Long-range electrostatic interactions in gold catalysis and fluorinating reagent development.

Our research focus is on applying two long range electrostatic interactions--coulombic interaction between ion pairs and hydrogen bonding—to two tasks: exploring counterion effects in gold catalysis and utilizing hydrogen bonding for fluorinating reagent development. Cationic gold catalysis is considered one of the most important breakthroughs in organic synthesis over the past two decades. A wealth of empirical information on counterion effects is now available regarding homogeneous gold catalysis. However, the rational understanding of the counterion effect on reactivity is still elusive. We proposed a widely applicable model to rationalize the kinetic effect in gold catalyzed reaction. We first solved the problem of the silver effect that existed in gold catalyst and provided a more stable gold catalyst preparation protocol. We discovered that the presence of silver activators almost always had adverse effects in many gold catalyzed reactions. However, using a pre-formed L-Au+X- complex by removing excess AgX before the reaction avoided this problem. The deleterious silver effect may be caused by the interaction of silver salts with key gold intermediates like vinyl gold complex in the gold catalytic cycle. With the new method of catalyst preparation, we investigated the counterion effect in various cationic gold catalyzed reactions. We found that gold affinity and hydrogen bonding basicity of counterions play critical roles in the reactivity of cationic gold catalysts. The impact of our studies may not be limited to gold catalysis but may also provide guidance in transition metal catalysis in general. We then applied the hydrogen bonding basicity scale of different anions for the development of a new generation of HF-based reagents. We utilized a novel acidic but strong hydrogen bonding acceptor as a stabilizer to fixate gaseous and toxic hydrogen fluoride as liquid. This new reagent has several advantages such as being inexpensive, easily handled, and more acidic than other commercially available HF reagent. We then utilized this HF reagent on the hydrofluorination of various highly functionalized alkenes. The excellent functional group tolerance, exclusive Markovnikov addition regioselectivity and high atom economy may facilitate the preparation of other fluorinated products at both the lab and industrial scale

Principal Stratification with Continuous Post-Treatment Variables: Nonparametric Identification and Semiparametric Estimation

Causal inference is often complicated by post-treatment variables, which appear in many scientific problems, including noncompliance, truncation by death, mediation, and surrogate endpoint evaluation. Principal stratification is a strategy that adjusts for the potential values of the post-treatment variables, defined as the principal strata. It allows for characterizing treatment effect heterogeneity across principal strata and unveiling the mechanism of the treatment on the outcome related to post-treatment variables. However, the existing literature has primarily focused on binary post-treatment variables, leaving the case with continuous post-treatment variables largely unexplored, due to the complexity of infinitely many principal strata that challenge both the identification and estimation of causal effects. We fill this gap by providing nonparametric identification and semiparametric estimation theory for principal stratification with continuous post-treatment variables. We propose to use working models to approximate the underlying causal effect surfaces and derive the efficient influence functions of the corresponding model parameters. Based on the theory, we construct doubly robust estimators and implement them in an R package

The distribution of vascular endothelial growth factor in human meniscus and a meniscal injury model

BACKGROUND: The meniscus plays an important role in controlling the complex biomechanics of the knee. Meniscus injury is common in the knee joint. The perimeniscal capillary plexus supplies the outer meniscus, whereas the inner meniscus is composed of avascular tissue. Angiogenesis factors, such as vascular endothelial growth factor (VEGF), have important roles in promoting vascularization of various tissues. VEGF-mediated neovascularization is beneficial to the healing of injured tissues. However, the distribution and angiogenic role of VEGF remains unclear in the meniscus and injured meniscus. We hypothesized that VEGF could affect meniscus cells and modulate the meniscus healing process. METHODS: Menisci were obtained from total knee arthroplasty patients. Meniscal injury was created ex vivo by a microsurgical blade. VEGF mRNA and protein expression were detected by the polymerase chain reaction and immunohistochemical analyses, respectively. RESULTS: In native meniscal tissue, the expression of VEGF and HIF-1α mRNAs could not be detected. However, VEGF and HIF-1α mRNAs were found in cultured meniscal cells (VEGF: outer > inner; HIF-1α: outer = inner). Injury increased mRNA levels of both VEGF and HIF-1α, with the increase being greatest in the outer area. Immunohistochemical analyses revealed that VEGF protein was detected mainly in the outer region and around injured areas of the meniscus. However, VEGF concentrations were similar between inner and outer menisci-derived media. CONCLUSIONS: This study demonstrated that both the inner and outer regions of the meniscus contained VEGF. HIF-1α expression and VEGF deposition were high in injured meniscal tissue. Our results suggest that injury stimulates the expression of HIF-1α and VEGF that may be preserved in the extracellular matrix as the healing stimulator of damaged meniscus, especially in the outer meniscus