MARCH5 promotes aerobic glycolysis to facilitate ovarian cancer progression via ubiquitinating MPC1.

MARCH5 is a ring-finger E3 ubiquitin ligase located in the outer membrane of mitochondria. A previous study has reported that MARCH5 was up-regulated and contributed to the migration and invasion of OC cells by serving as a competing endogenous RNA. However, as a mitochondrial localized E3 ubiquitin ligase, the function of MARCH5 in mitochondrial-associated metabolism reprogramming in human cancers remains largely unexplored, including OC. We first assessed the glycolysis effect of MARCH5 in OC both in vitro and in vivo. Then we analyzed the effect of MARCH5 knockdown or overexpression on respiratory activity by evaluating oxygen consumption rate, activities of OXPHOS complexes and production of ATP in OC cells with MARCH5. Co-immunoprecipitation, western-blot, and in vitro and vivo experiments were performed to investigate the molecular mechanisms underlying MARCH5-enhanced aerobic glycolysis s in OC. In this study, we demonstrate that the abnormal upregulation of MARCH5 is accompanied by significantly increased aerobic glycolysis in OC. Mechanistically, MARCH5 promotes aerobic glycolysis via ubiquitinating and degrading mitochondrial pyruvate carrier 1 (MPC1), which mediates the transport of cytosolic pyruvate into mitochondria by localizing on mitochondria outer membrane. In line with this, MPC1 expression is significantly decreased and its downregulation is closely correlated with unfavorable survival. Furthermore, in vitro and in vivo assays revealed that MARCH5 upregulation-enhanced aerobic glycolysis played a critical role in the proliferation and metastasis of OC cells. Taken together, we identify a MARCH5-regulated aerobic glycolysis mechanism by degradation of MPC1, and provide a rationale for therapeutic targeting of aerobic glycolysis via MARCH5-MPC1 axis inhibition.

miR-424-3p promotes metastasis of hepatocellular carcinoma via targeting the SRF-STAT1/2 axis.

Although emerging evidence has established the roles of miRNAs in hepatocellular carcinoma (HCC), the global functional implication of miRNAs in this malignancy remains largely uncharacterized. Here, we aim to systematically identify novel miRNAs involved in HCC and clarify the function and mechanism of specific novel candidate miRNA(s) in this malignancy. Through an integrative omics approach, we identified ten HCC-associated functional modules and a collection of candidate miRNAs. Among them, we demonstrated that miR-424-3p, exhibiting strong associations with extracellular matrix (ECM), promotes HCC cells migration and invasion in vitro and facilitates HCC metastasis in vivo. We further demonstrated that SRF is a direct functional target of miR-424-3p, and is required for the oncogenic activity of miR-424-3p. Finally, we found that miR-424-3p reduces the interferon pathway by attenuating the transactivation of SRF on STAT1/2 and IRF9 genes, which in turn enhances the matrix metalloproteinases (MMPs)-mediated ECM remodeling. This study provides comprehensive functional relevance of miRNAs in HCC by an integrative omics analysis, and further clarifies that miR-424-3p in ECM functional module plays an oncogenic role via reducing the SRF-STAT1/2 axis in this malignancy.

Associations between high-altitude adaptation and risk of cardiovascular diseases: a bidirectional Mendelian randomization study.

High-altitude adaptation (HAA) was reported to be significantly associated with reduced risks for multiple cardiovascular diseases (CVDs). However, the causality and direction of the associations are largely uncharacterized. We aimed to examine the potential causal relationships between HAA and six types of CVD, including coronary artery disease (CAD), cerebral aneurysm, ischemic stroke, peripheral artery disease, arrhythmia and atrial fibrillation. We obtained the summary data from largest available genome-wide association study of HAA and six types of CVD. Two-sample bidirectional Mendelian randomization (MR) analyses were performed to infer the causality between them. In the sensitivity analyses, MR-Egger regression analyses and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global analyses were used to assess the pleiotropic effects; Cochran's Q tests were used to test the heterogeneity by inverse variance-weighted (IVW) and MR-Egger methods; and the leave-one-out analyses were used to examine whether some single nucleotide polymorphisms (SNPs) could influence the results independently. The MR main analyses showed that the genetically instrumented HAA was significantly causally associated with the reduced risks of CAD (odds ratio [OR] = 0.029; 95% confidence interval [CI] = 0.004-0.234; P = 8.64 × 10-4). In contrast, there was no statistically significant relationship between CVDs and HAA. Our findings provide evidence for the causal effects of HAA on the reduced risks of CAD. However, there is no causality of CVDs on HAA. These findings might be helpful in developing the prevention and intervention strategies for CAD.

