Catalytic N-H Bond Formation Promoted by a Ruthenium Hydride Complex Bearing a Redox-Active Pyrimidine-Imine Ligand.

The synthesis of a piano-stool ruthenium hydride, [(η5-C5Me5)Ru(PmIm)H] (PmIm = (N-(1,3,5-trimethylphenyl)-1-(pyrimidin-2-yl)ethan-1-imine), for the dual purpose of catalytic dihydrogen activation and subsequent hydrogen atom transfer for the formation of weak chemical bonds is described. The introduction of a neutral, potentially redox-active PmIm supporting ligand was designed to eliminate the possibility of deleterious C(sp2)-H reductive coupling and elimination that has been identified as a deactivation pathway with related rhodium and iridium catalysts. Treatment of [(η5-C5Me5)RuCl2]n with one equivalent PmIm ligand in the presence of zinc and sodium methoxide resulted in the isolation of the diruthenium complex, [(η5-C5Me5)Ru(PmIm)]2, arising from the C-C bond formation between two PmIm chelates. Addition of H2 to the ruthenium dimer under both thermal and blue light irradiation conditions furnished the targeted hydride, [(η5-C5Me5)Ru(PmIm)H], which has a relatively weak DFT-calculated Ru-H bond dissociation free energy (BDFE) of 47.9 kcal/mol. Addition of TEMPO to [(η5-C5Me5)Ru(PmIm)H] generated the 17-electron metalloradical, [(η5-C5Me5)Ru(PmIm)], which was characterized by EPR spectroscopy. The C-C bond forming process was reversible as the irradiation of [(η5-C5Me5)Ru(PmIm)]2 generated [(η5-C5Me5)Ru(PmIm)H] and a piano-stool ruthenium complex containing an enamide ligand derived from H-atom abstraction from the PmIm chelate. Equilibration studies were used to establish an experimental estimate of the effective Ru-H BDFE, and a value of 50.8 kcal/mol was obtained, in agreement with the observed loss of H2 and the DFT-computed value. The ruthenium hydride was an effective catalyst for the thermal catalytic hydrogenation of TEMPO, acridine, and a cobalt-imido complex and for the selective reduction of azobenzene to diphenylhydrazine, highlighting the role of this complex in catalytic weak bond formation using H2 as the stoichiometric reductant.

Mechanistic Investigations of the Asymmetric Hydrogenation of Enamides with Neutral Bis(phosphine) Cobalt Precatalysts.

The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC, and 1-4FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(iPrDuPhos)Co]2(µ2-H)3(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(iPrDuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV-visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-(iPrDuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-(iPrDuPhos)Co(enamide) and H2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H2/D2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-(iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides.

Loss of liver X receptor ß in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice.

Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor ß (LXRß) is expressed in astrocytes, and LXRß global knockout mice shows impaired synaptic formation. In order to define the role of LXRß in astrocytes, we used a conditional Cre-loxP system to specifically remove LXRß from astrocytes. We found that this deletion caused anxiety-like but not depressive-like behaviors in adult male mice. This behavioral phenotype could be completely reproduced by selective deletion of LXRß in astrocytes in the medial prefrontal cortex (mPFC). Pyramidal neurons in layer V of mPFC are involved in mood behaviors. We found that there was an increased spontaneous excitatory synaptic transmission in layer V pyramidal neurons of the mPFC of these mice. This was concurrent with increased dendritic complexity, despite normal appearance and number of dendritic spines. In addition, gene ontology analysis of RNA sequencing revealed that deletion of astrocytic LXRß led to the enrichment of the process of synaptic transmission in mPFC. Finally, we also confirmed that renormalized excitatory synaptic transmission in layer V pyramidal neurons alleviated the anxiety in mice with astrocytic LXRß deletion in mPFC. Together, our findings reveal that astrocytic LXRß in mPFC is critical in the regulation of synaptic transmission, and this provides a potential new target for treatment of anxiety-like behavior.

Oxidative Addition of Aryl and Alkyl Halides to a Reduced Iron Pincer Complex.

