An Observational Prospective Cohort Study of Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection of an Aerosolized, Inhaled Adenovirus Type 5-Vectored Coronavirus Disease 2019 Vaccine Given as a Second Booster Dose in Guangzhou City, China.

Using a prospective, observational cohort study during the post-"dynamic COVID-zero" wave in China, we estimated short-term relative effectiveness against Omicron BA.5 infection of inhaled aerosolized adenovirus type 5-vectored ancestral strain coronavirus disease 2019 (COVID-19) vaccine as a second booster dose approximately 1 year after homologous boosted primary series of inactivated COVID-19 vaccine compared with no second booster. Participants reported nucleic acid or antigen test results weekly until they tested positive or completed predesignated follow-up. After excluding participants infected <14 days after study entry, relative effectiveness among the 6576 participants was 61% in 18- to 59-year-olds and 38% in ≥60-year-olds and was sustained for 12 weeks.

Three New Ionone Glycosides from Rhododendron capitatum Maxim.

Six ionone glycosides (1-3 and 5-7), including three new ones, named capitsesqsides A-C (1-3), together with an eudesmane sesquiterpenoid glycoside (4) and three known triterpenoid saponins (8-10) were isolated from Rhododendron capitatum. The structures of these compounds were determined by extensive spectroscopic techniques (MS, UV, 1D-NMR, and 2D-NMR) and comparison with data reported in the literature. The absolute configurations were determined by comparison of the experimental and theoretically calculated ECD curves and LC-MS analyses after acid hydrolysis and derivatization. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. Molecular docking demonstrated that 2 has a favorable affinity for NLRP3 and iNOS.

Discovery of Unusual Sesterterpenoids from Colquhounia coccinea var. mollis and Their Metabolic Implications.

Three unusual sesterterpenoids featuring unprecedented rearranged colquhounane (C25) and tetranorcolquhounane (C21) frameworks, colquhounoids E (1) and F (3) and norcolquhounoid F (2), were isolated from a Lamiaceae medicinal plant Colquhounia coccinea var. mollis. Their structures were elucidated by spectroscopic analysis and quantum chemical calculations. A biomimetic inspired regioselective cyclopropane cleavage was achieved under acidic conditions. The immunosuppressive activities of these new sesterterpenoids were also evaluated.

SNHG16 lncRNAs are overexpressed and may be oncogenic in human gastric cancer by regulating cell cycle progression.

The small nucleolar RNA host gene 16 (SNHG16) has recently been shown to be a putative oncogene in gastric cancer (GC) and other cancer types, but how its four lncRNA variants are expressed in any physiological and pathological situation remains unknown. To investigate the expression and function of the four lncRNA variants of SNHG16, mainly the variant 1, in GC, we performed quantitative PCR to determine the RNA levels of the four variants in 60 GC tissue samples and several cell lines. We also studied how knocking down of SNHG16 with siRNA affected proliferation, apoptosis, cell cycle progression, as well as migration and invasion of GC cells. Our results showed that variants 1 and 4 were overexpressed in GC tissues compared with adjacent uninvolved tissues. Knockdown of the four variants, mainly the variant 1, enhanced apoptosis and inhibited cell cycle progression of a GC cell line by arresting the cells at the G1 phase. These cellular effects were associated not only with decreased protein levels of c-Myc, PCNA, cyclins D1, E1, A2 and B, as well as CDKs 2 and 6, but also with increased protein levels of the p21, p27 and p53. Knockdown of total SNHG16 lncRNAs also inhibited invasion and migration of the GC cells in vitro. These results collectively suggest that SNHG16 may be oncogenic in GC by regulating cell cycle progression and may serve as a GC biomarker.

The Arabidopsis J-Protein AtDjC5 Facilitates Thermotolerance Likely by Aiding in the ER Stress Response.

