A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.

The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, "PRC2 associated LCOR isoform 1" (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. Pali1 and Aebp2 define mutually exclusive, antagonistic PRC2 subtypes that exhibit divergent H3K27-tri-methylation activities. The balance of these PRC2.1/PRC2.2 activities is required for the appropriate regulation of polycomb target genes during differentiation. PALI1/2 potentially link polycombs with transcriptional co-repressors in the regulation of cellular identity during development and in cancer.

Molecular mechanisms of PI4K regulation and their involvement in viral replication.

Lipid phosphoinositides are master signaling molecules in eukaryotic cells and key markers of organelle identity. Because of these important roles, the kinases and phosphatases that generate phosphoinositides must be tightly regulated. Viruses can manipulate this regulation, with the Type III phosphatidylinositol 4-kinases (PI4KA and PI4KB) being hijacked by many RNA viruses to mediate their intracellular replication through the formation of phosphatidylinositol 4-phosphate (PI4P)-enriched replication organelles (ROs). Different viruses have evolved unique approaches toward activating PI4K enzymes to form ROs, through both direct binding of PI4Ks and modulation of PI4K accessory proteins. This review will focus on PI4KA and PI4KB and discuss their roles in signaling, functions in membrane trafficking and manipulation by viruses. Our focus will be the molecular basis for how PI4KA and PI4KB are activated by both protein-binding partners and post-translational modifications, with an emphasis on understanding the different molecular mechanisms viruses have evolved to usurp PI4Ks. We will also discuss the chemical tools available to study the role of PI4Ks in viral infection.

SH-SY5Y cells undergo changes in peroxisomal metabolism when exposed to decanoic acid.

Medium-chain fatty acids (MCFAs), particularly decanoic acid (C10) and octanoic acid (C8), have garnered attention in recent years for their potential antiepileptic properties. A previous study from our laboratory demonstrated that C10 targets the PPARγ nuclear receptor, increasing the activity of the antioxidant enzyme catalase and thereby possibly modulating peroxisomal content. Here, we examined markers of peroxisomal content and activity in response to C10 and C8 exposure in neuronal-like SH-SY5Y cells. SH-SY5Y were treated with 250 mM C10 or C8 for a period of 6 days. Following this, biochemical markers of peroxisomal content and function were assessed, including acyl-coA oxidase activity, peroxisomal gene expression and peroxisomal VLCFA ß-oxidation. Our findings revealed that C10 treatment augments acyl-CoA oxidase 1 (ACOx1) activity by 129% in comparison to control cells. An exploration into genes related to peroxisomal biosynthesis showed 23% increased expression of PEX11α upon C10 exposure, implying peroxisomal proliferation. Furthermore, it was observed that C10 exposure not only elevated ACOx1 activity but also enhanced peroxisomal ß-oxidation of docosanoic acid (C22). Our findings bolster the premise that C10 functions as a peroxisome proliferator, influencing peroxisomal content and function. Further investigations are required to fully understand the mechanistic details as to how this may be beneficial in epilepsy and the potential implications with regards to peroxisomal disease.

Tyrosine phosphorylation of the lectin receptor-like kinase LORE regulates plant immunity.

Plant pattern recognition receptors (PRRs) perceive pathogen-associated molecular patterns (PAMPs) to activate immune responses. Medium-chain 3-hydroxy fatty acids (mc-3-OH-FAs), which are widely present in Gram-negative bacteria, were recently shown to be novel PAMPs in Arabidopsis thaliana. The Arabidopsis PRR LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) is a G-type lectin receptor-like kinase that recognizes mc-3-OH-FAs and subsequently mounts an immune response; however, the mechanisms underlying LORE activation and downstream signaling are unexplored. Here, we report that one of the mc-3-OH-FAs, 3-OH-C10:0, induces phosphorylation of LORE at tyrosine residue 600 (Y600). Phosphorylated LORE subsequently trans-phosphorylates the receptor-like cytoplasmic kinase PBL34 and its close paralogs, PBL35 and PBL36, and therefore activates plant immunity. Phosphorylation of LORE Y600 is required for downstream phosphorylation of PBL34, PBL35, and PBL36. However, the Pseudomonas syringae effector HopAO1 targets LORE, dephosphorylating the tyrosine-phosphorylated Y600 and therefore suppressing the immune response. These observations uncover the mechanism by which LORE mediates signaling in response to 3-OH-C10:0 in Arabidopsis.

