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Fulltext Meta-analysis of biomarkers for severe dengue infections

Soo KM, Khalid B, Ching SM, Tham CL, Basir R, Chee HY

PeerJ, 2017;5:e3589.
PMID: 28929009 DOI: 10.7717/peerj.3589

BACKGROUND: Dengue viral infection is an acute infection that has the potential to have severe complications as its major sequela. Currently, there is no routine laboratory biomarker with which to predict the severity of dengue infection or monitor the effectiveness of standard management. Hence, this meta-analysis compared biomarker levels between dengue fever (DF) and severe dengue infections (SDI) to identify potential biomarkers for SDI.

METHODS: Data concerning levels of cytokines, chemokines, and other potential biomarkers of DF, dengue hemorrhagic fever, dengue shock syndrome, and severe dengue were obtained for patients of all ages and populations using the Scopus, PubMed, and Ovid search engines. The keywords "(IL1* or IL-1*) AND (dengue*)" were used and the same process was repeated for other potential biomarkers, according to Medical Subject Headings terms suggested by PubMed and Ovid. Meta-analysis of the mean difference in plasma or serum level of biomarkers between DF and SDI patients was performed, separated by different periods of time (days) since fever onset. Subgroup analyses comparing biomarker levels of healthy plasma and sera controls, biomarker levels of primary and secondary infection samples were also performed, as well as analyses of different levels of severity and biomarker levels upon infection by different dengue serotypes.

RESULTS: Fifty-six studies of 53 biomarkers from 3,739 dengue cases (2,021 DF and 1,728 SDI) were included in this meta-analysis. Results showed that RANTES, IL-7, IL-8, IL-10, IL-18, TGF-b, and VEGFR2 levels were significantly different between DF and SDI. IL-8, IL-10, and IL-18 levels increased during SDI (95% CI, 18.1-253.2 pg/mL, 3-13 studies, n = 177-1,909, I(2) = 98.86%-99.75%). In contrast, RANTES, IL-7, TGF-b, and VEGFR2 showed a decrease in levels during SDI (95% CI, -3238.7 to -3.2 pg/mL, 1-3 studies, n = 95-418, I(2) = 97.59%-99.99%). Levels of these biomarkers were also found to correlate with the severity of the dengue infection, in comparison to healthy controls. Furthermore, the results showed that IL-7, IL-8, IL-10, TGF-b, and VEGFR2 display peak differences between DF and SDI during or before the critical phase (day 4-5) of SDI.

DISCUSSION: This meta-analysis suggests that IL-7, IL-8, IL-10, TGF-b, and VEGFR2 may be used as potential early laboratory biomarkers in the diagnosis of SDI. This can be used to predict the severity of dengue infection and to monitor the effectiveness of treatment. Nevertheless, methodological and reporting limitations must be overcome in future research to minimize variables that affect the results and to confirm the findings.
Fulltext RNA sequencing (RNA-Seq) of lymph node, spleen, and thymus transcriptome from wild Peninsular Malaysian cynomolgus macaque (Macaca fascicularis)

Ee Uli J, Yong CSY, Yeap SK, Rovie-Ryan JJ, Mat Isa N, Tan SG, et al.