The two-electron oxidative addition of aryl and alkyl halides to a reduced iron dinitrogen complex with a strong-field tridentate pincer ligand has been demonstrated. Addition of iodobenzene or bromobenzene to (3,5-Me2MesCNC)Fe(N2)2 (3,5-Me2MesCNC = 2,6-(2,4,6-Me-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) resulted in rapid oxidative addition and formation of the diamagnetic, octahedral Fe(II) products (3,5-Me2MesCNC)Fe(Ph)(N2)(X), where X = I or Br. Competition experiments established the relative rate of oxidative addition of aryl halides as I > Br > Cl. A linear free energy of relative reaction rates of electronically differentiated aryl bromides (ρ = 1.5) was consistent with a concerted-type pathway. The oxidative addition of alkyl halides such as methyl-, isobutyl-, or neopentyl halides was also rapid at room temperature, but substrates with more accessible ß-hydrogen positions (e.g., 1-bromobutane) underwent subsequent ß-hydride elimination. Cyclization of an alkyl halide containing a radical clock and epimerization of neohexyl iodide-d2 upon oxidative addition to (3,5-Me2MesCNC)Fe(N2)2 are consistent with radical intermediates during C(sp3)-X bond cleavage. Importantly, while C(sp2)-X and C(sp3)-X oxidative addition produces net two-electron chemistry, the preferred pathway for obtaining the products is concerted and stepwise, respectively.

Catalyst Design Principles Enabling Intermolecular Alkene-Diene [2+2] Cycloaddition and Depolymerization Reactions.

Aryl-substituted pyridine(diimine) iron complexes promote the catalytic [2 + 2] cycloadditions of alkenes and dienes to form vinylcyclobutanes as well as the oligomerization of butadiene to generate divinyl(oligocyclobutane), a microstructure of poly(butadiene) that is chemically recyclable. A systematic study on a series of iron butadiene complexes as well as their ruthenium congeners has provided insights into the essential features of the catalyst that promotes these cycloaddition reactions. Structural and computational studies on iron butadiene complexes identified that the structural rigidity of the tridentate pincer enables rare s-trans diene coordination. This geometry, in turn, promotes dissociation of one of the alkene arms of the diene, opening a coordination site for the incoming substrate to engage in oxidative cyclization. Studies on ruthenium congeners established that this step occurs without redox involvement of the pyridine(diimine) chelate. Cyclobutane formation occurs from a metallacyclic intermediate by reversible C(sp3)-C(sp3) reductive coupling. A series of labeling experiments with pyridine(diimine) iron and ruthenium complexes support the favorability of accessing the +3 oxidation state to trigger C(sp3)-C(sp3) reductive elimination, involving spin crossover from S = 0 to S = 1. The high density of states of iron and the redox-active pyridine(diimine) ligand facilitate this reactivity under thermal conditions. For the ruthenium congener, the pyridine(diimine) remains redox innocent and irradiation with blue light was required to promote the analogous reactivity. These structure-activity relationships highlight important design principles for the development of next generation catalysts for these cycloaddition reactions as well as the promotion of chemical recycling of cycloaddition polymers.

Synthesis, Electronic Structure, and Reactivity of a Planar Four-Coordinate, Cobalt-Imido Complex.

A four-coordinate cobalt-imido complex, (tBu mPNP)Co=NMes (tBu mPNP=modified PNP pincer ligand) has been synthesized from addition of 2,4,6-trimethylphenylazide (Mes-N3 ) to the corresponding dinitrogen complex. The solid-state structure determined by X-ray diffraction established a rare, idealized planar geometry with a Co=N bond distance of 1.716(2) Å. Magnetic measurements revealed an S=1 ground state with CAS-SCF calculations supporting radical character on the imide nitrogen. Thermolysis of the cobalt-imido compound induced selective insertion of the imido group into a Co-P bond and yielded a three-coordinate cobalt complex with a distorted T-shaped geometry. Transition state analysis conducted with DFT calculations established the thermodynamic stability of the P-N coupled product and provided insight into the exclusive selectivity.