UDP-glycosyltransferase UGT96C10 functions as a novel detoxification factor for conjugating the activated dinitrotoluene sulfonate in switchgrass.

Dinitrotoluene sulfonates (DNTSes) are highly toxic hazards regulated by the Resource Conservation and Recovery Act (RCRA) in the United States. The trinitrotoluene (TNT) red water formed during the TNT purification process consists mainly of DNTSes. Certain plants, including switchgrass, reed and alfalfa, can detoxify low concentrations of DNTS in TNT red water-contaminated soils. However, the precise mechanism by which these plants detoxify DNTS remains unknown. In order to aid in the development of phytoremediation resources with high DNTS removal rates, we identified and characterized 1-hydroxymethyl-2,4-dinitrobenzene sulfonic acid (HMDNBS) and its glycosylated product HMDNBS O-glucoside as the degradation products of 2,4-DNT-3-SO3Na, the major isoform of DNTS in TNT red water-contaminated soils, in switchgrass via LC-MS/MS- and NMR-based metabolite analyses. Transcriptomic analysis revealed that 15 UDP-glycosyltransferase genes were dramatically upregulated in switchgrass plants following 2,4-DNT-3-SO3Na treatment. We expressed, purified and assayed the activity of recombinant UGT proteins in vitro and identified PvUGT96C10 as the enzyme responsible for the glycosylation of HMDNBS in switchgrass. Overexpression of PvUGT96C10 in switchgrass significantly alleviated 2,4-DNT-3-SO3Na-induced plant growth inhibition. Notably, PvUGT96C10-overexpressing transgenic switchgrass plants removed 83.1% of 2,4-DNT-3-SO3Na in liquid medium after 28 days, representing a 3.2-fold higher removal rate than that of control plants. This work clarifies the DNTS detoxification mechanism in plants for the first time, suggesting that PvUGT96C10 is crucial for DNTS degradation. Our results indicate that PvUGT96C10-overexpressing plants may hold great potential for the phytoremediation of TNT red water-contaminated soils.

Health utility assessments in individuals undergoing diagnostic and surveillance colonoscopy: improved discrimination with a cancer-specific scale.

PURPOSE: To compare the sensitivity and discriminant validity of generic and cancer-specific measures for assessing health-related quality of life (HRQoL) for individuals undergoing diagnostic or surveillance colonoscopy for colorectal cancer. METHODS: HRQoL was assessed using EQ-5D-5L (generic), and EORTC QLQ-C30 (cancer-specific) scales, 14 days after (baseline) and one-year following colonoscopy (follow-up). Utility scores were calculated by mapping EORTC-QLQ-C30 onto QLU-C10D. Differences between participants with different indications for colonoscopy (positive faecal occult blood test (FOBT), surveillance, or symptoms) and colonoscopy findings (no polyps, polyps, or cancer) were tested using Wilcoxon-Mann-Whitney and Kruskal-Wallis H tests. Sensitivity was assessed by calculating the ceiling effects (proportion reporting the best possible level). RESULTS: 246 adults completed the survey, including those undergoing colonoscopy for symptoms (n = 87), positive FOBT (n = 92) or surveillance (n = 67). Those with symptoms had the lowest HRQoL at both baseline and follow-up, with differences observed within the HRQoL domains/areas of role function, appetite loss and bowel function on the QLU-C10D. No differences were found in HRQoL when stratified by findings at colonoscopy with both measures or when comparing baseline and follow-up responses. Participants reporting full health with EQ-5D-5L (21% at baseline and 16% at follow-up) still had problems on the QLU-C10D, with fatigue and sleep at baseline and with role function and fatigue at follow-up. CONCLUSION: Patients undergoing colonoscopy for symptoms had lower HRQoL compared to surveillance or positive FOBT. The cancer-specific QLU-C10D was more sensitive and had greater discriminant ability between patients undergoing colonoscopy for different indications.

Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells.

We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

Autosomal recessive congenital cataract is associated with a novel 4-bp splicing deletion mutation in a novel C10orf71 human gene.

Congenital cataract is one of the most genetically heterogeneous ocular conditions with different genes involved in its etiology. Here, we describe the analysis of a new candidate gene of a congenital bilateral cataract associated with polymalformative syndrome, moderate global developmental delay, microcephaly, axial hypotonia, intrauterine growth restriction and facial dysmorphism for two affected siblings. Molecular analysis included exome sequencing and genome wide homozygosity mapping revealed a region of homozygosity shared by the two affected siblings at 10q11.23. The new C10orf71 gene was included in this interval and direct sequencing of this gene revealed an already described homozygous c. 2123T > G mutation (p. L708R) for the two affected subjects. Interestingly, we revealed in contrast a 4-bp deletion on the 3'-splicing acceptor site of intron 3-exon 4, namely defined as IVS3-5delGCAA. The C10Orf71 gene expression analysis using RT-PCR showed an expression pattern in different fetal organs and tissues as well as in leukocytes and confirmed that the IVS3-5delGCAA deletion of the C10orf71 gene is a splicing mutation responsible for the shortening of the C10orf71 protein in the two related patients. The C10orf71 gene has not been described to date as associated to the autosomal recessive phenotype.

GPR15-C10ORF99 functional pairing initiates colonic Treg homing in amniotes.

Regulatory T lymphocyte (Treg) homing reactions mediated by G protein-coupled receptor (GPCR)-ligand interactions play a central role in maintaining intestinal immune homeostasis by restraining inappropriate immune responses in the gastrointestinal tract. However, the origin of Treg homing to the colon remains mysterious. Here, we report that the C10ORF99 peptide (also known as CPR15L and AP57), a cognate ligand of GPR15 that controls Treg homing to the colon, originates from a duplication of the flanking CDHR1 gene and is functionally paired with GPR15 in amniotes. Evolutionary analysis and experimental data indicate that the GPR15-C10ORF99 pair is functionally conserved to mediate colonic Treg homing in amniotes and their expression patterns are positively correlated with herbivore diet in the colon. With the first herbivorous diet in early amniotes, a new biological process (herbivorous diet short-chain fatty acid-C10ORF99/GPR15-induced Treg homing colon immune homeostasis) emerged, and we propose an evolutionary model whereby GPR15-C10ORF99 functional pairing has initiated the first colonic Treg homing reaction in amniotes. Our findings also highlight that GPCR-ligand pairing leads to physiological adaptation during vertebrate evolution.

Chinese utility weights for the EORTC cancer-specific utility instrument QLU-C10D.

OBJECTIVE: The aim of this study is to provide Chinese utility weights for the European Organization for Research and Treatment of Cancer Quality of Life Utility Measure-Core 10 Dimensions (EORTC QLU-C10D) which is a preference-based cancer-specific utility instrument derived from the EORTC QLQ-C30. METHODS: We conducted an online survey of the general population in China, with quota sampling for age and gender. Each respondent was asked to complete a discrete choice experimental survey consisting of 16 randomly selected choice sets. The conditional logit model and mixed logit model were used to analyze respondents' preferences, and the goodness of fit of the model was tested. RESULTS: A total of 2003 respondents were included in the analysis. Utility decrements within dimensions were typically monotonic. Monotonic inconsistency issues in the Fatigue, Sleep, and Nausea dimensions were normalized by monotonicity correction. Physical functioning, Pain, and Role functioning were associated with the greatest utility weights, with the smallest decrements being in Bowel problems and Emotional functioning. The utility value for the worst health state was 0.083, i.e. slightly higher than being dead. CONCLUSIONS: This study provides the first China-specific set of value for the QLU-C10D based on societal preferences of the Chinese adult general population. The value set can be used as a cancer-specific scoring system for economic evaluations of new oncology therapies and technologies in China.

