkanes resulted only in the decomposition of the organic reagent. The MoRe complex reacted with benzyl- or p-tolyl azide at room temperature to give the green complexes MoReCp(μ-η2 P,N:κP,N′ 2-PR*N3R)(CO)6 R = Bn, p-tol, which display bridging phosphatriazadiene ligands in a novel 6-electron donor coordination mode as a result of a formal 2 + 1 cycloaddition of the terminal N atom of the azide to the Mo–P double bond of the parent complex, followed by coordination of the distal NR nitrogen to the rhenium center. Denitrogenation was only observed for the p-tolyl azide derivative, which upon heating at 333 K yielded MoReCp{μ-κP:κN-PR*N(p-tol)}(CO)6, a molecule displaying a bridging phosphaimine ligand in a rare κP:κN coordination mode. Analogous reactions of the MoMn phosphinidene complex proceeded similarly at 273 K to give the phosphatriazadiene-bridged derivatives MoMnCp(μ-η2 P,N:κ2 P,N′-PR*N3R)(CO)6, but these were thermally unstable and degraded at room temperature to give the mononuclear triazenylphosphanyl complexes Mn2(κP,N-PR*NHNNR)(CO)3 as major products, along with small amounts of the phosphaimine-bridged complex MoMnCp{μ-κP:κN-PR*N(p-tol)}(CO)6 in the case of the p-tolyl azide derivative. The structure of the new complexes was analyzed in light of spectroscopic data and single-crystal diffraction studies on selected examples of each type of complex.
The triphosphorus complex Mo2Cp2(μ-η3:η3-P3)(μ-P t Bu2) was prepared in 83% yield by reacting the methyl complex Mo2Cp2(μ-κ1:η2-CH3)(μ-P t Bu2)(μ-CO) with P4 at 333 K, a process also giving small ...amounts of the methyldiphosphenyl complex Mo2Cp2(μ-η2:η2-P2Me)(μ-P t Bu2)(CO)2. The latter could be better prepared by first reacting the anionic complex NaMo2Cp2(μ-P t Bu2)(μ-CO)2 with P4 to give the diphosphorus derivative NaMo2Cp2(μ-η2:η2-P2)(μ-P t Bu2)(CO)2 and further reaction of the latter with MeI. Density functional theory calculations on the title complex revealed that its triphosphorus group can be viewed as an allylic-like P3 – ligand acting as a six-electron donor via the external P atoms, while coordination of the internal P atom involves donation from the π orbital of the ligand and back-donation to its π* orbital, both interactions having a weakening effect on the Mo–Mo and P–P connections. The reactivity of the title compound is dominated by the electron-donor ability associated with the lone pairs located at the P atoms. Its reaction with CF3SO3Me gave Mo2Cp2(μ-η3:η3-P3Me)(μ-P t Bu2)(CF3SO3) as a result of methylation at an external atom of the P3 ligand, while its reaction with Fe2(CO)9 enabled the addition of one, two, or three Fe(CO)4 fragments at these P atoms, but only the diiron derivative Mo2Fe2Cp2(μ-η3:η3:κ1:κ1-P3)(μ-P t Bu2)(CO)8 could be isolated. This complex bears a Fe(CO)4 fragment at each of the external atoms of the P3 ligand, and the central P atom of the latter displays the lowest 31P chemical shift reported to date (δP −721.8 ppm). The related complexes Mo2M2Cp2(μ-η3:η3:κ1:κ1-P3)(μ-P t Bu2)(CO)10 (M = Mo, W) were prepared by reacting the title compound with the corresponding M(CO)5(THF) complexes in toluene, while reaction with Mo(CO)4(THF)2 also enabled the formation of the heptanuclear derivative Mo7Cp4(μ-η3:η3:κ1:κ1-P3)2(μ-P t Bu2)2(CO)14. The interatomic distances in the above compounds indicate that the central Mo2P3 skeleton of these molecules is little modified by the attachment of 16-electron M(CO) n fragments at the external atoms of the P3 ligand.
