Palladium(0) π-Lewis Base Catalysis: Concept and Development.

The development of a new catalytic strategy plays a vital role in modern organic chemistry since it permits bond formation in an unprecedented and more efficient manner. Although the application of preformed metal complexes as π-base-activated reagents have enabled diverse transformations elegantly, the concept and strategy by directly utilizing transition metals as efficient π-Lewis base catalysts remain underdeveloped, especially in the field of asymmetric catalysis. Here, we outline our perspective on the discovery of palladium(0) as an efficient π-Lewis base catalyst, which is capable of increasing the highest occupied molecular orbital (HOMO) energy of both electron-neutral and electron-deficient 1,3-dienes and 1,3-enynes upon flexible η2-complexes formed in situ and resultant π-backdonation. Thus, fruitful carbon-carbon-forming reactions with diverse electrophiles can be achieved enantioselectively in a vinylogous addition pattern, which is conceptually different from the classical oxidative cyclization mechanism. Emphasis will be given to the concept and mechanism elucidation, catalytic features, and reaction design together with perspective on the further development of this emerging field.

Ultraviolet-Visible-Near Infrared Spectroscopy May Aid in the Qualitative Assessment of Early-Stage Cartilage Degradation.

Purpose: To assess the potential of ultraviolet-visible near-infrared spectroscopy to provide quantitative information on the cartilage surface at early osteoarthritis. Methods: We used a similar source and optical path to a standard arthroscope and constraining input to the range available to a standard detector/camera, further capturing and analyzing spectral information quantitatively in terms of specific electronic absorbance bands and scattering from the cartilage surface, with a focus on the early stages of degradation. Results: The ratio of the 320-nm and longer than 500-nm absorbances produced a distinct change from the normal to diseased states. The slopes between the wavelengths of 600 and 980 nm may show the transition of the single fibril to fibril bundles that occurs during early stages disease. Conclusions: Ultraviolet-visible near-infrared spectroscopy has good potential for use in integrated arthroscopic assessment. Clinical Relevance: This raises the possibility of advancing arthroscopy from a qualitative to a quantitative tool, without requiring modification of either the radiation (the light source and path) or instrumentation (the arthroscope itself) delivered to the patient, thus allowing a low-cost yet potentially high-value technology.

Pd(0)-Catalyzed Asymmetric Cyclization/Coupling Cascade of Alkyne-Tethered Unsaturated Carbonyls: Development and Mechanism Elucidation.

While the Pd(0)-catalyzed cyclization of alkyne-tethered unsaturated carbonyl substrates has been reported, the mechanism has not been well elucidated, and the potential asymmetric version remains to be developed. Here, we disclose that a chiral Pd(0) complex can efficiently promote the desymmetrizative cyclization of alkyne-tethered cyclohexadienones in CH3OH, and the resultant Pd(II) intermediates further undergo an array of tandem coupling reactions, including Suzuki, Sonogashira, and even chemoselective reduction by CH3OH in the absence of additional coupling partners. As a result, a broad spectrum of hydrobenzofuran derivatives, having a tetra- or trisubstituted exo-alkene motif, is constructed with moderate to outstanding enantioselectivity in an exclusive cis-difunctionalization pattern. In addition, this enantioselective protocol can be well expanded to linear alkyne-tethered unsaturated carbonyls, and a new desymmetrizative and asymmetric cyclization/coupling cascade of bis-alkyne-tethered enones is further realized efficiently, furnishing diversely structured frameworks with high stereoselectivity. Moreover, kinetic transformation for various racemic alkyne-tethered enones can be accomplished under similar catalytic conditions, and unusual kinetic reactions by chemoselectively undertaking Suzuki or Sonogashira coupling, or reduction by CH3OH, occur sequentially, finally yielding two types of chiral products, both with high enantioselectivity via either ligand- or substrate-based control. The experimental results demonstrate that the current Pd(0)-based strategy is superior to the classical Pd(II)-catalyzed carbopalladation/cyclization process of the identical substrates with regard to enantioselectivity and synthetic versatility. Moreover, density functional theory calculations are conducted to rationalize the Pd(0)-catalyzed oxidative cyclometalation pathway in the key cyclization step, which leads to the observed cis-difunctionalized products exclusively.