PeerJ, 2017;5:e3566.
PMID: 28828235 DOI: 10.7717/peerj.3566

The cynomolgus macaque (Macaca fascicularis) is an extensively utilised nonhuman primate model for biomedical research due to its biological, behavioural, and genetic similarities to humans. Genomic information of cynomolgus macaque is vital for research in various fields; however, there is presently a shortage of genomic information on the Malaysian cynomolgus macaque. This study aimed to sequence, assemble, annotate, and profile the Peninsular Malaysian cynomolgus macaque transcriptome derived from three tissues (lymph node, spleen, and thymus) using RNA sequencing (RNA-Seq) technology. A total of 174,208,078 paired end 70 base pair sequencing reads were obtained from the Illumina Hi-Seq 2500 sequencer. The overall mapping percentage of the sequencing reads to the M. fascicularis reference genome ranged from 53-63%. Categorisation of expressed genes to Gene Ontology (GO) and KEGG pathway categories revealed that GO terms with the highest number of associated expressed genes include Cellular process, Catalytic activity, and Cell part, while for pathway categorisation, the majority of expressed genes in lymph node, spleen, and thymus fall under the Global overview and maps pathway category, while 266, 221, and 138 genes from lymph node, spleen, and thymus were respectively enriched in the Immune system category. Enriched Immune system pathways include Platelet activation pathway, Antigen processing and presentation, B cell receptor signalling pathway, and Intestinal immune network for IgA production. Differential gene expression analysis among the three tissues revealed 574 differentially expressed genes (DEG) between lymph and spleen, 5402 DEGs between lymph and thymus, and 7008 DEGs between spleen and thymus. Venn diagram analysis of expressed genes revealed a total of 2,630, 253, and 279 tissue-specific genes respectively for lymph node, spleen, and thymus tissues. This is the first time the lymph node, spleen, and thymus transcriptome of the Peninsular Malaysian cynomolgus macaque have been sequenced via RNA-Seq. Novel transcriptomic data will further enrich the present M. fascicularis genomic database and provide future research potentials, including novel transcript discovery, comparative studies, and molecular markers development.
A comparison of the morphological and biochemical characteristics of Chlorella sorokiniana and Chlorella zofingiensis cultured under photoautotrophic and mixotrophic conditions

Azaman SNA, Nagao N, Yusoff FM, Tan SW, Yeap SK

PeerJ, 2017;5:e3473.
PMID: 28929006 DOI: 10.7717/peerj.3473

The responses of two species of microalgae, Chlorella sorokiniana and Chlorella zofingiensis, were compared regarding their morphological and biochemical properties under photoautotrophic and mixotrophic conditions. These microalgae were cultured under both conditions, and their crude ethanolic extracts were examined for their pigment and total phenolic contents. In addition, the microalgae's antioxidant activities were determined using a DPPH radical scavenging assay and a ferric reducing antioxidant power (FRAP) assay. Both strains showed increases in cell size due to the accumulation of lipid bodies and other cell contents, especially carotenoids, under the mixotrophic condition. Notably, reductions in phenolic and chlorophyll contents were observed to be associated with lower antioxidant activity. C. zofingiensis compared with C. sorokiniana, demonstrated higher antioxidant activity and carotenoid content. This study showed that different species of microalgae responded differently to varying conditions by producing different types of metabolites, as evidenced by the production of higher levels of phenolic compounds under the photoautotrophic condition and the production of the same levels of carotenoids under both photoautotrophic and mixotrophic conditions.
Fulltext Lectins: an effective tool for screening of potential cancer biomarkers

Hashim OH, Jayapalan JJ, Lee CS

PeerJ, 2017;5:e3784.
PMID: 28894650 DOI: 10.7717/peerj.3784

In recent years, the use of lectins for screening of potential biomarkers has gained increased importance in cancer research, given the development in glycobiology that highlights altered structural changes of glycans in cancer associated processes. Lectins, having the properties of recognizing specific carbohydrate moieties of glycoconjugates, have become an effective tool for detection of new cancer biomarkers in complex bodily fluids and tissues. The specificity of lectins provides an added advantage of selecting peptides that are differently glycosylated and aberrantly expressed in cancer patients, many of which are not possibly detected using conventional methods because of their low abundance in bodily fluids. When coupled with mass spectrometry, research utilizing lectins, which are mainly from plants and fungi, has led to identification of numerous potential cancer biomarkers that may be used in the future. This article reviews lectin-based methods that are commonly adopted in cancer biomarker discovery research.
Fulltext Fungi found in Mediterranean and North Sea sponges: how specific are they?

Naim MA, Smidt H, Sipkema D

PeerJ, 2017;5:e3722.
PMID: 28894639 DOI: 10.7717/peerj.3722

Fungi and other eukaryotes represent one of the last frontiers of microbial diversity in the sponge holobiont. In this study we employed pyrosequencing of 18S ribosomal RNA gene amplicons containing the V7 and V8 hypervariable regions to explore the fungal diversity of seven sponge species from the North Sea and the Mediterranean Sea. For most sponges, fungi were present at a low relative abundance averaging 0.75% of the 18S rRNA gene reads. In total, 44 fungal OTUs (operational taxonomic units) were detected in sponges, and 28 of these OTUs were also found in seawater. Twenty-two of the sponge-associated OTUs were identified as yeasts (mainly Malasseziales), representing 84% of the fungal reads. Several OTUs were related to fungal sequences previously retrieved from other sponges, but all OTUs were also related to fungi from other biological sources, such as seawater, sediments, lakes and anaerobic digesters. Therefore our data, supported by currently available data, point in the direction of mostly accidental presence of fungi in sponges and do not support the existence of a sponge-specific fungal community.
Fulltext Advances in the study of nodavirus

