Publications by authors named "Ting Fung Chan"

133 Publications

Analyzing the synergistic adverse effects of BPA and its substitute, BHPF, on ulcerative colitis through comparative metabolomics.

Chemosphere 2021 Sep 5;287(Pt 2):132160. Epub 2021 Sep 5.

Laboratory of Environmental Pollution and Integrative Omics, Guilin Medical University, Guilin, PR China. Electronic address:

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-term inflammation and ulcers in the colon and rectum. Approximately 3 million adults were diagnosed with IBD in the US in 2015, and its incidence rate is estimated to increase by 4-6 times in 2030. Industrial pollutants are largely responsible for this significant increase in UC cases. Several epidemiological and animal studies have demonstrated the correlation between pollutants and gastrointestinal diseases, but detailed molecular mechanisms responsible for adverse effects of environmental pollutants on UC are still unknown. In the present study, we used a dextran sulfate sodium (DSS)-induced colitis mouse model, comparative metabolomics analysis, and systematic bioinformatics analysis to delineate the synergistic adverse effects of bisphenol A (BPA) and its substitute fluorene-9-bisphenol (BHPF) on UC. Subsequently, a significant alteration in gut metabolites was observed by the BPA and BHPF treatments. Furthermore, the bioinformatics analysis indicated deregulation of sugar and fatty acid metabolisms in the DSS-induced colitis model by the BPA and BHPF treatments, respectively. Additionally, both the treatments induced an inflammatory response in the model. Particularly, some DSS-deregulated metabolites, which play important roles in gut inflammation, were synergistically induced or reduced by the BPA and BHPF treatments. To the best knowledge of the authors, the synergistic adverse effects of the BPA and BHPF treatments on UC were demonstrated for the first time through gut metabolism alterations. Therefore, the present study provides novel insights in the role of environmental pollutants, such as BPA and BHPF, in UC development.
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http://dx.doi.org/10.1016/j.chemosphere.2021.132160DOI Listing
September 2021

Detrimental effects of microplastic exposure on normal and asthmatic pulmonary physiology.

J Hazard Mater 2021 Aug 11;416:126069. Epub 2021 May 11.

The Department of Respiratory Diseases and Critic Care Unit, Shenzhen Institute of Respiratory Disease, Shenzhen Key Laboratory of Respiratory Disease, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China; Post-Doctoral Scientific Research Station of Basic Medicine, Jinan University, Guangzhou 510632, China. Electronic address:

Concerns that airborne microplastics (MP) may be detrimental to human health are rising. However, research on the effects of MP on the respiratory system are limited. We tested the effect of MP exposure on both normal and asthmatic pulmonary physiology in mice. We show that MP exposure caused pulmonary inflammatory cell infiltration, bronchoalveolar macrophage aggregation, increased TNF-α level in bronchoalveolar lavage fluid (BALF), and increased plasma IgG1 production in normal mice. MP exposure also affected asthma symptoms by increasing mucus production and inflammatory cell infiltration with notable macrophage aggregation. Further, we found co-labeling of macrophage markers with MP incorporating fluorescence, which indicates phagocytosis of the MP by macrophages. A comparative transcriptomic analysis showed that MP exposure altered clusters of genes related to immune response, cellular stress response, and programmed cell death. A bioinformatics analysis further uncovered the molecular mechanism whereby MP stimulated production of tumor necrosis factor and immunoglobulins to activate a group of transmembrane B-cell antigens, leading to the modulation of cellular stress and programmed cell death in the asthma model. In summary, we show that MP exposure had detrimental effects on the respiratory system in both healthy and asthmatic mice, which calls for urgent discourse and action to mitigate environmental microplastic pollutants.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126069DOI Listing
August 2021

Low-Dose Radiation Can Cause Epigenetic Alterations Associated With Impairments in Both Male and Female Reproductive Cells.

Front Genet 2021 2;12:710143. Epub 2021 Aug 2.

Hong Kong Branch of the Southern Marine Science and Engineering Guangdong Laboratory, Hong Kong, China.

Humans are regularly and continuously exposed to ionizing radiation from both natural and artificial sources. Cumulating evidence shows adverse effects of ionizing radiation on both male and female reproductive systems, including reduction of testis weight and sperm count and reduction of female germ cells and premature ovarian failure. While most of the observed effects were caused by DNA damage and disturbance of DNA repairment, ionizing radiation may also alter DNA methylation, histone, and chromatin modification, leading to epigenetic changes and transgenerational effects. However, the molecular mechanisms underlying the epigenetic changes and transgenerational reproductive impairment induced by low-dose radiation remain largely unknown. In this study, two different types of human ovarian cells and two different types of testicular cells were exposed to low dose of ionizing radiation, followed by bioinformatics analysis (including gene ontology functional analysis and Ingenuity Pathway Analysis), to unravel and compare epigenetic effects and pathway changes in male and female reproductive cells induced by ionizing radiation. Our findings showed that the radiation could alter the expression of gene cluster related to DNA damage responses through the control of MYC. Furthermore, ionizing radiation could lead to gender-specific reproductive impairment through deregulation of different gene networks. More importantly, the observed epigenetic modifications induced by ionizing radiation are mediated through the alteration of chromatin remodeling and telomere function. This study, for the first time, demonstrated that ionizing radiation may alter the epigenome of germ cells, leading to transgenerational reproductive impairments, and correspondingly call for research in this new emerging area which remains almost unknown.
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http://dx.doi.org/10.3389/fgene.2021.710143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365519PMC
August 2021

Characterization of PFOS toxicity on in-vivo and ex-vivo mouse pancreatic islets.

Environ Pollut 2021 Jul 26;289:117857. Epub 2021 Jul 26.