Neighboring Carboxylic Acid Boosts Peroxidase-Like Property of Metal-Phenolic Nano-Networks in Eradicating Streptococcus mutans Biofilms.

Developing nature-inspired nanomaterials with enzymatic activity is essential in combating bacterial biofilms. Here, it is reported that incorporating the carboxylic acid in phenolic/Fe nano-networks can efficiently manipulate their peroxidase-like activity via the acidic microenvironment and neighboring effect of the carboxyl group. The optimal gallic acid/Fe (GA/Fe) nano-networks demonstrate highly enzymatic activity in catalyzing H2 O2 into oxidative radicals, damaging the cell membrane and extracellular DNA in Streptococcus mutans biofilms. Theoretical calculation suggests that the neighboring carboxyl group can aid the H2 O2 adsorption, free radical generation, and catalyst reactivation, resulting in superb catalytic efficiency. Further all-atom simulation suggests the peroxidation of lipids can increase the cell membrane fluidity and permeability. Also, GA/Fe nano-networks show great potential in inhibiting tooth decay and treating other biofilm-associated diseases without affecting the commensal oral flora. This strategy provides a facile and scale-up way to prepare the enzyme-like materials and manipulate their enzymatic activity for biomedical applications.

High-flux wavelength tunable XUV source in the 12-40.8†eV photon energy range with adjustable energy and time resolution for Tr-ARPES applications.

High-order harmonic generation (HHG) has a broad spectrum covering vacuum ultraviolet to extreme ultraviolet (XUV) bands, which is useful for applications involving material analyses at different information depths. Such an HHG light source is perfect for time- and angle-resolved photoemission spectroscopy. Here, we demonstrate a high-photon flux HHG source driven by a two-color field. Applying a fused silica compression stage to reduce the driving pulse width, we obtained a high XUV photon flux of 2 × 1012 phs/s @21.6 eV on target. We designed a classical diffraction mounted (CDM) grating monochromator that can achieve a wide range of photon energy from 12 to 40.8 eV, while the time resolution is improved by reducing the pulse front tilt after the harmonic selection. We designed a spatial filtering method to adjust the time resolution using the CDM monochromator and significantly reduced the pulse front tilt of the XUV pulses. We also demonstrate a detailed prediction of the energy resolution broadening which is caused by the space charge effect.

Progresses on genetic susceptibility of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a broad clinical spectrum of coronavirus disease 2019 (COVID-19). Genetic factors might influence susceptibility to the SARS-CoV-2 infection or disease severity. Genome-wide association studies (GWASs) have identified multiple susceptible genes related to COVID-19 phenotypes, providing the scientific basis for the COVID-19 prevention and treatment. In this review, we summarize the recent progresses of COVID-19 susceptible genes, including the GWASs on multiple phenotypes of COVID-19, GWASs of COVID-19 in multiple ethnic populations, GWASs of COVID-19 based on multiple types of genetic variations, and the fine-mapping of the regions surrounding the susceptible genes.

The domain of unknown function 4005 (DUF4005) in an Arabidopsis IQD protein functions in microtubule binding.

