CUPRATE MEDIATED ALLYLIC SUBSTITUTIONS ON VINYLEPOXIDES AND CONJUGATE ADDITIONS ON 2-PYRIDONES

Regioselective control in allylic substitution reactions of vinylepoxides is difficult due to the competition between SN2- substitution and SN2\u27- allylic substitution pathway. Although excellent SN2\u27/SN2- and anti/syn- ratios were achieved by CuCN derived organozinc cuprates on 4,5-epoxy-2,3-enoates, application of this methodology to the vinylepoxide, trans-1-(tert-butyldimethylsilyloxy)-2,3-epoxy-4-hexene, is explored. Dialkyzinc reagents mediated by catalytic amounts of CuCN provide excellent regio-(SN2\u27/SN2) and diastereo-(olefinic E/Z and anti/syn-) selectivity with n-Bu, Et and t-Bu ligands, while reduced E/Z and SN2\u27/SN2- ratios were achieved with aromatic ligands (e.g., furyl and Ph). The assignment of regio- and stereoisomers were achieved by alternative syntheses of the authentic compounds. The epoxide opening allylic alcohol products were activated by converstion to allylic acetates or phosphates, which underwent allylic substitution reaction with lithium cyanocuprate in a highly anti-SN2\u27- controlled fashion. As a result of this sequential bis-allylic substitution, the synthesis of compounds with two contiguous stereogenic centers was realized. While many methods were reported for the synthesis of 2,3-dihydro-4-pyridone derivatives, access to substituted 2-piperidones from 2-pyridones is still underdeveloped because of their low reactivity towards conjugate additions and the difficulty in control of regioselectivity. N-Boc-2-pyridone underwent conjugate addition with CuI derived lithium dialkylcuprate with modest to excellent 1,4/1,6- regioselectivities, and various ligands (n-Bu, s-Bu, t-Bu, Me and Ph) were transferred in low to modest yields. Various organolithium reagents were added to the pyridinium salt derived from N-benzyl-2-pyridone in low to modest yields, with poor to modest 1,4,/1,6- regioselectivities. One pot synthesis of 3,4-dihydro-2-pyridones was realized in excellent diastereoselectivity. A facile (three steps) and efficient (65% over three steps) synthesis of enantiopure mono-substituted bicyclic amidines was developed. Alkylation of these mono-substituted amidines provided bis-substituted bicyclic amidines in modest yields (55%) and with decent diastereoselectivities (88:12). These chiral bicyclic amidines are potential organocatalysts for asymmetric addition such as acetoxybromination or halolactonization reactions based on our preliminary result from DBU and other literature reports. Success on DBU alkylation in high yields (up to 88%) and with various ligands (Me, Et and Bn) provides a promising methodology for synthesis of multi-alkylated (e.g., bis and tri-susbtituted) chiral cyclic amidines

Structural Performance of a Hybrid FRP-Aluminum Modular Triangular Truss System Subjected to Various Loading Conditions

A novel hybrid FRP-aluminum truss system has been employed in a two-rut modular bridge superstructure composed of twin inverted triangular trusses. The actual flexural behavior of a one-rut truss has been previously investigated under the on-axis loading test; however, the structural performance of the one-rut truss subjected to an off-axis load is still not fully understood. In this paper, a geometrical linear finite element model is introduced and validated by the on-axis loading test; the structural performance of the one-rut truss subjected to off-axis load was numerically obtained; the dissimilarities of the structural performance between the two different loading cases are investigated in detail. The results indicated that (1) the structural behavior of the off-axis load differs from that of the on-axis load, and the off-axis load is the critical loading condition controlling the structural performance of the triangular truss; (2) under the off-axis load, the FRP trussed members and connectors bear certain out-of-plane bending moments and are subjected to a complicated stress state; and (3) the stress state of these members does not match that of the initial design, and optimization for the redesign of these members is needed, especially for the pretightened teeth connectors

SR-BI as a target of natural products and its significance in cancer

Scavenger receptor class B type I (SR-BI) protein is an integral membrane glycoprotein. SR-BI is emerging as a multifunctional protein, which regulates autophagy, efferocytosis, cell survival and inflammation. It is well known that SR-BI plays a critical role in lipoprotein metabolism by mediating cholesteryl esters selective uptake and the bi-directional flux of free cholesterol. Recently, SR-BI has also been identified as a potential marker for cancer diagnosis, prognosis, or even a treatment target. Natural products are a promising source for the discovery of new drug leads. Multiple natural products were identified to regulate SR-BI protein expression. There are still a number of challenges in modulating SR-BI expression in cancer and in using natural products for modulation of such protein expression. In this review, our purpose is to discuss the relationship between SR-BI protein and cancer, and the molecular mechanisms regulating SR-BI expression, as well as to provide an overview of natural products that regulate SR-BI expression

Tryptophan, an important link in regulating the complex network of skin immunology response in atopic dermatitis