Croucher Institute for Environmental Sciences, Department of Biology, Hong Kong Baptist University, Hong Kong SAR, China. Electronic address:

Considerable human data have shown that the exposure to perfluorooctane sulfonate (PFOS) correlates to the risk of metabolic diseases, however the underlying effects are not clearly elucidated. In this study, we investigated the impacts of PFOS treatment, using in-vivo, ex-vivo and in-vitro approaches, on pancreatic β-cell functions. Mice were oral-gavage with 1 and 5 μg PFOS/g body weight/day for 21 days. The animals showed a significant increase in liver triglycerides, accompanied by a reduction of triglycerides in blood sera and glycogen in livers and muscles. Histological examination of pancreases showed no noticeable changes in the size and number of islets from the control and treatment groups. Immunohistochemistry showed a reduction of staining intensities of insulin and the transcriptional factors (Pdx-1, islet-1) in islets of pancreatic sections from PFOS-treated groups, but no changes in the intensity of Glut2 and glucagon were noted. Transcriptomic study of isolated pancreatic islets treated ex vivo with 1 μM and 10 μM PFOS for 24 h, underlined perturbations of the insulin signaling pathways. Western blot analysis of ex-vivo PFOS-treated islets revealed a significant reduction in the expression levels of the insulin receptor, the IGF1 receptor-β, Pdk1-Akt-mTOR pathways, and Pdx-1. Using the mouse β-cells (Min-6) treated with 1 μM and 10 μM PFOS for 24 h, Western blot analysis consistently showed the PFOS-treatment inhibited Akt-pathway and reduced cellular insulin contents. Moreover, functional studies revealed the inhibitory effects of PFOS on glucose-stimulated insulin-secretion (GSIS) and the rate of ATP production. Our data support the perturbing effects of PFOS on animal metabolism and demonstrate the underlying molecular targets to impair β-cell functions.
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http://dx.doi.org/10.1016/j.envpol.2021.117857DOI Listing
July 2021

Increased copy number of gibberellin 2-oxidase 8 genes reduced trailing growth and shoot length during soybean domestication.

Plant J 2021 Jul 10. Epub 2021 Jul 10.

School of Life Sciences and the Centre for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Copy number variations (CNVs) play important roles in crop domestication. However, there is only very limited information on the involvement of CNVs in soybean domestication. Trailing growth and long shoots are soybean adaptations for natural habitats but cause lodging that hampers yield in cultivation. Previous studies have focused on Dt1/2 affecting the indeterminate/determinate growth habit, whereas the possible role of the gibberellin pathway remained unclear. In the present study, quantitative trait locus (QTL) mapping of a recombinant inbred population of 460 lines revealed a trailing-growth-and-shoot-length QTL. A CNV region within this QTL was identified, featuring the apical bud-expressed gibberellin 2-oxidase 8A/B, the copy numbers of which were positively correlated with expression levels and negatively with trailing growth and shoot length, and their effects were demonstrated by transgenic soybean and Arabidopsis thaliana. Based on the fixation index, this CNV region underwent intense selection during the initial domestication process.
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http://dx.doi.org/10.1111/tpj.15414DOI Listing
July 2021

Differentially expressed microRNAs that target functional genes in mature soybean nodules.

Plant Genome 2021 Jul 10;14(2):e20103. Epub 2021 May 10.

School of Life Sciences and Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, HKSAR, Hong Kong.

MicroRNAs (miRNAs) are important regulators of biological functions in plants. To find out what roles miRNAs play in regulating symbiotic nitrogen fixation (SNF) in soybean [Glycine max (L.) Merr.], we identified high-confidence differentially expressed (DE) miRNAs from uninoculated roots (UR), rhizobium-inoculated roots (IR), and nodules (NODs) of soybean by robust small RNA sequencing (sRNA-seq). Based on their predicted target messenger RNAs (mRNAs), the expression profiles of some of these DE miRNAs could be linked to nodule functions. In particular, several miRNAs associated with nutrient transportation genes were differentially expressed in IRs and mature NODs. MiR399b, specifically, was highly induced in IRs and NODs, as well as by inorganic phosphate (Pi) starvation. In composite soybean plants overexpressing miR399b, PHOSPHATE2 (PHO2), a known target of miR399b that inhibits the activities of high-affinity Pi transporters, was strongly repressed. In addition, the overexpression of miR399b in the roots of transgenic composite plants significantly improved whole-plant Pi and ureide concentrations and the overall growth in terms of leaf node numbers and whole-plant dry weight. Our findings suggest that the induction of miR399b in NODs could enhance nitrogen fixation and soybean growth, possibly via improving Pi uptake to achieve a better Pi-nitrogen balance to promote SNF in nodules.
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http://dx.doi.org/10.1002/tpg2.20103DOI Listing
July 2021

CAG RNAs induce DNA damage and apoptosis by silencing expression in polyglutamine degeneration.

Proc Natl Acad Sci U S A 2021 May;118(19)

Laboratory of Drosophila Research, The Chinese University of Hong Kong, Hong Kong, China;

DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington's disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the () gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.
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http://dx.doi.org/10.1073/pnas.2022940118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126783PMC
May 2021

Comparative genomics of the coconut crab and other decapod crustaceans: exploring the molecular basis of terrestrial adaptation.

BMC Genomics 2021 Apr 30;22(1):313. Epub 2021 Apr 30.

School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Background: The complex life cycle of the coconut crab, Birgus latro, begins when an obligate terrestrial adult female visits the intertidal to hatch zoea larvae into the surf. After drifting for several weeks in the ocean, the post-larval glaucothoes settle in the shallow subtidal zone, undergo metamorphosis, and the early juveniles then subsequently make their way to land where they undergo further physiological changes that prevent them from ever entering the sea again. Here, we sequenced, assembled and analyzed the coconut crab genome to shed light on its adaptation to terrestrial life. For comparison, we also assembled the genomes of the long-tailed marine-living ornate spiny lobster, Panulirus ornatus, and the short-tailed marine-living red king crab, Paralithodes camtschaticus. Our selection of the latter two organisms furthermore allowed us to explore parallel evolution of the crab-like form in anomurans.