AtDjC5 belongs to the J-protein family in Arabidopsis thaliana. Its biological functions remain unclear. In this study, we examined the roles of AtDjC5 in resisting heat stress using reverse genetic analysis. After the seedlings were exposed directly to 44 °C for 90 min, AtDjC5 knockout seedlings displayed decreases in the survival rate, membrane system stability, and cell vitality compared to WT seedlings, indicating that AtDjC5 is involved in plant basal thermotolerance. The AtDjC5 knockout seedlings pre-exposed to 37 °C for 30 min exhibited decreases in the survival rate and total chlorophyll contents and increased cell death when they were subsequently exposed to 45 °C compared to the WT seedlings, indicating that AtDjC5 plays an important role in plant acquired thermotolerance. AtDjC5 was found to localize to the endoplasmic reticulum. The expression of the AtDjC5 gene was induced by heat and TM (an ER stress inducer) treatment. Furthermore, we found that the knockout of AtDjC5 inhibited ER stress-induced autophagy and the expression of ER stress-related genes. Taken together, these results suggest that AtDjC5 facilitates thermotolerance, likely by aiding in the ER stress response.

Immunosuppresive Sesterterpenoids and Norsesterterpenoids from Colquhounia coccinea var. mollis.

A pair of new C-14 epimeric sesterterpenoids, colquhounoid D (1) and 14-epi-colquhounoid D (2), and five degradation products featuring new C20 and C21 frameworks, norcolquhounoids A-E (3-7), were isolated from Colquhounia coccinea var. mollis. Their structures were elucidated by comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Degradation of the C25 skeleton to the C21 skeleton was also achieved using aqueous NaIO4 and RuCl3. Compounds 1 and 2 showed significant immunosuppressive activity on the cytokine IFN-γ secretion of mouse splenocytes induced by anti-CD3/CD4 monoclonal antibodies, with IC50 of 8.38 and 5.79 µM, respectively, and compounds 5 and 6 were moderately active.

A Geranylfarnesyl Diphosphate Synthase Provides the Precursor for Sesterterpenoid (C25) Formation in the Glandular Trichomes of the Mint Species Leucosceptrum canum.

Plant sesterterpenoids, an important class of terpenoids, are widely distributed in various plants, including food crops. However, little is known about their biosynthesis. Here, we cloned and functionally characterized a plant geranylfarnesyl diphosphate synthase (Lc-GFDPS), the enzyme producing the C25 prenyl diphosphate precursor to all sesterterpenoids, from the glandular trichomes of the woody plant Leucosceptrum canum. GFDPS catalyzed the formation of GFDP after expression in Escherichia coli. Overexpressing GFDPS in Arabidopsis thaliana also gave an extract catalyzing GFDP formation. GFDPS was strongly expressed in glandular trichomes, and its transcript profile was completely in accordance with the sesterterpenoid accumulation pattern. GFDPS is localized to the plastids, and inhibitor studies indicated its use of isoprenyl diphosphate substrates supplied by the 2-C-methyl-D-erythritol 4-phosphate pathway. Application of a jasmonate defense hormone induced GFDPS transcript and sesterterpenoid accumulation, while reducing feeding and growth of the generalist insect Spodoptera exigua, suggesting that these C25 terpenoids play a defensive role. Phylogenetic analysis suggested that GFDPS probably evolved from plant geranylgeranyl diphosphate synthase under the influence of positive selection. The isolation of GFDPS provides a model for investigating sesterterpenoid formation in other species and a tool for manipulating the formation of this group in plants and other organisms.

Cadaver skin allograft may improve mortality rate for burns involving over 30% of total body surface area: a propensity score analysis of data from four burn centers.

Cadaver skin is used for temporary wound covering, but there is insufficient evidence regarding its clinical usefulness in patients with major burns. We aimed to analyze the effect of cadaveric skin allograft on mortality rates in patients with burns involving > 30% of total body surface area (TBSA). Our study included 1282 patients with > 30% of TBSA burned admitted to four hospitals in Korea between June 1, 2008 and December 31, 2016. Of these, 698 patients underwent cadaver skin allograft (cadaver group), and 584 were treated with conventional treatment (non-cadaver group). We corrected the differences between the two groups using propensity score matching, and generated 474 propensity score-matched pairs. Overall 90-day in-hospital mortality rate among all patients was 35.3% (453/1282). There was a significant difference in 90-day in-hospital mortality between the two groups for both unmatched [cadaver vs. conventional, 31.7 vs. 39.7%; difference, 8.0; 95% confidence interval (CI) 2.8-13.3] and propensity-matched groups (37.8 vs. 47.3%; difference, 9.5; 95% CI 3.2-15.8). Logistic regression analyses showed a significant association between cadaver skin allograft and lower 90-day in-hospital mortality in the propensity-matched groups (odds ratio, 0.42; 95% CI 0.29-0.62). Patients with major burns who underwent cadaver skin allograft had a lower mortality rate compared to those who did not. Cadaver skin allograft may improve the survival of patients with major burns, especially in the early phase of injury.

