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  1. Fulltext Origin and evolution of European community-acquired methicillin-resistant Staphylococcus aureus
    Stegger M, Wirth T, Andersen PS, Skov RL, De Grassi A, Simões PM, et al.
    mBio, 2014 Aug 26;5(5):e01044-14.
    PMID: 25161186 DOI: 10.1128/mBio.01044-14
    Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was recognized in Europe and worldwide in the late 1990s. Within a decade, several genetically and geographically distinct CA-MRSA lineages carrying the small SCCmec type IV and V genetic elements and the Panton-Valentine leukocidin (PVL) emerged around the world. In Europe, the predominant CA-MRSA strain belongs to clonal complex 80 (CC80) and is resistant to kanamycin/amikacin and fusidic acid. CC80 was first reported in 1993 but was relatively rare until the late 1990s. It has since been identified throughout North Africa, the Middle East, and Europe, with recent sporadic reports in sub-Saharan Africa. While strongly associated with skin and soft tissue infections, it is rarely found among asymptomatic carriers. Methicillin-sensitive S. aureus (MSSA) CC80 strains are extremely rare except in sub-Saharan Africa. In the current study, we applied whole-genome sequencing to a global collection of both MSSA and MRSA CC80 isolates. Phylogenetic analyses strongly suggest that the European epidemic CA-MRSA lineage is derived from a PVL-positive MSSA ancestor from sub-Saharan Africa. Moreover, the tree topology suggests a single acquisition of both the SCCmec element and a plasmid encoding the fusidic acid resistance determinant. Four canonical SNPs distinguish the derived CA-MRSA lineage and include a nonsynonymous mutation in accessory gene regulator C (agrC). These changes were associated with a star-like expansion into Europe, the Middle East, and North Africa in the early 1990s, including multiple cases of cross-continent imports likely driven by human migrations.

    IMPORTANCE: With increasing levels of CA-MRSA reported from most parts of the Western world, there is a great interest in understanding the origin and factors associated with the emergence of these epidemic lineages. To trace the origin, evolution, and dissemination pattern of the European CA-MRSA clone (CC80), we sequenced a global collection of strains of the S. aureus CC80 lineage. Our study determined that a single descendant of a PVL-positive methicillin-sensitive ancestor circulating in sub-Saharan Africa rose to become the dominant CA-MRSA clone in Europe, the Middle East, and North Africa. In the transition from a methicillin-susceptible lineage to a successful CA-MRSA clone, it simultaneously became resistant to fusidic acid, a widely used antibiotic for skin and soft tissue infections, thus demonstrating the importance of antibiotic selection in the success of this clone. This finding furthermore highlights the significance of horizontal gene acquisitions and underscores the combined importance of these factors for the success of CA-MRSA.

    Matched MeSH terms: Bacterial Proteins/genetics; Bacterial Proteins/metabolism
  2. Fulltext Discovery of New Genes Involved in Curli Production by a Uropathogenic Escherichia coli Strain from the Highly Virulent O45:K1:H7 Lineage
    Nhu NTK, Phan MD, Peters KM, Lo AW, Forde BM, Min Chong T, et al.
    mBio, 2018 08 21;9(4).
