Five-year symptomatic hemorrhage risk of untreated brainstem cavernous malformations in a prospective cohort.

Hemorrhage of brainstem cavernous malformation (CM) would cause various symptoms and severe disability. The study aimed to elaborate on the 5-year actuarial cumulative hazard of symptomatic hemorrhage. Patients diagnosed in our institute between 2009 and 2013 were prospectively registered. All clinical data were obtained, follow-up was performed, and risk factors were evaluated. Four hundred sixty-eight patients (217 female, 46.4%) were included in the study with a median follow-up duration of 79.0 months. A total of 137 prospective hemorrhages occurred in 107 patients (22.9%) during 1854.0 patient-years. Multivariate Cox analysis found age ≥ 55 years (hazard ratio (HR) 2.166, p = 0.002), DVA (HR 1.576, p = 0.026), superficial-seated location (HR 1.530, p = 0.047), and hemorrhage on admission (HR 2.419, p = 0.026) as independent risk factors for hemorrhage. The 5-year cumulative hazard of hemorrhage was 30.8% for the overall cohort, 47.8% for 60 patients with age ≥ 55 years, 43.7% for 146 patients with DVA, 37.9% for 272 patients with superficial-seated lesions, and 37.2% for 341 patients with hemorrhage on admission. As a stratified analysis, within subcohort of 341 patients with a hemorrhagic presentation, age ≥ 55 years (HR 3.005, p < 0.001), DVA (HR 1.801, p = 0.010), and superficial-seated location (HR 2.276, p = 0.001) remained independently significant. The 5-year cumulative hazard of hemorrhage was 52.0% for 119 patients with both DVA and hemorrhagic presentation. The 5-year cumulative hemorrhagic risk was 30.8% and was higher in subgroups if harboring risk factors that helped to predict potential hemorrhagic candidates and were useful for treatment decision-making.Clinical Trial Registration-URL: http://www.chictr.org.cn Unique identifier: ChiCTR-POC-17011575.

Coumarin-3-formylpyrazoles as 3-carbon synthons in cyclocondensation for the synthesis of spiro-fused pentacyclic spirooxindoles.

Coumarin-3-formylpyrazoles have been synthesized and applied as 3-carbon synthons in reaction with 3-hydroxyoxindoles by using DABCO as the catalyst. A range of structurally diverse spiro-fused pentacyclic spirooxindoles, bearing a spirooxindole-γ-lactone and a 3,4-dihydrocoumarin substructure, could be smoothly obtained in good to excellent yields (up to 99%) with excellent diastereoselectivities (all cases >20 : 1 dr). The asymmetric version of this tandem reaction was preliminarily investigated by using chiral organocatalysts.

Recent (2000-2015) developments in the analysis of minor unknown natural products based on characteristic fragment information using LC-MS.

Liquid chromatography-Mass Spectrometry (LC-MS) has been widely used in natural product analysis. Global detection and identification of nontargeted components are desirable in natural product research, for example, in quality control of Chinese herbal medicine. Nontargeted components analysis continues to expand to exciting life science application domains such as metabonomics. With this background, the present review summarizes recent developments in the analysis of minor unknown natural products using LC-MS and mainly focuses on the determination of the molecular formulae, selection of precursor ions, and characteristic fragmentation patterns of the known compounds. This review consists of three parts. Firstly, the methods used to determine unique molecular formula of unknown compounds such as accurate mass measurements, MSn spectra, or relative isotopic abundance information, are introduced. Secondly, the methods improving signal-to-noise ratio of MS/MS spectra by manual-MS/MS or workflow targeting-only signals were elucidated; pure precursor ions can be selected by changing the precursor ion isolated window. Lastly, characteristic fragmentation patterns such as Retro-Diels-Alder (RDA), McLafferty rearrangements, "internal residue loss," and so on, occurring in the molecular ions of natural products are summarized. Classical application of characteristic fragmentation patterns in identifying unknown compounds in extracts and relevant fragmentation mechanisms are presented (RDA reactions occurring readily in the molecular ions of flavanones or isoflavanones, McLafferty-type fragmentation reactions of some natural products such as epipolythiodioxopiperazines; fragmentation by "internal residue loss" possibly involving ion-neutral complex intermediates). © 2016 Wiley Periodicals, Inc. Mass Spec Rev 37:202-216, 2018.

