Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes.

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction.

Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

pparß regulates lipid catabolism by mediating acox and cpt-1 genes in Scophthalmus maximus under heat stress.

Peroxisome proliferator-activated receptor ß (pparß) is a key gene-regulating lipid metabolism pathway, but its function in turbot remains unclear. In this study, the CDS of pparß was cloned from kidney for the first time. The CDS sequence length was 1533 bp encoding 510 amino acids. Structural analysis showed that the pparß protein contained a C4 zinc finger and HOLI domain, suggesting that the pparß gene of turbot has high homology with the PPAR gene of other species. The high expression patterns of pparß, acox, and cpt-1 at high temperatures, as shown through qPCR, indicated that high temperatures activated the transcriptional activity of pparß and increased the activity of the acox and cpt-1 genes. The expression of acox and cpt-1 was significantly inhibited when pparß was downregulated using RNAi technology and inhibitor treatments, suggesting that pparß positively regulated acox and cpt-1 expression at high temperatures and, thus, modulates lipid catabolism activity. These results demonstrate that pparß is involved in the regulation of lipid metabolism at high temperatures and expand a new perspective for studying the regulation of lipid metabolism in stress environments of teleost.

Palladium-Catalyzed Intramolecular Heck/Aminocarbonylation of Alkene-Tethered Iodobenzenes with Nitro Compounds: Synthesis of Carbamoyl-Substituted Benzoheterocycles.

A palladium-catalyzed intramolecular Heck/aminocarbonylation of alkene-tethered iodobenzenes with nitro compounds has been developed for the synthesis of carbamoyl-substituted benzoheterocycles. Using Mo(CO)6 as a solid CO source, no external reductant or additives were needed in this procedure. Both nitroarenes and nitroalkanes were well tolerated. A range of carbamoyl-substituted dihydrobenzofurans and indolines were prepared in moderate to high yields.

Genotype by Temperature Interaction for Plasma Physiological Indexes in Turbot (Scophthalmus maximus) under Acute Heat Stress─Exploring a Method for Screening Physiological Biomarkers of Nontoxic Stress in Aquatic Environments.

This paper presents a method for exploring the genetic mechanism underlying the plasma physiological indexes under heat stress in aquatic environments and for screening reliable stress biomarkers based on split-split-plot analysis (SSP), additive main effects and multiplicative interaction (AMMI) analysis, and genotype main effects and genotype × environment interaction (GGE) biplot analysis. The methodology developed was illustrated by applying it to a specific turbot heat stress case study. Five plasma physiological indexes (epinephrine, cortisol, alkaline phosphatase, superoxide dismutase, and blood glucose levels) were measured in turbot (Scophthalmus maximus) under acute heat stress at four temperatures (18, 21, 24, and 27 °C) for various exposure times (3, 6, 9, 12, 24, 48, and 72 h). The SSP analysis showed that exposure time and temperature × gene interactions had significant (P < 0.01) effects on the activity/content of turbot plasma physiological indexes. The AMMI analysis showed the following: (1) that at each exposure time, the genotype effect > the genotype × temperature interaction > the temperature effect; (2) that during the whole experiment, the change trend of the contribution of the genotype × temperature interactions was similar to that of the temperature effect, and the changing trends of the contributions of the genotype × temperature interaction and the genotype effect were clearly completely reversed; and (3) that the 3-24-h period was the key period for the changes in the physiological indexes due to acute heat stress. The GGE biplot analysis showed that blood glucose and cortisol levels were reliable biomarkers and could be used as early warning markers for numerical simulations of physiological behavior.

K2CO3-Promoted oxy-Michael Addition/Cyclization of α,ß-Unsaturated Carbonyl Compounds with Naphthols: Synthesis of Naphthopyrans.

A potassium carbonate promoted tandem oxy-Michael addition/cyclization of α,ß-unsaturated carbonyl compounds with naphthol derivatives for the synthesis of 2-substituted naphthopyrans was developed. Using the readily available, inexpensive potassium carbonate as the promoter, a range of different substituted naphthopyrans were prepared.

Base-promoted [4 + 2] annulation of pyrrole-2-carbaldehyde derivatives with ß,γ-unsaturated α-ketoesters: syntheses of 5,6-dihydroindolizines.