The dynamic responses of microtubules (MTs) to internal and external signals are modulated by a plethora of microtubule-associated proteins (MAPs). In higher plants, many plant-specific MAPs have emerged during evolution as advantageous to their sessile lifestyle. Some members of the IQ67 domain (IQD) protein family have been shown to be plant-specific MAPs. However, the mechanisms of interaction between IQD proteins and MTs remain elusive. Here we demonstrate that the domain of unknown function 4005 (DUF4005) of the Arabidopsis IQD family protein ABS6/AtIQD16 is a novel MT-binding domain. Cosedimentation assays showed that the DUF4005 domain binds directly to MTs in vitro. GFP-labeled DUF4005 also decorates all types of MT arrays tested in vivo. Furthermore, we showed that a conserved stretch of 15 amino acid residues within the DUF4005 domain, which shares sequence similarity with the C-terminal MT-binding domain of human MAP Kif18A, is required for the binding to MTs. Transgenic lines overexpressing the DUF4005 domain displayed a spectrum of developmental defects, including spiral growth and stunted growth at the organismal level. At the cellular level, DUF4005 overexpression caused defects in epidermal pavement cell and trichome morphogenesis, as well as abnormal anisotropic cell elongation in the hypocotyls of dark-grown seedlings. These data establish that the DUF4005 domain of ABS6/AtIQD16 is a new MT-binding domain, overexpression of which perturbs MT homeostasis in plants. Our findings provide new insights into the MT-binding mechanisms of plant IQD proteins.

Supervised Contrastive Learning and Intra-Dataset Adversarial Adaptation for Iris Segmentation.

Precise iris segmentation is a very important part of accurate iris recognition. Traditional iris segmentation methods require complex prior knowledge and pre- and post-processing and have limited accuracy under non-ideal conditions. Deep learning approaches outperform traditional methods. However, the limitation of a small number of labeled datasets degrades their performance drastically because of the difficulty in collecting and labeling irises. Furthermore, previous approaches ignore the large distribution gap within the non-ideal iris dataset due to illumination, motion blur, squinting eyes, etc. To address these issues, we propose a three-stage training strategy. Firstly, supervised contrastive pretraining is proposed to increase intra-class compactness and inter-class separability to obtain a good pixel classifier under a limited amount of data. Secondly, the entire network is fine-tuned using cross-entropy loss. Thirdly, an intra-dataset adversarial adaptation is proposed, which reduces the intra-dataset gap in the non-ideal situation by aligning the distribution of the hard and easy samples at the pixel class level. Our experiments show that our method improved the segmentation performance and achieved the following encouraging results: 0.44%, 1.03%, 0.66%, 0.41%, and 0.37% in the Nice1 and 96.66%, 98.72%, 93.21%, 94.28%, and 97.41% in the F1 for UBIRIS.V2, IITD, MICHE-I, CASIA-D, and CASIA-T.

Genome-wide association study identifies 7q11.22 and 7q36.3 associated with noise-induced hearing loss among Chinese population.

Noise-induced hearing loss (NIHL) seriously affects the life quality of humans and causes huge economic losses to society. To identify novel genetic loci involved in NIHL, we conducted a genome-wide association study (GWAS) for this symptom in Chinese populations. GWAS scan was performed in 89 NIHL subjects (cases) and 209 subjects with normal hearing who have been exposed to a similar noise environment (controls), followed by a replication study consisting of 53 cases and 360 controls. We identified that four candidate pathways were nominally significantly associated with NIHL, including the Erbb, Wnt, hedgehog and intraflagellar transport pathways. In addition, two novel index single-nucleotide polymorphisms, rs35075890 in the intron of AUTS2 gene at 7q11.22 (combined P = 1.3 × 10-6 ) and rs10081191 in the intron of PTPRN2 gene at 7q36.3 (combined P = 2.1 × 10-6 ), were significantly associated with NIHL. Furthermore, the expression quantitative trait loci analyses revealed that in brain tissues, the genotypes of rs35075890 are significantly associated with the expression levels of AUTS2, and the genotypes of rs10081191 are significantly associated with the expressions of PTPRN2 and WDR60. In conclusion, our findings highlight two novel loci at 7q11.22 and 7q36.3 conferring susceptibility to NIHL.

Long Noncoding RNA p53-Stabilizing and Activating RNA Promotes p53 Signaling by Inhibiting Heterogeneous Nuclear Ribonucleoprotein K deSUMOylation and Suppresses Hepatocellular Carcinoma.