Yong CY, Yeap SK, Omar AR, Tan WS

PeerJ, 2017;5:e3841.
PMID: 28970971 DOI: 10.7717/peerj.3841

Nodaviruses are small bipartite RNA viruses which belong to the family of Nodaviridae. They are categorized into alpha-nodavirus, which infects insects, and beta-nodavirus, which infects fishes. Another distinct group of nodavirus infects shrimps and prawns, which has been proposed to be categorized as gamma-nodavirus. Our current review focuses mainly on recent studies performed on nodaviruses. Nodavirus can be transmitted vertically and horizontally. Recent outbreaks have been reported in China, Indonesia, Singapore and India, affecting the aquaculture industry. It also decreased mullet stock in the Caspian Sea. Histopathology and transmission electron microscopy (TEM) are used to examine the presence of nodaviruses in infected fishes and prawns. For classification, virus isolation followed by nucleotide sequencing are required. In contrast to partial sequence identification, profiling the whole transcriptome using next generation sequencing (NGS) offers a more comprehensive comparison and characterization of the virus. For rapid diagnosis of nodavirus, assays targeting the viral RNA based on reverse-transcription PCR (RT-PCR) such as microfluidic chips, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) and RT-LAMP coupled with lateral flow dipstick (RT-LAMP-LFD) have been developed. Besides viral RNA detections, diagnosis based on immunological assays such as enzyme-linked immunosorbent assay (ELISA), immunodot and Western blotting have also been reported. In addition, immune responses of fish and prawn are also discussed. Overall, in fish, innate immunity, cellular type I interferon immunity and humoral immunity cooperatively prevent nodavirus infections, whereas prawns and shrimps adopt different immune mechanisms against nodavirus infections, through upregulation of superoxide anion, prophenoloxidase, superoxide dismutase (SOD), crustin, peroxinectin, anti-lipopolysaccharides and heat shock proteins (HSP). Potential vaccines for fishes and prawns based on inactivated viruses, recombinant proteins or DNA, either delivered through injection, oral feeding or immersion, are also discussed in detail. Lastly, a comprehensive review on nodavirus virus-like particles (VLPs) is presented. In recent years, studies on prawn nodavirus are mainly focused on Macrobrachium rosenbergii nodavirus (MrNV). Recombinant MrNV VLPs have been produced in prokaryotic and eukaryotic expression systems. Their roles as a nucleic acid delivery vehicle, a platform for vaccine development, a molecular tool for mechanism study and in solving the structures of MrNV are intensively discussed.
Fulltext Virus like particles as a platform for cancer vaccine development

Ong HK, Tan WS, Ho KL

PeerJ, 2017;5:e4053.
PMID: 29158984 DOI: 10.7717/peerj.4053

Cancers have killed millions of people in human history and are still posing a serious health problem worldwide. Therefore, there is an urgent need for developing preventive and therapeutic cancer vaccines. Among various cancer vaccine development platforms, virus-like particles (VLPs) offer several advantages. VLPs are multimeric nanostructures with morphology resembling that of native viruses and are mainly composed of surface structural proteins of viruses but are devoid of viral genetic materials rendering them neither infective nor replicative. In addition, they can be engineered to display multiple, highly ordered heterologous epitopes or peptides in order to optimize the antigenicity and immunogenicity of the displayed entities. Like native viruses, specific epitopes displayed on VLPs can be taken up, processed, and presented by antigen-presenting cells to elicit potent specific humoral and cell-mediated immune responses. Several studies also indicated that VLPs could overcome the immunosuppressive state of the tumor microenvironment and break self-tolerance to elicit strong cytotoxic lymphocyte activity, which is crucial for both virus clearance and destruction of cancerous cells. Collectively, these unique characteristics of VLPs make them optimal cancer vaccine candidates. This review discusses current progress in the development of VLP-based cancer vaccines and some potential drawbacks of VLPs in cancer vaccine development. Extracellular vesicles with close resembling to viral particles are also discussed and compared with VLPs as a platform in cancer vaccine developments.
Fulltext Whole genome sequencing of Rhodotorula mucilaginosa isolated from the chewing stick (Distemonanthus benthamianus): insights into Rhodotorula phylogeny, mitogenome dynamics and carotenoid biosynthesis

Gan HM, Thomas BN, Cavanaugh NT, Morales GH, Mayers AN, Savka MA, et al.