Chiral Bifunctional Amine-Squaramide-Catalyzed Highly Diastereo- and Enantioselective Michael/Aldol Cascade Reaction of 2-Mercaptobenzaldehyde and α,ß-Unsaturated 7-Azaindoline Amides.

A highly diastereo- and enantioselective Michael/aldol cascade reaction of 2-mercaptobenzaldehyde and α,ß-unsaturated 7-azaindoline amides has been developed. Using as low as 1 mol % cinchonidine-derived bifunctional squaramide as the catalyst, a range of enantioenriched thiochromenes containing three contiguous stereogenic centers were smoothly obtained in excellent results (all cases >20:1 dr, 88-99% yield and ≥99% ee). The 7-azaindoline moiety of α,ß-unsaturated 7-azaindoline amides has been demonstrated to be vital for the high reactivity and excellent stereoselectivity.

Organocatalyzed Asymmetric Dearomative Aza-Michael/Michael Addition Cascade of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes with 2-Aminochalcones.

An organocatalyzed dearomative aza-Michael/Michael addition cascade of 2-nitrobenzofurans and 2-nitrobenzothiophenes with 2-aminochalcones has been developed, opening a new channel to access a series of optically active tetrahydrobenzofuro[3,2- b]quinolines and tetrahydrobenzo[4,5]thieno[3,2- b]quinolines bearing three contiguous stereocenters with excellent diastereo- and enantioselectivities (all cases >20:1 dr, up to 99% ee). This study features the first asymmetric dearomative cascade reaction of 2-nitrobenzofurans and 2-nitrobenzothiophenes beginning with aza-Michael addition. The potential applications of the methodology were demonstrated by the preparative-scale experiment and the versatile transformations of the products.

Phosphine-catalyzed dearomative (3 + 2) annulation of 2-nitrobenzofurans and nitrobenzothiophenes with allenoates.

An efficient Ph2PMe-catalyzed dearomative (3 + 2) annulation of 2-nitrobenzofurans, 2-nitrobenzothiophenes, and 3-nitrobenzothiophenes with allenoates has been developed. With the developed protocol, a series of structurally important cyclopenta[b]benzofurans and cyclopenta[b]benzothiophenes were obtained in good to excellent yields (up to 98%) under mild conditions. In addition, preparative-scale experiments and transformations were conducted to exemplify the synthetic utility. The asymmetric version of this dearomative (3 + 2) annulation reaction was tentatively investigated by using chiral phosphine catalysts.

Organocatalyzed Enantioselective Conjugated Addition of Sodium Bisulfite to ß-Trifluoromethyl-α,ß-unsaturated Ketones.

An efficient organocatalyzed enantioselective conjugated addition of sodium bisulfite to ß-trifluoromethyl-α,ß-unsaturated ketones using a cinchona alkaloid-derived squaramide catalyst is presented. A series of optically active sulfonic acids, bearing a tertiary stereocenter connecting a CF3 group and a SO3H group, were obtained in excellent yields with high enantioselectivities (up to 99% yield and 97% ee) under mild conditions. This method will provide an efficient, economic, and green route to access chiral sulfonic acid compounds.

An asymmetric organocatalytic vinylogous Mannich reaction of 3-methyl-5-arylfuran-2(3H)-ones with N-(2-pyridinesulfonyl) imines: enantioselective synthesis of δ-amino γ,γ-disubstituted butenolides.

An asymmetric organocatalytic vinylogous Mannich reaction of 3-methyl-5-arylfuran-2(3H)-ones with N-(2-pyridinesulfonyl)imines has been developed with 5 mol% thiourea-tertiary amine as the catalyst. A series of δ-amino γ,γ-disubstituted butenolides bearing adjacent quaternary and tertiary stereocenters are efficiently obtained with satisfactory results (up to 90% yield, 90 : 10 dr, and 95 : 5 er).

Synthesis of polycyclic spirooxindoles via an asymmetric catalytic one-pot stepwise Aldol/chloroetherification/aromatization procedure.