A base-promoted [4 + 2] annulation of pyrrole-2-carbaldehyde derivatives with ß,γ-unsaturated α-ketoesters for the syntheses of multisubstituted 5,6-dihydroindolizines was developed. Using DBN as a base, the reaction proceeds smoothly under mild conditions to provide the target products in moderate to high yields, and many useful functional groups can be tolerated.

Plasma chromogranin A levels are associated with acute ischemic stroke with anterior circulation large vessel occlusion.

BACKGROUND AND AIMS: To investigate the relationship between chromogranin A (CgA) levels and acute ischemic stroke (AIS), especially anterior circulation large vessel occlusion (LVO). METHODS AND RESULTS: 587 subjects were included in this study, including 205 AIS patients with anterior circulation LVO and 205 nonocclusive patients, as well as 177 healthy controls. On admission, plasma CgA levels were measured and neurological deficits were assessed by the NIH Stroke Scale. Outcomes were assessed by the modified Rankin Scale at 3 months. The predictive properties of CgA were evaluated by receiver operating characteristic (ROC) curve analysis. Binary logistic analysis assessed the association of CgA levels and AIS or anterior circulation LVO. AIS patients had lower CgA levels than health controls (p < 0.001). Anterior circulation LVO patients had lower CgA levels than nonocclusive patients (p < 0.001). The area under the ROC curve of plasma CgA levels in predicting anterior circulation LVO from AIS was 0.744 and the optimal cutoff value was 15.49 ng/mL with a Youden value of 0.332. Logistic analysis showed that CgA ≤15.49 ng/mL remained an independent risk factor for anterior circulation LVO after adjusting for related factors (OR = 6.519, 95% CI: 3.790-11.214, p < 0.001). CgA was an independent protective factor for mild stroke and good prognosis (p = 0.009, p = 0.005); however, the association disappeared after adjusting for occlusion (p = 0.768, p = 0.335). CONCLUSION: CgA levels were lower in AIS patients, especially in anterior circulation LVO patients. Lower CgA levels are potential biomarker for anterior circulation LVO, and they may indicate good prognosis at 3 months in AIS.

Blood Neutrophil-to-Lymphocyte Ratio as a Predictor of Cerebral Small-Vessel Disease.

BACKGROUND In recent studies, neutrophil-to-lymphocyte ratio (NLR) was reported to be a good predictor of acute ischemic stroke (AIS), but its role in cerebral small-vessel disease (CSVD) is still controversial. We aimed to explore the value of NLR to identify CSVD. MATERIAL AND METHODS We enrolled 466 CSVD patients and 413 controls. The total burden score of CSVD was calculated according to MRI results, and imaging subgroups were divided according to MRI. The 90-day outcome was evaluated using the modified Rankin scale (mRS). NIHSS score, mRS, clinical information, biochemical parameters, and NLR were recorded, and we analyzed the relationship between NLR and CSVD. RESULTS NLR was a risk factor for CSVD (OR 1.58, 95%CI 1.015~1.322; P=0.029). NLR was positively correlated with CSVD (r=0.259; P=0.001). The AUC was 0.774, with a cut-off value of 1.89 (95% CI 0.742~0.806), P=0.000. NLR was significantly different among the different total burden score groups of CSVD (P=0.009). NLRs were significant different among enlarged perivascular space (EPVS) groups (P=0.017), periventricular white matter high signal (PWMHS) groups (P=0.028), and deep white matter high signal (DWMHS) groups (P=0.004), but no significant difference was found among cerebral microbleeds (CMBs) groups (P=0.118). NLR was correlated with short-term outcome of CSVD (P=0.000). The AUC was 0.732 (95% CI 0.684~0.779), with a cut-off value of 2.413 for predicting a poor CSVD prognosis. CONCLUSIONS NLR has potential diagnostic value for CSVD, and it can predict the short-term outcome of CSVD. Therefore, NLR may be a useful biomarker to predict CSVD and its outcome.

Sex-specific relationship between serum uric acid levels and the prevalence of large vessel occlusion in acute ischemic stroke.