Atopic dermatitis (AD) is a common chronic relapsing inflammatory skin disease, of which the pathogenesis is a complex interplay between genetics and environment. Although the exact mechanisms of the disease pathogenesis remain unclear, the immune dysregulation primarily involving the Th2 inflammatory pathway and accompanied with an imbalance of multiple immune cells is considered as one of the critical etiologies of AD. Tryptophan metabolism has long been firmly established as a key regulator of immune cells and then affect the occurrence and development of many immune and inflammatory diseases. But the relationship between tryptophan metabolism and the pathogenesis of AD has not been profoundly discussed throughout the literatures. Therefore, this review is conducted to discuss the relationship between tryptophan metabolism and the complex network of skin inflammatory response in AD, which is important to elucidate its complex pathophysiological mechanisms, and then lead to the development of new therapeutic strategies and drugs for the treatment of this frequently relapsing disease

Family-clinician shared decision making in intensive care units : cluster randomized trial in China

We thank the China Medical Board, which financially supported our study.Objective To investigate if a Family-Clinician Shared Decision-Making (FCSDM) intervention benefits patients, families and intensive care units (ICUs) clinicians.  Methods Six ICUs in China were allocated to intervention or usual care. 548 patients with critical illness, 548 family members and 387 ICU clinicians were included into the study. Structured FCSDM family meetings were held in the intervention group. Scales of SSDM, HADS, QoL2 and CSACD were used to assess families’ satisfaction and distress, patients’ quality of life, and clinicians’ collaboration respectively.  Results Comparing the intervention group with the control group at post-intervention, there were significant differences in the families’ satisfaction (P =0.0001), depression level (P =0.005), and patients’ quality of life (P =0.0007). The clinicians’ mean CSCAD score was more positive in the intervention group than controls (P < 0.05). There was no significant between-group differences on ICU daily medical cost, but the intervention group demonstrated shorter number of days’ stay in ICU (P=0.0004).  Conclusion The FCSDM intervention improved families’ satisfaction and depression, shortened patients’ duration of ICU stay, and enhanced ICU clinicians’ collaboration.  Practice implications Further improvement and promotion of the FCSDM model are needed to provide more evidence to this field in China.Publisher PDFPeer reviewe

Non-Invasive Chromosome Screening for Embryo Preimplantation Using Cell-Free DNA

Preimplantation genetic testing (PGT) is widely adopted to select embryos with normal ploidy but requires invasive embryo biopsy procedures. Therefore, non-invasive PGT (niPGT) detection of cell-free DNA (cfDNA) in blastocyst culture medium has gradually become a hot area in the field of assisted reproduction. This chapter will systematically summarize how researchers use embryonic cfDNA to conduct niPGT detection worldwide. It will also thoroughly review the factors that affect the accuracy of the test and its underlying issues, as well as prospective applications. We hope to provide a useful reference for the standardized operation of non-invasive PGT that can be widely applied in clinical practice

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety

PURPOSE: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety.METHODS: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations.RESULTS: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression.CONCLUSIONS: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.</p

Evaluation of the Observational Associations and Shared Genetics Between Glaucoma With Depression and Anxiety

PURPOSE: Glaucoma, a leading cause of blindness worldwide, is suspected to exhibit a notable association with psychological disturbances. This study aimed to investigate epidemiological associations and explore shared genetic architecture between glaucoma and mental traits, including depression and anxiety.METHODS: Multivariable logistic regression and Cox proportional hazards regression models were employed to investigate longitudinal associations based on UK Biobank. A stepwise approach was used to explore the shared genetic architecture. First, linkage disequilibrium score regression inferred global genetic correlations. Second, MiXeR analysis quantified the number of shared causal variants. Third, specific shared loci were detected through conditional/conjunctional false discovery rate (condFDR/conjFDR) analysis and characterized for biological insights. Finally, two-sample Mendelian randomization (MR) was conducted to investigate bidirectional causal associations.RESULTS: Glaucoma was significantly associated with elevated risks of hospitalized depression (hazard ratio [HR] = 1.54; 95% confidence interval [CI], 1.01-2.34) and anxiety (HR = 2.61; 95% CI, 1.70-4.01) compared to healthy controls. Despite the absence of global genetic correlations, MiXeR analysis revealed 300 variants shared between glaucoma and depression, and 500 variants shared between glaucoma and anxiety. Subsequent condFDR/conjFDR analysis discovered 906 single-nucleotide polymorphisms (SNPs) jointly associated with glaucoma and depression and two associated with glaucoma and anxiety. The MR analysis did not support robust causal associations but indicated the existence of pleiotropic genetic variants influencing both glaucoma and depression.CONCLUSIONS: Our study enhances the existing epidemiological evidence and underscores the polygenic overlap between glaucoma and mental traits. This observation suggests a correlation shaped by pleiotropic genetic variants rather than being indicative of direct causal relationships.</p