    PMID: 30131362 DOI: 10.1128/mBio.01462-18
    Curli are bacterial surface-associated amyloid fibers that bind to the dye Congo red (CR) and facilitate uropathogenic Escherichia coli (UPEC) biofilm formation and protection against host innate defenses. Here we sequenced the genome of the curli-producing UPEC pyelonephritis strain MS7163 and showed it belongs to the highly virulent O45:K1:H7 neonatal meningitis-associated clone. MS7163 produced curli at human physiological temperature, and this correlated with biofilm growth, resistance of sessile cells to the human cationic peptide cathelicidin, and enhanced colonization of the mouse bladder. We devised a forward genetic screen using CR staining as a proxy for curli production and identified 41 genes that were required for optimal CR binding, of which 19 genes were essential for curli synthesis. Ten of these genes were novel or poorly characterized with respect to curli synthesis and included genes involved in purine de novo biosynthesis, a regulator that controls the Rcs phosphorelay system, and a novel repressor of curli production (referred to as rcpA). The involvement of these genes in curli production was confirmed by the construction of defined mutants and their complementation. The mutants did not express the curli major subunit CsgA and failed to produce curli based on CR binding. Mutation of purF (the first gene in the purine biosynthesis pathway) and rcpA also led to attenuated colonization of the mouse bladder. Overall, this work has provided new insight into the regulation of curli and the role of these amyloid fibers in UPEC biofilm formation and pathogenesis.IMPORTANCE Uropathogenic Escherichia coli (UPEC) strains are the most common cause of urinary tract infection, a disease increasingly associated with escalating antibiotic resistance. UPEC strains possess multiple surface-associated factors that enable their colonization of the urinary tract, including fimbriae, curli, and autotransporters. Curli are extracellular amyloid fibers that enhance UPEC virulence and promote biofilm formation. Here we examined the function and regulation of curli in a UPEC pyelonephritis strain belonging to the highly virulent O45:K1:H7 neonatal meningitis-associated clone. Curli expression at human physiological temperature led to increased biofilm formation, resistance of sessile cells to the human cationic peptide LL-37, and enhanced bladder colonization. Using a comprehensive genetic screen, we identified multiple genes involved in curli production, including several that were novel or poorly characterized with respect to curli synthesis. In total, this study demonstrates an important role for curli as a UPEC virulence factor that promotes biofilm formation, resistance, and pathogenesis.
    Matched MeSH terms: Escherichia coli Proteins/genetics*; Escherichia coli Proteins/metabolism
  3. Fulltext Genome-Wide Discovery of Genes Required for Capsule Production by Uropathogenic Escherichia coli
    Goh KGK, Phan MD, Forde BM, Chong TM, Yin WF, Chan KG, et al.
    mBio, 2017 10 24;8(5).
    PMID: 29066548 DOI: 10.1128/mBio.01558-17
    Uropathogenic Escherichia coli (UPEC) is a major cause of urinary tract and bloodstream infections and possesses an array of virulence factors for colonization, survival, and persistence. One such factor is the polysaccharide K capsule. Among the different K capsule types, the K1 serotype is strongly associated with UPEC infection. In this study, we completely sequenced the K1 UPEC urosepsis strain PA45B and employed a novel combination of a lytic K1 capsule-specific phage, saturated Tn5 transposon mutagenesis, and high-throughput transposon-directed insertion site sequencing (TraDIS) to identify the complement of genes required for capsule production. Our analysis identified known genes involved in capsule biosynthesis, as well as two additional regulatory genes (mprA and lrhA) that we characterized at the molecular level. Mutation of mprA resulted in protection against K1 phage-mediated killing, a phenotype restored by complementation. We also identified a significantly increased unidirectional Tn5 insertion frequency upstream of the lrhA gene and showed that strong expression of LrhA induced by a constitutive Pcl promoter led to loss of capsule production. Further analysis revealed loss of MprA or overexpression of LrhA affected the transcription of capsule biosynthesis genes in PA45B and increased sensitivity to killing in whole blood. Similar phenotypes were also observed in UPEC strains UTI89 (K1) and CFT073 (K2), demonstrating that the effects were neither strain nor capsule type specific. Overall, this study defined the genome of a UPEC urosepsis isolate and identified and characterized two new regulatory factors that affect UPEC capsule production.IMPORTANCE Urinary tract infections (UTIs) are among the most common bacterial infections in humans and are primarily caused by uropathogenic Escherichia coli (UPEC). Many UPEC strains express a polysaccharide K capsule that provides protection against host innate immune factors and contributes to survival and persistence during infection. The K1 serotype is one example of a polysaccharide capsule type and is strongly associated with UPEC strains that cause UTIs, bloodstream infections, and meningitis. The number of UTIs caused by antibiotic-resistant UPEC is steadily increasing, highlighting the need to better understand factors (e.g., the capsule) that contribute to UPEC pathogenesis. This study describes the original and novel application of lytic capsule-specific phage killing, saturated Tn5 transposon mutagenesis, and high-throughput transposon-directed insertion site sequencing to define the entire complement of genes required for capsule production in UPEC. Our comprehensive approach uncovered new genes involved in the regulation of this key virulence determinant.
