Asymmetric bifunctionalization of allenes with aryl iodides and amino acids enabled by chiral aldehyde/palladium combined catalysis.

Even though catalytic asymmetric bifunctionalization of allenes has been extensively studied, almost all of the reported examples have been achieved in a two-component manner. In this study, we report a highly efficient asymmetric bifunctionalization of allenes with iodohydrocarbons and NH2-unprotected amino acid esters. The adopted chiral aldehyde/palladium combined catalytic system precisely governs the chemoselectivity, regioselectivity, and stereoselectivity of this three-component reaction. A wide range of substituted aryl iodides, allenes and amino acid esters can well participate in this reaction and deliver structurally diverse α,α-disubstituted α-amino acid esters with excellent experimental outcomes. One of the resulting products is utilized for the total synthesis of the molecule (S,R)-VPC01091.

STOP1 regulates CCX1-mediated Ca2+ homeostasis for plant adaptation to Ca2+ deprivation.

Calcium (Ca) is essential for plant growth and stress adaptation, yet its availability is often limited in acidic soils, posing a major threat to crop production. Understanding the intricate mechanisms orchestrating plant adaptation to Ca deficiency remains elusive. Here, we show that the Ca deficiency-enhanced nuclear accumulation of the transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) in Arabidopsis thaliana confers tolerance to Ca deprivation, with the global transcriptional responses triggered by Ca deprivation largely impaired in the stop1 mutant. Notably, STOP1 activates the Ca deprivation-induced expression of CATION/Ca2+ EXCHANGER 1 (CCX1) by directly binding to its promoter region, which facilitates Ca2+ efflux from endoplasmic reticulum to cytosol to maintain Ca homeostasis. Consequently, the constitutive expression of CCX1 in the stop1 mutant partially rescues the Ca deficiency phenotype by increasing Ca content in the shoots. These findings uncover the pivotal role of the STOP1-CCX1 axis in plant adaptation to low Ca, offering alternative manipulating strategies to improve plant Ca nutrition in acidic soils and extending our understanding of the multifaceted role of STOP1.

Exploration of the complex origins of primary constipation.

Constipation is a common gastrointestinal disorder characterized by infrequent bowel movements and difficulty in passing stools. It can significantly affect an individual's quality of life and overall well-being. Understanding the causes of constipation is important for its effective management and treatment. In this paper, we have reviewed the primary causes of constipation or functional constipation. Primary constipation is a bowel disorder associated with colonic or anorectal sensorimotor or neuromuscular dysfunction. As per the literature, it is multifactorial and involves factors such as decreased interstitial cells of Cajal, altered colonic motility, enteric nervous system dysfunction, intestinal flora disturbances, and psychological influences. Clinical symptoms include difficulty in defecation, decreased frequency of defecation, or a feeling of incomplete evacuation. A comprehensive evaluation and management of constipation require an interdisciplinary approach incorporating dietary modifications, lifestyle changes, pharmacotherapy, and psychological interventions. Further research is imperative to explain the intricate mechanisms underlying constipation and develop targeted therapies for improved patient outcomes.

Asymmetric three-component Tsuji-Trost allylation reaction enabled by chiral aldehyde/palladium combined catalysis.

Despite the long-standing exploration of the catalytic asymmetric Tsuji-Trost allylation reaction since the mid-20th century, most reported instances have adhered to a two-component approach. Here, we present a remarkably efficient three-component asymmetric allylation reaction enabled by the collaborative action of chiral aldehyde and palladium. A diverse array of NH2-unprotected amino acid esters, aryl or alkenyl iodides, and allyl alcohol esters exhibit robust participation in this reaction, resulting in the synthesis of structurally diverse non-proteinogenic α-amino acid esters with favorable experimental outcomes. Mechanistic investigations reveal the dominance of the allylation/Heck coupling cascade in reactions involving electron-rich aryl iodides, while the Heck coupling/allylation cascade emerges as the dominant pathway in reactions involving electron-deficient aryl iodides. This chiral aldehyde/palladium combining catalytic system precisely governs the chemoselectivity of C-allylation and N-allylation, the regioselectivity of linear and branched allylation, and the enantioselectivity of C-allylation products.