PeerJ, 2017;5:e4030.
PMID: 29158974 DOI: 10.7717/peerj.4030

In industry, the yeast Rhodotorula mucilaginosa is commonly used for the production of carotenoids. The production of carotenoids is important because they are used as natural colorants in food and some carotenoids are precursors of retinol (vitamin A). However, the identification and molecular characterization of the carotenoid pathway/s in species belonging to the genus Rhodotorula is scarce due to the lack of genomic information thus potentially impeding effective metabolic engineering of these yeast strains for improved carotenoid production. In this study, we report the isolation, identification, characterization and the whole nuclear genome and mitogenome sequence of the endophyte R. mucilaginosa RIT389 isolated from Distemonanthus benthamianus, a plant known for its anti-fungal and antibacterial properties and commonly used as chewing sticks. The assembled genome of R. mucilaginosa RIT389 is 19 Mbp in length with an estimated genomic heterozygosity of 9.29%. Whole genome phylogeny supports the species designation of strain RIT389 within the genus in addition to supporting the monophyly of the currently sequenced Rhodotorula species. Further, we report for the first time, the recovery of the complete mitochondrial genome of R. mucilaginosa using the genome skimming approach. The assembled mitogenome is at least 7,000 bases larger than that of Rhodotorula taiwanensis which is largely attributed to the presence of large intronic regions containing open reading frames coding for homing endonuclease from the LAGLIDADG and GIY-YIG families. Furthermore, genomic regions containing the key genes for carotenoid production were identified in R. mucilaginosa RIT389, revealing differences in gene synteny that may play a role in the regulation of the biotechnologically important carotenoid synthesis pathways in yeasts.
Fulltext Genomic characterization of a new endophytic Streptomyces kebangsaanensis identifies biosynthetic pathway gene clusters for novel phenazine antibiotic production

Remali J, Sarmin N'M, Ng CL, Tiong JJL, Aizat WM, Keong LK, et al.

PeerJ, 2017;5:e3738.
PMID: 29201559 DOI: 10.7717/peerj.3738

Background: Streptomyces are well known for their capability to produce many bioactive secondary metabolites with medical and industrial importance. Here we report a novel bioactive phenazine compound, 6-((2-hydroxy-4-methoxyphenoxy) carbonyl) phenazine-1-carboxylic acid (HCPCA) extracted from Streptomyces kebangsaanensis, an endophyte isolated from the ethnomedicinal Portulaca oleracea.
Methods: The HCPCA chemical structure was determined using nuclear magnetic resonance spectroscopy. We conducted whole genome sequencing for the identification of the gene cluster(s) believed to be responsible for phenazine biosynthesis in order to map its corresponding pathway, in addition to bioinformatics analysis to assess the potential of S. kebangsaanensis in producing other useful secondary metabolites.
Results: The S. kebangsaanensis genome comprises an 8,328,719 bp linear chromosome with high GC content (71.35%) consisting of 12 rRNA operons, 81 tRNA, and 7,558 protein coding genes. We identified 24 gene clusters involved in polyketide, nonribosomal peptide, terpene, bacteriocin, and siderophore biosynthesis, as well as a gene cluster predicted to be responsible for phenazine biosynthesis.
Discussion: The HCPCA phenazine structure was hypothesized to derive from the combination of two biosynthetic pathways, phenazine-1,6-dicarboxylic acid and 4-methoxybenzene-1,2-diol, originated from the shikimic acid pathway. The identification of a biosynthesis pathway gene cluster for phenazine antibiotics might facilitate future genetic engineering design of new synthetic phenazine antibiotics. Additionally, these findings confirm the potential of S. kebangsaanensis for producing various antibiotics and secondary metabolites.
Fulltext Automated classification of tropical shrub species: a hybrid of leaf shape and machine learning approach