    Matched MeSH terms: Escherichia coli Proteins/genetics*; Escherichia coli Proteins/isolation & purification; Escherichia coli Proteins/metabolism
  4. Fulltext Unsupervised Network Analysis of the Plastic Supraoptic Nucleus Transcriptome Predicts Caprin2 Regulatory Interactions
    Loh SY, Jahans-Price T, Greenwood MP, Greenwood M, Hoe SZ, Konopacka A, et al.
    eNeuro, 2017 12 21;4(6).
    PMID: 29279858 DOI: 10.1523/ENEURO.0243-17.2017
    The supraoptic nucleus (SON) is a group of neurons in the hypothalamus responsible for the synthesis and secretion of the peptide hormones vasopressin and oxytocin. Following physiological cues, such as dehydration, salt-loading and lactation, the SON undergoes a function related plasticity that we have previously described in the rat at the transcriptome level. Using the unsupervised graphical lasso (Glasso) algorithm, we reconstructed a putative network from 500 plastic SON genes in which genes are the nodes and the edges are the inferred interactions. The most active nodal gene identified within the network was Caprin2. Caprin2 encodes an RNA-binding protein that we have previously shown to be vital for the functioning of osmoregulatory neuroendocrine neurons in the SON of the rat hypothalamus. To test the validity of the Glasso network, we either overexpressed or knocked down Caprin2 transcripts in differentiated rat pheochromocytoma PC12 cells and showed that these manipulations had significant opposite effects on the levels of putative target mRNAs. These studies suggest that the predicative power of the Glasso algorithm within an in vivo system is accurate, and identifies biological targets that may be important to the functional plasticity of the SON.
    Matched MeSH terms: RNA-Binding Proteins/genetics; RNA-Binding Proteins/metabolism*
  5. Fulltext Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis
    Lee WC, Russell B, Sobota RM, Ghaffar K, Howland SW, Wong ZX, et al.
    Elife, 2020 02 18;9.
    PMID: 32066522 DOI: 10.7554/eLife.51546
    In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.
    Matched MeSH terms: Insulin-Like Growth Factor Binding Proteins/metabolism*
  6. Fulltext Regulation of nerve growth and patterning by cell surface protein disulphide isomerase
    Cook GM, Sousa C, Schaeffer J, Wiles K, Jareonsettasin P, Kalyanasundaram A, et al.
    Elife, 2020 05 28;9.
    PMID: 32452761 DOI: 10.7554/eLife.54612
    Contact repulsion of growing axons is an essential mechanism for spinal nerve patterning. In birds and mammals the embryonic somites generate a linear series of impenetrable barriers, forcing axon growth cones to traverse one half of each somite as they extend towards their body targets. This study shows that protein disulphide isomerase provides a key component of these barriers, mediating contact repulsion at the cell surface in chick half-somites. Repulsion is reduced both in vivo and in vitro by a range of methods that inhibit enzyme activity. The activity is critical in initiating a nitric oxide/S-nitrosylation-dependent signal transduction pathway that regulates the growth cone cytoskeleton. Rat forebrain grey matter extracts contain a similar activity, and the enzyme is expressed at the surface of cultured human astrocytic cells and rat cortical astrocytes. We suggest this system is co-opted in the brain to counteract and regulate aberrant nerve terminal growth.
    Matched MeSH terms: Membrane Proteins/genetics; Membrane Proteins/metabolism*
  7. Fulltext RNA binding protein Caprin-2 is a pivotal regulator of the central osmotic defense response
    Konopacka A, Greenwood M, Loh SY, Paton J, Murphy D
    Elife, 2015 Nov 12;4.