Reactions of MoReCp(μ-PMes*)(CO)6 with internal alkynes RCCR yielded the phosphapropenylidene-bridged complexes MoReCp(μ-κ2 P,C:η3-PMes*CRCR)(CO)5 (Mes* = 2,4,6-C6H2 t Bu3; R = CO2Me, Ph). ...Terminal alkynes HCCR1 gave mixtures of isomers MoReCp(μ-κ2 P,C:η3-PMes*CHCR1)(CO)5 and MoReCp(μ-κ2 P,C:η3-PMes*CR1CH)(CO)5, with the first isomer being major (R1 = CO2Me) or unique (R1 = t Bu), indicating the relevance of steric repulsions during the 2 + 2 cycloaddition step between MoP and CC bonds in these reactions. Similar reactions were observed for MoMnCp(μ-PMes*)(CO)6. Addition of ligands to these complexes promoted rearrangement of the phosphapropenylidene ligand into the allyl-like μ-η3:κ1 C mode, as shown by the reaction of MoReCp(μ-κ2 P,C:η3-PMes*CHC(CO2Me)}(CO)5 with CN(p-C6H4OMe) to give MoReCp{μ-η3:κ1 C-PMes*CHC(CO2Me)}(CO)5{CN(p-CH4OMe)}2. The MoRe phosphinidene complex reacted with SCNPh to give as major products the phosphametallacyclic complex MoReCp{μ-κ2 P,S:κ2 P,S-PMes*C(NPh)S}(CO)5 and its thiophosphinidene-bridged isomer MoReCp(μ-η2:κ1 S-SPMes*)(CO)5(CNPh). The first product follows from a 2 + 2 cycloaddition between MoP and CS bonds, with specific formation of PC bonds, whereas the second one would arise from the alternative cycloaddition involving the formation of PS bonds, more favored on steric grounds. The prevalence of the μ-η2:κ1 S coordination mode of the SPMes* ligand over the μ-η2:κ1 p mode was investigated theoretically to conclude that steric congestion favors the first mode, while the kinetic barrier for interconversion between isomers is low in any case.
Reactions of complexes MoMCp(μ-PMes*)(CO)6 with H2 and several p-block element (E) hydrides mostly resulted in the cleavage of E–H bonds under mild conditions M = Re (1a) and Mn (1b); Mes* = ...2,4,6-C6H2 t Bu3. The reaction with H2 (ca. 4 atm) proceeded even at 295 K to give the hydrides MoMCp(μ-H)(μ-PHMes*)(CO)6. The same result was obtained in the reactions with H3SiPh and, for 1a, upon reduction with Na(Hg) followed by protonation of the resulting anion MoReCp(μ-PHMes*)(CO)6−. The latter reacted with AuCl{P(p-tol)3} to yield the related heterotrimetallic cluster MoReAuCp(μ-PHMes*)(CO)6{P(p-tol)3}. The reaction of 1a with thiophenol gave the thiolate-bridged complex MoReCp(μ-PHMes*)(μ-SPh)(CO)6, which evolved readily to the pentacarbonyl derivative MoReCp(μ-PHMes*)(μ-SPh)(CO)5. In contrast, no P–H bond cleavage was observed in reactions of complexes 1a,b with PHCy2, which just yielded the substituted derivatives MoMCp(μ-PMes*)(CO)5(PHCy2). Reactions with HSnPh3 again resulted in E–H bond cleavage, but now with the stannyl group terminally bound to M, while 1a reacted with BH3·PPh3 to give the hydride-bridged derivatives MoReCp(μ-H)(μ-PHMes*)(CO)5(PPh3) and MoReCp(μ-H){μ-P(CH2CMe2)C6H2 t Bu2}(CO)5(PPh3), which follow from hydrogenation, C–H cleavage, and CO/PPh3 substitution steps. Density functional theory calculations on the PPh-bridged analogue of 1a revealed that hydrogenation likely proceeds through the addition of H2 to the MoP double bond of the complex, followed by rearrangement of the Mo fragment to drive the resulting terminal hydride into a bridging position.
Reactions of MoReCp(μ-PR*)(CO)6 with S8 were strongly dependent on experimental conditions (R* = 2,4,6-C6H2 t Bu3). When using 1 equiv of sulfur, complex MoReCp(μ-η2:κ1 S-SPR*)(CO)6 was slowly ...formed at 313 K, with a thiophosphinidene ligand unexpectedly bridging the dimetal center in the novel μ-κ1 S:η2 coordination mode, as opposed to the μ-κ1 P:η2 mode usually found in related complexes. The latter underwent fast decarbonylation at 363 K to give MoReCp(μ-η2:η2-SPR*)(CO)5, with a six-electron donor thiophosphinidene ligand rearranged into the rare μ-η2:η2 coordination mode. Depending on reaction conditions, reactions with excess sulfur involved the addition of two or three S atoms to the phosphinidene ligand to give new complexes identified as the dithiophosphinidene-bridged complex MoReCp(μ-η2:κ2 S,S′-S2PR*)(CO)5, its dithiophosphonite-bridged isomer MoReCp(μ-κ2 S,S′:κ2 S,S′-S2PR*)(CO)5, or the trithiophosphonate-bridged derivative MoReCp(μ-κ2 S,S′:κ2 S,S′-S3PR*)(CO)5, all of them displaying novel coordination modes of their PRS2 and PRS3 ligands, as determined by X-ray diffraction studies. In contrast, the related MoMn complex yielded MoMnCp(μ-η2:η2-SPR*)(CO)5 under most conditions. A similar output was obtained in reactions with gray selenium for either MoRe or MoMn phosphinidene complexes, which under different conditions only gave the pentacarbonyl complexes MoMCp(μ-η2:η2-SePR*)(CO)5 (M = Re, Mn), these providing a new coordination mode for selenophosphinidene ligands.