Murat M, Chang SW, Abu A, Yap HJ, Yong KT

PeerJ, 2017;5:e3792.
PMID: 28924506 DOI: 10.7717/peerj.3792

Plants play a crucial role in foodstuff, medicine, industry, and environmental protection. The skill of recognising plants is very important in some applications, including conservation of endangered species and rehabilitation of lands after mining activities. However, it is a difficult task to identify plant species because it requires specialized knowledge. Developing an automated classification system for plant species is necessary and valuable since it can help specialists as well as the public in identifying plant species easily. Shape descriptors were applied on the myDAUN dataset that contains 45 tropical shrub species collected from the University of Malaya (UM), Malaysia. Based on literature review, this is the first study in the development of tropical shrub species image dataset and classification using a hybrid of leaf shape and machine learning approach. Four types of shape descriptors were used in this study namely morphological shape descriptors (MSD), Histogram of Oriented Gradients (HOG), Hu invariant moments (Hu) and Zernike moments (ZM). Single descriptor, as well as the combination of hybrid descriptors were tested and compared. The tropical shrub species are classified using six different classifiers, which are artificial neural network (ANN), random forest (RF), support vector machine (SVM), k-nearest neighbour (k-NN), linear discriminant analysis (LDA) and directed acyclic graph multiclass least squares twin support vector machine (DAG MLSTSVM). In addition, three types of feature selection methods were tested in the myDAUN dataset, Relief, Correlation-based feature selection (CFS) and Pearson's coefficient correlation (PCC). The well-known Flavia dataset and Swedish Leaf dataset were used as the validation dataset on the proposed methods. The results showed that the hybrid of all descriptors of ANN outperformed the other classifiers with an average classification accuracy of 98.23% for the myDAUN dataset, 95.25% for the Flavia dataset and 99.89% for the Swedish Leaf dataset. In addition, the Relief feature selection method achieved the highest classification accuracy of 98.13% after 80 (or 60%) of the original features were reduced, from 133 to 53 descriptors in the myDAUN dataset with the reduction in computational time. Subsequently, the hybridisation of four descriptors gave the best results compared to others. It is proven that the combination MSD and HOG were good enough for tropical shrubs species classification. Hu and ZM descriptors also improved the accuracy in tropical shrubs species classification in terms of invariant to translation, rotation and scale. ANN outperformed the others for tropical shrub species classification in this study. Feature selection methods can be used in the classification of tropical shrub species, as the comparable results could be obtained with the reduced descriptors and reduced in computational time and cost.
Fulltext Status of the undisturbed mangroves at Brunei Bay, East Malaysia: a preliminary assessment based on remote sensing and ground-truth observations

Satyanarayana B, M Muslim A, Izzaty Horsali NA, Mat Zauki NA, Otero V, Nadzri MI, et al.

PeerJ, 2018;6:e4397.
PMID: 29479500 DOI: 10.7717/peerj.4397

Brunei Bay, which receives freshwater discharge from four major rivers, namely Limbang, Sundar, Weston and Menumbok, hosts a luxuriant mangrove cover in East Malaysia. However, this relatively undisturbed mangrove forest has been less scientifically explored, especially in terms of vegetation structure, ecosystem services and functioning, and land-use/cover changes. In the present study, mangrove areal extent together with species composition and distribution at the four notified estuaries was evaluated through remote sensing (Advanced Land Observation Satellite-ALOS) and ground-truth (Point-Centred Quarter Method-PCQM) observations. As of 2010, the total mangrove cover was found to be ca. 35,183.74 ha, of which Weston and Menumbok occupied more than two-folds (58%), followed by Sundar (27%) and Limbang (15%). The medium resolution ALOS data were efficient for mapping dominant mangrove species such asNypa fruticans,Rhizophora apiculata,Sonneratia caseolaris,S. albaandXylocarpus granatumin the vicinity (accuracy: 80%). The PCQM estimates found a higher basal area at Limbang and Menumbok-suggestive of more mature vegetation, compared to Sundar and Weston. Mangrove stand structural complexity (derived from the complexity index) was also high in the order of Limbang > Menumbok > Sundar > Weston and supporting the perspective of less/undisturbed vegetation at two former locations. Both remote sensing and ground-truth observations have complementarily represented the distribution ofSonneratiaspp. as pioneer vegetation at shallow river mouths,N. fruticansin the areas of strong freshwater discharge,R. apiculatain the areas of strong neritic incursion andX. granatumat interior/elevated grounds. The results from this study would be able to serve as strong baseline data for future mangrove investigations at Brunei Bay, including for monitoring and management purposes locally at present.
Fulltext Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, downregulates the expression of proteins associated with dengue virus infection

