👤 Zijin Tan

Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC Show less

Atherosclerosis is the most common cause of cardiovascular disease, such as myocardial infarction and stroke. Previous study revealed that microRNA (miR)-134 promotes lipid accumulation and proinflammatory cytokine secretion through angiopoietin-like 4 (ANGPTL4)/lipid lipoprotein (LPL) signaling in THP-1 macrophages. ApoE KO male mice on a C57BL/6 background were fed a high-fat/high-cholesterol Western diet, from 8 to 16 weeks of age. Mice were divided into four groups, and received a tail vein injection of miR-134 agomir, miR-134 antagomir, or one of the corresponding controls, respectively, once every 2 weeks after starting the Western diet. After 8 weeks we measured aortic atherosclerosis, LPL Activity, mRNA and protein levels of ANGPTL4 and LPL, LPL/ low-density lipoprotein receptor related protein 1 Complex Formation, proinflammatory cytokine secretion and lipid levels. Despite this finding, the influence of miR-134 on atherosclerosis in vivo remains to be determined. Using the well-characterized mouse atherosclerosis model of apolipoprotein E knockout, we found that systemic delivery of miR-134 agomir markedly enhanced the atherosclerotic lesion size, together with a significant increase in proinflammatory cytokine secretion and peritoneal macrophages lipid contents. Moreover, overexpression of miR-134 decreased ANGPTL4 expression but increased LPL expression and activity in both aortic tissues and peritoneal macrophages, which was accompanied by increased formation of LPL/low-density lipoprotein receptor-related protein 1 complexes in peritoneal macrophages. However, an opposite effect was observed in response to miR-134 antagomir. These findings suggest that miR-134 accelerates atherogenesis by promoting lipid accumulation and proinflammatory cytokine secretion via the ANGPTL4/LPL pathway. Therefore, targeting miR-134 may offer a promising strategy for the prevention and treatment of atherosclerotic cardiovascular disease. Show less

Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis. We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient. We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort. Together these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association. Show less

High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943. Show less

Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD. Show less

To evaluate the 3D static articulation accuracy of 3 model scanner-CAD systems (Ceramill Map400 [AG], inEos X5 [SIR], Scanner S600 Arti [ZKN]) using a coordinate measuring machine (CMM). Trueness and precision for each system will be reported in Part I. The master model simulated a single crown opposing a 3-unit fixed dental prosthesis. Five mounted stone cast sets were prepared, and one set was randomly selected. Reference values were obtained by measuring interarch and interocclusal reference features with the CMM. The stone cast set was scanned 5 times consecutively and articulated virtually with each system (3 test groups, n = 5). STL files of the virtual models were measured with CMM software. dR For trueness values, mean interarch global distortions ranged from 13.1 to 40.3 μm for dR The overall interarch global distortion of all three model scanner-CAD systems was low and did not exceed 0.6%. Variations in scanner technology, virtual articulation algorithm, and use of physical articulators contributed to the differences in distortion observed among all three groups. Show less

Accurate maxillomandibular relationship transfer is important for CAD/CAM prostheses. This study compared the 3D-accuracy of virtual model static articulation in three laboratory scanner-CAD systems (Ceramill Map400 [AG], inEos X5 [SIR], Scanner S600 Arti [ZKN]) using two virtual articulation methods: mounted models (MO), interocclusal record (IR). The master model simulated a single crown opposing a 3-unit fixed partial denture. Reference values were obtained by measuring interarch and interocclusal reference features with a coordinate measuring machine (CMM). MO group stone casts were articulator-mounted with acrylic resin bite registrations while IR group casts were hand-articulated with poly(vinyl siloxane) bite registrations. Five test model sets were scanned and articulated virtually with each system (6 test groups, 15 data sets). STL files of the virtual models were measured with CMM software. dR Mean interarch 3D distortion ranged from -348.7 to 192.2 μm for dR Interarch and interocclusal distances increased in MO groups, while they decreased in IR groups. AG-IR had the greatest interarch distortion as well as interocclusal superior-inferior distortion. The other groups performed similarly to each other, and the overall interarch distortion did not exceed 0.7%. In these systems and articulation methods, interocclusal distortions may result in hyper- or infra-occluded prostheses. Show less

Prior studies have defined the accuracy of intraoral scanner (IOS) systems but the accuracy of the digital static interocclusal registration function of these systems has not been reported. This study compared the three-dimensional (3D) accuracy of the digital static interocclusal registration of 3 IOS systems using the buccal bite scan function. Three IOS systems compared were 3M Mean 3D distortion ranged from -471.9 to 31.7 μm for dR Interarch and global interocclusal distortions for the three IOS systems were significantly different. TRC performed overall the best and TDS was the worst. The interarch (dR Show less