Cobalt-Catalyzed Asymmetric Hydrogenation of α,ß-Unsaturated Carboxylic Acids by Homolytic H2 Cleavage.

The asymmetric hydrogenation of α,ß-unsaturated carboxylic acids using readily prepared bis(phosphine) cobalt(0) 1,5-cyclooctadiene precatalysts is described. Di-, tri-, and tetra-substituted acrylic acid derivatives with various substitution patterns as well as dehydro-α-amino acid derivatives were hydrogenated with high yields and enantioselectivities, affording chiral carboxylic acids including Naproxen, (S)-Flurbiprofen, and a d-DOPA precursor. Turnover numbers of up to 200 were routinely obtained. Compatibility with common organic functional groups was observed with the reduced cobalt(0) precatalysts, and protic solvents such as methanol and isopropanol were identified as optimal. A series of bis(phosphine) cobalt(II) bis(pivalate) complexes, which bear structural similarity to state-of-the-art ruthenium(II) catalysts, were synthesized, characterized, and proved catalytically competent. X-band EPR experiments revealed bis(phosphine)cobalt(II) bis(carboxylate)s were generated in catalytic reactions and were identified as catalyst resting states. Isolation and characterization of a cobalt(II)-substrate complex from a stoichiometric reaction suggests that alkene insertion into the cobalt hydride occurred in the presence of free carboxylic acid, producing the same alkane enantiomer as that from the catalytic reaction. Deuterium labeling studies established homolytic H2 (or D2) activation by Co(0) and cis addition of H2 (or D2) across alkene double bonds, reminiscent of rhodium(I) catalysts but distinct from ruthenium(II) and nickel(II) carboxylates that operate by heterolytic H2 cleavage pathways.

Catalytic Hydrogenation of a Manganese(V) Nitride to Ammonia.

The catalytic hydrogenation of a metal nitride to produce free ammonia using a rhodium hydride catalyst that promotes H2 activation and hydrogen-atom transfer is described. The phenylimine-substituted rhodium complex (η5-C5Me5)Rh(MePhI)H (MePhI = N-methyl-1-phenylethan-1-imine) exhibited higher thermal stability compared to the previously reported (η5-C5Me5)Rh(ppy)H (ppy = 2-phenylpyridine). DFT calculations established that the two rhodium complexes have comparable Rh-H bond dissociation free energies of 51.8 kcal mol-1 for (η5-C5Me5)Rh(MePhI)H and 51.1 kcal mol-1 for (η5-C5Me5)Rh(ppy)H. In the presence of 10 mol% of the phenylimine rhodium precatalyst and 4 atm of H2 in THF, the manganese nitride (tBuSalen)Mn≡N underwent hydrogenation to liberate free ammonia with up to 6 total turnovers of NH3 or 18 turnovers of H• transfer. The phenylpyridine analogue proved inactive for ammonia synthesis under identical conditions owing to competing deleterious hydride transfer chemistry. Subsequent studies showed that the use of a non-polar solvent such as benzene suppressed formation of the cationic rhodium product resulting from the hydride transfer and enabled catalytic ammonia synthesis by proton-coupled electron transfer.

Pyridine(diimine) Iron Diene Complexes Relevant to Catalytic [2+2]-Cycloaddition Reactions.

The synthesis, characterization, and catalytic activity of pyridine(diimine) iron piperylene and isoprene complexes are described. These diene complexes are competent precatalysts for (i) the selective cross-[2+2]-cycloaddition of butadiene or (E)-piperylene with ethylene and α-olefins and (ii) the 1,4-hydrovinylation of isoprene with ethylene. In the former case, kinetic analysis implicates the diamagnetic η4-piperylene complex as the resting state prior to rate-determining oxidative cyclization. Variable temperature 1H NMR and EXSY experiments established that diene exchange from the diamagnetic, 18e- complexes occurs rapidly in solution at ambient temperature through a dissociative mechanism. The solid-state structure of (Me(Et)PDI)Fe(η4-piperylene) (Me(Et)PDI = 2,6-(2,6-Me2-C6H3N═CEt)2C5H3N), was determined by single-crystal X-ray diffraction and confirmed the s-trans coordination of the monosubstituted 1,3-diene. Possible relationships between ligand-controlled diene coordination geometry, metallacycle denticity, and chemoselectivity of iron-mediated cycloaddition reactions are discussed.