To identify hepatocellular carcinoma (HCC)-implicated long noncoding RNAs (lncRNAs), we performed an integrative omics analysis by integrating mRNA and lncRNA expression profiles in HCC tissues. We identified a collection of candidate HCC-implicated lncRNAs. Among them, we demonstrated that an lncRNA, which is named as p53-stabilizing and activating RNA (PSTAR), inhibits HCC cell proliferation and tumorigenicity through inducing p53-mediated cell cycle arrest. We further revealed that PSTAR can bind to heterogeneous nuclear ribonucleoprotein K (hnRNP K) and enhance its SUMOylation and thereby strengthen the interaction between hnRNP K and p53, which ultimately leads to the accumulation and transactivation of p53. PSTAR is down-regulated in HCC tissues, and the low PSTAR expression predicts poor prognosis in patients with HCC, especially those with wild-type p53. Conclusion: This study sheds light on the tumor suppressor role of lncRNA PSTAR, a modulator of the p53 pathway, in HCC.

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.

Boosting Catalytic Purification of Soot Particles over Double Perovskite-Type La2-xKxNiCoO6 Catalysts with an Ordered Macroporous Structure.

The catalytic performances for soot purification over the perovskite-type ABO3 oxides, as one of the most potential non-noble metal catalysts, are closely correlated with the substitution of A-site and B-site ions. Herein, three-dimensional ordered macroporous (3DOM) structural catalysts of double perovskite-type La2-xKxNiCoO6 were prepared by a method of colloidal crystal template. The contact efficiency between the catalyst and soot particles is significantly promoted by the 3DOM structure, and the partial substitution of A-site (La) with low-valence potassium (K) ions in La2-xKxNiCoO6 catalysts boosts the increasing surface density of coordinatively unsaturated active B-sites (Co and Ni) and active oxygen. 3DOM La2-xKxNiCoO6 catalysts exhibited superior performance during the purification of soot particles, and the 3DOM La1.80K0.20NiCoO6 catalyst exhibited the highest activity, that is, the values of T50, SCO2, and turnover frequency are 346 °C, 99.3%, and 0.204 h-1 (at 300 °C), respectively. According to the results of multiple experimental characterizations and density functional theory calculations, the mechanism of the samples during soot removal is proposed: the increase in surface oxygen density induced by the doping of K ions significantly promotes the critical step of the oxidation from NO to NO2 in catalyzing soot purification. It is one new strategy to develop the high-efficient non-noble metal catalysts for soot purification in practical application.

Facilitating Catalytic Purification of Auto-Exhaust Carbon Particles via the Fe2O3{113} Facet-dependent Effect in Pt/Fe2O3 Catalysts.

The purification efficiency of auto-exhaust carbon particles in the catalytic aftertreatment system of vehicle exhaust is strongly dependent on the interface nanostructure between the noble metal component and oxide supports. Herein, we have elaborately synthesized the catalysts (Pt/Fe2O3-R) of Pt nanoparticles decorated on the hexagonal bipyramid α-Fe2O3 nanocrystals with co-exposed twelve {113} and six {104} facets. The area ratios (R) of co-exposed {113} to {104} facets in α-Fe2O3 nanocrystals were adjusted by the fluoride ion concentration in the hydrothermal method. The strong Pt-Fe2O3{113} facet interaction boosts the formation of coordination unsaturated ferric sites for enhancing adsorption/activation of O2 and NO. Pt/Fe2O3-R catalysts exhibited the Fe2O3{113} facet-dependent performance during catalytic purification of soot particles in the presence of H2O. Among the catalysts, the Pt/Fe2O3-19 catalyst exhibits the highest catalytic activities (T50 = 365 °C, TOF = 0.13 h-1), the lowest apparent activation energy (69 kJ mol-1), and excellent catalytic stability during soot purification. Combined with the results of characterizations and density functional theory calculations, the catalytic mechanism is proposed: the active sites located at the Pt-Fe2O3{113} interface can boost the key step of NO oxidation to NO2. The crystal facet engineering is an effective strategy to obtain efficient catalysts for soot purification in practical applications.

The combinations of sulfur and molybdenum fertilizations improved antioxidant capacity of grazing Guizhou semi-fine wool sheep under copper and cadmium stress.