Tan WL, Lee YK, Ho YF, Yusof R, Abdul Rahman N, Karsani SA

PeerJ, 2018;5:e3939.
PMID: 29404200 DOI: 10.7717/peerj.3939

Dengue is endemic throughout tropical and subtropical regions of the world. Currently, there is no clinically approved therapeutic drug available for this acute viral infection. Although the first dengue vaccine Dengvaxia has been approved for use in certain countries, it is limited to those without a previous dengue infection while the safety and efficacy of the vaccine in those elderly and younger children still need to be identified. Therefore, it is becoming increasingly important to develop therapeutics/drugs to combat dengue virus (DENV) infection. YK51 is a synthetic analogue of 4-Hydroxypandurantin A (a compound found in the crude extract of the rhizomes of Boesenbergia rotunda) that has been extensively studied by our research group. It has been shown to possess outstanding antiviral activity due to its inhibitory activity against NS2B/NS3 DENV2 protease. However, it is not known how YK51 affects the proteome of DENV infected cells. Therefore, we performed a comparative proteomics analysis to identify changes in protein expression in DENV infected HepG2 cells treated with YK51. Classical two-dimensional gel electrophoresis followed by protein identification using tandem mass spectrometry was employed in this study. Thirty proteins were found to be down-regulated with YK51 treatment. In silico analysis predicted that the down-regulation of eight of these proteins may inhibit viral infection. Our results suggested that apart from inhibiting the NS2B/NS3 DENV2 protease, YK51 may also be causing the down-regulation of a number of proteins that may be responsible in, and/or essential to virus infection. However, functional characterization of these proteins will be necessary before we can conclusively determine their roles in DENV infection.
Fulltext Ant mosaics in Bornean primary rain forest high canopy depend on spatial scale, time of day, and sampling method

Yusah KM, Foster WA, Reynolds G, Fayle TM

PeerJ, 2018;6:e4231.
PMID: 29423344 DOI: 10.7717/peerj.4231

Background: Competitive interactions in biological communities can be thought of as giving rise to "assembly rules" that dictate the species that are able to co-exist. Ant communities in tropical canopies often display a particular pattern, an "ant mosaic", in which competition between dominant ant species results in a patchwork of mutually exclusive territories. Although ant mosaics have been well-documented in plantation landscapes, their presence in pristine tropical forests remained contentious until recently. Here we assess presence of ant mosaics in a hitherto under-investigated forest stratum, the emergent trees of the high canopy in primary tropical rain forest, and explore how the strength of any ant mosaics is affected by spatial scale, time of day, and sampling method.
Methods: To test whether these factors might impact the detection of ant mosaics in pristine habitats, we sampled ant communities from emergent trees, which rise above the highest canopy layers in lowland dipterocarp rain forests in North Borneo (38.8-60.2 m), using both baiting and insecticide fogging. Critically, we restricted sampling to only the canopy of each focal tree. For baiting, we carried out sampling during both the day and the night. We used null models of species co-occurrence to assess patterns of segregation at within-tree and between-tree scales.
Results: The numerically dominant ant species on the emergent trees sampled formed a diverse community, with differences in the identity of dominant species between times of day and sampling methods. Between trees, we found patterns of ant species segregation consistent with the existence of ant mosaics using both methods. Within trees, fogged ants were segregated, while baited ants were segregated only at night.
Discussion: We conclude that ant mosaics are present within the emergent trees of the high canopy of tropical rain forest in Malaysian Borneo, and that sampling technique, spatial scale, and time of day interact to determine observed patterns of segregation. Restricting sampling to only emergent trees reveals segregatory patterns not observed in ground-based studies, confirming previous observations of stronger segregation with increasing height in the canopy.
Fulltext Analyses of antioxidant status and nucleotide alterations in genes encoding antioxidant enzymes in patients with benign and malignant thyroid disorders

