Phlecarinatones H-N: Abietane-type diterpenoids from Phlegmariurus carinatus with proliferative inhibitory effect on U251 glioblastoma cells.

Thirteen abietane-type diterpenoids, including seven previously undescribed compounds and six known analogs, were isolated from the root and aerial parts of Phlegmariurus carinatus. Their structures were elucidated by comprehensive spectroscopic data analysis (UV, IR, NMR, and HRESIMS) and quantum chemical calculations (calculated ECD or C NMR). Notably, these compounds exhibited high structural diversity.

APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4.

Indole produced during dysbiosis mediates host-microorganism chemical communication.

An imbalance of the gut microbiota, termed dysbiosis, has a substantial impact on host physiology. However, the mechanism by which host deals with gut dysbiosis to maintain fitness remains largely unknown. In , , which is its bacterial diet, proliferates in its intestinal lumen during aging.

APOE2 gene therapy reduces amyloid deposition, and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease.

Unlabelled: Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE ε2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE ε2, or if APOE ε2 has a protective, neuro-modulatory effect.

Ethanol mediates the interaction between and the nematophagous fungus .

Accurately recognizing pathogens by the host is vital for initiating appropriate immune response against infecting microorganisms. has no known receptor to recognize pathogen-associated molecular pattern. However, recent studies showed that nematodes have a strong specificity for transcriptomes infected by different pathogens, indicating that they can identify different pathogenic microorganisms.

-derived ependyma promoter drives increased therapeutic protein secretion into the CSF.

Recombinant adeno-associated viral vectors (rAAVs) are a promising strategy to treat neurodegenerative diseases because of their ability to infect non-dividing cells and confer long-term transgene expression. Despite an ever-growing library of capsid variants, widespread delivery of AAVs in the adult central nervous system remains a challenge. We have previously demonstrated successful distribution of secreted proteins by infection of the ependyma, a layer of post-mitotic epithelial cells lining the ventricles of the brain and central column of the spinal cord, and subsequent protein delivery via the cerebrospinal fluid (CSF).

Arthrocolins Synergizing with Fluconazole Inhibit Fluconazole-Resistant Candida albicans by Increasing Riboflavin Metabolism and Causing Mitochondrial Dysfunction and Autophagy.

Our previous study reported that seminaturally occurring arthrocolins A to C with unprecedented carbon skeletons could restore the antifungal activity of fluconazole against fluconazole-resistant Candida albicans. Here, we showed that arthrocolins synergized with fluconazole, reducing the fluconazole minimum and dramatically augmenting the survivals of 293T human cells and nematode Caenorhabditis elegans infected with fluconazole-resistant C. albicans.

Modulating Activity Evaluation of Gut Microbiota with Versatile Toluquinol.

Gut microbiota have important implications for health by affecting the metabolism of diet and drugs. However, the specific microbial mediators and their mechanisms in modulating specific key intermediate metabolites from fungal origins still remain largely unclear. Toluquinol, as a key versatile precursor metabolite, is commonly distributed in many fungi, including species and their strains for food production.

Enantioselective Total Synthesis of (-)-Hamigeran F and Its Rearrangement Product.

Herein, we report the first enantioselective total synthesis of the highly complex hamigeran diterpenoid (-)-hamigeran F and its rearrangement product. The synthetic strategy features key steps of asymmetric hydrogenation, Horner-Wadsworth-Emmons olefination, and intramolecular Friedel-Crafts acylation to construct the [6,6,5]-tricyclic skeleton bearing three consecutive stereocenters, a sequence of steps involving Rosenmund reduction, Wittig reaction, dihydroxylation to assemble the α-acetoxy ketone group, and an intramolecular aldol reaction to build the tetracyclic core structure.

Acetylation of Sesquiterpenyl Epoxy-Cyclohexenoids Regulates Fungal Growth, Stress Resistance, Endocytosis, and Pathogenicity of Nematode-Trapping Fungus via Metabolism and Transcription.

Sesquiterpenyl epoxy-cyclohexenoids (SECs) that depend on a polyketide synthase-terpenoid synthase (PKS-TPS) pathway are widely distributed in plant pathogenic fungi. However, the biosynthesis and function of the acetylated SECs still remained cryptic. Here, we identified that 00215 273 (273) was responsible for the acetylation of SECs in via the construction of Δ273, in which the acetylated SECs were absent and major antibacterial nonacetylated SECs accumulated.

Skin transcriptome analysis identifies the key genes underlying fur development in Chinese Tan sheep in the birth and Er-mao periods.

Hair follicle development in Tan sheep differs significantly between the birth and Er-mao periods, but the underlying molecular mechanism is still unclear. We profiled the skin transcriptomes of Tan sheep in the birth and Er-mao periods via RNA-seq technology. The Tan sheep examined consisted of three sheep in the birth period and three sheep in the Er-mao period.

Asymmetric Hydrogenation of Racemic α-Aryl-β-ethoxycarbonyl Cyclopentanones via Dynamic Kinetic Resolution and Its Application to the Synthesis of (+)-Burmaniol A.

An efficient asymmetric hydrogenation of racemic α-aryl-β-ethoxycarbonyl cyclopentanones via dynamic kinetic resolution is reported. Via catalysis by a chiral iridium Ir-SpiroPAP catalyst, a range of racemic α-aryl-β-ethoxycarbonyl cyclopentanones were hydrogenated to the corresponding ester-functionalized chiral 2-arylcyclopentanols with three contiguous stereocenters in high yields with excellent enantio- and diastereoselectivities. This method was successfully applied in the enantioselective synthesis of cyclopentane-based γ-amino ester/alcohol derivatives and phenylpropanoid (+)-burmaniol A.

Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain.

RNA interference (RNAi) for spinocerebellar ataxia type 1 can prevent and reverse behavioral deficits and neuropathological readouts in mouse models, with safety and benefit lasting over many months. The RNAi trigger, expressed from adeno-associated virus vectors (AAV.miS1), also corrected misregulated microRNAs (miRNA) such as miR150.

[Clinical Significance of Tfh/Tfr Cell Imbalance in Patients with B-Cell Lymphoma].

Objective: To explore the role of follicular helper T cell (Tfh)/ follicular regulatory T cell (Tfr) imbalance in B-cell lymphoma (BCL).

Methods: Sixteen BCL patients who were admitted to the Department of Hematology of The First People's Hospital of Yichang and 20 healthy people from December 2019 to November 2020 were enrolled and respectively divided into observation group and control group. The levels of Tfh and Tfr in peripheral blood were detected by flow cytometry.

Polyketide Synthase-Terpenoid Synthase Hybrid Pathway Regulation of Trap Formation through Ammonia Metabolism Controls Soil Colonization of Predominant Nematode-Trapping Fungus.

Polyketide synthase-terpenoid synthase (PKS-TPS) hybrid pathways for biosynthesis of unique sesquiterpenyl epoxy-cyclohexenoids (SECs) have been found to be widely distributed in plant pathogenic fungi. However, the natural and ecological functions of these pathways and their metabolites still remain cryptic. In this study, the whole PKS-TPS hybrid pathway in the predominant nematode-trapping fungus was first proposed according to all the intermediates and their derivatives from all the mutants with a deficiency in each gene involved in SEC biosynthesis.

Novel Polyketide-Terpenoid Hybrid Metabolites from a Potent Nematicidal Mutant Δ.

Here, we reported that detailed investigation on trace targeted metabolites from nematode-trapping fungus mutant with deletion of P450 gene led to isolation of 9 new polyketide-terpenoid hybrid derivatives, including four new glycosides of the key precursor farnesyl hydrotoluquinol () and, surprisingly, four new sesquiterpenyl epoxy-cyclohexenoids (SECs) analogues. Among them, two major target metabolites and displayed moderate nematode inhibitory ability. Moreover, the mutant lacking could form far more nematode-capturing traps within 6 h in contact with nematodes and show rapid potent nematicidal activity with killing 93.

Novel Polyketide-Terpenoid Hybrid Metabolites and Increased Fungal Nematocidal Ability by Disruption of Genes and in Nematode-Trapping Fungus .

Nematode-trapping fungus can produce a type of sesquiterpenyl epoxy-cyclohexenoid (SEC) metabolites that are regarded as characteristic chemtaxonomic markers. Here, we reported investigation on the functions of a putatively cupin-like family gene and a dehydrogenase gene by gene engineering, chemical metabolite profiling and phenotype analysis. Ten targeted metabolites were isolated from two mutants Δ and Δ and four novel metabolites including three polyketide-terpenoid (PK-TP) hybrid ones were characterized.

Prediction of intravenous immunoglobulin resistance in Kawasaki disease in children.

Background: We aimed to explore predictive measures for intravenous immunoglobulin (IVIG) resistance in children with Kawasaki disease (KD).

Methods: Patients diagnosed with KD were enrolled in this study. Univariate analysis and multiple logistic regression were utilized to analyze the clinical features and laboratory results prior to IVIG-treatment of the two groups.

Sesquiterpenyl Epoxy-Cyclohexenoids and their Signaling Functions in Nematode-Trapping Fungus .

In this study, we purified three new sesquiterpenyl epoxy-cyclohexenoid (SEC) analogues, arthrobotrisin D () and its two derivatives, from nematode-trapping fungus . Our results revealed that arthrobotrisin type SEC metabolites could be detected in all the test fungal strains from geographically distinct regions grown on different nutrient media, indicative of unique diagnostic character as chemical indicators for . The time course designs over short-term intervals of the fungus under direct contact and indirect contact with living or dead nematodes revealed that arthrobotrisin B and D ( and ) displayed significant relationships (positive or negative correlation) with fungal saprophytic and pathogenic stages during a nematode predation event.

Unexpected Biosynthesis of Fluorescein-Like Arthrocolins against Resistant Strains in an Engineered .

Here we provide an unprecedented biofactory where fluorescent dye-like complex xanthenes could be produced in an engineered . Feeding the strain with toluquinol or hydroquinones resulted in production of novel "unnatural" natural products including four arthrocolins embedded with indolyltriphenyl quaternary carbons. Arthrocolins - potently inhibited various human cancer cell lines including paclitaxel-resistant cell line A549/Taxol and methicillin-resistant and immensely restored the sensitivity of intractable fluconazole-resistant human pathogen to fluconazole.

Adeno-Associated Virus Production, Purification, and Titering.

Adeno-associated virus (AAV) vectors are exemplary tools for studying gene function in vivo and are particularly favorable for transferring genes of interest into brain tissues. They have shown great promise as a gene therapy vector for preclinical and clinical applications. However, the ability to use this tool is often hampered because the viruses themselves are not readily available.

Viral Vectors for Gene Transfer.

Viral vectors are a promising tool for effective delivery of genetic material into cells. They take advantage of the natural ability of a virus to deliver a genetic payload into cells while being genetically modified such that their ability to replicate is crippled or removed. Here, an updated overview of routinely used viral vectors, including adeno-associated viruses (AAV), retroviruses/lentiviruses, and adenoviruses (Ads), is provided, as well as perspectives on their advantages and disadvantages in research and gene therapy.