Synthesis and Reactivity of Organometallic Intermediates Relevant to Cobalt-Catalyzed Hydroformylation.

Intermediates relevant to cobalt-catalyzed alkene hydroformylation have been isolated and evaluated in fundamental organometallic transformations relevant to aldehyde formation. The 18-electron (R,R)-(iPr DuPhos)Co(CO)2 H has been structurally characterized, and it promotes exclusive hydrogenation of styrene in the presence of 50 bar of H2 /CO gas (1:1) at 100 °C. Deuterium-labeling studies established reversible 2,1-insertion of styrene into the Co-D bond of (R,R)-(iPr DuPhos)Co(CO)2 D. Whereas rapid ß-hydrogen elimination from cobalt alkyls occurred under an N2 atmosphere, alkylation of (R,R)-(iPr DuPhos)Co(CO)2 Cl in the presence of CO enabled the interception of (R,R)-(iPr DuPhos)Co(CO)2 C(O)CH2 CH2 Ph, which upon hydrogenolysis under 4 atm H2 produced the corresponding aldehyde and cobalt hydride, demonstrating the feasibility of elementary steps in hydroformylation. Both the hydride and chloride derivatives, (X=H- , Cl- ), underwent exchange with free 13 CO. Under reduced pressure, (R,R)-(iPr DuPhos)Co(CO)2 Cl underwent CO dissociation to form (R,R)-(iPr DuPhos)Co(CO)Cl.

Regio- and Diastereoselective Iron-Catalyzed [4+4]-Cycloaddition of 1,3-Dienes.

A family of single-component iron precatalysts for the [4+4]-cyclodimerization and intermolecular cross-[4+4]-cycloaddition of monosubstituted 1,3-dienes is described. Cyclooctadiene products were obtained with high regioselectivity, and catalyst-controlled access to either cis- or trans-diastereomers was achieved using 4-substituted diene substrates. Reactions conducted either with single-component precatalysts or with iron dihalide complexes activated in situ proved compatible with common organic functional groups and were applied on multigram scale (up to >100 g). Catalytically relevant, S = 1 iron complexes bearing 2-(imino)pyridine ligands, (RPI)FeL2 (RPI = [2-(2,6-R2-C6H3-N═CMe)-C5H4N] where R = iPr or Me, L2 = bis-olefin), were characterized by single-crystal X-ray diffraction, Mößbauer spectroscopy, magnetic measurements, and DFT calculations. The structural and spectroscopic parameters are consistent with an electronic structure description comprised of a high spin iron(I) center ( SFe = 3/2) engaged in antiferromagnetically coupling with a ligand radical anion ( SPI = -1/2). Mechanistic studies conducted with these single-component precatalysts, including kinetic analyses, 12C/13C isotope effect measurements, and in situ Mößbauer spectroscopy, support a mechanism involving oxidative cyclization of two dienes that determines regio- and diastereoselectivity. Topographic steric maps derived from crystallographic data provided insights into the basis for the catalyst control through stereoselective oxidative cyclization and subsequent, stereospecific allyl-isomerization and C-C bond-forming reductive elimination.

Syntheses and Catalytic Hydrogenation Performance of Cationic Bis(phosphine) Cobalt(I) Diene and Arene Compounds.

