New approaches toward the generation of late first-row metal catalysts that efficiently facilitate two-electron reductive transformations (e.g., hydrogenation) more typical of noble-metal catalysts ...is an important goal. Herein we describe the synthesis of a structurally unusual S = 1 bimetallic Co complex, ( Cy PBP)CoH 2 (1), supported by bis(phosphino)boryl and bis(phosphino)hydridoborane ligands. This complex reacts reversibly with a second equivalent of H2 (1 atm) and serves as an olefin hydrogenation catalyst under mild conditions (room temperature, 1 atm H2). A bimetallic Co species is invoked in the rate-determining step of the catalysis according to kinetic studies. A structurally related NiINiI dimer, ( Ph PBP)Ni 2 (3), has also been prepared. Like Co catalyst 1, Ni complex 3 displays reversible reactivity toward H2, affording the bimetallic complex ( Ph PBHP)NiH 2 (4). This reversible behavior is unprecedented for NiI species and is attributed to the presence of a boryl–Ni bond. Lastly, a series of monomeric ( tBu PBP)NiX complexes (X = Cl (5), OTf (6), H (7), OC(H)O (8)) have been prepared. The complex ( tBu PBP)NiH (7) shows enhanced catalytic olefin hydrogenation activity when directly compared with its isoelectronic/isostructural analogues where the boryl unit is substituted by a phenyl or amine donor, a phenomenon that we posit is related to the strong trans influence exerted by the boryl ligand.
Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut ...microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD.
Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls.
Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 95% confidence interval 0.474 to 0.758, P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 95% CI: 0.102-0.887, P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 95% CI - 0.043-0.852, P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03).
This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD.
The mechanism of Ru-catalyzed ring-opening metathesis polymerization (ROMP) is studied in detail using a pair of third generation ruthenium catalysts with varying sterics of the N-heterocyclic ...carbene (NHC) ligand. Experimental evidence for polymer chelation to the Ru center is presented in support of a monomer-dependent mechanism for polymerization of norbornene monomers using these fast-initiating catalysts. A series of kinetic experiments, including rate measurements for ROMP, rate measurements for initiation, monomer-dependent kinetic isotope effects, and activation parameters were useful for distinguishing chelating and nonchelating monomers and determining the effect of chelation on the polymerization mechanism. The formation of a chelated metallacycle is enforced by both the steric bulk of the NHC and by the geometry of the monomer, leading to a ground-state stabilization that slows the rate of polymerization and also alters the reactivity of the propagating Ru center toward different monomers in copolymerizations. The results presented here add to the body of mechanistic work for olefin metathesis and may inform the continued design of catalysts for ROMP to access new polymer architectures and materials.
We describe the synthesis of a cobalt(I)–N2 complex (2) supported by a meridional bis-phosphino-boryl (PBP) ligand. Complex 2 undergoes a clean reaction with 2 equiv of dihydrogen to afford a ...dihydridoboratocobalt dihydride (3). The ability of boron to switch between a boryl and a dihydridoborate conformation makes possible the reversible conversion of 2 and 3. Complex 3 reacts with HMe2N–BH3 to give a hydridoborane cobalt tetrahydridoborate complex. We explore this boryl–cobalt system in the context of catalytic olefin hydrogenation as well as amine–borane dehydrogenation/transfer hydrogenation.
Abstract
Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we ...show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of
Txndc5
markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of
Txndc5
mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.
Competitive endogenous RNA (ceRNA) represents a novel mechanism of gene regulation that controls several biological and pathological processes. Recently, an increasing number of
in silico
methods ...have been developed to accelerate the identification of such regulatory events. However, there is still a need for a tool supporting the hypothesis that ceRNA regulatory events only occur at specific miRNA expression levels. To this end, we present an R package, ceRNAR, which allows identification and analysis of ceRNA-miRNA triplets via integration of miRNA and RNA expression data. The ceRNAR package integrates three main steps: (i) identification of ceRNA pairs based on a rank-based correlation between pairs that considers the impact of miRNA and a running sum correlation statistic, (ii) sample clustering based on gene-gene correlation by circular binary segmentation, and (iii) peak merging to identify the most relevant sample patterns. In addition, ceRNAR also provides downstream analyses of identified ceRNA-miRNA triplets, including network analysis, functional annotation, survival analysis, external validation, and integration of different tools. The performance of our proposed approach was validated through simulation studies of different scenarios. Compared with several published tools, ceRNAR was able to identify true ceRNA triplets with high sensitivity, low false-positive rates, and acceptable running time. In real data applications, the ceRNAs common to two lung cancer datasets were identified in both datasets. The bridging miRNA for one of these, the ceRNA for
MAP4K3
, was identified by ceRNAR as hsa-let-7c-5p. Since similar cancer subtypes do share some biological patterns, these results demonstrated that our proposed algorithm was able to identify potential ceRNA targets in real patients. In summary, ceRNAR offers a novel algorithm and a comprehensive pipeline to identify and analyze ceRNA regulation. The package is implemented in R and is available on GitHub (
https://github.com/ywhsiao/ceRNAR
).