1. This study provides the first China-specific set of value for the QLU-C10D based on societal preferences of the Chinese adult general population. 2. The value set can be used as a cancer-specific scoring system for economic evaluations of new oncology therapies and technologies in China.

Japanese value set for the EORTC QLU-C10D: A multi-attribute utility instrument based on the EORTC QLQ-C30 cancer-specific quality-of-life questionnaire.

PURPOSE: This study aimed to develop a Japanese value set for the EORTC QLU-C10D, a multi-attribute utility measure derived from the cancer-specific health-related quality-of-life (HRQL) questionnaire, the EORTC QLQ-C30. The QLU-C10D contains ten HRQL dimensions: physical, role, social and emotional functioning, pain, fatigue, sleep, appetite, nausea, and bowel problems. METHODS: Quota sampling of a Japanese online panel was used to achieve representativeness of the Japanese general population by sex and age (≥ 18 years). The valuation method was an online discrete choice experiment. Each participant considered 16 choice pairs, randomly assigned from 960 choice pairs. Each pair included two QLU-C10D health states and life expectancy. Data were analyzed using conditional logistic regression, parameterized to fit the quality-adjusted life-year framework. Preference weights were calculated as the ratio of each dimension-level coefficient to the coefficient for life expectancy. RESULTS: A total of 2809 eligible panel members consented, 2662/2809 (95%) completed at least one choice pair, and 2435/2662 (91%) completed all choice pairs. Within dimensions, preference weights were generally monotonic. Physical functioning, role functioning, and pain were associated with the largest utility weights. Intermediate utility weights were associated with social functioning and nausea; the remaining symptoms and emotional functioning were associated with smaller utility decrements. The value of the worst health state was - 0.221, lower than that seen in most other existing QLU-C10D country-specific value sets. CONCLUSIONS: The Japan-specific QLU-C10D value set is suitable for evaluating the cost and utility of oncology treatments for Japanese health technology assessment and decision-making.

Extended treatment in cerebral ischemia score 2c or 3 as goal of successful endovascular treatment is associated with clinical benefit.

BACKGROUND AND PURPOSE: Successful reperfusion, defined as a modified treatment in cerebral ischemia (mTICI) score 2b or 3, is an important goal for endovascular treatment (EVT) of stroke. Recently, an extension of the mTICI score with an additional grade 2c indicating near-complete reperfusion (expanded TICI, eTICI) and a revised definition of success as eTICI 2c or 3 were proposed. We evaluate whether eTICI 2c translates into improved clinical outcome compared to eTICI 2b. MATERIAL AND METHODS: Consecutive patients with large vessel occlusion in the anterior circulation who underwent EVT between December 2013 and December 2020 were included. Clinical outcome measures were favorable functional outcome at 90 days (modified Rankin Scale [mRS] scores 0 to 2 or return to pre-stroke mRS) and early neurological improvement (National Institutes of Health Stroke Scale [NIHSS] improvement ≥4 points or a score of 0-1 at 24 h). RESULTS: Of 1282 included patients (median age 76, median NIHSS 16), reperfusion was classified as eTICI 2b in 410 (32%), eTICI 2c in 242 (19%) and eTICI 3 in 464 (36%). eTICI 2c differed significally from 2b with respect to early neurological improvement (aOR = 1.49, 95% CI = 1.01-2.19). No statistically significant difference in favorable functional outcome at 90 days was found (eTICI 2c vs 2b, aOR = 1.31, 95% CI = 0.88-2.00). CONCLUSION: Our study indicates early clinical benefit at 24 h of achieving eTICI 2c compared to eTICI 2b, but no significant difference was seen in favorable functional outcome at 90 days. Our results support eTICI 2c and 3 as the goal of a successful thrombectomy but do not exclude eTICI 2b as an acceptable result.