TGF-β signaling is a therapeutic target in advanced cancers. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a key component mediating pro-oncogenic TGF-β-induced SMAD ...and non-SMAD signaling. Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-β type I receptor (TβRI). Both processes contribute to TβRI stabilization on the plasma membrane and thereby enhance TGF-β signaling. In addition, the TGF-β receptor-TRAF4 interaction triggers Lys 63-linked TRAF4 polyubiquitylation and subsequent activation of the TGF-β-activated kinase (TAK)1. TRAF4 is required for efficient TGF-β-induced migration, epithelial-to-mesenchymal transition, and breast cancer metastasis. Elevated TRAF4 expression correlated with increased levels of phosphorylated SMAD2 and phosphorylated TAK1 as well as poor prognosis among breast cancer patients. Our results demonstrate that TRAF4 can regulate the TGF-β pathway and is a key determinant in breast cancer pathogenesis.
•TRAF4 mediates efficient activation of TGF-β-initiated SMAD and non-SMAD signaling•TRAF4 targets SMURF2 degradation and TAK1 activation on TGF-β receptor complex•TRAF4 is needed for efficient TGF-β-induced EMT and metastasis•TRAF4 amplification correlates with SMAD/TAK1 activation and poor prognosis
The heterometallic complex MoReCp(μ-PR*)(CO)6 (3) was prepared in 60% overall yield from syn-MoCp(PHR*)(CO)2 via a three-step procedure involving complexes syn-MoCp(PClR*)(CO)2 and ...MoReCp(μ-PR*)(CO)7 as intermediate species (R* = 2,4,6-C6H2 t Bu3). The PR* ligand in 3 displays a novel asymmetric interaction with the dimetal center, involving a double bond with one atom (Mo) and a dative single bond with the other one (Re). Compound 3 underwent thermal isomerization involving a C–H bond cleavage to yield the hydride MoReCp(μ-H){μ-P(CH2CMe2)C6H2 t Bu2}(CO)6 and reacted with I2 to give MoReCpI2(μ-PR*)(CO)6, which displays a symmetrical phosphinidene bridge. Its reaction with methyl propiolate at 293 K proceeded with 2 + 2 cycloaddition of the alkyne and decarbonylation to yield the phosphapropenylidene-bridged complex MoReCp{μ-κ2 P,C:η3-PR*CHC(CO2Me)}(CO)5 as the major product, whereas its reaction with excess CN(4-C6H4OMe) at 273 K proceeded with formal 2 + 1 cycloaddition of the isocyanide and further isocyanide addition at the Re site to yield the complex MoReCp{μ-η2 P,C:κ1 P-PR*CN(4-C6H4OMe)}(CO)6{CN(4-C6H4OMe)}, which displays an azaphosphaallene ligand in a novel bridging coordination mode.
Extended reduction of Mo2Cp2(μ-Cl)(μ-P t Bu2)(NO)2 (1) with Na(Hg) in acetonitrile (MeCN) at room temperature resulted in an unprecedented full cleavage of the CN bond of a coordinated MeCN ...molecule to yield the vinylidene derivative NaMo2Cp2(μ-P t Bu2)(μ-CCH2)(NO)2, which upon protonation with (NH4)PF6 gave the ethylidyne complex Mo2Cp2(μ-P t Bu2)(μ-CMe)(NO)2 Mo1–Mo2 = 2.9218(2) Å in a selective and reversible way. Controlled reduction of 1 at 273 K yielded instead, after protonation, the 30-electron acetamidinate complex Mo2Cp2(μ-P t Bu2)(μ-κN:κN′-HNCMeNH)(μ-NO)PF6 Mo1–Mo2 = 2.603(2) Å, in a process thought to stem from the paramagnetic MeCN-bridged intermediate Mo2Cp2(μ-P t Bu2)(μ-NCMe)(NO)2, followed by a complex sequence of elementary steps including cleavage of the NO bond of a nitrosyl ligand.
Complex Mo2Cp2(μ-PCy2)(μ-NO)(NO)2 (1) was prepared by reacting Mo2Cp2(μ-H)(μ-PCy2)(CO)4 with 2 equiv of NOBF4 and then treating the resulting product Mo2Cp2(μ-PCy2)(CO)2(NO)2(BF4) with NaNO2 ...at 323 K, and it was shown to display a bridging nitrosyl ligand with significant pyramidalization at the N atom, a circumstance related to an unusual behavior concerning degradation of the bridging nitrosyl. Indeed, complex 1 reacts with HBF4·OEt2 to give the nitroxyl-bridged derivative Mo2Cp2(μ-PCy2)(μ-κ1:η2-HNO)(NO)2(BF4), is reduced by Zn(Hg) in the presence of trace H2O to give the amido complex Mo2Cp2(μ-PCy2)(μ-NH2)(NO)2, and reacts with excess P(OPh)3 to give the phosphoraniminato-bridged derivative Mo2Cp2(μ-PCy2){μ-NP(OPh)3}(NO)2.
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