A general method for the synthesis of chiral pentacyclic spirooxindoles containing a tetrahydropyrano[2,3-b]indole scaffold through a one-pot stepwise sequence from 3-(3-indolomethyl)oxindole, paraformaldehyde and NCS is reported. Furthermore, the pentacyclic spirooxindoles could be transformed to bispirooxindole and other structurally diverse spirocyclic oxindoles.

Facile synthesis of fused polycyclic compounds via intramolecular oxidative cyclization/aromatization of ß-tetralone or ß-tetralone oximes.

A mild and efficient NBS promoted intramolecular oxidative cyclization/aromatization of ß-tetralone oximes has been explored. Under the optimized conditions, fused α-carbolines containing pentacyclic rings were obtained in moderate to good yields. Furthermore, various benzo[5,6]chromeno[2,3-b]indoles were successfully synthesized in moderate yields from ß-tetralones using slightly modified conditions. We proposed a possible reaction pathway based on the experimental results.

An organocatalytic asymmetric Mannich reaction of pyrazoleamides with cyclic trifluoromethyl ketimines: enantioselective access to dihydroquinazolinone skeletons.

An organocatalyzed asymmetric Mannich reaction of pyrazoleamides and cyclic trifluoromethyl ketimines with a chiral bifunctional amine-squaramide as the catalyst was developed. A wide range of trifluoromethyl dihydroquinazolinone derivatives bearing adjacent quaternary and tertiary stereogenic centers were readily obtained in good to excellent yields (up to 99%) with high diastereo- and enantioselectivities (up to 99% ee and >20 : 1 dr). The large scale experiment and transformation of the product have also been demonstrated.

Organocatalytic Asymmetric Michael Addition of 3-Pyrrolyloxindoles to ß-Phthalimidonitroethene for the Synthesis of 3,3'-Disubstituted Oxindoles Bearing Contiguous 3,α,ß-Triamino Functionality.

An organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to ß-phthalimidonitroethene has been developed with a bifunctional thiourea-tertiary amine as the catalyst. A range of 3,3'-disubstituted oxindoles bearing contiguous 3,α,ß-triamino functionality could be obtained in high yields with good diastereoselectivities and high enantioselectivities (up to 99% yield, 99:1 dr, and 98% ee). The higher reactivity of ß-phthalimidonitroethene compared to the reactivity of ordinary nitroalkenes in the reaction with 3-pyrrolyloxindoles was demonstrated by contrast experiments.

A Neber approach for the synthesis of spiro-fused 2H-azirine-pyrazolone.

A base-mediated Neber reaction of enaminopyrazolones, which are the tautomers of 4-acyloxime-2-pyrazolin-5-ones, with sulfonyl chlorides was achieved. With this developed approach, a range of spiro-fused 2H-azirine-pyrazolones were obtained in good yields under mild conditions. A preliminary trial of a catalytic asymmetric version of the Neber reaction was conducted and gave promising enantioselectivity.

The organocatalytic asymmetric Neber reaction for the enantioselective synthesis of spirooxindole 2H-azirines.

The asymmetric Neber reaction of 3-O-sulfonyl ketoxime, in situ generated from isatin ketoxime and sulfonyl chloride, for the synthesis of chiral spirocyclic oxindole compounds is reported. With the developed protocol, a range of chiral spirooxindole 2H-azirines could be obtained in good to excellent yields and up to a 92 : 8 enantiomeric ratio by using (DHQD)2PHAL as the catalyst. This methodology is the only example of the catalytic asymmetric construction of spirooxindole 2H-azirine compounds.

Enantioselective synthesis of chiral α,ß-unsaturated γ-substituted butyrolactams by organocatalyzed direct asymmetric vinylogous Michael addition of α,ß-unsaturated γ-butyrolactam to 2-enoylpyridines.

An organocatalyzed direct asymmetric vinylogous Michael addition reaction of α,ß-unsaturated γ-butyrolactam to 2-enoylpyridines has been developed with a chiral bifunctional amine-squaramide as the catalyst. This approach provides easy access to a series of optically active α,ß-unsaturated γ-substituted butyrolactams in high yields (up to 99%) with excellent diastereoselectivities (up to >99 : 1) and enantioselectivities (up to >99% ee).