Results: All three assembled genomes are large, repeat-rich and AT-rich. Functional analysis reveals that the coconut crab has undergone proliferation of genes involved in the visual, respiratory, olfactory and cytoskeletal systems. Given that the coconut crab has atypical mitochondrial DNA compared to other anomurans, we argue that an abundance of kif22 and other significantly proliferated genes annotated with mitochondrial and microtubule functions, point to unique mechanisms involved in providing cellular energy via nuclear protein-coding genes supplementing mitochondrial and microtubule function. We furthermore detected in the coconut crab a significantly proliferated HOX gene, caudal, that has been associated with posterior development in Drosophila, but we could not definitively associate this gene with carcinization in the Anomura since it is also significantly proliferated in the ornate spiny lobster. However, a cuticle-associated coatomer gene, gammacop, that is significantly proliferated in the coconut crab, may play a role in hardening of the adult coconut crab abdomen in order to mitigate desiccation in terrestrial environments.

Conclusion: The abundance of genomic features in the three assembled genomes serve as a source of hypotheses for future studies of anomuran environmental adaptations such as shell-utilization, perception of visual and olfactory cues in terrestrial environments, and cuticle sclerotization. We hypothesize that the coconut crab exhibits gene proliferation in lieu of alternative splicing as a terrestrial adaptation mechanism and propose life-stage transcriptomic assays to test this hypothesis.
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http://dx.doi.org/10.1186/s12864-021-07636-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086120PMC
April 2021

RNA G-quadruplexes (rG4s): genomics and biological functions.

Nucleic Acids Res 2021 06;49(10):5426-5450

Department of Chemistry and State Key Laboratory of Marine Pollution, City University of Hong Kong, Kowloon Tong, Hong Kong SAR, China.

G-quadruplexes (G4s) are non-classical DNA or RNA secondary structures that have been first observed decades ago. Over the years, these four-stranded structural motifs have been demonstrated to have significant regulatory roles in diverse biological processes, but challenges remain in detecting them globally and reliably. Compared to DNA G4s (dG4s), the study of RNA G4s (rG4s) has received less attention until recently. In this review, we will summarize the innovative high-throughput methods recently developed to detect rG4s on a transcriptome-wide scale, highlight the many novel and important functions of rG4 being discovered in vivo across the tree of life, and discuss the key biological questions to be addressed in the near future.
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http://dx.doi.org/10.1093/nar/gkab187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191793PMC
June 2021

Pan-cancer investigation reveals mechanistic insights of planar cell polarity gene in carcinogenesis.

Aging (Albany NY) 2021 02 26;13(5):7259-7283. Epub 2021 Feb 26.

Nexus of Rare Neurodegenerative Diseases, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.

The fuzzy planar cell polarity protein (Fuz) is an effector component of the planar cell polarity (PCP) signaling. Together with other core and effector proteins, the PCP pathway controls polarized cell movements. Fuz was also reported as a negative regulator of cell survival. In this study, we performed a pan-cancer survey to demonstrate the role of Fuz in multiple types of cancer. In head-neck squamous cell carcinoma and lung adenocarcinoma tumor samples, a reduction of transcript expression was detected. This coincides with the poor overall survival probabilities of these patients. We further showed that promoter hypermethylation contributes to its transcriptional downregulation. Meanwhile, we also identified a relatively higher mutation frequency at the 404 arginine amino acid residue in the coding sequence of locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz. In summary, our study unveiled an intriguing relationship between dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.
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http://dx.doi.org/10.18632/aging.202582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993721PMC
February 2021

Authentication of Hedyotis products by adaptor ligation-mediated PCR and metabarcoding.

J Pharm Biomed Anal 2021 Mar 26;196:113920. Epub 2021 Jan 26.

Li Dak Sum Yip Yio Chin R & D Center for Chinese Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; State Key Laboratory of Research on Bioactivities and Clinical Application of Medicinal Plants, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Electronic address:

DNA barcoding is a widely used tool for species identification and authentication. However, it may not be applicable to highly processed herbal products due to severe DNA fragmentation. The emergence of DNA metabarcoding provides an alternative way to solve the problem. In this study, we are the first to combine the use of adaptor ligation-mediated PCR method and metabarcoding to reveal species identities in herbal products. As an illustration, we applied the method on three Hedyotis herbal products collected from China and Thailand. Results showed that H. diffusa and H. corymbosa were present in the products which were consistent with their label claims. Our study indicated that the adaptor ligation-mediated PCR with metabarcoding approach is useful for authentication of highly processed herbal products.
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http://dx.doi.org/10.1016/j.jpba.2021.113920DOI Listing
March 2021

Horseshoe crab genomes reveal the evolution of genes and microRNAs after three rounds of whole genome duplication.

Commun Biol 2021 01 19;4(1):83. Epub 2021 Jan 19.

School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, China.

Whole genome duplication (WGD) has occurred in relatively few sexually reproducing invertebrates. Consequently, the WGD that occurred in the common ancestor of horseshoe crabs ~135 million years ago provides a rare opportunity to decipher the evolutionary consequences of a duplicated invertebrate genome. Here, we present a high-quality genome assembly for the mangrove horseshoe crab Carcinoscorpius rotundicauda (1.7 Gb, N50 = 90.2 Mb, with 89.8% sequences anchored to 16 pseudomolecules, 2n = 32), and a resequenced genome of the tri-spine horseshoe crab Tachypleus tridentatus (1.7 Gb, N50 = 109.7 Mb). Analyses of gene families, microRNAs, and synteny show that horseshoe crabs have undergone three rounds (3R) of WGD. Comparison of C. rotundicauda and T. tridentatus genomes from populations from several geographic locations further elucidates the diverse fates of both coding and noncoding genes. Together, the present study represents a cornerstone for improving our understanding of invertebrate WGD events on the evolutionary fates of genes and microRNAs, at both the individual and population level. We also provide improved genomic resources for horseshoe crabs, of applied value for breeding programs and conservation of this fascinating and unusual invertebrate lineage.
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http://dx.doi.org/10.1038/s42003-020-01637-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815833PMC
January 2021

Smad3 deficiency promotes beta cell proliferation and function in mice restoring Pax6 expression.