Tyrosine sulfation and O-glycosylation of chemoattractant receptor GPR15 differentially regulate interaction with GPR15L.

GPR15 is a G-protein-coupled receptor (GPCR) that directs lymphocyte homing to the colon and skin. Recent studies have identified a chemokine-like protein GPR15L (also known as C10orf99) as a functional ligand of GPR15. In this study, we examined the structural elements that regulate the GPR15-GPR15L interaction with primary focus on post-translational modifications (PTMs) of receptor N-terminus and on the C-terminus of the ligand. Our findings reveal that the GPR15 receptor is sulfated on the N-terminal tyrosine residue(s) and disruption of tyrosine sulfation inhibits binding of GPR15L. In contrast, the disruption of O-glycosylation on the N-terminal threonine or serine residues, or the removal of α2,3-linked sialic acids from O-glycans, enhances the GPR15L binding. Thus, GPR15 represents a unique chemoattractant receptor in which different N-terminal PTMs regulate its ligand binding in a contrasting manner. We further demonstrate that, unlike canonical chemokines, GPR15L activity critically requires its extreme C-terminal residue and that its hydrophobicity may be a key attribute that facilitates an optimal interaction with the receptor. Our results reveal novel insights into chemoattractant receptor-ligand interaction and provide a valid footing for potential intervention targeting the GPR15-GPR15L axis.

C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2 O2 ), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2 O2 , whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2 O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2 O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.

The European Organisation for Research and Treatment of Cancer Quality of Life Utility-Core 10 Dimensions: Development and Investigation of General Population Utility Norms for Canada, France, Germany, Italy, Poland, and the United Kingdom.

OBJECTIVES: The European Organisation for Research and Treatment of Cancer Quality of Life Utility-Core 10 Dimensions (EORTC QLU-C10D) is a cancer-specific preference-based measure, providing health utilities for use in economic evaluations derived from the widely used health-related quality of life measure, EORTC QLQ-C30. Several EORTC QLU-C10D country-specific value sets are available. This article aimed to provide EORTC QLU-C10D general population utility norms for Canada, France, Germany, Italy, Poland, and the United Kingdom, to aid interpretability of obtained utilities in these countries. METHODS: Data were collected in aforementioned countries via a quota-sampled, cross-sectional online survey (n = 100/age-sex group; N = approximately 1000/country). Participants were asked to complete the EORTC QLQ-C30 and provide sociodemographic data. Country-specific utility norms were calculated using the respective country tariff on the country's EORTC QLQ-C30 data after weighting to achieve population representativeness for age and sex. Norm values are provided as means (SDs) by country, age, and sex groups. Tukey's multiple comparison test investigated mean differences among countries. The impact of country, age, and sex on utility values was investigated with a multiple linear regression model. RESULTS: Country-specific mean utilities range from 0.724 (United Kingdom) to 0.843 (Italy). Country-, sex-, and age-specific mean utilities range from 0.664 for 30- to 39-year-old male Canadians to 0.899 for > 70-year-old male Italians. Utilities were lower in females in 4 of 6 countries, and the impact of age differed among countries. Independent of the impact of age and sex, between-country differences were found (P ≤ .05). CONCLUSION: Results showed a varying impact of age and sex on EORTC QLU-C10D utilities and significant between-country differences. Using national utility norms and utility decrements is recommended.