Functional-Group-Directed Regiodivergent (3 + 2) Annulations of Electronically Distinct 1,3-Dienes and 2-Formyl Arylboronic Acids.

Presented herein is a palladium-catalyzed asymmetric (3 + 2) annulation reaction between 1,3-dienes and 2-formylarylboronic acids, proceeding in a cascade vinylogous addition and Suzuki coupling process. Both electron-neutral and electron-deficient 1,3-dienes are compatible under similar catalytic conditions, and distinct regioselectivity is observed via functional-group control of 1,3-diene substrates. A collection of 1-indanols with dense functionalities is constructed stereoselectively.

Enantioselective Construction of Eight-Membered N-Heterocycles from Simple 1,3-Dienes via Pd(0) Lewis Base Catalysis.

We report herein an unprecedented enantioselective (4+4) cycloaddition of simple 1,3-dienes with azadienes for the construction of fused eight-membered N-heterocycles. In this transformation, the π-Lewis basic Pd(0) catalyst achieves activation of 1,3-dienes to induce nucleophilic addition to azadienes followed by ring cyclization via a selective terminal allylic substitution. Furthermore, highly efficient and diastereoselective derivatizations of the eight-membered rings provide a facile access to diverse enantiopure fused tetra- to hexacyclic compounds with potential application in medicinal chemistry.

Palladium(0)-Catalyzed Enantioselective Construction of Multifunctional Piperidine Derivatives from 1,3-Dienes, N-Cyano Imines, and Beyond.

An enantioselective (4 + 2) reaction between 1,3-dienes and N-cyano imines has been developed under Pd(0) catalysis, proceeding through a cascade vinylogous addition and intramolecular allylic amination sequence. 2,6-cis-Disubstituted-1,2,3,6-tetrahydropyridines were furnished as single diastereomers in moderate to good yields and enantiocontrol. Moreover, a more challenging three-component (2 + 2 + 2) annulation of 1,3-dienes, N-cyano imines, and activated alkenes was efficiently realized to afford piperidines with high structural complexity, albeit with moderate enantioselectivity.

[Relationship between Iron Metabolic Parameters and Platelet Counts in Blood Donors].

OBJECTIVE: To investigate the correlation of iron metabolic parameters with platelet counts in blood donors. METHODS: A total of 400 blood donors who met requirements of apheresis platelet donation were collected, and their hematological parameters were analyzed. The donors were divided into low ferritin group and normal group, the differences of hematological parameters between the two groups were compared, and the correlation of iron metabolic parameters and routine hematology parameters with platelet counts were analyzed. RESULTS: Whether male or female, low ferritin group had higher platelet counts than normal group (P < 0.01). Among the iron metabolic parameters, the platelet counts was negatively correlated with serum ferritin (SF), serum iron (SI), and transferrin saturation (TSAT) (r =-0.162, r =-0.153, r =-0.256), and positively correlated with total iron binding capacity (TIBC) and unsaturated iron binding capacity (UIBC) (r =0.219, r =0.294) in female blood donors. Platelet counts was also negatively correlated with SF, SI and TSAT (r =-0.188, r =-0.148, r =-0.224) and positively correlated with UIBC (r =0.220) in male blood donors. Among the routine hematology parameters, platelet counts was negatively correlated with mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and reticulocyte hemoglobin equivalent (Ret-He) in female blood donors (r =-0.236, r =-0.267, r =-0.213, r =-0.284). Platelet counts was also negatively correlated with MCH, MCHC and Ret-He in male blood donors (r =-0.184, r =-0.221, r =-0.209). CONCLUSION: In blood donors with low C-reactive protein level, the lower the iron store capacity, the lower the iron utilization, and the platelet counts tends to rise.

Asymmetric Friedel-Crafts reaction of unsaturated carbonyl-tethered heteroarenes via vinylogous activation of Pd0-π-Lewis base catalysis.