Grafting density is an important structural parameter that exerts significant influences over the physical properties of architecturally complex polymers. In this report, the physical consequences of ...varying the grafting density (z) were studied in the context of block polymer self-assembly. Well-defined block polymers spanning the linear, comb, and bottlebrush regimes (0 ≤ z ≤ 1) were prepared via grafting-through ring-opening-metathesis polymerization. ω-Norbornenyl poly(d,l-lactide) and polystyrene macromonomers were copolymerized with discrete comonomers in different feed ratios, enabling precise control over both the grafting density and molecular weight. Small-angle X-ray scattering experiments demonstrate that these graft block polymers self-assemble into long-range-ordered lamellar structures. For 17 series of block polymers with variable z, the scaling of the lamellar period with the total backbone degree of polymerization (d* ∼ N bb α) was studied. The scaling exponent α monotonically decreases with decreasing z and exhibits an apparent transition at z ≈ 0.2, suggesting significant changes in the chain conformations. Comparison of two block polymer systems, one that is strongly segregated for all z (System I) and one that experiences weak segregation at low z (System II), indicates that the observed trends are primarily caused by the polymer architectures, not segregation effects. A model is proposed in which the characteristic ratio (C ∞), a proxy for the backbone stiffness, scales with N bb as a function of the grafting density: C ∞ ∼ N bb f(z). The scaling behavior disclosed herein provides valuable insights into conformational changes with grafting density, thus introducing opportunities for block polymer and material design.
Bifunctional EH activation offers a promising approach for the design of two-electron-reduction catalysts with late first-row metals, such as Ni. To this end, we have been pursuing H2 activation ...reactions at late-metal boratranes and herein describe a diphosphine-borane-supported Ni-(H2 ) complex, ((Ph) DPB(iPr) )Ni(H2 ), which has been characterized in solution. (1) H NMR spectroscopy confirms the presence of an intact H2 ligand. A range of data, including electronic-structure calculations, suggests a d(10) configuration for ((Ph) DPB(iPr) )Ni(H2 ) as most appropriate. Such a configuration is highly unusual among transition-metal H2 adducts. The nonclassical H2 adduct is an intermediate in the complete activation of H2 across the NiB interaction. Reaction-coordinate analysis suggests synergistic activation of the H2 ligand by both the Ni and B centers of the nickel boratrane subunit, thus highlighting an important role of the borane ligand both in stabilizing the d(10) Ni-(H2 ) interaction and in the H-H cleavage step.
The characterization of protein stability is essential for understanding the functions of proteins. Hydroxysteroid dehydrogenase is involved in the biosynthesis of steroid hormones and the ...detoxification of xenobiotic carbonyl compounds. However, the stability of hydroxysteroid dehydrogenases has not yet been characterized in detail. Here, we determined the changes in Gibbs free energy, enthalpy, entropy, and heat capacity of unfolding for 3α‐hydroxysteroid dehydrogenase/carbonyl reductase (3α‐HSD/CR) by varying the pH and urea concentration through differential scanning fluorimetry and presented pH‐dependent protein stability as a function of temperature. 3α‐HSD/CR shows the maximum stability of 30.79 kJ mol−1 at 26.4°C, pH 7.6 and decreases to 7.74 kJ mol−1 at 25.7°C, pH 4.5. The change of heat capacity of 30.25 ± 1.38 kJ mol−1 K−1 is obtained from the enthalpy of denaturation as a function of melting temperature at varied pH. Two proton uptakes are linked to protein unfolding from residues with differential pKa of 4.0 and 6.5 in the native and denatured states, respectively. The large positive heat capacity change indicated that hydrophobic interactions played an important role in the folding of 3α‐HSD/CR. These studies reveal the mechanism of protein unfolding in HSD and provide a convenient method to extract thermodynamic parameters for characterizing protein stability using differential scanning fluorimetry.
BiZness as usual? Not exactly! The bismuth atom of the tridentate diphosphinobismuthine (o‐(Ph2P)C6H4)2BiCl behaves as a Z rather than L ligand when in the coordination sphere of late transition ...metals such as gold. The σ‐acceptor behavior of Bi is supported by its disphenoid coordination geometry and theoretical studies, which show a Au→Bi interaction.
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