PURPOSE: Previous studies have found that uric acid (UA) plays a neuroprotective role in ischemic stroke patients. However, the relationship between serum UA of acute ischemic stroke (AIS) and large vessel occlusion (LVO) strokes is unclear. METHODS: In this retrospective study, 1318 AIS patients were enrolled. All patients underwent imaging examinations to assess the intracranial and carotid vessels. Multivariate logistic regression analysis was conducted to evaluate the relationship between UA levels and the prevalence of LVO. RESULTS: The 1318 enrolled AIS patients were comprised of 287 LVO and 1031 non-LVO patients. UA levels in males were higher than females (321.04 ± 91.28 vs. 274.43 ± 82.11, p < .001). The association between serum UA levels and LVO was modified by sex (p = .007). When serum UA levels were continuous, after adjusting for related risk factors, higher serum UA levels were still associated with a lower prevalence of LVO in males (odds ratio (OR) 0.997, 95% confidence interval (CI) 0.994-0.999), but not in female subjects (OR 0.998, 95% CI 0.995-1.001). When serum UA levels were divided into tertiles, higher UA levels had a lower risk of LVO than the moderate (p = .006) and lower tertiles of UA levels (p = .010) in males, but not in females (p = .402 and p = .206 for moderate and low tertiles, respectively). CONCLUSIONS: AIS patients with higher serum UA levels tend to be associated with a lower risk of LVO in males, but not in females.

Genotype × ammonia interaction effects on plasma physiological indexes in turbot (Scophthalmus maximus) cultured under acute ammonia stress for different periods of times.

We evaluated six plasma physiological indexes (epinephrine, cortisol, alkaline phosphatase, superoxide dismutase, reduced glutathione, and blood glucose) in turbot (Scophthalmus maximus) cultured in five ammonia concentrations (30.28, 35.90, 42.56, 50.47, and 59.82) at different exposure times (4, 8, 12, 24, and 48 h). Then, we conducted additive main effects and multiplicative interaction (AMMI) and genotype main effects and genotype × environment interaction (GGE) biplot analyses to analyze the genotype × ammonia interaction effects on the plasma physiological indexes. The AMMI analysis results revealed that the contributions of ammonia effect first decreased sharply (4-8 h), then decreased slowly (8-24 h), and then increased slowly (24-48 h). The contributions of genotype effect first decreased sharply (4-8 h), then increased slowly (8-24 h), and then decreased slowly (24-48 h). The contributions of genotype × ammonia interactions showed a sharp rise (4-8 h), a sharp decline (8-12 h), a slow decline (12-24 h), and finally a slow increase (24-48 h). The GGE biplot analysis revealed that alkaline phosphatase and reduced glutathione contents/activities are reliable biomarkers that can be used to establish an online early warning system for behavior numerical simulation.

Digital RNA-seq analysis of the cardiac transcriptome response to thermal stress in turbot Scophthalmus maximus.

The hearts of fish play a major role in their physiological plasticity and acclimation to different thermal conditions. To understand the precise mechanism and the pathways activated by thermal cardiac stress in fish, we sampled cardiac tissue from juvenile turbot (Scophthalmus maximus) exposed to control (14°C) and test (20°C, 24°C, and 28°C) conditions, and performed digital RNA sequencing (RNA-seq). A total of 3359 differentially expressed genes (DEGs) were identified. The results of an expression tendency analysis and KEGG annotation analysis of the DEGs demonstrated that energy metabolism played a core role in thermal stress in turbot for the majority of the up-regulated genes. This was followed by lipid metabolism, mitochondrial function, glycolysis, and carbohydrate metabolism. RNA modifications are gaining the interest of biologists worldwide. In this study, at the transcriptome level, our results showed that 246 m6A-containing genes were detected in the DEGs, which were related to EIF3C, EIF3D, EIF3J, METTL16, RBM15B, VIRMA, and YTHDC1. This indicates that m6A is involved in the regulation of heat stress in turbot. This study is an important step towards understanding the cardiac adaptive response to thermal stress. Importantly, the plasticity of cardiac tissue could predict the adaptability of fish species to environmental temperature.

Structural and functional characterization of turbot pparγ: Activation during high temperature and regulation of lipid metabolism.