Theranostics 2021 1;11(6):2845-2859. Epub 2021 Jan 1.

Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong.

Transforming Growth Factor-beta (TGF-β) /Smad3 signaling has been shown to play important roles in fibrotic and inflammatory diseases, but its role in beta cell function and type 2 diabetes is unknown. The role of Smad3 in beta cell function under type 2 diabetes condition was investigated by genetically deleting Smad3 from mice. Phenotypic changes of pancreatic islets and beta cell function were compared between Smad3 knockout (Smad3KO-) mice and Smad3 wild-type (Smad3WT-) mice, and other littermate controls. Islet-specific RNA-sequencing was performed to identify Smad3-dependent differentially expressed genes associated with type 2 diabetes. beta cell proliferation assay and insulin secretion assay were carried out to validate the mechanism by which Smad3 regulates beta cell proliferation and function. The results showed that Smad3 deficiency completely protected against diabetes-associated beta cell loss and dysfunction in mice. By islet-specific RNA-sequencing, we identified 8160 Smad3-dependent differentially expressed genes associated with type 2 diabetes, where Smad3 deficiency markedly prevented the down-regulation of those genes. Mechanistically, Smad3 deficiency preserved the expression of beta cell development mediator Pax6 in islet, thereby enhancing beta cell proliferation and function in mice and in Min6 cells . Taken together, we discovered a pathogenic role of Smad3 in beta cell loss and dysfunction via targeting the protective Pax6. Thus, Smad3 may represent as a novel therapeutic target for type 2 diabetes prevention and treatment.
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http://dx.doi.org/10.7150/thno.51857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806493PMC
July 2021

Investigating the role of dachshund b in the development of the pancreatic islet in zebrafish.

J Diabetes Investig 2021 May 28;12(5):710-727. Epub 2021 Feb 28.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

Aims/introduction: β-Cell dysfunction is a hallmark of type 2 diabetes. In a previous pilot study, we identified an association between genetic variants within the human DACH1 gene and young-onset type 2 diabetes. Here, we characterized the function of dachb, the only dach homologue to be expressed in the pancreas, in developing zebrafish embryos.

Materials And Methods: We injected one-cell stage embryos with a dachb-morpholino (MO) or with the dachb-MO and dachb messenger ribonucleic acid, and determined the effect on the development of the pancreatic islet. We also carried out quantitative polymerase chain reaction and ribonucleic acid sequencing on the dachb-MO group to determine the effect of dachb knockdown on gene expression.

Results: MO-mediated dachb knockdown resulted in impaired islet cell development, with a significant decrease in both the β-cell and islet cell numbers. This islet developmental defect was rescued when embryos were co-injected with dachb-MO and dachb messenger ribonucleic acid. Knockdown of dachb was associated with a significant downregulation of the β-cell specific marker gene, insa, and the somatostatin cell marker, sst2, as well as regulators of pancreas development, ptf1a, neuroD, pax6a and nkx6.1, and the cell cycle gene, insm1a. Furthermore, ribonucleic sequencing analysis showed an upregulation of genes enriched in the forkhead box O and mitogen-activated protein kinase signaling pathways in the dachb-MO group, when compared with the control groups.

Conclusions: Together, our results suggest the possible role of dachb in islet development in zebrafish.
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http://dx.doi.org/10.1111/jdi.13503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089008PMC
May 2021

Identification of Smad3-related transcriptomes in type-2 diabetic nephropathy by whole transcriptome RNA sequencing.

J Cell Mol Med 2021 02 25;25(4):2052-2068. Epub 2020 Dec 25.

Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Smad3 deficiency prevents the development of type 2 diabetic nephropathy; however, the underlying molecular mechanisms remain unknown. In this study, we aimed to identify Smad3-related genes involved in the pathogenesis of diabetic kidney disease. High-throughput RNA sequencing was performed to profile the whole transcriptome in the diabetic kidney of Smad3 WT-db/db, Smad3 KO-db/db, Smad3 db/db and their littermate control db/m mice at 20 weeks. The gene ontology, pathways and alternative splicing of differentially expressed protein-coding genes and long non-coding RNAs related to Smad3 in diabetic kidney were analysed. Compared to Smad3 WT-db/db mice, Smad3 KO-db/db mice exhibited an alteration of genes associated with RNA splicing and metabolism, whereas heterozygosity deletion of Smad3 (Smad3 db/db mice) significantly altered genes related to cell division and cell cycle. Notably, three protein-coding genes (Upk1b, Psca and Gdf15) and two lncRNAs (NONMMUG023520.2 and NONMMUG032975.2) were identified to be Smad3-dependent and to be associated with the development of diabetic nephropathy. By using whole transcriptome RNA sequencing, we identified novel Smad3 transcripts related to the development of diabetic nephropathy. Thus, targeting these transcripts may represent a novel and effective therapy for diabetic nephropathy.
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http://dx.doi.org/10.1111/jcmm.16133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882931PMC
February 2021

Multi-omic approach provides insights into osmoregulation and osmoconformation of the crab Scylla paramamosain.

Sci Rep 2020 12 10;10(1):21771. Epub 2020 Dec 10.

Simon F. S. Li Marine Science Laboratory, School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China.