Palladium-Catalyzed Construction of Tetracyclic Scaffolds via the 1,7-Enyne Carbocyclization/Iodophenol Dearomatization Cascade.

An efficient palladium-catalyzed dearomatizing [2+2+1] carbocyclization of 1,7-enynes with iodophenols has been developed. A type of tetracyclic scaffold was built in this reaction, exhibiting a broad substrate scope with moderate to excellent yields. More importantly, this method provides a potential strategy for the synthesis of tetracyclic skeleton natural products.

New Antifeedant Grayanane Diterpenoids from the Flowers of Pieris formosa.

Three new grayanane diterpenoids, pierisoids C‒E (1-3), as well as 10 known ones (4-13), were evaluated from the flowers of Pieris formosa, which is used as an insecticide in rural areas of China. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses. Significant antifeedant activity of 1, 3 and 10 against the beet armyworm (Spodoptera exigua) was found, indicating that these diterpenoids might also be involved in the plant defense against insect herbivores.

TGF-ß1 pathway affects the protein expression of many signaling pathways, markers of liver cancer stem cells, cytokeratins, and TERT in liver cancer HepG2 cells.

Liver cancer is one of the most common human malignancies, and transforming growth factor-beta (TGF-ß) pathway plays a key role in its pathogenesis. To study the relationship between TGF-ß pathway and the related protein expression of many signaling pathway, markers of stem cells, CK family, and others, liver cancer HepG2 cells were transfected with siRNA directed against TGF-ß1 or were treated with exogenous TGF-ß1. Then, these protein levels were measured by Western blotting. After siRNA transfection, TGF-ß1 protein level was decreased, indicating that the siRNA against it was effective. In exogenous TGF-ß1 group, the expression of smad4, smad2/3, and ß-catenin proteins was increased, whereas that of p-smad2/3, CD133, cleaved Notch1, and epithelial cell adhesion molecule (EpCAM) proteins at 48 h was decreased. The expression of CK8 and CK18 proteins was increased at 24 h and was decreased at 48 and 96 h. In TGF-ß1-silenced group, the expression of smad2/3, ß-catenin, cleaved-notch1, and CK18 proteins was decreased, while that of smad4, p-smad2/3, CD133, EpCAM, and CK8 proteins was increased. TERT protein expression was slightly increased in exogenous TGF-ß1 group at 48 h and in TGF-ß1-silenced group at 96 h. TGF-ß1 did not affect the protein expression of CK19 and HIF-1. Thus, TGF-ß1 pathway plays an important role in cell regulation of liver cancer through the modulation of these proteins. These data will contribute to the understanding of the pathogenesis of liver cancer and the role of TGF-ß pathway in this process.

Isobutylhydroxyamides from Zanthoxylum bungeanum and Their Suppression of NO Production.

Four new unsaturated aliphatic acid amides, named zanthoamides A-D (1-4), and eight known ones-tetrahydrobungeanool (5), ZP-amide A (6), ZP-amide B (7), ZP-amide C (8), ZP-amide D (9), ZP-amide E (10), bugeanumamide A (11), and (2E,7E,9E)-N-(2-hydroxy-2-methylpropyl)-6,11-dioxo-2,7,9-dodecatrienamide (12)-were isolated from the pericarps of Zanthoxylum bungeanum. The structures of these compounds were elucidated by extensive use of spectroscopic methods, including HRESIMS, 1D and 2D NMR analyses and comparison with previously reported data. Compound 4 contained a rare C6 fatty acid unit with an acetal group. Results revealed that compounds 1, 5, 6, and 12 showed inhibitory effects on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages, with IC50values of 48.7 ± 0.32, 27.1 ± 1.15, 49.8 ± 0.38, and 39.4 ± 0.63 µM, respectively, while the other compounds were inactive (IC50 > 60 µM). They could contribute to the anti-inflammatory effects of Z. bungeanum by suppression of NO production.