Transcription factors of the peroxisome proliferator-activated receptor gamma (pparγ) is a ligand-activated receptor that plays key roles in lipid metabolism and inflammation. In this study, we cloned the pparγ cDNA of turbot (Scophthalmus maximus). It has a 1659 bp coding sequence (CDS) and encodes 552 amino acids. The deduced PPARγ protein of turbot contains two highly conserved domains, a C4-type zinc finger, a nuclear hormone receptor DNA-binding region signature, and a HOLI domain (ligand-binding domain of hormone receptors) identical to that of in other species. qPCR results showed that the expression level of pparγ and the expression of the fatty acid transporters fatp and cd36 were significantly increased under high-temperature stress. This indicates that high temperatures activate the transcriptional activity of pparγ, and lipid metabolism plays an important role in turbot under high-temperature stress. In addition, RNA interference was used to explore the regulation of pparγ on lipid metabolism of turbot at high temperatures. The results showed that the mRNA level of pparγ was significantly decreased. After the expression level of pparγ was inhibited, the expression levels of fatp and cd36 were significantly decreased. At the same time, GW9662 (a pparγ antagonist) was used to inhibit pparγ activity in turbot kidney cells, and fatp and cd36 gene expressions were detected. The mRNA expression levels of pparγ, fatp, and cd36 were significantly decreased. Our results suggest that high temperatures activate pparγ in turbot and that pparγ regulates lipid transport and maintains lipid metabolism homeostasis through positive regulation of the expression of downstream genes fatp and cd36. This study further elucidates that the pparγ-mediated signaling pathway may play an important role in regulating lipid metabolism during heat stress in teleost fish.

Genetic Mechanism of Tissue-Specific Expression of PPAR Genes in Turbot (Scophthalmus maximus) at Different Temperatures.

In this study, we used PCR to measure the levels of the peroxisome proliferator activated receptor genes PPARα1, PPARα2, PPARß, and PPARγ in the intestine, liver, gill, heart, kidney, brain, muscle, spleen, skin, and stomach of turbot (Scophthalmus maximus) cultured under different temperature conditions (14, 20, 23, 25, and 28 °C). We used split-split-plot (SSP) analysis of variance, additive main effects and multiplicative interaction (AMMI) analysis, and genotype main effects and genotype × environment interaction (GGE) biplot analysis to evaluate the genotype × tissue interaction effects on gene expression. The results of the SSP analysis of variance showed that temperature and tissue × gene have highly significant (p < 0.01) effect on the expression of S. maximus PPAR genes. The AMMI analysis results revealed that the expression of PPAR genes at the appropriate temperature (14 °C) mainly depended on genotype × tissue interaction and tissue effects. Under stress temperatures, genotype effects, tissue effects, and genotype × tissue interaction, all had significant effects on the expression of PPAR genes. The contribution of the genotype effect slowly increased with increasing temperature; it increased faster at 20 °C and then slowly declined at 25 °C. The contribution of the tissue effect slowly increased from 14 to 20 °C, where it sharply decreased, and then it stabilized after a slight fluctuation. The contribution of the genotype × tissue interaction effect showed a fluctuating upward trend throughout the experiment, and it had a significant impact on PPAR gene expression. The key temperature at which the three effects changed was 20 °C, indicating that it is the limit temperature for active lipid metabolism under high-temperature stress. The GGE biplot analysis results showed that under suitable water temperature, the expression difference of PPAR genes in the liver was the largest; at 20 and 23 °C, the expression difference in the gill was the largest; and at 25 and 28 °C, the expression difference in the brain was the largest. Overall, our results suggest that the mechanism responsible for PPAR gene expression under the three high temperatures (23, 25, and 28 °C) was relatively consistent, but it differed from that at 20 °C.

Formal (3 + 4)-Annulation of Propargylic p-Quinone Methides with 2-Indolylmethanols: Synthesis of Polysubstituted Indole-Fused Oxepines.

A novel Brønsted acid catalyzed 1,8-addition mediated (3 + 4)-annulation of in situ generated propargylic p-quinone methides with 2-indolylmethanols is described. This method provides a convenient and mild approach to structurally interesting and synthetically important polysubstituted indole-fused oxepines in high yields. Moreover, 2-indolylmethanols as four-atom synthons in the (3 + 4)-annulations under Brønsted acid conditions have been explored for the first time.

Dearomatization of 2,3-Disubstituted Indoles via 1,8-Addition of Propargylic (Aza)-para-Quinone Methides.