The alkyne group can undergo facile transformations under palladium catalysis, such as hydropalladation, Wacker reaction, etc. Here we demonstrate that a chiral Pd0 complex can chemoselectively dihapto-coordinate to the alkyne moiety of 2-indolyl propiolates, and raise the Highest Occupied Molecular Orbital (HOMO)-energy ofthe deactivated heteroarenes via π-Lewis base catalysis. As a result, asymmetric C3-selective Friedel-Crafts addition to activated alkenes occurs, finally affording [3 + 2] or [3 + 4] annulation products with high enantioselectivity and exclusive E-selectivity. Moreover, this π-Lewis base vinylogous HOMO-activation strategy can be extended to remote Friedel-Crafts reaction of diverse five-membered heteroarenes tethered to a 2-enone or 2-acrylate motif with imines or 1-azadienes, and excellent enantiocontrol is generally achieved for the multifunctional adducts, which can be effectively converted to diverse frameworks with higher molecular complexity. In addition, NMR and density functional theory calculation studies are conducted to elucidate the catalytic mechanism.

The Use of Hypochlorous Acid, Test-and-removal, and Cross-fostering to Eradicate Mouse Pathogens in an Animal Facility.

Hypochlorous acid (HOCl), used as a liquid or a fog, has broad antimicrobial and deodorizing effects. Our facility was the first in Taiwan that was built with a system to supply stabilized, biosafe HOCl solution (50 ppm available chlorine concentration, pH 6) into a new animal barrier facility that housed genetically modified mice. The HOCl system creates an extremely clean environment that allows us to raise mice in static, filter-top cages and to handle them on open tables without the need for biologic safety cabinets (BSC). Our animal facility (AF) sometimes receives mice from outside sources that are infected with pathogens, notably murine norovirus (MNV), Helicobacter spp., and trichomonads. We found that our standard operation procedure (SOP) prevented cross-contamination to other mice, including those in adjacent cages. After the removal of infected mice from a room, the remaining mice remained uninfected, without the need for extensive environmental decontamination. Learning this allowed us to use a test-and-removal method to eliminate pathogens. In addition, infected mouse strains that were not commercially available were rederived by using cross-fostering. After finding unexpected infections, we were able to identify all infected mice by widespread screening. We then removed contaminated cages and performed cross-fostering as needed. This approach was able to successfully eliminate murine norovirus, Helicobacter spp., and trichomonads. Over the 12 y in which we managed this AF, we refined our husbandry methods and our approach to the detection and eradication of pathogens by using HOCl fog and solution, the test-and-removal, and cross-fostering.

Plasma-Enabled Graphene Quantum Dot Hydrogel-Magnesium Composites as Bioactive Scaffolds for In Vivo Bone Defect Repair.

Bioactive and mechanically stable metal-based scaffolds are commonly used for bone defect repair. However, conventional metal-based scaffolds induce nonuniform cell growth, limiting damaged tissue restoration. Here, we develop a plasma nanotechnology-enhanced graphene quantum dot (GQD) hydrogel-magnesium (Mg) composite scaffold for functional bone defect repair by integrating a bioresource-derived nitrogen-doped GQD (NGQD) hydrogel into the Mg ZK60 alloy. Each scaffold component brings major synergistic advantages over the current alloy-based state of the art, including (1) mechanical support of the cortical bone and calcium deposition by the released Mg2+ during degradation; (2) enhanced uptake, migration, and distribution of osteoblasts by the porous hydrogel; and (3) improved osteoblast adhesion and proliferation, osteogenesis, and mineralization by the NGQDs in the hydrogel. Through an in vivo study, the hybrid scaffold with the much enhanced osteogenic ability induced by the above synergy promotes a more rapid, uniform, and directional bone growth across the hydrogel channel, compared with the control Mg-based scaffold. This work provides insights into the design of multifunctional hybrid scaffolds, which can be applied in other areas well beyond the demonstrated bone defect repair.