    PMID: 26559902 DOI: 10.7554/eLife.09656
    In response to an osmotic challenge, the synthesis of the antidiuretic hormone arginine vasopressin (AVP) increases in the hypothalamus, and this is accompanied by extension of the 3' poly(A) tail of the AVP mRNA, and the up-regulation of the expression of RNA binding protein Caprin-2. Here we show that Caprin-2 binds to AVP mRNAs, and that lentiviral mediated shRNA knockdown of Caprin-2 in the osmotically stimulated hypothalamus shortens the AVP mRNA poly(A) tail at the same time as reducing transcript abundance. In a recapitulated in vitro system, we confirm that Caprin-2 over-expression enhances AVP mRNA abundance and poly(A) tail length. Importantly, we show that Caprin-2 knockdown in the hypothalamus decreases urine output and fluid intake, and increases urine osmolality, urine sodium concentration, and plasma AVP levels. Thus Caprin-2 controls physiological mechanisms that are essential for the body's response to osmotic stress.
    Matched MeSH terms: RNA-Binding Proteins/metabolism*
  8. Fulltext Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells
    Bhattacharya P, Ellegård R, Khalid M, Svanberg C, Govender M, Keita ÅV, et al.
    Elife, 2020 Sep 02;9.
    PMID: 32876566 DOI: 10.7554/eLife.57869
    HIV transmission via genital and colorectal mucosa are the most common routes of dissemination. Here, we explored the effects of free and complement-opsonized HIV on colorectal tissue. Initially, there was higher antiviral responses in the free HIV compared to complement-opsonized virus. The mucosal transcriptional response at 24 hr revealed the involvement of activated T cells, which was mirrored in cellular responses observed at 96 hr in isolated mucosal T cells. Further, HIV exposure led to skewing of T cell phenotypes predominantly to inflammatory CD4+ T cells, that is Th17 and Th1Th17 subsets. Of note, HIV exposure created an environment that altered the CD8+ T cell phenotype, for example expression of regulatory factors, especially when the virions were opsonized with complement factors. Our findings suggest that HIV-opsonization alters the activation and signaling pathways in the colorectal mucosa, which promotes viral establishment by creating an environment that stimulates mucosal T cell activation and inflammatory Th cells.
    Matched MeSH terms: Complement System Proteins/immunology; Complement System Proteins/metabolism; Complement System Proteins/chemistry; Opsonin Proteins/immunology; Opsonin Proteins/metabolism; Opsonin Proteins/chemistry
  9. Fulltext ING2 (inhibitor of growth protein-2) plays a crucial role in preimplantation development
    Zhou L, Wang P, Zhang J, Heng BC, Tong GQ
    Zygote, 2016 Feb;24(1):89-97.
    PMID: 25672483 DOI: 10.1017/S0967199414000768
    ING2 (inhibitor of growth protein-2) is a member of the ING-gene family and participates in diverse cellular processes involving tumor suppression, DNA repair, cell cycle regulation, and cellular senescence. As a subunit of the Sin3 histone deacetylase complex co-repressor complex, ING2 binds to H3K4me3 to regulate chromatin modification and gene expression. Additionally, ING2 recruits histone methyltransferase (HMT) activity for gene repression, which is independent of the HDAC class I or II pathway. However, the physiological function of ING2 in mouse preimplantation embryo development has not yet been characterized previously. The expression, localization and function of ING2 during preimplantation development were investigated in this study. We showed increasing expression of ING2 within the nucleus from the 4-cell embryo stage onwards; and that down-regulation of ING2 expression by endoribonuclease-prepared small interfering RNA (esiRNA) microinjection results in developmental arrest during the morula to blastocyst transition. Embryonic cells microinjected with ING2-specific esiRNA exhibited decreased blastulation rate compared to the negative control. Further investigation of the underlying mechanism indicated that down-regulation of ING2 significantly increased expression of p21, whilst decreasing expression of HDAC1. These results suggest that ING2 may play a crucial role in the process of preimplantation embryo development through chromatin regulation.