Predictors of Mortality in Acute Ischemic Stroke Intervention: Analysis of the North American Solitaire Acute Stroke Registry.

BACKGROUND AND PURPOSE: Failure to recanalize predicts mortality in acute ischemic stroke. In the North American Solitaire Acute Stroke registry, we investigated parameters associated with mortality in successfully recanalized patients. METHODS: Logistic regression was used to evaluate baseline characteristics and recanalization parameters for association with 90-day mortality. A multivariable model was developed based on backward selection with retention criteria of P<0.05 from factors with at least marginal significance (P≤0.10), then refit to minimize the number of excluded cases (missing data). RESULTS: Successfully recanalized patients had lower mortality (25.2% [59/234] versus 46.9% [38/81] P<0.001). There was no difference in symptomatic intracranial hemorrhage between patients with successful versus failed recanalization (9% [21/234] versus 14% [11/79]; P=0.205). However, mortality was significantly higher in patients with symptomatic intracranial hemorrhage (72% [23/32] versus 26% [73/281]; P<0.001). Proximal occlusion (internal carotid artery or vertebrobasilar), initial National Institutes of Health Stroke Scale≥18, use of rescue therapy (P<0.05), and 3+ passes (P<0.10) were associated with mortality in recanalized patients. In the multivariate model with good predictive power (c index=0.72), proximal occlusion, initial National Institutes of Health Stroke Scale≥18, and use of rescue therapy remained significant independent predictors of 90-day mortality. CONCLUSIONS: Failure to recanalize and presence of symptomatic intracranial hemorrhage resulted in increased mortality. Despite successful recanalization, proximal occlusion, high National Institutes of Health Stroke Scale, and need for rescue therapy were predictors of mortality.

C­H bond functionalization via [1,5]-hydride shift/cyclization sequence: approach to spiroindolenines.

A concise synthesis of spiroindolenines from 2-substituted (Me, Et) indoles and 2-(pyrrolidin-1-yl)benzaldehydes has been developed via a [1,5]-hydride shift/cyclization sequence. This method features a wide substrate scope and an operationally simple procedure, affording the spiroindolenines in good to excellent yields and moderate diastereoselectivity (3.5/1 dr). When the inseparable mixture of spiroindolenine isomers were washed with isopropyl ether after flash chromatography, the major isomers could be obtained in up to >20/1 dr.

Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity.

1. Rhein, an active ingredient in the root of rhubarb, is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. However, its hepatotoxicity has been reported in recent years. Rhein belongs to the conjugate structure which could be activated to reactive metabolites (RMs) inducing side-effects. This study is to explore the relationship between RMs and hepatotoxicity. 2. Based on the early detection of RMs, we have established a series of key technologies to research rhein hepatotoxicity mechanism: IC50 shift experiments and reduced glutathione (GSH) trapping experiment are adopted to identify RMs. The model of low activity of CYP450 enzymes (CYPs) in primary rat hepatocyte is constructed to analyze the relationship between the primary metabolic enzyme and hepatotoxicity of rhein better. 3. The IC50 shift value for CYP2C19 is 1.989, it suggests that CYP2C19 could activate rhein to RM. The structure of RM is epoxide intermediate. Besides, it is found that CYP2C19 is a primary metabolic enzyme for rhein. In the cytotoxicity assay, it is reported that rhein could cause mitochondrial dysfunction. Furthermore, mitochondrial membrane potential (Δψm) and AST levels could be restored by adding inhibitor of CYP2C19 together with rhein, which further shows that CYP2C19 could mediate the hepatotoxicity of rhein. 4. We put forward the possible mechanism that reactive metabolite activation by CYP2C19 mediated rhein hepatotoxicity, it provides important information on predicting in vivo drug-induced liver injury (DILI).