Asymmetric Construction of Multifunctional γ-Lactams from 1,3-Dienes and α-Ketoamides via Pd(0)-π-Lewis Base Catalysis.

A straightforward approach for the asymmetric synthesis of multifunctionalized γ-lactams, including those bearing two tetrasubstituted stereogenic centers, has been developed through a palladium-catalyzed vinylogous addition/allylic amination process between 1,3-dienes and α-ketoamides. This protocol features advantages of ready substrate availability, broad applicability, high efficiency, and excellent stereoselectivity, making it an attractive complementary tool to the previous strategies.

Nurse-led coaching of shared decision-making for wound treatment of pressure injury: A pilot study of a randomized trial.

Objectives: International guidelines for managing pressure injury (PI) and ulcers recommend that family members and caregivers should be involved in making decisions for appropriate wound care. However, the effect of shared decision-making (SDM) in the context of PI remains unknown. This study investigated the efficacy of nurse-led medical SDM for PI treatment. Materials and Methods: We constructed a patient decision aid (PDA) for PI treatment on the basis of nursing evidence. Subsequently, we conducted a pilot randomized controlled trial to evaluate the efficacy of SDM compared with that of usual care (control group, [CG]) for PI treatment. Participants with stage 3, stage 4, or unstageable PI were included and randomized into two groups. In the SDM group (SDMG), 10 participants received the SDM intervention for PI before treatment. All participants were followed up for 4 weeks. Primary outcomes were measured using the nine-item SDM Questionnaire (SDM-Q-9) and Decisional Conflict Scale (DCS). Secondary outcomes included wound size and cost of wound management. Results: The expert validity (medical professors and general population) of the PDA designed for PI was measured, and the content validity index was 0.96-0.97. A total of 20 participants were enrolled (10 received SDM and 10 received usual care). The mean age of the participants was 55.7 ± 8.8 years. No significant difference in baseline characteristics (sex, age, staging, or wound area) was observed between the two groups. The SDMG had higher SDM-Q-9 (P < 0.001) and DCS (P < 0.01) scores than did the CG. For the secondary outcomes, the SDMG had a decreased change of wound size and lower wound management costs than did the CG; nevertheless, the differences were not statistically significant. Conclusion: We constructed a PDA for PI treatment, which can be applied in clinical care. The pilot test results revealed that the participants had a lower cost related wound treatment and decreasing wound size in SDMG than CG after the intervention of SDM-PI for 4 weeks. In the future, clinical studies should conduct large-scale randomized trials based on the results of this pilot study.

Quantum pBac: An effective, high-capacity piggyBac-based gene integration vector system for unlocking gene therapy potential.

Recent advances in gene therapy have brought novel treatment options for cancer. However, the full potential of this approach has yet to be unlocked due to the limited payload capacity of commonly utilized viral vectors. Virus-free DNA transposons, including piggyBac, have the potential to obviate these shortcomings. In this study, we improved a previously modified piggyBac system with superior transposition efficiency. We demonstrated that the internal domain sequences (IDS) within the 3' terminal repeat domain of hyperactive piggyBac (hyPB) donor vector contain dominant enhancer elements. Plasmid-free donor vector devoid of IDS was used in conjunction with a helper plasmid expressing Quantum PBase™ v2 to generate an optimal piggyBac system, Quantum pBac™ (qPB), for use in T cells. qPB outperformed hyPB in CD20/CD19 CAR-T production in terms of performance as well as yield of the CAR-T cells produced. Furthermore, qPB also produced CAR-T cells with lower donor-associated variabilities compared to lentiviral vector. Importantly, qPB yielded mainly CD8+ CAR-TSCM cells, and the qPB-produced CAR-T cells effectively eliminated CD20/CD19-expressing tumor cells both in vitro and in vivo. Our findings confirm qPB as a promising virus-free vector system with an enhanced payload capacity to incorporate multiple genes. This highly efficient and potentially safe system will be expected to further advance gene therapy applications.

A metal π-Lewis base activation model for Pd-catalyzed hydroamination of amines and 1,3-dienes.

