Mechanistic Origins of Activity and Selectivity in Transition Metal Catalyzed Organic Reactions

Transition states are the gate keepers of chemical reactions. The free energies associated with transition states determine everything of interest in a chemical reaction, namely the rate and product distribution. Attempts to categorize the repulsive and attractive forces that dictate structural and energetic features of transition states dominate mechanistic organic chemistry. Kinetic isotope effects (KIEs) provide a direct quantitative probe into transition structure because they report directly upon changes in bond strength. Furthermore, KIEs provide a satisfying means of comparison with computational efforts. However, KIE methods are almost exclusively applied to spot to spot reactions with only a single product. The information provided by studying these somewhat rare, well-behaved reactions, can be helpful, but more versatile methods are needed to investigate reactions that yield more than one product. In this dissertation, product-specific KIE, a new method developed in the lab which can simultaneously measure the KIE of all pathways in a multi-product reaction, will be introduced. In principle, the product-specific KIE methodology is able to reveal the energetic landscape of all pathways by analysis of the isotopic fractionation which records the bonding changes that occur along a reaction pathway. The information provided can be illuminating to discover the branching events in chemo-, regio- and stereo-selective reactions. Secondly, the mechanisms of two transition-metal catalyzed multi-product reactions have been discussed as examples for the application of this method with both natural abundance 13C and deuterium KIE experiments. One of them is cobalt catalyzed [2+2] and Alder-ene reaction, where a common intermediate was found before it branches to two different products. In another case, a dirhodium tetraacetate catalyzed C-H insertion was found to proceed via an initial hydride transfer transition state, followed by formation of two interconverting zwitterion intermediates before the formation of two diastereomers. Product-specific KIEs have the potential to address mechanistic questions in reactions under development and provide a basic understanding of the key transition state features necessary to develop more selective catalysis

A General Approach to Mechanism in Multiproduct Reactions: Product-Specific Intermolecular Kinetic Isotope Effects

Here we report a general method for the measurement of ¹³C kinetic isotope effects at natural abundance for reactions that yield two or more products concurrently. We use, as an example, a recently reported Co-catalyzed reaction between cyclopentene and 1-phenyl-1-propyne. High-precision intermolecular ¹³C isotope effects are reported for both the formal [2+2] cycloaddition (major) and Alder–ene (minor) reaction products. Mechanistic possibilities that are in accord with observed isotope effect measurements are discussed

Knockdown of liver cancer cell‐secreted exosomal PSMA5 controls macrophage polarization to restrain cancer progression by blocking JAK2/STAT3 signaling

Abstract Introduction Tumor‐associated macrophages, a major component of the tumor microenvironment, undergo polarization into M2 macrophages (M2), and thereby exert an immunosuppressive effect to induce cancer metastasis. This study strives to uncover a molecular mechanism underlying this event in hepatocellular carcinoma (HCC). Methods Proteasome subunit alpha 5 (PSMA5) expression in liver hepatocellular carcinoma (LIHC) tissues and its association with LIHC patients were predicted using StarBase. PSMA5 level in human HCC cells was manipulated via transfection. Exosomes were isolated from HCC cells, and internalized into macrophages which were cocultured with HCC cells. Exosome internalization was observed after fluorescence labeling. HCC cell migration and invasion were evaluated by wound healing and Transwell assays. Xenograft assay was performed to investigate the role of PSMA5 in in vitro tumorigenesis. M2 polarization was assessed by enzyme‐linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. PSMA5 expression in exosomes and Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation in macrophages and tumors were detected by Western blot analysis. Results High PSMA5 expression was observed in LIHC tissues and associated with compromised survival of LIHC patients. PSMA5 knockdown inhibited HCC cell migration and invasion. PSMA5 knockdown in HCC cells downregulated PSMA5 level in exosomes from these HCC cells. HCC cell‐isolated exosomes were successfully internalized into macrophages, and facilitated M2 polarization and JAK2/STAT3 pathway activation. HCC cell‐secreted exosomal PSMA5 knockdown inhibited the exosome‐induced effect on macrophages, and attenuated the promotion induced by exosome‐treated macrophages on HCC cell migration/invasion and tumorigenesis along with in vivo M2 polarization and JAK2/STAT3 pathway activation. Conclusion HCC cell‐secreted exosomal PSMA5 knockdown hinders M2 polarization to suppress cancer progression by restraining JAK2/STAT3 signaling

A Six-Gene Prognostic Risk Prediction Model In Hepatitis B Virus-Associated Hepatocellular Carcinoma