Dearomatization of indole is a useful strategy to access indolimines: a motif widely exists in biologically active molecules and natural products. Herein, an efficient method for the dearomatization of 2,3-disubstituted indoles to generate diverse indolimines with tetrasubstituted allenes is described. This work accomplishes dearomatization of 2,3-disubstituted indoles through 1,8-addition of (aza)-para-quinone methides, which are generated in situ from propargylic alcohols. A series of synthetically useful indolimines containing quaternary carbon centers and tetrasubstituted allenes can be accessed in good yields (up to 99%). Additionally, the separability of product isomers, diversified product transformations, and easy scale-up of the reaction demonstrate the potential application of this method.

Brønsted Acid-Catalyzed Formal (3+3)-Annulation of Propargylic (Aza)-para-Quinone Methides with 4-Hydroxycoumarins and 1,3-Dicarbonyl Compounds.

Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Brønsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.

Dissection of genotype × tissue interactions for immunological factors in turbot (Scophthalmus maximus) infected with Vibrio anguillarum.

Seven immune factors, lysozyme, hepcidin, heat-shock protein (HSP) 70, HSP90, immunoglobulin M, C-type lectin, and Lily-type lectin, were measured by PCR in the livers, spleens, and head kidneys of turbot infected with Vibrio anguillarum. Additive main effects and multiplicative interaction (AMMI) and genotype main effects and genotype × environment interaction (GGE) biplot analysis were used to analyze genotype × tissue interactions for immunological factors. The AMMI analysis revealed that immune factor expression was significantly affected by genotype, tissue, and genotype × tissue interactions. Genotype (65.85%) was the major contributor to the total variation in immune factor expression in comparison to tissue effects (7.54%) and genotype × tissue interactions (12.52%). GGE biplot analysis revealed differences in the ranking of the seven immune factors in the three tissues; head kidney possessed the strongest ability to distinguish the seven immune factors. The test tissue locations were divided into liver-spleen and head kidneys regions; HSP70 was expressed the highest in the liver-spleen regions, and lysozyme had the highest expression in the head kidney region. Overall, HSP70 and HSP90 had the best expression and stability in the three tissues.

Genetic parameter estimates for three antioxidant factors in cultured Takifugu rubripes.

Genetic parameters of three antioxidant factors, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX), were evaluated in liver samples from 840 Takifugu rubripes individuals from 28 full-sib families. Heritability values of SOD, CAT, and GPX were 0.17, 0.18, and 0.14, respectively, and the full-sib family effect values for these antioxidant factors were 0.46, 0.47, and 0.49, respectively. The ranges of phenotypic and genetic correlations among the three immune factors were 0.748-0.848 and 0.726-0.806, respectively. Considering the low heritability and high full-sib family effect of the three antioxidant indexes, the use of both genome-wide selection and clustered regularly interspaced short palindromic repeats (CRISPR) is promising for genetically improving the three antioxidant indexes in cultured fish. In addition, given positive phenotypic and genetic correlations among the three antioxidant enzymes SOD, CAT and GPX, the antioxidant competence of Takifugu rubripes can be improved by genetically improving these three antioxidant traits via multi-trait integrated breeding technology or indirect selection.

Association between uric acid and the prognosis of acute ischemic stroke: A systematic review and meta-analysis.

AIMS: Meta-analysis was performed to assess the value of serum uric acid in the prognosis of ischemic stroke. DATA SYNTHESIS: We searched the databases of PubMed, Embase, and Web of Science. The literature we searched was published from the establishment of the database to January 2021. The references of the included literature were also collected. Two researchers sifted through the literature according to the inclusion and exclusion criteria and extracted the data. Stata 16.0 software was used for meta-analysis, and funnel plots were used to evaluate publication bias. Ten studies fulfilled the research criteria and were eventually included, and the analysis results showed that there was no significant association between serum uric acid and the functional outcome (OR = 0.99, 95% CI; 0.97-1.10), poor outcome (OR = 1.07, 95% CI; 0.99-1.15), vascular events (OR = 0.86, 95% CI; 0.52-1.41), and mortality (OR = 1.08, 95% CI; 0.93-1.24) related to ischemic stroke. CONCLUSIONS: There was no significant correlation between serum uric acid level and prognosis of ischemic stroke.