Identification and characterization of microRNAs in the ovaries of multiple and uniparous goats (Capra hircus) during follicular phase.

BACKGROUND: Superior kidding rate is an important economic trait in production of meat goat, and ovulation rate is the precondition of kidding rate. MicroRNAs (miRNAs) play critical roles in almost all ovarian biological processes, including folliculogenesis, follicle development, follicle atresia, luteal development and regression. To find out the different ovarian activity and follicle recruitment with miRNA-mediated posttranscriptional regulation, the small RNAs expressed pattern in the ovarian tissues of multiple and uniparous Anhui White goats during follicular phase was analyzed using Solexa sequencing data. RESULTS: 1008 miRNAs co-expressed, 309 and 433 miRNAs specifically expressed in the ovaries of multiple and uniparous goats during follicular phase were identified. The 10 most highly expressed miRNAs in the multiple library were also the highest expressed in the uniparous library, and there were no significantly different between each other. The highest specific expressed miRNA in the multiple library was miR-29c, and the one in the uniparous library was miR-6406. 35 novel miRNAs were predicted in total. GO annotation and KEGG Pathway analyses were implemented on target genes of all miRNA in two libraries. RT-PCR was applied to detect the expression level of 5 randomly selected miRNAs in multiple and uniparous hircine ovaries, and the results were consistent with the Solexa sequencing data. CONCLUSIONS: In the present study, the different expression of miRNAs in the ovaries of multiple and uniparous goats during follicular phase were characterized and investigated using deep sequencing technology. The result will help to further understand the role of miRNAs in kidding rate regulation and also may help to identify miRNAs which could be potentially used to increase hircine ovulation rate and kidding rate in the future.

Biologically active dichapetalins from Dichapetalum gelonioides.

A phytochemical investigation of the toxic tropical plant Dichapetalum gelonioides led to the isolation and identification of 14 new dichapetalins (1-14) and the known dichapetalins A (15) and K (16). The structures of the new compounds were determined by analyses of their NMR, MS, electronic circular dichroism, and X-ray diffraction data. The esterification at C-25 by 4-hydroxyphenylpropanoic acid and the hydroxylation at C-2' are unique in this unusual class of natural products. In addition to the known cytotoxicity, an array of biological activities, including antifeedant, nematicidal, antifungal, and NO and AChE inhibitory activities, were observed for this class of compounds. These findings suggested that dichapetalin hybrid triterpenoids as a class have broad biologically active cellular functions including defense against insect herbivores and pathogens.

Peltate glandular trichomes of Colquhounia seguinii harbor new defensive clerodane diterpenoids.

Glandular trichomes produce a wide variety of secondary metabolites that are considered as major defensive chemicals against herbivore attack. The morphology and secondary metabolites of the peltate glandular trichomes of a lianoid Labiatae, Colquhounia seguinii Vaniot, were investigated. Three new clerodane diterpenoids, seguiniilactones A-C (1-3), were identified through precise trichome collection with laser microdissection, metabolic analysis with ultra performance liquid chromatography-tandem mass spectrometer, target compound isolation with classical phytochemical techniques, structure elucidation with spectroscopic methods. All compounds showed significant antifeedant activity against a generalist plant-feeding insect Spodoptera exigua. Seguiniilactone A (1) was approximately 17-fold more potent than the commercial neem oil. α-Substituted α,ß-unsaturated γ-lactone functionality was found to be crucial for strong antifeedant activity of this class of compounds. Quantitative results indicated that the levels of these compounds in the peltate glandular trichomes and leaves were sufficiently high to deter the feeding by generalist insects. Moderate antifungal activity was observed for seguiniilactone C (3) against six predominant fungal species isolated from the diseased leaves of C. seguinii, while seguiniilactones A and B were generally inactive. These findings suggested that seguiniilactones A-C might be specialized secondary metabolites in peltate glandular trichomes for the plant defense against insect herbivores and pathogens.

Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolecular [1,5]-hydride shift/isomerization reaction.

Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomerization reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N-arylpyrrole containing amines are obtained in high yields.