Computed Tomography-Based Intratumor Heterogeneity Predicts Response to Immunotherapy Plus Chemotherapy in Esophageal Squamous Cell Carcinoma.

RATIONALE AND OBJECTIVES: This study explored the intratumor heterogeneity (ITH) of esophageal squamous cell carcinoma (ESCC) using computed tomography (CT) and investigated the value of CT-based ITH in predicting the response to immune checkpoint inhibitor (ICI) plus chemotherapy in patients with ESCC. MATERIALS AND METHODS: This retrospective study included 416 patients with ESCC who received ICI plus chemotherapy at two independent hospitals between January 2019 and July 2022. Multiparametric CT features were extracted from ESCC lesions and screened using hierarchical clustering and dimensionality reduction algorithms. Logistic regression and machine learning models based on selected features were developed to predict treatment response and validated in separate datasets. ITH was quantified using the score calculated by the best-performing model and visualized through feature clustering and feature contribution heatmaps. A gene set enrichment analysis (GSEA) was performed to identify the biological pathways underlying the CT-based ITH. RESULTS: The extreme gradient boosting model based on CT-derived ITH had higher discriminative power, with areas under the receiver operating characteristic curve of 0.864 (95% confidence interval [CI]: 0.774-0.954) and 0.796 (95% CI: 0.698-0.893) in the internal and external validation sets. The CT-based ITH pattern differed significantly between responding and non-responding patients. The GSEA indicated that CT-based ITH was associated with immunity-, keratinization-, and epidermal cell differentiation-related pathways. CONCLUSION: CT-based ITH is an effective biomarker for identifying patients with ESCC who could benefit from ICI plus chemotherapy. Immunity-, keratinization-, and epidermal cell differentiation-related pathways may influence the patient's response to ICI plus chemotherapy.

[Coupling Mechanisms of Eco-environmental Quality and Human Activities in China and Their Influencing Factors].

In the context of sustainable development, it is important to thoroughly investigate the coupling mechanism between China's eco-environmental quality and human activities, as well as identify the influencing factors, in order to provide scientific references for achieving sustainable development goals in China. This study applied trend analysis, coupling coordination degree, LMDI, and optimal parameter geographic detector models to explore and evaluate the coupling mechanism between China's eco-environmental quality and human activities. The findings of the study were as follows:① During the research period, there was a growth trend in China's coupling coordination degree, human activities, and eco-environmental quality. Human activities and coupling coordination degree exhibited a spatial differentiation pattern with the Hu Line as the boundary, showing an "east high, west low" distribution. The eco-environmental quality demonstrated a "south high, north low" differentiation pattern. ② The overall trend of China's coupling coordination type transformation was shifting from lower-level to higher-level coordination types. ③ Based on the geographic detector and LMDI models, the dominant factors influencing the coupling coordination degree in most provinces east of the Hu Line were social and economic factors, as well as the comprehensive coordination index. In contrast, the dominant factors in most provinces west of the Hu Line were natural environmental factors and coupling degree. ④ The evaluation of the impact of changes in human activities on eco-environmental quality revealed that the regions east of the Hu Line were mainly characterized by favorable development and effective protection, whereas the regions west of the line were mainly characterized by destructive development and ineffective protection. It is suggested that the regions on both sides of the Hu Line should prioritize development based on local prerequisites influencing the coupling coordination degree and the relative relationship between human activities and eco-environmental quality. It is crucial to actively adjust development strategies and pursue a sustainable development path towards the high-level coordination between eco-environmental quality and human activities.

Surgical Treatment of Multiple Large Tuberous and Tendinous Xanthoma Secondary to Familial Hypercholesterolaemia: A Case Report.

Xanthomas are well-circumscribed skin lesions that are commonly seen in patients with familial hypercholesterolemia (FH). The aim of this report is to present a rare case of multiple large tuberous and tendinous xanthomas. A 17-year-old female patient in this report presented with multiple asymptomatic and papulo-nodular masses in both sides of palms, elbows, buttocks, knees, and Achilles tendons. Surgical removal of the masses was carried out in combination with lipid-lowering therapy. A following up of 3 months showed all wounds were healing well, and no recurrence of masses was observed. Therefore, for patients with xanthomas related with familial hypercholesterolaemia, lipid-lowering therapy has reportedly reduced the size of masses, but surgical treatment may be essential for large xanthomas caused pain or limitation of daily activities.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

Translation and psychometric testing of the Chinese version of the Perinatal Missed Care Survey.