    Matched MeSH terms: Homeodomain Proteins/physiology*; Tumor Suppressor Proteins/physiology*
  10. A diminutive new species of cave-dwelling Wolf Snake (Colubridae: Lycodon Boie, 1826) from Peninsular Malaysia
    Grismer LL, Quah ES, Anuar M S S, Muin MA, Wood PL, Nor SA
    Zootaxa, 2014.
    PMID: 24943599 DOI: 10.11646/zootaxa.3815.1.3
    A newly discovered, diminutive, cave-dwelling, lowland species of the colubrid snake genus Lycodon Boie is described from a limestone cave along the Thai-Malaysian border in the state of Perlis, northwestern Peninsular Malaysia. Lycodon cavernicolus sp. nov. is most closely related to L. butleri Boulenger, an endemic, upland, forest-dwelling species from Peninsular Malaysia of the fasciatus group but is separated from L. butleri and all other species of the L. fasciatus group and the closely related L. ruhstrati group by having the combination of 245 (male) and 232 (female) ventral scales; 113 (male) and 92 (female) paired, subcaudal scales; a single precloacal plate; nine or 10 supralabials; 10 or 11 infralabials; a maximum total length of 508 mm (female); a relative tail length of 0.25-0.27; an immaculate venter in juveniles and dark-brown, posterior, ventral scale margins in adults; and dorsal and caudal bands in juveniles white. The discovery of L. cavernicolus sp. nov. adds to a rapidly growing list of newly discovered reptiles from karst regions and limestone forests of Peninsular Malaysia, underscoring the fact that these areas should be studied before they are quarried as they harbor a significant portion of the Peninsular Malaysia's herpetological diversity.
    Matched MeSH terms: Reptilian Proteins/genetics
  11. A new species of upland Stream Toad of the genus Ansonia Stoliczka, 1870 (Anura: Bufonidae) from northeastern Peninsular Malaysia
    Chan KO, Wood PL, Anuar S, Muin MA, Quah ES, Sumarli AX
    Zootaxa, 2014;3764:427-40.
    PMID: 24870645 DOI: 10.11646/zootaxa.3764.4.3
    A new species of Ansonia is described based on genetic and morphological differentiation. Ansonia lumut sp. nov. is most closely related to three other Peninsular Malaysian species, A. penangensis, A. malayana, and A. jeetsukumarani but differs from these and other congeners by at least 6.9% sequence divergence at the 12S, 16S rRNA and t-RNA-val genes and the following combination of morphological characters: (1) SVL 21.0-23.6 mm in males, 27.7-31.6 mm in females; (2) first finger shorter than second; (3) interorbital and tarsal ridges absent; (4) light interscapular spot absent; (5) presence of large, yellow rictal tubercle; (6) dorsum black with greenish-yellow reticulations; (7) flanks with small yellow spots; (8) fore and hind limbs with yellow cross-bars; and (9) venter light gray with fine, white spotting.
    Matched MeSH terms: Amphibian Proteins/genetics
  12. Phylogenetic relationships and description of a new upland species of Bent-toed Gecko (Cyrtodactylus Gray, 1827) of the C. sworderi complex from northeastern Peninsular Malaysia
    Grismer LL, Anuar S, Muin MA, Quah ES, Wood PL
    Zootaxa, 2013;3616:239-52.
    PMID: 24758805 DOI: 10.11646/zootaxa.3616.3.2
    Molecular and morphological analyses indicate that a new upland species of the Cyrtodactylus sworderi complex, C. tebuensis sp. nov. from Gunung Tebu, Terengganu, Malaysia is most closely related to C. sworderi and together they form the sister lineage to C. quadrivirgatus. Cyrtodactylus tebuensis sp. nov. is differentiated from all other species of Sundaland Cyrtodactylus on the basis of having the unique combination of large, conical, keeled body tubercles; tubercles present on top of head, occiput, nape, and limbs, and extending posteriorly beyond base of tail; 43-51 ventral scales; no transversely enlarged, median subcaudal scales; proximal, subdigital lamellae transversely expanded; 17-21 subdigital lamellae on fourth toe; an abrupt transition between posterior and ventral femoral scales; enlarged femoral scales; no femoral or precloacal pores; no precloacal groove; body bearing four wide, bold, dark brown stripes (lateral stripe on each flank and a pair of paravertebral stripes); and a pairwise sequence divergence of 13.0% from its closest relative C. sworderi based on the mitochondrial gene ND2. Cyrtodactylus tebuensis sp. nov. is the first endemic upland species of gekkonid from northeastern Peninsular Malaysia and underscores the necessity for additional field work in all upland systems.