Purpose: This study aimed to screen hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC)-related feature ribonucleic acids (RNAs) and to establish a prognostic model. Methods: The transcriptome expression data of HBV-associated HCC were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus database. Differential RNAs between HBV-associated HCC and normal controls were identified by a meta-analysis of TCGA, GSE55092 and GSE121248. Weighted gene co-expression network analysis was performed to identify key RNAs and modules. A prognostic score model was established using TCGA as a training set by Cox regression analysis and was validated in E-TABM-36 dataset. Additionally, independent prognostic clinical factors were screened, and the function of lncRNAs waspredicted through Gene Set Enrichment Analysis. Results: A total of 710 consistent differential RNAs between HBV-associated HCC and normal controls were obtained, including five lncRNAs and 705 mRNAs. An optimized combination of six differential RNAs (DSCR4, DBH, ECM1, GDAP1, MATR3 and RFC4) was selected and a prognostic score model was constructed. Kaplan-Meier analysis demonstrated that the prognosis of the high-risk and low-risk groups separated by this model was significantly different in the training set and the validation set. Gene Set Enrichment Analysis showed that the co-expression genes of DSCR4 were significantly correlated with neuroactive ligand receptor interactionpathway. Conclusion: A prognostic model based on DSCR4, DBH, ECM1, GDAP1, MATR3 and RFC4 was developed that can accurately predict the prognosis of patients with HBV-associated HCC. These genes, as well as histologic grade, may serve as independent prognostic factors in HBV-associated HCC

Interface energy band alignment at the all-transparent p-n heterojunction based on NiO and BaSnO\u3csub\u3e3\u3c/sub\u3e

\u3cp\u3eTransparent oxide semiconductors hold great promise for many optoelectronic devices such as transparent electronics, UV-emitting devices, and photodetectors. A p-n heterojunction is the most ubiquitous building block to realize these devices. In this work, we report the fabrication and characterization of the interface properties of a transparent heterojunction consisting of p-type NiO and n-type perovskite BaSnO\u3csub\u3e3\u3c/sub\u3e. We show that high-quality NiO thin films can be epitaxially grown on BaSnO\u3csub\u3e3\u3c/sub\u3e with sharp interfaces because of a small lattice mismatch (∼1.3%). The diode fabricated from this heterojunction exhibits rectifying behavior with a ratio of 500. X-ray photoelectron spectroscopy reveals a type II or staggered band alignment with valence and conduction band offsets of 1.44 eV and 1.86 eV, respectively. Moreover, a large upward band bending potential of 0.90 eV for BaSnO\u3csub\u3e3\u3c/sub\u3e and a downward band bending potential of 0.15 eV for NiO were observed in the interface region. Such electronic properties have important implication for optoelectronic applications as the large built-in potential provides favorable energetics for photo-generated electron-hole separation/migration.\u3c/p\u3

Interface energy band alignment at the all-transparent p-n heterojunction based on NiO and BaSnO3

Transparent oxide semiconductors hold great promise for many optoelectronic devices such as transparent electronics, UV-emitting devices, and photodetectors. A p-n heterojunction is the most ubiquitous building block to realize these devices. In this work, we report the fabrication and characterization of the interface properties of a transparent heterojunction consisting of p-type NiO and n-type perovskite BaSnO3. We show that high-quality NiO thin films can be epitaxially grown on BaSnO3 with sharp interfaces because of a small lattice mismatch (∼1.3%). The diode fabricated from this heterojunction exhibits rectifying behavior with a ratio of 500. X-ray photoelectron spectroscopy reveals a type II or "staggered" band alignment with valence and conduction band offsets of 1.44 eV and 1.86 eV, respectively. Moreover, a large upward band bending potential of 0.90 eV for BaSnO3 and a downward band bending potential of 0.15 eV for NiO were observed in the interface region. Such electronic properties have important implication for optoelectronic applications as the large built-in potential provides favorable energetics for photo-generated electron-hole separation/migration

Effect of denosumab on glucose metabolism in postmenopausal osteoporotic women with prediabetes: a study protocol for a 12-month multicenter, open-label, randomized controlled trial

Abstract Background Participants with prediabetes are at a high risk of developing type 2 diabetes (T2D). Recent studies have suggested that blocking the receptor activator of nuclear factor-κB ligand (RANKL) may improve glucose metabolism and delay the development of T2D. However, the effect of denosumab, a fully human monoclonal antibody that inhibits RANKL, on glycemic parameters in the prediabetes population is uncertain. We aim to examine the effect of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. Methods This is a 12-month multicenter, open-label, randomized controlled trial involving postmenopausal women who have been diagnosed with both osteoporosis and prediabetes. Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density T score of ≤ − 2.5, as measured by dual-energy X-ray absorptiometry (DXA). Prediabetes is defined as (i) a fasting plasma glucose level of 100–125 mg/dL, (ii) a 2-hour plasma glucose level of 140–199 mg/dL, or (iii) a glycosylated hemoglobin A1c (HbA1c) level of 5.7–6.4%. A total of 346 eligible subjects will be randomly assigned in a 1:1 ratio to receive either subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg every week for 12 months. The primary outcome is the change in HbA1c levels from baseline to 12 months. Secondary outcomes include changes in fasting and 2-hour blood glucose levels, serum insulin levels, C-peptide levels, and insulin sensitivity from baseline to 12 months, and the incidence of T2D at the end of the study. Follow-up visits will be scheduled at 3, 6, 9, and 12 months. Discussion This study aims to provide evidence on the efficacy of denosumab on glucose metabolism in postmenopausal women with osteoporosis and prediabetes. The results derived from this clinical trial may provide insight into the potential of denosumab in preventing T2D in high-risk populations. Trial registration This study had been registered in the Chinese Clinical Trials Registry. Registration number: ChiCTR2300070789 on April 23, 2023. https://www.chictr.org.cn