Objective: This study aimed to translate and evaluate the psychometric properties of the Perinatal Missed Care Survey in China. Methods: The Perinatal Missed Care Survey was translated according to the guidelines of the cross-cultural debugging scale recommended by the American Academy of Orthopaedic Surgeons Evidence-Based Medicine Committee, including forward translation, back translation, cultural adaption, and content validation, and its Chinese version was used in a cross-sectional study conducted from February to April in 2023. A total of 491 midwives from 14 different level hospitals in southwest China were recruited through a convenience sampling method. The discrimination ability of the items was tested through item analysis, and construct validity was assessed through exploratory factory and confirmatory factor analyses. The content validity index and Cronbach's α coefficients evaluated content validity and reliability, respectively. Results: The Chinese version's item-total correlation coefficients ranged from 0.641 to 0.866 in part A and from 0.644 to 0.819 in part B (P < 0.001). Parts A and B's scale-level content validity indexes were 0.95, and the item-level content validity indexes were from 0.86 to 1.00. The three common factors of part A (necessary care, basic care, and postnatal care) and part B (communication, labor resources, and material resources) were extracted, accounting for 70.186% and 71.984% of the total variance, respectively. Confirmatory factor analysis indicated that the good fit of the three-factor models was acceptable. The Cronbach's α coefficients were 0.968 (part A) and 0.940 (part B). Conclusion: The Chinese version of the Perinatal Missed Care Survey is a reliable and valid instrument for assessing nursing care missed by midwives during labor and birth and the reasons it was missed. Studies with large sample sizes are needed to verify the instrument's applicability in China.

Chitosan Hydrogel Dressing Loaded with Adipose Mesenchymal Stem Cell-Derived Exosomes Promotes Skin Full-Thickness Wound Repair.

Cutaneous trauma repair is still a challenge in the clinic due to the scar formation and slow healing rate, especially for diabetic patients. Various drug-loading wound dressings have been explored to solve this problem. Mesenchymal stem cell (MSC)-derived exosomes have been considered as a potential cell-free drug because of their anti-inflammation function and tissue repair property that are comparable to that of MSCs. Herein, a composite wound dressing (Exo/Gel) consisting of the chitosan hydrogel and adipose MSC-derived exosome (ADMSC-Exo) was designed and fabricated by a physical mixing method to promote the skin full-thickness wound repair. The exosomes were slowly released from the Exo/Gel dressing with the degradation of the chitosan hydrogel. The Exo/Gel displayed enhanced cell migration and angiogenic properties in vitro. And the results in the rat skin wound model showed that the Exo/Gel could promote the regular collagen deposition, angiogenesis, and hair follicle mosaicism regeneration. These results proved that the hydrogel dressing with ADMSCs-derived exosomes can accelerate skin wound healing, which is a strategy for developing wound dressings.

An Injectable Composite Hydrogel of Verteporfin-Bonded Carboxymethyl Chitosan and Oxidized Sodium Alginate Facilitates Scarless Full-Thickness Skin Regeneration.

Full-thickness skin defect has always been a major challenge in clinics due to fibrous hyperplasia in the repair process. Hydrogel composite dressings loaded with anti-fibrotic drugs have been considered as a promising strategy for scarless skin regeneration. In this work, a hydrogel composite (VP-CMCS-OSA) of carboxymethyl chitosan (CMCS) and oxidized sodium alginate (OSA), with loading anti-fibrotic drug verteporfin (VP), is developed based on two-step chemical reactions. Verteporfin is bonded with carboxymethyl chitosan through EDC/NHS treatment to form VP-CMCS, and then VP-CMCS is crosslinked with oxidized sodium alginate by Schiff base reaction to form VP-CMCS-OSA hydrogel. The characterization by SEM, FTIR, and UV-Vis shows the microstructure and chemical bonding of VP-CMCS-OSA. VP-CMCS-OSA hydrogel demonstrates the properties of high tissue adhesion, strong self-healing, and tensile ability. In the full-thickness skin defect model, the VP-CMCS-OSA composite hydrogels hasten wound healing due to the synergistic effects of hydrogels and verteporfin administration. The histological examination reveals the regular collagen arrangement and more skin appendages after VP-CMCS-OSA composite hydrogel treatment, indicating the full-thickness skin regeneration without potential scar formation. The outcomes suggest that the verteporfin-loaded composite hydrogel could be a potential method for scarless skin regeneration.