Chloride abstraction from [(R,R)-(iPr DuPhos)Co(µ-Cl)]2 with NaBArF 4 (BArF 4 =B[(3,5-(CF3 )2 )C6 H3 ]4 ) in the presence of dienes, such as 1,5-cyclooctadiene (COD) or norbornadiene (NBD), yielded long sought-after cationic bis(phosphine) cobalt complexes, [(R,R)-(iPr DuPhos)Co(η2 ,η2 -diene)][BArF 4 ]. The COD complex proved substitutionally labile undergoing diene substitution with tetrahydrofuran, NBD, or arenes. The resulting 18-electron, cationic cobalt(I) arene complexes, as well as the [(R,R)-(iPr DuPhos)Co(diene)][BArF 4 ] derivatives, proved to be highly active and enantioselective precatalysts for asymmetric alkene hydrogenation. A cobalt-substrate complex, [(R,R)-(iPr DuPhos)Co(MAA)][BArF 4 ] (MAA=methyl 2-acetamidoacrylate) was crystallographically characterized as the opposite diastereomer to that expected for productive hydrogenation demonstrating a Curtin-Hammett kinetic regime similar to rhodium catalysis.

Iron-Mediated Coupling of Carbon Dioxide and Ethylene: Macrocyclic Metallalactones Enable Access to Various Carboxylates.

Treatment of (iPrPDI)Fe(N2)2 (iPrPDI, 2,6-(2,6-iPr2C6H3N═CMe)2C5H3N) with CO2 and ethylene resulted in the formation of a homologous series of saturated and unsaturated iron carboxylate products, (iPrPDI)Fe(O2CR), the distribution of which depends on the ratio of the reagents. The solid-state and electronic structures of a saturated product, (iPrPDI)Fe(O2CC2H5), were elucidated. Product distributions, deuterium labeling studies, and stoichiometric experiments support initial formation of a five-membered metallalactone intermediate, which undergoes subsequent ethylene insertions to generate macrocyclic metallalactones. Competitive ß-hydride elimination, CO2 insertion, or reaction with H2 determines the fate of the metallalactone, the latter accounting for formation of iron complexes with saturated carboxylates. Similar reactivity was observed upon addition of propiolactone and ethylene to (iPrPDI)Fe(N2)2, supporting C-O oxidative addition and C-C bond formation through metallacycle intermediates.

Insights into Activation of Cobalt Pre-Catalysts for C(sp2)-H Functionalization.

The activation of readily prepared, air-stable cobalt (II) bis(carboxylate) pre-catalysts for the functionalization of C(sp2)-H bonds has been systematically studied. With the pyridine bis(phosphine) chelate, iPrPNP, treatment of 1-(O2CtBu)2 with either B2Pin2 or HBPin generated cobalt boryl products. With the former, reduction to (iPrPNP)CoIBPin was observed while with the latter, oxidation to the cobalt(III) dihydride boryl, trans-(iPrPNP)Co(H)2BPin occurred. The catalytically inactive cobalt complex, Co[PinB(O2CtBu)2]2, accompanied formation of the cobalt-boryl products in both cases. These results demonstrate that the pre-catalyst activation from cobalt(II) bis(carboxylates), although effective and utilizes an air-stable precursor, is less efficient than activation of cobalt(I) alkyl or cobalt(III) dihydride boryl complexes, which are quantitatively converted to the catalytically relevant cobalt(I) boryl. Related cobalt(III) dihydride silyl and cobalt(I) silyl complexes were also synthesized from treatment of trans-(iPrPNP)Co(H)2BPin and (iPrPNP)CoPh with HSi(OEt)3, respectively. No catalytic silylation of arenes was observed with either complex likely due to the kinetic preference for reversible C-H reductive elimination rather than product- forming C-Si bond formation from cobalt(III). Syntheses of the cobalt(II) bis(carboxylate) and cobalt(I) alkyl of iPrPONOP, a pincer where the methylene spacers have been replaced by oxygen atoms, were unsuccessful due to deleterious P-O bond cleavage of the pincer. Despite their structural similarity, the rich catalytic chemistry of iPrPNP was not translated to iPrPONOP due to the inability to access stable cobalt precursors as a result of ligand decomposition via P-O bond cleavage.

LXR agonist rescued the deficit in the proliferation of the cerebellar granule cells induced by dexamethasone.