    Matched MeSH terms: Reptilian Proteins/genetics
  13. Amphicnemis valentini sp. nov. from the Cardamom ecoregion in Cambodia and Vietnam (Odonata: Coenagrionidae)
    Kosterin OE, Kompier T
    Zootaxa, 2018 Jun 06;4429(2):281-294.
    PMID: 30313268 DOI: 10.11646/zootaxa.4429.2.4
    Amphicnemis valentini sp. nov. is described from the Ream Peninsula of Cambodia (holotype: Cambodia, Preah Sihanouk Province, Ream Peninsula, 10.52258 N 103.69556 E, RMNH) and Phú Quốc Island, Kien Giang Province of Vietnam, both in the Cardamom ecoregion. It is similar to A. gracilis Krüger, 1898, which occurs in Peninsular Malaysia and Sumatra, but differs from it by a long process on the male prothorax.
    Matched MeSH terms: Tumor Suppressor Proteins
  14. Fulltext [TRIMCyp frequency of the cynomolgus macaque (Macaca fascicularis) in captivity in China]
    Tian S, Meng YH, Liu MY, Sun F, Chen JH, Du HL, et al.
    Zool Res, 2013 Apr;34(2):97-102.
    PMID: 23572358 DOI: 10.3724/SP.J.1141.2013.02097
    In most Old world monkey species, TRIM5α plays a role in combating retroviruses and restricting HIV-1. Alongside TRIM5α, the TRIMCyp fusion gene formed by the retrotransposition of a CypA pseudogene cDNA to 3' terminal or 3'-UTR of TRIM5 gene in these monkeys has become a key research area in anti HIV-1 factors. The regional differences, gene frequencies, genotypes, and retrovirus restrictive activities of TRIMCyp vary among different primate species. While the frequencies of cynomolgus TRIMCyp have been studied in several areas of Southeast Asia, the frequency and prevalence of cynomolgus TRIMCyp in China remains unclear. In this study, we screened 1, 594 cynomolgus samples from 11 monkey manufacturers located across 5 provinces in China. Our results showed that the frequencies of TRIMCyp range from 7.65% to 19.79%, markedly lower than the frequencies found in monkey species in the Philippines, Malaysia and Indonesia (ranging from 34.85% to 100%). We speculate that potentially the latter were isolated groups established since 1978. The NE haplotype frequencies of cynomolgus TRIMCyp were 4.93% in China, also significantly lower than those found in species in the Philippines, Malaysia and Indonesia (from 11.1% to 14.3%). Our research provides interesting findings that contribute towards a more firm basis of further studies of HIV-1 animal models and relevant pathogenesis.
    Matched MeSH terms: Mutant Chimeric Proteins/genetics*
  15. [Molecular regulatory mechanisms of hypoxia-inducible factor and interventional effect of Chinese herbal medicine]
    Bu-Hui L, Mei-Zi W, Wei S, Yi-Gang W, Wei WU, Qi-Jun F, et al.
    Zhongguo Zhong Yao Za Zhi, 2020 Oct;45(20):4805-4811.