Ultrahigh pressure field: A friendly pathway for regulating the cellular adhesion and migration capacity of collagen.

Customized control of the biological response between the material matrix and cells is a crucial aspect in the development of the next generation of collagen materials. This study aims to investigate the effects of ultrahigh pressure treatment on the interaction between collagen and cells by subjecting bovine tendon collagen to different intensities of ultrahigh pressure field. The results indicate that ultrahigh pressure treatment alters the spatial folding of collagen, causing distortion of its triple helical conformation and exposing more free amino groups and hydrophobic regions. As a result, collagen's cell adhesion capability and ability to promote cell migration are significantly enhanced. Optimal cell adhesion and migration capabilities are observed in collagen samples treated at 500 MPa for 15 min. However, further increasing the intensity of the ultrahigh pressure treatment leads to severe damage to the triple-helical structure of collagen, along with re-aggregation of free amino groups and hydrophobic moieties, thereby reducing collagen's cell adhesion capability and ability to promote cell migration. Therefore, ultrahigh pressure treatment offers a promising method to effectively regulate collagen-cell adhesion and promote cell migration without the need for external components. This provides a potential means for the customized enhancement of collagen-based material interfaces.

Core Structure-Oriented Asymmetric α-Allenylic Alkylation of Amino Acid Esters Enabled by Chiral Aldehyde/Palladium Catalysis.

Aiming at the reported chiral synthons leading to manzacidins A and D, here we report a highly efficient catalytic asymmetric α-allenylic alkylation reaction of NH2-unprotected amino acid esters that is promoted by combined chiral aldehyde/palladium catalysis. Fifty examples of unnatural α,α-disubstituted amino acid esters are reported with good-to-excellent yields and stereoselectivities. Based on this methodology, a key intermediate leading to manzacidin C and its other three stereoisomers is prepared accordingly.

Electrospun Nanofibrous Conduit Filled with a Collagen-Based Matrix (ColM) for Nerve Regeneration.

Traumatic nerve defects result in dysfunctions of sensory and motor nerves and are usually accompanied by pain. Nerve guidance conduits (NGCs) are widely applied to bridge large-gap nerve defects. However, few NGCs can truly replace autologous nerve grafts to achieve comprehensive neural regeneration and function recovery. Herein, a three-dimensional (3D) sponge-filled nanofibrous NGC (sf@NGC) resembling the structure of native peripheral nerves was developed. The conduit was fabricated by electrospinning a poly(L-lactide-co-glycolide) (PLGA) membrane, whereas the intraluminal filler was obtained by freeze-drying a collagen-based matrix (ColM) resembling the extracellular matrix. The effects of the electrospinning process and of the composition of ColM on the physicochemical performance of sf@NGC were investigated in detail. Furthermore, the biocompatibility of the PLGA sheath and ColM were evaluated. The continuous and homogeneous PLGA nanofiber membrane had high porosity and tensile strength. ColM was shown to exhibit an ECM-like architecture characterized by a multistage pore structure and a high porosity level of over 70%. The PLGA sheath and ColM were shown to possess stagewise degradability and good biocompatibility. In conclusion, sf@NGC may have a favorable potential for the treatment of nerve reconstruction.

Self-Reconstructed Two-Dimensional Cluster-Based Co-Organic Layer Heterojunctions for Enhanced Oxygen Evolution Reactions.