In randomized trials, supplementation of n-3 (ω-3) long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy has resulted in increased size at birth, which is attributable to longer gestation. We examined this finding by using a Mendelian randomization approach utilizing fatty acid desaturase (FADS) gene variants affecting LC-PUFA metabolism. As part of a tri-ethnic mother-offspring cohort in Singapore, 35 genetic variants in FADS1, FADS2, and FADS3 were genotyped in 898 mothers and 1103 offspring. Maternal plasma n-3 and n-6 PUFA concentrations at 26-28 wk of gestation were measured. Gestation duration was derived from an ultrasound dating scan in early pregnancy and from birth date. Birth length and weight were measured. Eight FADS variants were selected through a tagging-SNP approach and examined in association with PUFA concentrations, gestation duration among spontaneous labors, and birth size with the use of ethnicity-adjusted linear regressions and survival models that accounted for the competing risks of induced labor and prelabor cesarean delivery. Maternal FADS1 variant rs174546, tagging for 8 other variants located on FADS1 and FADS2, was strongly related to plasma n-6 but not n-3 LC-PUFA concentrations. Offspring and maternal FADS3 variants were associated with gestation duration among women who had spontaneous labor: each copy of rs174450 minor allele C was associated with a shorter gestation by 2.2 d (95% CI: 0.9, 3.4 d) and 1.9 d (0.7, 3.0 d) for maternal and offspring variants, respectively. In survival models, rs174450 minor allele homozygotes had reduced time to delivery after spontaneous labor compared with major allele homozygotes [HR (95% CI): 1.51 (1.18, 1.95) and 1.51 (1.20, 1.89) for mothers and offspring, respectively]. With the use of a Mendelian randomization approach, we observed associations between FADS variants and gestation duration. This suggests a potential role of LC-PUFAs in gestation duration. This trial was registered at http://www.clinicaltrials.gov as NCT01174875. Show less

Communication disorder is common in Koolen de Vries syndrome (KdVS), yet its specific symptomatology has not been examined, limiting prognostic counselling and application of targeted therapies. Here we examine the communication phenotype associated with KdVS. Twenty-nine participants (12 males, 4 with KANSL1 variants, 25 with 17q21.31 microdeletion), aged 1.0-27.0 years were assessed for oral-motor, speech, language, literacy, and social functioning. Early history included hypotonia and feeding difficulties. Speech and language development was delayed and atypical from onset of first words (2; 5-3; 5 years of age on average). Speech was characterised by apraxia (100%) and dysarthria (93%), with stuttering in some (17%). Speech therapy and multi-modal communication (e.g., sign-language) was critical in preschool. Receptive and expressive language abilities were typically commensurate (79%), both being severely affected relative to peers. Children were sociable with a desire to communicate, although some (36%) had pragmatic impairments in domains, where higher-level language was required. A common phenotype was identified, including an overriding 'double hit' of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development. Remarkably however, speech prognosis was positive; apraxia resolved, and although dysarthria persisted, children were intelligible by mid-to-late childhood. In contrast, language and literacy deficits persisted, and pragmatic deficits were apparent. Children with KdVS require early, intensive, speech motor and language therapy, with targeted literacy and social language interventions as developmentally appropriate. Greater understanding of the linguistic phenotype may help unravel the relevance of KANSL1 to child speech and language development. Show less

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype. Show less

Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an increase in cellular metabolic activity to drive epithelial-mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient's samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins. Show less

In adult skin wounds, collagen expression rapidly re-establishes the skin barrier, although the resultant scar is aesthetically and functionally inferior to unwounded tissue. Although TGFβ signaling and fibroblasts are known to be responsible for scar-associated collagen production, there are currently no prophylactic treatments for scar management. Fibroblasts in crosstalk with wound keratinocytes orchestrate collagen expression, although the precise paracrine pathways involved remain poorly understood. Herein, we showed that the matricellular protein, angiopoietin-like 4 (ANGPTL4), accelerated wound closure and reduced collagen expression in diabetic and ANGPTL4-knockout mice. Similar observations were made in wild-type rat wounds. Using human fibroblasts as a preclinical model for mechanistic studies, we systematically elucidated that ANGPTL4 binds to cadherin-11, releasing membrane-bound β-catenin which translocate to the nucleus and transcriptionally upregulate the expression of Inhibitor of DNA-binding/differentiation protein 3 (ID3). ID3 interacts with scleraxis, a basic helix-loop-helix transcription factor, to inhibit scar-associated collagen types 1α2 and 3α1 production by fibroblasts. We also showed ANGPTL4 interaction with cadherin-11 in human scar tissue. Our findings highlight a central role for matricellular proteins such as ANGPTL4 in the attenuation of collagen expression and may have a broader implication for other fibrotic pathologies. Show less

Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin α5β1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation. Show less

Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits (P < 5 × 10 Show less

The purpose of this study was to investigate the correlation between serum levels of serum apolipoprotein M (ApoM), A5 (ApoA5), and high-density lipoprotein (HDL) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and study the effects of nasal continuous positive airway pressure treatment on these serum biomarkers. Thirty OSAHS patients and 15 non-OSAHS probands as control were selected for the study. Serum HDL, ApoM, and ApoA5 levels in two groups were detected; differences and association among them were analyzed. Patients with moderate and severe OSAHS underwent 3-month auto-continuous positive airway pressure treatment, and a comparative study was conducted to investigate the changes in blood lipids, serum ApoM, and ApoA5. In comparison to the control group, the HDL, ApoM, and ApoA5 serum levels were lower (P < 0.05). HDL was positively correlated to ApoM and ApoA5 (P < 0.001), and ApoM was positively correlated to ApoA5 (r = 0.536, P < 0.001). HDL, ApoM, and ApoA5 were significantly increased in the patients of moderate and severe OSAHS after auto-continuous positive airway pressure treatment for 3 months (P < 0.05). The HDL level was significantly lower in OSAHS patients. The decrease in serum ApoM and ApoA5 in OSAHS patients was correlated to the severity of OSAHS and HDL levels. Auto-continuous positive airway pressure treatment increased serum levels of ApoM, ApoA5, and HDL in OSAHS patients. Show less

The RING finger protein Rnf146 encodes an E3 ubiquitin ligase capable of targeting poly-ADP-ribosylated substrates for proteasomal degradation. Rnf146 has been identified as a critical regulator of Axin1 and thus of Wnt/β-catenin signaling. However its physiological significance in vertebrate embryonic development remains to be demonstrated. In this study, we take advantages of early Xenopus embryos to demonstrate that Rnf146 is essential for embryonic pattern formation. Depletion of zygotic Rnf146 using a translation blocking morpholino oligo (MO) results in anteriorized development and increased expression the anterior marker gene Otx2, consistent the notion that Rnf146 is a positive regulator of Wnt/β-catenin signaling through negatively regulating Axin1 expression. This notion is further supported by examination of the role of maternal Rnf146 in the context of Spemann organizer formation and dorsal axis development. Depletion of maternal Rnf146 using an antisense oligodeoxynucleic acid (ODN) leads to ventralized development and diminished expression of organizer genes. Together, we have provided evidence for the first time that Rnf146 is a critical regulator of embryonic pattern formation in vertebrates. Show less

Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci. Show less

Major depressive disorder (MDD) is a leading cause of disease burden worldwide. While the incidence, symptoms and treatment of MDD all point toward major sex differences, the molecular mechanisms underlying this sexual dimorphism remain largely unknown. Here, combining differential expression and gene coexpression network analyses, we provide a comprehensive characterization of male and female transcriptional profiles associated with MDD across six brain regions. We overlap our human profiles with those from a mouse model, chronic variable stress, and capitalize on converging pathways to define molecular and physiological mechanisms underlying the expression of stress susceptibility in males and females. Our results show a major rearrangement of transcriptional patterns in MDD, with limited overlap between males and females, an effect seen in both depressed humans and stressed mice. We identify key regulators of sex-specific gene networks underlying MDD and confirm their sex-specific impact as mediators of stress susceptibility. For example, downregulation of the female-specific hub gene Dusp6 in mouse prefrontal cortex mimicked stress susceptibility in females, but not males, by increasing ERK signaling and pyramidal neuron excitability. Such Dusp6 downregulation also recapitulated the transcriptional remodeling that occurs in prefrontal cortex of depressed females. Together our findings reveal marked sexual dimorphism at the transcriptional level in MDD and highlight the importance of studying sex-specific treatments for this disorder. Show less