    PMID: 33350250 DOI: 10.19540/j.cnki.cjcmm.20200630.602
    Hypoxia-inducible factors(HIFs)are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits,α and β,in which,the molecular regulatory mechanism of HIF-1α involves the main processes of its degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways,including "von hippel-lindau protein(pVHL)-dependent pathway" and "pVHL-independent pathway". The activation of HIF-1α is regulated by oxygen-independent pathways,including mammalian target of rapamycin(mTOR)/eukaryotic initiation factor 4 E-binding protein 1(4 EBP1)/HIF-1α pathway,phosphatidylinositol 3-kinase(PI3 K)/proteirrserinc-threonine kinases(Akt)/HIF-1α pathway and silent information regulator1(Sirt1)/HIF-1α pathway. In recent years,based on the molecular regulatory mechanism of HIFs,Roxadustat,a new drug for the treatment of renal anemia has been developed. Besides, some macromolecular substances with similar pharmacological effect to HIFs have been found in the extracts from Chinese herbal medicine(CHM),such as emodin,notoginseng triterpenes,honokiol and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response,epigenetic modification and auto-phagy. It is worth noting that,for common hypoxic-related diseases including diabetic kidney disease,HIFs-mediated "pyroptosis" may be a new target of CHMs for clearing dampness and heat and its representative classical prescriptions(Ermiao Pills)in treating inflammatory injury in cells and tissues.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt
  16. Proteomic Profiling of Zebrafish Challenged by Spring Viremia of Carp Virus Provides Insight into Skin Antiviral Response
    Liu R, Hu X, Lü A, Song Y, Lian Z, Sun J, et al.
    Zebrafish, 2020 04;17(2):91-103.
    PMID: 32176570 DOI: 10.1089/zeb.2019.1843
    Spring viremia of carp virus (SVCV) causes the skin hemorrhagic disease in cyprinid species, but its molecular mechanism of skin immune response remains unclear at the protein level. In the present study, the differential proteomics of the zebrafish (Danio rerio) skin in response to SVCV infection were examined by isobaric tags for relative and absolute quantitation and quantitative polymerase chain reaction (qPCR) assays. A total of 3999 proteins were identified, of which 320 and 181 proteins were differentially expressed at 24 and 96 h postinfection, respectively. The expression levels of 16 selected immune-related differentially expressed proteins (DEPs) were confirmed by qPCR analysis. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that DEPs were significantly associated with complement, inflammation, and antiviral response. The protein-protein interaction network of cytoskeleton-associated proteins, ATPase-related proteins, and parvalbumins from DEPs was shown to be involved in skin immune response. This is first report on the skin proteome profiling of zebrafish against SVCV infection, which will contribute to understand the molecular mechanism of local mucosal immunity in fish.
    Matched MeSH terms: Fish Proteins/immunology*
  17. High Melatonin Conditions by Constant Darkness and High Temperature Differently Affect Melatonin Receptor mt1 and TREK Channel trek2a in the Brain of Zebrafish
    Loganathan K, Moriya S, Parhar IS
    Zebrafish, 2018 10;15(5):473-483.
    PMID: 30102584 DOI: 10.1089/zeb.2018.1594
    Ambient light and temperature affect reproductive function by regulating kisspeptin and gonadotrophin-releasing hormone (GnRH) in vertebrates. Melatonin and melatonin receptors, as well as the two-pore domain K+ channel-related K+ (TREK) channels, are affected by light and/or temperature; therefore, these molecules could modulate kisspeptin and GnRH against ambient light and temperature. In this study, we investigated the effect of light and temperature, which affect melatonin levels in gene expression levels of TREK channels, kisspeptin, and GnRH. We first investigated the effects of different light and temperature conditions on brain melatonin concentrations by ELISA. Fish were exposed to either constant darkness, constant light, high temperature (35°C), or low temperature (20°C) for 72 h. Brain melatonin levels were significantly high under constant darkness and high temperature. We further investigated the effects of high brain melatonin levels by constant darkness and high temperature on gene expression levels of melatonin receptors (mt1, mt2, and mel1c), TREK channels (trek1b, trek2a, and trek2b), gnrh3, and kiss2 in the adult zebrafish brain by real-time polymerase chain reaction. Fish were exposed to constant darkness or elevated temperatures (35°C) for 72 h. trek2a, kiss2, and gnrh3 levels were increased under constant darkness. High temperature decreased gene expression levels of mt1, mt2, mel1c, and gnrh3 in the preoptic area, whereas other genes remained unchanged. Melatonin receptors, TREK channels, gnrh3, and kiss2 responded differently under high melatonin conditions. The melatonin receptors and the TREK channels could play roles in the regulation of reproduction by environmental cues, especially ambient light and temperature.