Osmoregulation and osmoconformation are two mechanisms through which aquatic animals adapt to salinity fluctuations. The euryhaline crab Scylla paramamosain, being both an osmoconformer and osmoregulator, is an excellent model organism to investigate salinity adaptation mechanisms in brachyurans. In the present study, we used transcriptomic and proteomic approaches to investigate the response of S. paramamosain to salinity stress. Crabs were transferred from a salinity of 25 ppt to salinities of 5 ppt or 33 ppt for 6 h and 10 days. Data from both approaches revealed that exposure to 5 ppt resulted in upregulation of ion transport and energy metabolism associated genes. Notably, acclimation to low salinity was associated with early changes in gene expression for signal transduction and stress response. In contrast, exposure to 33 ppt resulted in upregulation of genes related to amino acid metabolism, and amino acid transport genes were upregulated only at the early stage of acclimation to this salinity. Our study reveals contrasting mechanisms underlying osmoregulation and osmoconformation within the salinity range of 5-33 ppt in the mud crab, and provides novel candidate genes for osmotic signal transduction, thereby providing insights on understanding the salinity adaptation mechanisms of brachyuran crabs.
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http://dx.doi.org/10.1038/s41598-020-78351-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728780PMC
December 2020

In-silico Exploration of Channel Type and Efflux Silicon Transporters and Silicification Proteins in 80 Sequenced Viridiplantae Genomes.

Plants (Basel) 2020 Nov 20;9(11). Epub 2020 Nov 20.

N.I. Vavilov All-Russian Institute of Plant Genetic Resources, 42, 44 Bolshaya Morskaya Street, 190000 St. Petersburg, Russia.

Silicon (Si) accumulation protects plants from biotic and abiotic stresses. It is transported and distributed within the plant body through a cooperative system of channel type (e.g., ) and efflux (Lsi2s e.g., ) Si transporters (SITs) that belong to Noduline-26 like intrinsic protein family of aquaporins and an uncharacterized anion transporter family, respectively. Si is deposited in plant tissues as phytoliths and the process is known as biosilicification but the knowledge about the proteins involved in this process is limited. In the present study, we explored channel type SITs and Lsi2s, and siliplant1 protein (Slp1) in 80 green plant species. We found 80 channel type SITs and 133 Lsi2s. The channel type SITs characterized by the presence of two NPA motifs, GSGR or STAR selectivity filter, and 108 amino acids between two NPA motifs were absent from Chlorophytes, while Streptophytes evolved two different types of channel type SITs with different selectivity filters. Both channel type SITs and Lsi2s evolved two types of gene structures each, however, Lsi2s are ancient and were also found in Chlorophyta. Homologs of Slp1 (225) were present in almost all Streptophytes regardless of their Si accumulation capacity. In Si accumulator plant species, the Slp1s were characterized by the presence of H, D-rich domain, P, K, E-rich domain, and P, T, Y-rich domain, while moderate Si accumulators lacked H, D-rich domain and P, T, Y-rich domains. The digital expression analysis and coexpression networks highlighted the role of channel type and Lsi2s, and how Slp1 homologs were ameliorating plants' ability to withstand different stresses by co-expressing with genes related to structural integrity and signaling. Together, the in-silico exploration made in this study increases our knowledge of the process of biosilicification in plants.
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http://dx.doi.org/10.3390/plants9111612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709012PMC
November 2020

Terpenes and Terpenoids in Plants: Interactions with Environment and Insects.

Int J Mol Sci 2020 Oct 6;21(19). Epub 2020 Oct 6.

School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.

The interactions of plants with environment and insects are bi-directional and dynamic. Consequently, a myriad of mechanisms has evolved to engage organisms in different types of interactions. These interactions can be mediated by allelochemicals known as volatile organic compounds (VOCs) which include volatile terpenes (VTs). The emission of VTs provides a way for plants to communicate with the environment, including neighboring plants, beneficiaries (e.g., pollinators, seed dispersers), predators, parasitoids, and herbivores, by sending enticing or deterring signals. Understanding terpenoid distribution, biogenesis, and function provides an opportunity for the design and implementation of effective and efficient environmental calamity and pest management strategies. This review provides an overview of plant-environment and plant-insect interactions in the context of terpenes and terpenoids as important chemical mediators of these abiotic and biotic interactions.
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http://dx.doi.org/10.3390/ijms21197382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583029PMC
October 2020

Millipede genomes reveal unique adaptations during myriapod evolution.

PLoS Biol 2020 09 29;18(9):e3000636. Epub 2020 Sep 29.

School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong.

The Myriapoda, composed of millipedes and centipedes, is a fascinating but poorly understood branch of life, including species with a highly unusual body plan and a range of unique adaptations to their environment. Here, we sequenced and assembled 2 chromosomal-level genomes of the millipedes Helicorthomorpha holstii (assembly size = 182 Mb; shortest scaffold/contig length needed to cover 50% of the genome [N50] = 18.11 Mb mainly on 8 pseudomolecules) and Trigoniulus corallinus (assembly size = 449 Mb, N50 = 26.78 Mb mainly on 17 pseudomolecules). Unique genomic features, patterns of gene regulation, and defence systems in millipedes, not observed in other arthropods, are revealed. Both repeat content and intron size are major contributors to the observed differences in millipede genome size. Tight Hox and the first loose ecdysozoan ParaHox homeobox clusters are identified, and a myriapod-specific genomic rearrangement including Hox3 is also observed. The Argonaute (AGO) proteins for loading small RNAs are duplicated in both millipedes, but unlike in insects, an AGO duplicate has become a pseudogene. Evidence of post-transcriptional modification in small RNAs-including species-specific microRNA arm switching-providing differential gene regulation is also obtained. Millipedes possesses a unique ozadene defensive gland unlike the venomous forcipules found in centipedes. We identify sets of genes associated with the ozadene that play roles in chemical defence as well as antimicrobial activity. Macro-synteny analyses revealed highly conserved genomic blocks between the 2 millipedes and deuterostomes. Collectively, our analyses of millipede genomes reveal that a series of unique adaptations have occurred in this major lineage of arthropod diversity. The 2 high-quality millipede genomes provided here shed new light on the conserved and lineage-specific features of millipedes and centipedes. These findings demonstrate the importance of the consideration of both centipede and millipede genomes-and in particular the reconstruction of the myriapod ancestral situation-for future research to improve understanding of arthropod evolution, and animal evolutionary genomics more widely.
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http://dx.doi.org/10.1371/journal.pbio.3000636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523956PMC
September 2020

SCRaMbLE-in: A Fast and Efficient Method to Diversify and Improve the Yields of Heterologous Pathways in Synthetic Yeast.