Novel graphitic carbon nitride/CuO (g-C₃N₄/CuO) nanocomposite was synthesized through a facile precipitation method. Due to the strong ion-dipole interaction between copper ions and nitrogen atoms of g-C₃N₄, CuO nanorods (length 200-300 nm, diameter 5-10 nm) were directly grown on g-C₃N₄, forming a g-C₃N₄/CuO nanocomposite, which was confirmed via X-ray diffraction (XRD), transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and X-ray photoelectron spectroscopy (XPS). Finally, thermal decomposition of ammonium perchlorate (AP) in the absence and presence of the prepared g-C₃N₄/CuO nanocomposite was examined by differential thermal analysis (DTA), and thermal gravimetric analysis (TGA). The g-C₃N₄/CuO nanocomposite showed promising catalytic effects for the thermal decomposition of AP. Upon addition of 2 wt % nanocomposite with the best catalytic performance (g-C₃N₄/20 wt % CuO), the decomposition temperature of AP was decreased by up to 105.5 °C and only one decomposition step was found instead of the two steps commonly reported in other examples, demonstrating the synergistic catalytic activity of the as-synthesized nanocomposite. This study demonstrated a successful example regarding the direct growth of metal oxide on g-C₃N₄ by ion-dipole interaction between metallic ions, and the lone pair electrons on nitrogen atoms, which could provide a novel strategy for the preparation of g-C₃N₄-based nanocomposite. Show less

Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P = .38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P = .001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P = .001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P = .003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P < .001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P = .001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P < 5 × 10-8), including a novel DPYD variant (rs75267292; P = 1.57 × 10-10), and variants in the MACF1 (rs183324967, P = 4.80 × 10-11; rs148221738, P = 5.73 × 10-10) and SPRY2 (rs117876855, P < 1.01 × 10-8; rs139544515, P = 1.30 × 10-8) genes involved in wound healing. Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. clinicaltrials.gov Identifier: NCT00486213. Show less

The attachment of monocytes to human brain microvascular endothelial cells (HBMVEs) caused by oxidized low-density lipoprotein (ox-LDL) is associated with an early event and the pathological progression of cerebrovascular diseases. Oxytocin (OT) is a human peptide hormone that is traditionally used as a medication to facilitate childbirth. However, little information is available regarding the physiological function of OT in brain endothelial dysfunction. In the present study, our results indicate that the oxytocin receptor (OTR) was expressed in human brain microvascular endothelial cells (HBMVEs) and was upregulated in response to ox-LDL in a concentration-dependent manner. Notably, OT significantly suppressed ox-LDL-induced attachment of THP-1 monocytes to HBMVEs. Furthermore, we found that OT reduced the expression of adhesion molecules, such as VCAM-1 and E-selectin. Interestingly, it was shown that OT could restore ox-LDL-induced reduction of KLF4 in HBMVEs. Importantly, knockdown of KLF4 abolished the inhibitory effects of OT on ox-LDL-induced expressions of VCAM-1 and E-selectin as well as the adhesion of human monocytic THP-1 cells to endothelial HBMVEs. Mechanistically, we found that the stimulatory effects of OT on KLF4 expression are mediated by the MEK5/MEF2A pathway. Show less

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus, Show less

Alzheimer disease (AD) is the most common neurodegenerative disease characterized by the deposition of amyloid plaque in the brain. The autophagy-associated PIK3C3-containing phosphatidylinositol 3-kinase (PtdIns3K) complex has been shown to interfere with APP metabolism and amyloid beta peptide (Aβ) homeostasis via poorly understood mechanisms. Here we report that NRBF2 (nuclear receptor binding factor 2), a key component and regulator of the PtdIns3K, is involved in APP-CTFs homeostasis in AD cell models. We found that NRBF2 interacts with APP in vivo and its expression levels are reduced in hippocampus of 5XFAD AD mice; we further demonstrated that NRBF2 overexpression promotes degradation of APP C-terminal fragments (APP-CTFs), and reduces Aβ Show less

TNKS1BP1 is a member of the poly(ADP-ribose) polymerase (PARP) superfamily. Our previous studies have demonstrated that TNKS1BP1 plays an important role in DNA damage response. But whether and how TNKS1BP1 associates with cancer is still not clear. Here, we found that TNKS1BP1 was upregulated in human lung adenocarcinoma (LAC) tissues, and was associated with poor overall survival (OS) in LAC patients. Dysregulation of TNKS1BP1 affected the sensitivity of A549 cells to several DNA damage agents including cisplatin, bleomycin, and ionizing radiation. Mechanically, overexpression of TNKS1BP1 increased the accumulation of S phase cells, which was accompanied by a decrease in M phase cells. More importantly, we found TNKS1BP1 regulated genome stability, mainly through affecting the homologous recombination pathway of DNA double-strand breaks by inhibiting the RAD51 foci formation. Overall, our study indicates that, in LAC, aberrant expressions of TNKS1BP1 are common events, and overexpression of TNKS1BP1 might affect outcomes of cancer patients to chemotherapy and radiotherapy. Show less