    Matched MeSH terms: Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism*
  18. Improvement of isolated caprine islet survival and functionality in vitro by enhancing of PDX1 gene expression
    Hani H, Allaudin ZN, Mohd-Lila MA, Sarsaifi K, Rasouli M, Tam YJ, et al.
    Xenotransplantation, 2017 05;24(3).
    PMID: 28397308 DOI: 10.1111/xen.12302
    BACKGROUND: Dead islets replaced with viable islets are a promising offer to restore normal insulin production to a person with diabetes. The main reason for establishing a new islet source for transplantation is the insufficiency of human donor pancreas while using xenogeneic islets perhaps assists this problem. The expression of PDX1 is essential for the pancreas expansion. In mature β-cells, PDX1 has several critical roles such as glucose sensing, insulin synthesis, and insulin secretion. In this study, we aimed to evaluate the expression of pancreatic duodenal homeobox-1 (PDX1) in treated caprine islets in culture and to assess the protective effects of antioxidant factors on the PDX1 gene in cultured caprine islets.

    MATERIALS AND METHODS: Purified islets were treated with serum-free, serum, IBMX, tocopherol, or IBMX and tocopherol media. Quantitative polymerase chain reaction and Western blotting were carried out to compare the expression levels of PDX1 in treated purified islets cultured with different media.

    RESULTS: Islets treated with IBMX/tocopherol exhibited the highest fold change in the relative expression of PDX1 on day 5 post-treatment (relative expression: 6.80±2.08), whereas serum-treated islets showed the lowest fold changes in PDX1 expression on day 5 post-treatment (0.67±0.36), as compared with the expression on day 1 post-treatment. Insulin production and viability tests of purified islets showed superiority of islet at supplemented serum-free media with IBMX/tocopherol compared to other cultures (53.875%±1.59%).

    CONCLUSIONS: Our results indicated that supplemented serum-free medium with tocopherol and IBMX enhances viability and PDX1 gene expression compared to serum-added and serum-free media.

    Matched MeSH terms: Homeodomain Proteins/genetics*; Homeodomain Proteins/physiology*
  19. Fulltext Epstein-Barr virus latent membrane protein-1 (LMP-1) 30-bp deletion and Xho I-loss is associated with type III nasopharyngeal carcinoma in Malaysia
    See HS, Yap YY, Yip WK, Seow HF
    World J Surg Oncol, 2008;6:18.
    PMID: 18275617 DOI: 10.1186/1477-7819-6-18
    Nasopharyngeal carcinoma (NPC) is a human epithelial tumour with high prevalence amongst Chinese in Southern China and South East Asia and is associated with the Epstein-Barr virus (EBV). The viral genome harbours an oncogene, namely, the latent membrane protein 1 (LMP1) gene and known variants such as the 30-bp deletion and loss of XhoI restriction site have been found. Less is known about the relationship between these variants and the population characteristics and histological type.
    Matched MeSH terms: Cytoskeletal Proteins; Viral Matrix Proteins/genetics*; Intracellular Signaling Peptides and Proteins/genetics*; Adaptor Proteins, Signal Transducing; LIM Domain Proteins
  20. Breast Cancer Outcomes as Defined by the Estrogen Receptor, Progesterone Receptor, and Human Growth Factor Receptor-2 in a Multi-ethnic Asian Country
    Subramaniam S, Bhoo-Pathy N, Taib NA, Tan GH, See MH, Jamaris S, et al.
    World J Surg, 2015 Oct;39(10):2450-8.
    PMID: 26138872 DOI: 10.1007/s00268-015-3133-2
    Breast cancer can be divided into four subtypes based on the expressions of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 (HER2). Each subtype has different clinicopathological features and outcomes.
    Matched MeSH terms: Neoplasm Proteins/metabolism
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