Mineral development and metal smelting are the main sources of heavy metal pollution, and copper (Cu) and cadmium (Cd) are the most serious mineral elements in heavy metal pollution. Food chain is the main channel for Cu and Cd to enter human body. Excessive accumulation of Cu and Cd can lead to a variety of diseases and threaten human health. Therefore, it is urgent to repair Cu and Cd-contaminated soil. Previous several studies found that sulfur (S) and molybdenum (Mo) had the effect of alleviating the decrease of antioxidant capacity caused by heavy metal poisoning. To investigate the co-combinations of S and Mo fertilizations on antioxidant capacity of grazing Guizhou semi-fine wool sheep in Cu and Cd-contaminated meadow, and explore the control methods of co-pollutions of Cu and Cd in natural pastures, fertilizing and grazing experiments were carried out in the Wumeng Prairie in the northwest of Guizhou Province, Southwest China. 24 hm2 Cu and Cd-polluted meadows were fenced, and were randomly divided into four groups with 3 replications per group and 2 hm2 per replication. The tested groups included the control group (no fertilizer) and the three treatment groups, applied 40 kg S + 1 kg Mo, 80 kg S + 2 kg Mo, and 120 kg S + 3 kg Mo per hectare for group I, group II, and group III, respectively. 72 healthy Guizhou semi-fine wool sheep (one year old, 33.9 ± 1.2 kg) were randomly assigned to the tested pastures with 18 sheep per group. The grazing experiment lasted for 60 days. The results showed that the contents of Mn, Zn, Mo, and S in herbage in fertilized pastures were higher than that in the control group (P < 0.05). The content of Cu in herbage in fertilized pastures was lower than that in the control group (P < 0.05). The contents of Mn, Zn, Mo, and S in serum of grazing Guizhou semi-fine wool sheep were higher than that in the control group (P < 0.05). The content of Cu in serum of grazing Guizhou semi-fine wool sheep was lower than that in the control group (P < 0.05). The levels of blood Hb, RBC, and PCV, and the activities of serum SOD, GSH-Px, T-AOC, CAT, and Cp in group Ⅲ were higher than that in the control group, group Ⅰ, and group Ⅱ (P < 0.05). The MDA content of sheep in group Ⅲ was lower than that in the other treatment sheep (P < 0.05). In summary, the combinations of S and Mo fertilizers influenced the mineral contents in herbage and serum of grazing Guizhou semi-fine wool sheep. The combinations of 120 kg S + 3 kg Mo fertilizer reduced the toxicity and improved antioxidant capacity of grazing Guizhou semi-fine wool sheep in Cu and Cd-polluted grasslands.

ABNORMAL SHOOT 6 interacts with KATANIN 1 and SHADE AVOIDANCE 4 to promote cortical microtubule severing and ordering in Arabidopsis.

Plant interphase cortical microtubules (cMTs) mediate anisotropic cell expansion in response to environmental and developmental cues. In Arabidopsis thaliana, KATANIN 1 (KTN1), the p60 catalytic subunit of the conserved MT-severing enzyme katanin, is essential for cMT ordering and anisotropic cell expansion. However, the regulation of KTN1-mediated cMT severing and ordering remains unclear. In this work, we report that the Arabidopsis IQ67 DOMAIN (IQD) family gene ABNORMAL SHOOT 6 (ABS6) encodes a MT-associated protein. Overexpression of ABS6 leads to elongated cotyledons, directional pavement cell expansion, and highly ordered transverse cMT arrays. Genetic suppressor analysis revealed that ABS6-mediated cMT ordering is dependent on KTN1 and SHADE AVOIDANCE 4 (SAV4). Live imaging of cMT dynamics showed that both ABS6 and SAV4 function as positive regulators of cMT severing. Furthermore, ABS6 directly interacts with KTN1 and SAV4 and promotes their recruitment to the cMTs. Finally, analysis of loss-of-function mutant combinations showed that ABS6, SAV4, and KTN1 work together to ensure the robust ethylene response in the apical hook of dark-grown seedlings. Together, our findings establish ABS6 and SAV4 as positive regulators of cMT severing and ordering, and highlight the role of cMT dynamics in fine-tuning differential growth in plants.

Coating of a Novel Antimicrobial Nanoparticle with a Macrophage Membrane for the Selective Entry into Infected Macrophages and Killing of Intracellular Staphylococci.