The gut microbiota plays profound roles in host metabolism and the inflammatory response associated with the development of obesity. Dusp6-deficient mice have been shown to be resistant to diet-induced obesity, but the mechanism behind this remains unclear. 16S ribosomal RNA gene analysis demonstrated that dusp6-deficient mice harbour unique gut microbiota with resistance to diet-induced-obesity-mediated alteration of the gut microbiome. Using a germ-free mouse model, we found that faecal/gut microbiota derived from dusp6-deficient mice significantly increased energy expenditure and reduced weight gain in recipient wild-type mice fed on a high-fat diet. On analysis of the intestinal transcriptome of dusp6-deficient mice, we found that dusp6 deficiency mainly induced biological processes involved in metabolism and the extracellular matrix, particularly the peroxisome proliferator-activated receptor gamma (Pparγ) pathway and tight-junction genes. Furthermore, dusp6-deficient mice have a high-fat-diet-specific transcriptomic response to reverse the expression of genes associated with intestinal barrier functions and mucosal immunity involved in microbiome homeostasis. This study demonstrates that dusp6 deficiency is a strong genetic factor shaping gut microbiota, and that it confers obesity protection by ameliorating the gut microbiota response to diet-mediated stress. Show less

Multiple osteochondromas (MO), also known as hereditary multiple exostoses, is an autosomal dominant bone disorder. Mutations in exostosin glycosyl transferase‑1 (EXT1) and exostosin glycosyl transferase‑2 (EXT2), including missense, nonsense, frameshift and splice‑site mutations, account for up to 80% of reported cases. The proteins EXT1 and EXT2 form a hetero‑oligomeric complex that functions in heparan sulfate proteoglycan biosynthesis. A heterozygous EXT2 mutation, c.939+1G>T, was identified in a five‑generation 33‑member MO family, and was present in all 13 affected members. The mutation results in deletion of exon 5 in the mRNA, producing a frameshift that leads to a premature termination codon. The present study extends the mutational spectrum of EXT2. Show less

Essential tremor is one of the most common adult-onset movement disorders. While it is recognized that genes play a major role in ET with ≥50% of the affected individuals having a positive family history, identifying underlying genes in both monogenic and complex forms of ET has been a challenging task. Recent discoveries linking LINGO1, FUS and TENM4 to essential tremor have been met with cautious optimism since reproducibility and pathogenicity have been contentious in previously implicated genes. The lack of gold standard diagnostic criteria together with clinical and genetic heterogeneity have presented considerable obstacles. Nevertheless, future genetic studies should adopt a multi-prong genomic approach with adequate sample size, supported by both functional in vitro and in vivo studies. Elucidation of the pathophysiologic mechanism will lead to better therapeutic strategies and management. Show less

Sudden cardiac arrest (SCA) ranks among the most common causes of death worldwide. Because SCA is most often lethal, yet mostly occurs in individuals without previously known cardiac disease, the identification of patients at risk for SCA could save many lives. In unselected SCA victims from the community, common genetic variants (which are not disease-causing per se, but may increase susceptibility to ventricular fibrillation) are found to be associated with increased SCA risk. However, whether rare genetic variants contribute to SCA risk in the community is largely unexplored. We here investigated the involvement of rare genetic variants in SCA risk at the population level by studying the prevalence of 6 founder genetic variants present in the Dutch population (PLN-p.Arg14del, MYBPC3-p.Trp792fsX17, MYBPC3-p.Arg943X, MYBPC3-p.Pro955fsX95, PKP2-p.Arg79X, and the Chr7q36 idiopathic ventricular fibrillation risk haplotype) in a cohort of 1440 unselected Dutch SCA victims included in the Amsterdam Resuscitation Study (ARREST). The six studied founder mutations were found to be more prevalent (1.1%) in the ARREST SCA cohort compared with an ethnically and geographically matched set of controls (0.4%, n=1379; P<0.05) or a set of Dutch individuals drawn from the Genome of the Netherlands (GoNL) study (0%, n=500; P<0.02). This finding provides proof-of-concept for the notion that rare genetic variants contribute to some extent to SCA risk in the community. Show less