Methods Mol Biol 2020 ;2205:305-327

Manchester Institute of Biotechnology (MIB), School of Chemistry, The University of Manchester, Manchester, UK.

The synthetic chromosome rearrangement and modification by LoxP-mediated evolution (SCRaMbLE) system is a key component of the synthetic yeast genome (Sc2.0) project, an international effort to construct an entire synthetic genome in yeast. SCRaMbLE involves the introduction of thousands of symmetrical LoxP (LoxPsym) recombination sites downstream of every nonessential gene in all 16 chromosomes, enabling numerous genome rearrangements in the form of deletions, inversions, duplications, and translocations by the Cre-LoxPsym recombination system. We highlight a two-step protocol for SCRaMbLE-in (Liu, Nat Commun 9(1):1936, 2018), a recombinase-based combinatorial method to expedite genetic engineering and exogenous pathway optimization, using a synthetic β-carotene pathway as an example. First, an in vitro phase uses a recombinase toolkit to diversify gene expression by integrating various regulatory elements into the target pathway. This combinatorial pathway library can be transformed directly into yeast for traditional screening. Once an optimized pathway which is flanked by LoxPsym sites is identified, it is transformed into Sc2.0 yeast for the in vivo SCRaMbLE phase, where LoxPsym sites in the synthetic yeast genome and Cre recombinase catalyze massive genome rearrangements. We describe all the conditions necessary to perform SCRaMbLE and post-SCRaMbLE experiments including screening, spot test analysis, and PCRTag analysis to elucidate genotype-phenotype relationships.
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http://dx.doi.org/10.1007/978-1-0716-0908-8_17DOI Listing
March 2021

Advances in optical mapping for genomic research.

Comput Struct Biotechnol J 2020 1;18:2051-2062. Epub 2020 Aug 1.

School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.

Recent advances in optical mapping have allowed the construction of improved genome assemblies with greater contiguity. Optical mapping also enables genome comparison and identification of large-scale structural variations. Association of these large-scale genomic features with biological functions is an important goal in plant and animal breeding and in medical research. Optical mapping has also been used in microbiology and still plays an important role in strain typing and epidemiological studies. Here, we review the development of optical mapping in recent decades to illustrate its importance in genomic research. We detail its applications and algorithms to show its specific advantages. Finally, we discuss the challenges required to facilitate the optimization of optical mapping and improve its future development and application.
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http://dx.doi.org/10.1016/j.csbj.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419273PMC
August 2020

Osmotic stress induces gut microbiota community shift in fish.

Environ Microbiol 2020 09 2;22(9):3784-3802. Epub 2020 Aug 2.

Center for Promotion of International Education and Research, Faculty of Agriculture, Kyushu University, Fukuoka, 819-0395, Japan.

Alteration of the gut microbiota plays an important role in animal health and metabolic diseases. However, little is known with respect to the influence of environmental osmolality on the gut microbial community. The aim of the current study was to determine whether the reduction in salinity affects the gut microbiota and identify its potential role in salinity acclimation. Using Oryzias melastigma as a model organism to perform progressive hypotonic transfer experiments, we evaluated three conditions: seawater control (SW), SW to 50% sea water transfer (SFW) and SW to SFW to freshwater transfer (FW). Our results showed that the SFW and FW transfer groups contained higher operational taxonomic unit microbiota diversities. The dominant bacteria in all conditions constituted the phylum Proteobacteria, with the majority in the SW and SFW transfer gut comprising Vibrio at the genus level, whereas this population was replaced by Pseudomonas in the FW transfer gut. Furthermore, our data revealed that the FW transfer gut microbiota exhibited a reduced renin-angiotensin system, which is important in SW acclimation. In addition, induced detoxification and immune mechanisms were found in the FW transfer gut microbiota. The shift of the bacteria community in different osmolality environments indicated possible roles of bacteria in facilitating host acclimation.
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http://dx.doi.org/10.1111/1462-2920.15150DOI Listing
September 2020

Jellyfish genomes reveal distinct homeobox gene clusters and conservation of small RNA processing.

Nat Commun 2020 06 19;11(1):3051. Epub 2020 Jun 19.

School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, Hong Kong.

The phylum Cnidaria represents a close outgroup to Bilateria and includes familiar animals including sea anemones, corals, hydroids, and jellyfish. Here we report genome sequencing and assembly for true jellyfish Sanderia malayensis and Rhopilema esculentum. The homeobox gene clusters are characterised by interdigitation of Hox, NK, and Hox-like genes revealing an alternate pathway of ANTP class gene dispersal and an intact three gene ParaHox cluster. The mitochondrial genomes are linear but, unlike in Hydra, we do not detect nuclear copies, suggesting that linear plastid genomes are not necessarily prone to integration. Genes for sesquiterpenoid hormone production, typical for arthropods, are also now found in cnidarians. Somatic and germline cells both express piwi-interacting RNAs in jellyfish revealing a conserved cnidarian feature, and evidence for tissue-specific microRNA arm switching as found in Bilateria is detected. Jellyfish genomes reveal a mosaic of conserved and divergent genomic characters evolved from a shared ancestral genetic architecture.
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http://dx.doi.org/10.1038/s41467-020-16801-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305137PMC
June 2020

Micro-RNA Clusters Integrate Evolutionary Constraints on Expression and Target Affinities: The miR-6/5/4/286/3/309 Cluster in Drosophila.