An unprecedented protocol for the synthesis of 3-hydroxy-3-phenacyloxindole derivatives with indolin-2-ones and α-substituted ketones.

An unprecedented reaction between indolin-2-ones and α-substituted ketones has been developed. Using this protocol, a wide range of biologically important 3-hydroxy-3-phenacyloxindole derivatives could be obtained in good yield (up to 93%) under mild reaction conditions. A possible mechanism of this reaction was tentatively proposed based on some control experiments and MS spectrometry analysis.

Organocatalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones with bifunctional amine-thiourea catalysts bearing multiple hydrogen-bond donors.

For the first time, a catalytic asymmetric Henry reaction of 1H-pyrrole-2,3-diones was achieved with a chiral bifunctional amine-thiourea as a catalyst possessing multiple hydrogen-bond donors. With this developed method, a range of 3-hydroxy-3-nitromethyl-1H-pyrrol-2(3H)-ones bearing quaternary stereocenters were obtained in acceptable yield (up to 75%) and enantioselectivity (up to 73% ee).

CCAAT/enhancer-binding protein CEBP-2 controls fat consumption and fatty acid desaturation in Caenorhabditis elegans.

Mammalian CCAAT/enhancer-binding proteins (C/EBPs) are generally known as regulators in adipocyte differentiation. However, more understanding of the role of C/EBPs in lipid and glucose metabolism remains to be discovered. In this study, we verified the effect of CEBP-2, the homolog of CEBPs, on fat storage in Caenorhabditis elegans. Expressions of 85 genes that encode the major enzymes in energy metabolic pathways were then screened in cebp-2-deficient worms using a quantitative real-time polymerase chain reaction (QRT-PCR). Our data implied that loss of function of CEBP-2 displayed a low-fat phenotype in C. elegans owing to increased expression of ech-1.1 and decreased expression of fat-5. Our findings indicated that cebp-2 controls total body fat content by governing fatty acid mitochondrial ß-oxidation and desaturation in C. elegans. These data provide insights into how C/EBPs may affect lipid metabolism in mammals in addition to regulating adipocyte differentiation.

Toxicity of metal oxide nanoparticles: mechanisms, characterization, and avoiding experimental artefacts.

Metal oxide nanomaterials are widely used in practical applications and represent a class of nanomaterials with the highest global annual production. Many of those, such as TiO2 and ZnO, are generally considered non-toxic due to the lack of toxicity of the bulk material. However, these materials typically exhibit toxicity to bacteria and fungi, and there have been emerging concerns about their ecotoxicity effects. The understanding of the toxicity mechanisms is incomplete, with different studies often reporting contradictory results. The relationship between the material properties and toxicity appears to be complex and diifficult to understand, which is partly due to incomplete characterization of the nanomaterial, and possibly due to experimental artefacts in the characterization of the nanomaterial and/or its interactions with living organisms. This review discusses the comprehensive characterization of metal oxide nanomaterials and the mechanisms of their toxicity.

Freeze-thaw Caenorhabditis elegans freeze-thaw stress response is regulated by the insulin/IGF-1 receptor daf-2.

BACKGROUND: Adaption to cold temperatures, especially those below freezing, is essential for animal survival in cold environments. Freezing is also used for many medical, scientific, and industrial purposes. Natural freezing survival in animals has been extensively studied. However, the underlying mechanisms remain unclear. Previous studies demonstrated that animals survive in extremely cold weather by avoiding freezing or controlling the rate of ice-crystal formation in their bodies, which indicates that freezing survival is a passive thermodynamic process. RESULTS: Here, we showed that genetic programming actively promotes freezing survival in Caenorhabditis elegans. We found that daf-2, an insulin/IGF-1 receptor homologue, and loss-of-function enhanced survival during freeze-thaw stress, which required the transcription factor daf-16/FOXO and age-independent target genes. In particular, the freeze-thaw resistance of daf-2(rf) is highly allele-specific and has no correlation with lifespan, dauer formation, or hypoxia stress resistance. CONCLUSIONS: Our results reveal a new function for daf-2 signaling, and, most importantly, demonstrate that genetic programming contributes to freezing survival.