A new simpler and reliable method for determining mineral oil in sewage sludge: Influence of biogenic compounds for the quantitative analysis of C10-C40 hydrocarbons.

The characterization of organic contaminants in sewage sludge is a fundamental step to address the relevant most appropriate management practice. In this perspective, C10-C40 hydrocarbon content was considered in Italy a crucial parameter to be considered, in spite of its irrelevance in the literature. The very complex mixture of organic substances of both biogenic and anthropogenic origin the sludge is made up of makes sewage sludge a matrix of uniqueness nature, and the analytic determination of hydrocarbon content through conventional procedures may be subjected to overestimation. In this work, optimization of two conventional protocols for the determination of mineral oil (EN14039 and IRSA CNR gravimetric method) were run with attention to anthropogenic compounds potentially affecting the C10-C40 mineral hydrocarbons determination. Effects from the first manipulations of sewage sludge samples to extraction procedure and clean-up operations were investigated. A new simple procedure was set up and tested on 30 samples from different wastewater treatment plants (WWTPs). Through a simple extraction with hexane (12 mL per 2 g of dried sludge, acidified with HCl conc.) at room temperature for 2 h, followed by a clean-up on Florisil column (10 mL-2 g) a confident determination of C10-C40 were obtained with respect to conventional optimized procedures. Variability within the range 0.06-9.49% was calculated with respect to the average value determined using three different methods, with an average value of 2.48 ± 2.37%, demonstrating the robustness of the determination. Up to 3% of the total hydrocarbons were identified as naturally occurring, namely terpenes, squalenes and deoxygenized sterols, passed through the clean-up Florisil column. A significant incidence (up to 75%) of the final overall C10-C40 content was found to be related to the C10-C20 component, originally present in the commercial polyelectrolytes in emulsion, widely used for conditioning before mechanical dewatering.

Effects of C10orf10 on growth and prognosis of glioma under hypoxia. / 低氧环境下C10orf10对胶质瘤生长和预后的影响.

OBJECTIVES: Glioma is the most common malignant tumor in the central nervous system, and the hypoxic microenvironment is prevalent in solid tumors. This study aims to investigate the up-regulation of genes under the condition of hypoxia and their roles in glioma growth, as well as their impact on glioma prognosis. METHODS: The hypoxia-related dataset with glioma was screened in the Gene Expression Omnibus database (GEO), and the differentially expressed genes were analyzed between hypoxia and normoxia through bioinformatics, and chromosome 10 open reading frame 10 (C10orf10) was verified and screened in hypoxia-treated cells through real-time PCR and Western blotting. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) datasets were downloaded to analyze the mRNA expression of C10orf10 in different grades of glioma and its impact on prognosis. The glioma specimens and follow-up data of 68 gliomas who underwent surgical treatment in Xiangya Hospital of Central South University from March 2017 to January 2021 were collected, and real-time PCR was used to detect the mRNA expression of C10orf10 in different grades of glioma, and the Kaplan-Meier method was used to analyze the relationship between the expression C10orf10 and prognosis. The glioma cells, which could interfere the expression of C10orf10, were constructed, and the effect of C10orf10 on the proliferation of glioma cells was evaluated by cell counting kit-8 (CCK-8) and colony formation assays. RESULTS: Compared with the condition of normoxia, the expression levels of C10orf10 mRNA and protein were significantly up-regulated in glioma cells under hypoxia (P<0.001), and the mRNA expression level of C10orf10 in glioma tissues was up-regulated with the increase of WHO grade in glioma (P<0.001). Based on Kaplan-Meier survival analysis, the higher the mRNA expression level of C10orf10 was, the shorter the survival time of the patient was (P<0.05). And the expression of C10orf10 mRNA was higher in recurrent gliomas than that in primary gliomas in the CGGA database (P<0.001). Knockdown of C10orf10 could significantly inhibit the growth of glioma cells both under hypoxia and normoxia (both P<0.001). CONCLUSIONS: The expression level of C10orf10 can promote the proliferation and prognosis of glioma, which is expected to become a prognostic marker and therapeutic target for glioma.