Mol Biol Evol 2020 10;37(10):2955-2965

School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong.

A striking feature of micro-RNAs is that they are often clustered in the genomes of animals. The functional and evolutionary consequences of this clustering remain obscure. Here, we investigated a micro-RNA cluster miR-6/5/4/286/3/309 that is conserved across drosophilid lineages. Small RNA sequencing revealed expression of this micro-RNA cluster in Drosophila melanogaster leg discs, and conditional overexpression of the whole cluster resulted in leg appendage shortening. Transgenic overexpression lines expressing different combinations of micro-RNA cluster members were also constructed. Expression of individual micro-RNAs from the cluster resulted in a normal wild-type phenotype, but either the expression of several ancient micro-RNAs together (miR-5/4/286/3/309) or more recently evolved clustered micro-RNAs (miR-6-1/2/3) can recapitulate the phenotypes generated by the whole-cluster overexpression. Screening of transgenic fly lines revealed downregulation of leg-patterning gene cassettes in generation of the leg-shortening phenotype. Furthermore, cell transfection with different combinations of micro-RNA cluster members revealed a suite of downstream genes targeted by all cluster members, as well as complements of targets that are unique for distinct micro-RNAs. Considered together, the micro-RNA targets and the evolutionary ages of each micro-RNA in the cluster demonstrate the importance of micro-RNA clustering, where new members can reinforce and modify the selection forces on both the cluster regulation and the gene regulatory network of existing micro-RNAs. Key words: micro-RNA, cluster, evolution.
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http://dx.doi.org/10.1093/molbev/msaa146DOI Listing
October 2020

Hypoxia causes sex-specific hepatic toxicity at the transcriptome level in marine medaka (Oryzias melastigma).

Aquat Toxicol 2020 Jul 19;224:105520. Epub 2020 May 19.

Department of Chemistry, City University of Hong Kong, Hong Kong, PR China; State Key Laboratory of Marine Pollution, City University of Hong Kong, Hong Kong, PR China. Electronic address:

Hypoxia, a low environmental oxygen level, is a common problem in the ocean globally. Hypoxia has been known to cause disruption to the endocrine system of marine organisms in both laboratory and field studies. Our previous studies have demonstrated the sex-specific response to hypoxia in the neural and reproductive systems of marine fish. In the current report, we aim to study the sex-specific hepatic response of fish at the transcriptome level to hypoxic stress. By using a comparative transcriptome analysis, followed by a systematic bioinformatics analysis including Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA), we found that hypoxia altered expression of genes related to cell proliferation and apoptosis of hepatocytes, which are associated with human pathologies, such as liver inflammation hepatic steatosis and steatohepatitis. Furthermore, we observed sex-specific responses in the livers of fish through different cell signaling pathways. In female fish, hypoxia causes dysregulation of expression of genes related to impairment in endoplasmic reticulum structure and liver metabolism. In male fish, genes associated with redox homeostasis and fatty acid metabolism were altered by hypoxic stress. The findings of this study support the notion that hypoxia could cause sex-specific changes (hepatic toxicity and changes) in marine fish.
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http://dx.doi.org/10.1016/j.aquatox.2020.105520DOI Listing
July 2020

Monochorionic twins with selective fetal growth restriction: insight from placental whole-transcriptome analysis.

Am J Obstet Gynecol 2020 11 11;223(5):749.e1-749.e16. Epub 2020 May 11.

Department of Obstetrics and Gynaecology, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address:

Background: The underlying pathomechanism in placenta-related selective fetal growth restriction in monochorionic diamniotic twin pregnancy is not known.

Objective: This study aimed to investigate any differences in placental transcriptomic profile between the selectively growth-restricted twins and the normally grown cotwins in monochorionic diamniotic twin pregnancies.

Study Design: This was a prospective study of monochorionic diamniotic twin pregnancies complicated by selective fetal growth restriction. Placental biopsy specimens were obtained from the subjects in the delivery suite. The placental transcriptome of the selectively growth-restricted twin was compared with that of the normally grown cotwin. This study was divided into 2 stages: (1) gene discovery phase in which placental tissues from 5 monochorionic diamniotic twin pregnancies complicated by selective fetal growth restriction plus 2 control twin pregnancies underwent transcriptome profiling, and transcriptome profiling was carried out using whole-genome RNA sequencing; and (2) validation phase in which placental tissues from 13 monochorionic diamniotic twin pregnancies with selective fetal growth restriction underwent RNA and protein validation. RNA and protein expression levels of candidate genes were determined using quantitative real-time polymerase chain reaction and immunohistochemistry staining.

Results: A total of 1429 transcripts were differentially expressed in the placentae of selectively growth-restricted twin pairs, where 610 were up-regulated and 819 were down-regulated. Endoplasmic reticulum lectin and mannose 6-phosphate receptor were consistently differentially up-regulated in all placentae of selectively growth-restricted twins. Quantitative real-time polymerase chain reaction and immunohistochemistry staining were used to validate the results (P<.05).

Conclusion: The expression of endoplasmic reticulum lectin and mannose 6-phosphate receptor, which are important for angiogenesis and fetal growth, was significantly increased in the placentae of selectively growth-restricted twin of a monochorionic twin pair.
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http://dx.doi.org/10.1016/j.ajog.2020.05.008DOI Listing
November 2020

Integrative omics analyses uncover the mechanism underlying the immunotoxicity of perfluorooctanesulfonate in human lymphocytes.

Chemosphere 2020 Oct 13;256:127062. Epub 2020 May 13.

Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, 541004, PR China. Electronic address:

Perfluorooctanesulfonate (PFOS) is a man-made chemical widely used in industrial products. Due to its high persistence, PFOS has been detected in most animal species including the human population, wild animals, and aquatic organisms. Both cross-sectional studies and laboratory animal studies have shown hepatotoxicity, renal toxicity, and reproductive toxicity caused by PFOS exposure. Recently, a limited number of PFOS studies have raised concerns about its potential immune system effects. However, the molecular mechanism underlying the immunotoxicity of PFOS remains unknown. In this study, we used primary human lymphocytes as a model, together with integrative omics analyses, including the transcriptome and lipidome, and bioinformatics analysis, to resolve the immune toxicity effects of PFOS. Our results demonstrated that PFOS could alter the production of interleukins in human lymphocytes. Additionally, PFOS exposure could dysregulate clusters of genes and lipids that play important roles in immune functions, such as lymphocyte differentiation, inflammatory response, and immune response. The findings of this study offer novel insight into the molecular mechanisms underlying the immunotoxicity of PFOS, and open the potential of using the identified PFOS-responsive genes and lipids as biomarkers for risk assessment.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127062DOI Listing
October 2020

rG4-seeker enables high-confidence identification of novel and non-canonical rG4 motifs from rG4-seq experiments.

RNA Biol 2020 07 26;17(7):903-917. Epub 2020 Apr 26.

School of Life Sciences, and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong , Shatin, Hong Kong SAR, China.

We recently developed the rG4-seq method to detect and map RNA G-quadruplex (rG4s) structures on a transcriptome-wide scale. rG4-seq of purified human HeLa RNA has revealed many non-canonical rG4s and the effects adjacent sequences have on rG4 formation. In this study, we aimed to improve the outcomes and false-positive discrimination in rG4-seq experiments using a bioinformatic approach. By establishing connections between rG4-seq library preparation chemistry and the underlying properties of sequencing data, we identified how to mitigate indigenous sampling errors and background noise in rG4-seq. We applied these findings to develop a novel bioinformatics pipeline named rG4-seeker (https://github.com/TF-Chan-Lab/rG4-seeker), which uses tailored noise models to autonomously assess and optimize rG4 detections in a replicate-independent manner. Compared with previous methods, rG4-seeker exhibited better false-positive discrimination and improved sensitivity for non-canonical rG4s. Using rG4-seeker, we identified novel features in rG4 formation that were missed previously. rG4-seeker provides a reliable and sensitive approach for rG4-seq investigations, laying the foundations for further elucidation of rG4 biology.
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http://dx.doi.org/10.1080/15476286.2020.1740470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577744PMC
July 2020

Quantification of breast milk trans fatty acids and trans fat intake by Hong Kong lactating women.

Eur J Clin Nutr 2020 05 16;74(5):765-774. Epub 2020 Mar 16.

Food and Nutritional Sciences Programme, School of Life Sciences, Chinese University of Hong Kong, Hong Kong, China.

Background/objectives: Diet westernization in Hong Kong may increase trans fat intake, whereas it may decrease intake of polyunsaturated fatty acids. The present study was to determine the current breast milk fatty acid composition and trans fat intake by Hong Kong lactating mothers.

Methods: Sixty lactating women were recruited for the study. Each participant donated 15 ml of milk at week 4 and 6 after delivery. Dietary data were collected using a 3-day food record method, covering 2 weekdays and 1 weekend day. Milk fatty acids were analyzed using a gas chromatography method. Trans fat consumption was assessed using the Nutrition Data System for Research or calculating the intake based on percentage of trans fatty acids in the breast milk.

Results: Linoleic acid, α-linolenic acid, arachidonic acid, and docosahexaenoic acid in breast milk were 16.23%, 1.52%, 0.59%, and 0.66% total milk lipids, respectively. Mean daily intakes of total fat, saturated fatty acids, monounsaturated fatty acids, were 79, 24, 29, and 18 g, respectively. Total trans fat intake was estimated to be 1.15-1.20 g daily and accounted for 0.50-0.52% total energy.

Conclusions: Breast milk of Hong Kong Chinese lactating women contained relatively higher contents of arachidonic and docosahexaenoic acids compared with those of Western countries. Compared with the previous study conducted in 1995, breast milk total trans fatty acids in 2018 still remained low. Total trans fat intake by Hong Kong lactating women in 2018 was a half of WHO's recommendation that total trans fat intake should be <1% total energy.
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http://dx.doi.org/10.1038/s41430-020-0604-9DOI Listing
May 2020

Transcriptomic analysis reveals the oncogenic role of S6K1 in hepatocellular carcinoma.

J Cancer 2020 19;11(9):2645-2655. Epub 2020 Feb 19.

Guanxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, PR China.

The p70 ribosomal protein S6 kinase 1 (S6K1), a serine/threonine kinase, is commonly overexpressed in a variety of cancers. However, its expression level and functional roles in hepatocellular carcinoma (HCC), which ranks as the third leading cause of cancer-related death worldwide, is still largely unknown. In the current report, we show the and overexpression of S6K1 in HCC. In the functional analysis, we demonstrate that S6K1 is required for the proliferation and colony formation abilities in HCC. By using comparative transcriptomic analysis followed by gene ontology enrichment analysis and Ingenuity Pathway Analysis, we find that the depletion of S6K1 can elevate the expression of a cluster of apoptotic genes, tumor suppressor genes and immune responsive genes. Moreover, the knockdown of S6K1 is predicted to reduce the tumorigenicity of HCC through the regulation of hubs of genes including STAT1, HDAC4, CEBPA and ONECUT1. In conclusion, we demonstrate the oncogenic role of S6K1 in HCC, suggesting the possible use of S6K1 as a therapeutic target for HCC treatment.
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http://dx.doi.org/10.7150/jca.40726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065997PMC
February 2020
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