Dexamethasone (DEX) exposure during early postnatal life produces permanent neuromotor and intellectual deficits and stunts cerebellar growth. The liver X receptor (LXR) plays important roles in CNS development. However, the effects of LXR on the DEX-mediated impairment of cerebellar development remain undetermined. Thus, mice were pretreated with LXR agonist TO901317 (TO) and were later exposed to DEX to evaluate its protective effects on DEX-mediated deficit during cerebellar development. The results showed that an acute exposure of DEX on postnatal day 7 resulted in a significant impairment in cerebellar development and decreased the proliferation of granule neuron precursors in the external granule layer of cerebellum. This effect was attenuated by pretreatment with TO. We further found that the decrease in the proliferation caused by DEX occurred via up-regulation of glucocorticoid receptor and p27kip1, which could be partially prevented by LXR agonist pretreatment. Overall, our results suggest that LXR agonist pretreatment could protect against DEX-induced deficits in cerebellar development in postnatal mice and may thus be perspective recruited to counteract such GC side effects.

Novel diagnostic indicators for acute angle closure secondary to lens subluxation based on anterior segment and lens parameters.

Purpose: To explore stable and sensitive indicators for clinical diagnosis of acute angle closure (AAC) secondary to lens subluxation (LS) through quantitative analysis of CASIA 2 imaging.Design: A prospective cross-sectional study. Methods: Setting: Clinical practice.Participants: 23 patients with unilateral acute angle closure secondary to lens subluxation and 23 cataract patients without lens subluxation were recruited. Lens subluxation was confirmed by ultrasound biomicroscope diagnosis. The contralateral eyes without LS served as fellow control group. The cataract eyes without LS were enrolled in blank control group.Intervention: Participants underwent ophthalmologic examinations including slit-lamp biomicroscope, best corrected visual acuity, intraocular pressure, central corneal thickness measurement, axial length, gonioscopy, ultrasound biomicroscope and 360-degree anterior chamber and crystalline lens scan protocols of CASIA 2 system.Main outcome measures: Automated circumferential anterior segment and lens morphological parameters under anterior segment optical coherence tomography were analyzed via three-dimensional analysis. Results: Significant differences were found in the front and back radius of the lens, the front and back radius of steep curvature of the lens, lens thickness, lens decentration, lens diameter, iris-trabecular contact (ITC) index, ITC area, anterior chamber depth (ACD), lens vault (LV), and iris volume between LS and controls. Among these parameters, LV, the anterior radius of steep curvature of the lens and ACD demonstrated the highest prediction power (AUC = 0.87, 0.89, and 0.86, respectively). The prediction power of tilt/axis was much higher in the Gaussian Naive Bayes model (AUCs = 0.90) than in the logistic model (AUCs = 0.74). Combination of LV_mean, LV_std, tilt and tilt axis in Gaussian Naive Bayes model presented as most stable and excellent diagnostic markers for AAC secondary to LS (AUCs = 0.98). Conclusions: The combination of markers including lens tilt and lens vault in the mathematic model facilitate clinical work as it not only provides novel diagnostic indications and possible prompt treatment for AAC secondary to lens subluxations, but also enhances our understanding of the pathogenic role of zonulopathy in angle closure glaucoma.

Development and preliminary application of a quadruplex real-time PCR assay for differential detection of porcine circovirus 1-4 in Chengdu, China.

Porcine circovirus (PCV) typically causes severe immune suppression in pigs, leading to mixed clinical infections with various pathogens that can cause significant harm to the pig industry. PCV has four subgenotypes, with PCV4 being an emerging virus that requires investigation due to its potential for epidemic outbreaks. Therefore, there is a need to develop a method that can detect all four PCV strains simultaneously. In this study, four pairs of specific primers and TaqMan probes were designed based on the conserved sequence of the PCV1-4 ORF2 gene to establish a PCV1-4 TaqMan multiplex real-time quantitative PCR method. The novel method was compared to six commercial testing kits for its efficacy. Then, a total of 595 mixed samples of spleen and lymph node collected from 12 districts in Chengdu from July to December 2021 were tested using the novel method. The results showed that the novel PCV1-4 TaqMan multiplex real-time quantitative PCR detection method has satisfied specificity, sensitivity, and repeatability. The positive rates of PCV1, PCV2, and PCV3 in Chengdu were 2.18%, 31.60%, and 15.29%, respectively, while no positive PCV4 was detected. The mixed infection rate of PCV2 and PCV3 was 5.21%. Our novel method may be as a potential method for PCV1-4 detection. Currently, PCV2 is the main epidemic PCV subtype in Chengdu, while the potential threat of PCV4 should also be considered.