As a general mechanism proposal, a Pd(ii)-H migration insertion process is not able to well explicate the Pd-catalyzed hydroamination of amines and 1,3-dienes. Here we demonstrate that 1,3-dienes form electron-neutral and HOMO-raised η2-complexes with Pd(0) via π-Lewis base activation, which undergoes protonation with a variety of acidic sources, such as Brønsted acids, Lewis acid-activated indazoles, and Pd(ii) pre-catalyst triggered ammonium salts. The resultant π-allyl palladium complexes undergo the amination reaction to give the final observed products. FMO and NPA analyses have revealed the nature of Pd(0) mediated π-Lewis base activation of 1,3-dienes. The calculation results show that the π-Lewis base activation pathway is more favourable than the Pd(ii)-H species involved one in different reactions. Further control experiments corroborated our mechanistic proposal, and an efficient Pd(0) mediated hydroamination reaction was developed.

Asymmetric 2,4-Dienylation/[4 + 2] Annulation Cascade to Construct Fused Frameworks via Auto-Tandem Palladium Catalysis.

A palladium catalyzed tandem reaction between ortho-functionalized aryl enones and 2,4-dienyl carbonates has been presented, proceeding through sequential 2,4-dienylation/Michael addition/π-σ-π isomerization/allylic alkylation. A broad array of enantioenriched architectures having fused and spirocyclic frameworks are constructed in moderate to excellent yields and stereoselectivity. Notably, the intrinsic intramolecular Diels-Alder reaction pattern of the dienylated intermediates is well reversed via Pd(0)-π-Lewis base catalysis.

Palladium-Catalyzed Inverse and Normal Dehydrogenative Aza-Morita-Baylis-Hillman Reactions with γ,δ-Unsaturated Compounds.

σ-Lewis base-catalyzed regio- and enantioselective aza-Morita-Baylis-Hillman (MBH) reaction of α,ß,γ,δ-unsaturated systems remains a challenge due to the intrinsic covalent activation mode. Here we demonstrate that a Pd0 complex can mediate the dehydrogenative reaction of γ,δ-unsaturated compounds to give corresponding electron-poor dienes, which further undergo δ-regioselective umpolung Friedel-Crafts-type addition to imines via auto-tandem Pd0 -π-Lewis base catalysis. After ß-H elimination of in situ formed PdII -complexes, unprecedented and chemically inverse aza-MBH-type adducts are finally furnished with fair to outstanding enantioselectivity, and a diversity of functional groups and both ketimine and aldimine acceptors can be well tolerated. Moreover, switchable α-regioselective normal aza-MBH-type reaction also can be realized by tuning catalytic conditions, whereas moderate to good enantioselectivity with low to excellent Z/E-selectivity is attained.

Dynamic Ultrasound Examination for Extensor Pollicis Longus Tendon Rupture after Palpation-Guided Corticosteroid Injection.

This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed.

Simplified Derivatives of Tetrandrine as Potent and Specific P-gp Inhibitors to Reverse Multidrug Resistance in Cancer Chemotherapy.

Targeted inhibition of a drug efflux transporter P-glycoprotein (P-gp) is an important strategy to reverse multidrug resistance in cancer chemotherapy. In this study, a rationally structural simplification to natural tetrandrine was performed based on molecular dynamics simulation and fragment growth, leading to an easily prepared, novel, and simplified compound OY-101 with high reversal activity and low cytotoxicity. Its excellent synergistic anti-cancer effect with vincristine (VCR) against drug-resistant cells Eca109/VCR was confirmed by reversal activity assay, flow cytometry, plate clone formation assay, and drug synergism analysis (IC50 = 9.9 nM, RF = 690). Further mechanism study confirmed that the OY-101 was a specific and efficient P-gp inhibitor. Importantly, OY-101 increased VCR sensitization in vivo without obvious toxicity. Overall, our findings may provide an alternative strategy for the design of novel specific P-gp inhibitor as an anti-tumor chemotherapy sensitizer.