Characterization of the c10orf76-PI4KB complex and its necessity for Golgi PI4P levels and enterovirus replication.

The lipid kinase PI4KB, which generates phosphatidylinositol 4-phosphate (PI4P), is a key enzyme in regulating membrane transport and is also hijacked by multiple picornaviruses to mediate viral replication. PI4KB can interact with multiple protein binding partners, which are differentially manipulated by picornaviruses to facilitate replication. The protein c10orf76 is a PI4KB-associated protein that increases PI4P levels at the Golgi and is essential for the viral replication of specific enteroviruses. We used hydrogen-deuterium exchange mass spectrometry to characterize the c10orf76-PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA-dependent phosphorylation. Complex-disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76-PI4KB complex is required for the replication of c10orf76-dependent enteroviruses. Intriguingly, c10orf76 also contributed to proper Arf1 activation at the Golgi, providing a putative mechanism for the c10orf76-dependent increase in PI4P levels at the Golgi.

New diarylheptanoid dimers as GLP-1 secretagogues and multiple-enzyme inhibitors from Alpinia katsumadai.

Ten new diarylheptanoid dimers, katsumadainols C1 - C10 (1-10), were isolated from the seeds of Alpinia katsumada and elucidated by extensive spectroscopic methods, ECD calculations, and single-crystal X-ray diffraction. Their antidiabetic effects were evaluated by the stimulation of GLP-1 secretion in STC-1 cells and inhibition against four diabetes-related enzymes, GPa, α-glucosidase, PTP1B, and DPP4. Compounds 1-5 and 7-10 significantly stimulated GLP-1 secretion by 267.5-433.1% (25.0 µM) and 117.8-348.2% (12.5 µM). Compounds 1-4 exhibited significant inhibition on GPa with IC50 values of 18.0-31.3 µM; compounds 1-5 showed obvious inhibition on α-glucosidase with IC50 values of 6.9-18.2 µM; compounds 1-5 and 10 possessed PTP1B inhibitory activity with IC50 values ranging from 35.5 to 80.1 µM. This investigation first disclosed compounds 1-4 as intriguing GLP-1 secretagogues and GPa, α-glucosidase, and PTP1B inhibitors, which provided valuable clues for searching multiple-target antidiabetic candidates from Zingiberaceae plants.

Simultaneous analysis of quaternary ammonium cations and corresponding halide counterions by pyrolysis gas chromatography / mass spectrometry.

The use of quaternary ammonium compounds (QACs) as disinfectants has increased tremendously in the COVID-10 pandemic to inactivate Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2). Dialkyldimethylammonium halides represent a frequently used type among QACs. Different halide anions, each ionically linked to the same quaternary ammonium cation, show clear differences in biocidal activity, toxicity and allergic potential. Likewise, the alkyl chain length at the ammonium cation induces different biocidal efficacy and toxicology. Therefore, the object of this research was to develop a rapid and reliable method for the detection of ammonium cation and halide anion in a single analytical run. For that purpose, a gas chromatography mass spectrometry (GC/MS) method was developed for QACs of the dialkyldimethylammonium type. Pyrolytic conversion of the QACs in the injector port of the gas chromatograph into volatile molecule species allows fast and reliable subsequent GC/MS analysis. The developed method is suited for the determination of both the quaternary ammonium cation and the corresponding halide anion in a single gas chromatographic run. The application of this method to bulk material and standard material of explicitly specified didecyldimethylammonium chloride revealed deviations from the manufacturer's specifications in a range up to four-fifths. Furthermore, didecyldimethylammonium chloride was detected in a disinfectant that does not comply with the labeling requirement for biocidal ingredients. With the method presented, results can be obtained for disinfectants with minimum effort within seven minutes.