Internalization of Staphylococcus aureus by macrophages can inactivate bacterial killing mechanisms, allowing intracellular residence and dissemination of infection. Concurrently, these staphylococci can evade antibiotics that are frequently unable to pass mammalian cell membranes. A binary, amphiphilic conjugate composed of triclosan and ciprofloxacin is synthesized that self-assemble through micelle formation into antimicrobial nanoparticles (ANPs). These novel ANPs are stabilized through encapsulation in macrophage membranes, providing membrane-encapsulated, antimicrobial-conjugated NPs (Me-ANPs) with similar protein activity, Toll-like receptor expression and negative surface charge as their precursor murine macrophage/human monocyte cell lines. The combination of Toll-like receptors and negative surface charge allows uptake of Me-ANPs by infected macrophages/monocytes through positively charged, lysozyme-rich membrane scars created during staphylococcal engulfment. Me-ANPs are not engulfed by more negatively charged sterile cells possessing less lysozyme at their surface. The Me-ANPs kill staphylococci internalized in macrophages in vitro. Me-ANPs likewise kill staphylococci more effectively than ANPs without membrane-encapsulation or clinically used ciprofloxacin in a mouse peritoneal infection model. Similarly, organ infections in mice created by dissemination of infected macrophages through circulation in the blood are better eradicated by Me-ANPs than by ciprofloxacin. These unique antimicrobial properties of macrophage-monocyte Me-ANPs provide a promising direction for human clinical application to combat persistent infections.

Downregulation of ZC3H14 driven by chromosome 14q31 deletion promotes hepatocellular carcinoma progression by activating integrin signaling.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Genomic copy number deletion at chromosome 14q31.1-32.13 was frequently observed in HCC; however, the relevant functional target(s) at that locus is not well determined. Here, we performed integrative genomic analyses and identified zinc finger CCCH-type containing 14 (ZC3H14) as a promising candidate at 14q31.1-32.13. We observed frequent copy number deletion (17.1%) and downregulation of ZC3H14 in primary HCC tissues. Downregulation of ZC3H14 was significantly associated with poor outcomes of patients with HCC. Overexpression of ZC3H14 in HCC cell lines significantly suppressed HCC cells growth in vitro and metastasis in vivo. In contrast, RNA interference silencing of ZC3H14 inhibited its tumor-suppressive function. Mechanismly, through combing bioinformatics analyses and experimental investigation, we demonstrated that loss of ZC3H14 promotes HCC progression through enhancing integrin pathway. This study suggests that ZC3H14 functions as a novel tumor suppressor and is a candidate prognostic biomarker for HCC patients.

Association of MCP-1 promoter polymorphism with susceptibility to nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is prevalent among populations from southern China and is influenced by both genetic and environmental risk factors. The monocyte chemoattractant protein-1 (MCP-1), a member of cysteine-cysteine chemokine family, plays critical roles in cancers. A polymorphism within the MCP-1 promoter, rs1024611, has been shown to be significantly associated with the risk of several cancers. Our purpose was to assess the role of rs1024611 in NPC susceptibility. By polymerase chain reaction-restriction fragment length polymorphism method, we genotyped rs1024611 in 593 patients with NPC (cases) and 480 cancer-free subjects (controls) among Guangxi population from southern China. We observed that the G allele of rs1024611 was significantly associated with the increased risk of NPC in an additive model and dominant model, respectively (P = 0.018 and 0.010, odds ratio = 1.25 and 1.41, respectively). No appreciable variation of the effects was found across the subgroups stratified by age, sex, nationality, smoking and drinking status, and smoking level. In addition, significantly higher messenger RNA (mRNA) expression level of MCP-1 was observed in NPC tissues than that in normal nasopharyngeal tissues, and the G allele of rs1024611 was significantly associated with elevated mRNA expression level of MCP-1 in Epstein-Barr virus-transformed lymphocytes. In conclusion, our findings suggested that rs1024611 at the MCP-1 promoter may be a risk factor for NPC. Further studies with larger sample size are necessary to confirm these findings.

Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53.

BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co-immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low-frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV-related HCC (overall P = 3.17 × 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest.

Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis.

PURPOSE: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease. METHODS: Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. RESULTS: Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice. CONCLUSION: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.