PEG-grafted arsenic trioxide-loaded mesoporous silica nanoparticles endowed with pH-triggered delivery for liver cancer therapy.

Liver cancer (LC), one of the most common malignant primary tumors, presents a poor prognosis, high morbidity rate, and poor clinical outcomes. Despite conventional treatments have been applied prior to the deterioration, their clinical benefits were still limited. Arsenic trioxide (ATO), a toxic Chinese medicine, has been proven to efficiently inhibit the growth of LC both in vitro and in vivo. However, its therapeutic effects are hindered by poor pharmacokinetics and dose-limited toxicity. In this study, we developed a pH-responsive nanoplatform (PEG-MSN@ATO) consisting of mesoporous silica nanoparticles (MSN) that were modified with amino groups, loaded with ATO, and grafted with PEG to achieve the pH-triggered release and regulate CD8+ T cells and Treg cells in the tumor microenvironment (TME). PEG-MSN@ATO were characterized by uniform size, good loading efficiency, pH-responsive release features, decreased macrophage uptake, and enhanced dendritic cell activation in vitro. Furthermore, in vivo studies demonstrated that PEG-MSN@ATO enhanced the antitumor efficacy by inducing apoptosis and ROS production, inhibiting tumor cell proliferation and metastasis, and activating antitumor immunity within the TME. PEG-MSN@ATO also reduced the system toxicity of ATO by controlling the pH-trigger release in the tumor site. These results indicate that the PEG-MSN@ATO represents a promising drug delivery platform for reducing toxicity and enhancing the therapeutic efficacy of ATO against LC.

Engineered tumor microvesicles modified by SP94 peptide for arsenic trioxide targeting drug delivery in liver cancer therapy.

Liver cancer is among the leading cause of cancer related death worldwide. There is growing interest in using traditional Chinese medicines such as arsenic trioxide (ATO) to treat liver cancer. ATO have attracted attention due to its wide range of anti-cancer activities. However, the current ATO formulations are associated with drawbacks such as short half-life, lack of targeting ability towards solid tumors and apparent toxic side effects. Tumor microvesicles (TMVs) has shown encouraging results for the delivery of drugs to solid tumor. In this work, we designed ATO loaded TMVs further modified by SP94 peptide as liver cancer specific ligand (ATO@SP94-TMVs). This drug delivery system utilized SP94 peptide that selectively targets liver cancer cells while TMVs increase the accumulation of ATO at tumor site and activate immune response owing to the associated antigens. ATO@SP94-TMVs exhibited high encapsulation efficiency and tumor microenvironment triggered enhanced release of ATO in vitro. Cytotoxicity and uptake studies revealed remarkable inhibition and specific targeting of H22 cells. In addition, excellent immune response was detected in vitro, enhancing anti-tumor efficacy. Furthermore, a tumor inhibition rate of about 53.23 % was observed in H22 bearing tumor model. Overall, these results confirm that ATO@SP94-TMVs can be a promising nano drug delivery system for the future liver cancer therapy and improve its clinical applications.

Nickel-Catalyzed Enantioselective Hydrothiocarbonylation of Cyclopropenes.

Hydrothiocarbonylation of olefins using carbon monoxide and thiols is a powerful method to synthesize thioesters from simple building blocks. Owing to the intrinsic challenges of catalyst poisoning, transition-metal-catalyzed asymmetric thiocarbonylation, particularly when utilizing earth abundant metals, remains rare in the literature. Herein, we report a nickel-catalyzed enantioselective hydrothiocarbonylation of cyclopropenes for the synthesis of a diverse collection of functionalized thioesters in good to excellent yields with high stereoselectivity. This new method employs an inexpensive, air-stable nickel(II) precursor, which provides enhanced catalyst fidelity against CO poisoning compared to nickel(0) catalysts.