When it comes to an efficient catalytic oxygen evolution reaction (OER) in the production of renewable energy and chemicals, the construction of heterogeneous structures is crucial to break the linear scalar relationship of a single catalyst. This heterogeneous structure construction helps creatively achieve high activity and stability. However, the synthesis process of heterogeneous crystalline materials is often complex and challenging to capture and reproduce, which limits their application. Here, the dynamic process of structural changes in Co-MOFs in alkali was captured by in situ powder X-ray diffraction, FT-IR spectroscopy, and Raman spectroscopy, and several self-reconfigured MOF heterogeneous materials with different structures were stably isolated. The created ß-Co(OH)2/Co-MOF heterojunction structure facilitates rapid mass-charge transfer and exposure of active sites, which significantly enhanced OER activity. Experimental results show that this heterogeneous structure achieves a low overpotential of 333 mV at 10 mA cm-2. The findings provide new insights and directions for the search for highly reactive cobalt-based MOFs for sustainable energy technologies.

The effects of Spinosad on zebrafish larvae and THP-1 cells: Associated with immune cell damage and NF-kappa B signaling pathway activation.

Spinosad is a highly effective macrolide insecticide with a wide range of applications. However, few studies have been reported on the effects of Spinosad on immune cells. The immune system is an important line of defense in the human body and plays an important role in maintaining the normal functioning of the organism. Meanwhile, macrophages, neutrophils and Thymic T cells are an important component of the immune system. We studied the immunotoxicity of Spinosad using zebrafish and THP-1 cells. In vivo, Spinosad (0-20 µM) did not cause developmental toxicity in zebrafish, but induced damage to immune cells. In vitro, Spinosad (0-20 µM) inhibited THP-1 cells viability and induced mitochondrial damage and oxidative stress production. In further studies, it impaired phagocytosis of THP-1 cells and interfered with lipid metabolism. In addition, we found that Spinosad can promote the formation of the inflammatory body NLRP3 (NLR family, pyrin domain-containing 3) and activate the NF-kappa B (NF-κB) signaling pathway. These results suggest that Spinosad has a potential risk for inducing immunotoxicity. This study has drawn attention to Spinosad-induced immunotoxicity.

High-efficiency all fluorescence white OLEDs with high color rendering index by manipulating excitons in co-host recombination layers.

All fluorescence white organic light-emitting diodes (WOLEDs) based on thermally activated delayed fluorescence (TADF) emitters are an attractive route to realize highly efficient and high color quality white light sources. However, harvesting triplet excitons in these devices remains a formidable challenge, particularly for WOLEDs involving conventional fluorescent emitters. Herein, we report a universal design strategy based on a co-host system and a cascaded exciton transfer configuration. The co-host system furnishes a broad and charge-balanced exciton generation zone, which simultaneously endows the devices with low efficiency roll-off and good color stability. A yellow TADF layer is put forward as an intermediate sensitizer layer between the blue TADF light-emitting layer (EML) and the red fluorescence EML, which not only constructs an efficient cascaded Förster energy transfer route but also blocks the triplet exciton loss channel through Dexter energy transfer. With the proposed design strategy, three-color all fluorescence WOLEDs reach a maximum external quantum efficiency (EQE) of 22.4% with a remarkable color rendering index (CRI) of 92 and CIE coordinates of (0.37, 0.40). Detailed optical simulation confirms the high exciton utilization efficiency. Finally, by introducing an efficient blue emitter 5Cz-TRZ, a maximum EQE of 30.1% is achieved with CIE coordinates of (0.42, 0.42) and a CRI of 84 at 1000 cd m-2. These outstanding results demonstrate the great potential of all fluorescence WOLEDs in solid-state lighting and display panels.

Asymmetric α-Allylation of N-Unprotected Amino Acid Esters with 1,3-Disubstituted Allyl Acetates Enabled by Chiral-Aldehyde/Palladium Catalysis.

A chiral aldehyde/palladium catalysis-enabled asymmetric α-allylation of NH2-unprotected amino acid esters with 1,3-disubstituted allyl acetates is described in this work. With the utilization of different chiral phosphine ligands, both the anti- and syn-selective allylation reactions are achieved enantioselectively. A series of α,α-disubstituted amino acid esters bearing two adjacent chiral centers are produced in moderate-to-excellent yields, diastereoselectivities, and enantioselectivities.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.