Ramli NSF, Mat Junit S, Leong NK, Razali N, Jayapalan JJ, Abdul Aziz A

PeerJ, 2017;5:e3365.
PMID: 28584708 DOI: 10.7717/peerj.3365

BACKGROUND: Synthesis of thyroid hormones and regulation of their metabolism involve free radicals that may affect redox balance in the body. Thyroid disorders causing variations in the levels of thyroid hormones may alter cellular oxidative stress. The aim of this study was to measure the antioxidant activities and biomarkers of oxidative stress in serum and red blood cells (RBC) of patients with benign and malignant thyroid disorders and to investigate if changes in the antioxidant activities in these patients were linked to alterations in genes encoding the antioxidant enzymes.
METHODS: Forty-one patients with thyroid disorders from University of Malaya Medical Centre were recruited. They were categorised into four groups: multinodular goitre (MNG) (n = 18), follicular thyroid adenoma (FTA) (n = 7), papillary thyroid cancer (PTC) (n = 10), and follicular thyroid cancer (FTC) (n = 6). Serum and RBC of patients were analysed for antioxidant activities, antioxidant enzymes, and biomarkers of oxidative stress. Alterations in genes encoding the antioxidant enzymes were analysed using whole exome sequencing and PCR-DNA sequencing.
RESULTS: Patients with thyroid disorders had significantly higher serum superoxide dismutase (SOD) and catalase (CAT) activities compared to control, but had lower activities in RBC. There were no significant changes in serum glutathione peroxidase (GPx) activity. Meanwhile, GPx activity in RBC was reduced in PTC and FTC, compared to control and the respective benign groups. Antioxidant activities in serum were decreased in the thyroid disorder groups when compared to the control group. The levels of malondialdehyde (MDA) were elevated in the serum of FTA group when compared to controls, while in the RBC, only the MNG and PTC groups showed higher MDA equivalents than control. Serum reactive oxygen species (ROS) levels in PTC group of both serum and RBC were significantly higher than control group. Whole exome sequencing has resulted in identification of 49 single nucleotide polymorphisms (SNPs) in MNG and PTC patients and their genotypic and allelic frequencies were calculated. Analyses of the relationship between serum enzyme activities and the total SNPs identified in both groups revealed no correlation.
DISCUSSION: Different forms of thyroid disorders influence the levels of antioxidant status in the serum and RBC of these patients, implying varying capability of preventing oxidative stress. A more comprehensive study with a larger target population should be done in order to further evaluate the relationships between antioxidant enzymes gene polymorphisms and thyroid disorders, as well as strengthening the minor evidences provided in literatures.
Fulltext 13C based proteinogenic amino acid (PAA) and metabolic flux ratio analysis of Lactococcus lactis reveals changes in pentose phosphate (PP) pathway in response to agitation and temperature related stresses

Azizan KA, Ressom HW, Mendoza ER, Baharum SN

PeerJ, 2017;5:e3451.
PMID: 28695065 DOI: 10.7717/peerj.3451

Lactococcus lactis subsp. cremoris MG1363 is an important starter culture for dairy fermentation. During industrial fermentations, L. lactis is constantly exposed to stresses that affect the growth and performance of the bacterium. Although the response of L. lactis to several stresses has been described, the adaptation mechanisms at the level of in vivo fluxes have seldom been described. To gain insights into cellular metabolism, 13C metabolic flux analysis and gas chromatography mass spectrometry (GC-MS) were used to measure the flux ratios of active pathways in the central metabolism of L. lactis when subjected to three conditions varying in temperature (30°C, 37°C) and agitation (with and without agitation at 150 rpm). Collectively, the concentrations of proteinogenic amino acids (PAAs) and free fatty acids (FAAs) were compared, and Pearson correlation analysis (r) was calculated to measure the pairwise relationship between PAAs. Branched chain and aromatic amino acids, threonine, serine, lysine and histidine were correlated strongly, suggesting changes in flux regulation in glycolysis, the pentose phosphate (PP) pathway, malic enzyme and anaplerotic reaction catalysed by pyruvate carboxylase (pycA). Flux ratio analysis revealed that glucose was mainly converted by glycolysis, highlighting the stability of L. lactis' central carbon metabolism despite different conditions. Higher flux ratios through oxaloacetate (OAA) from pyruvate (PYR) reaction in all conditions suggested the activation of pyruvate carboxylate (pycA) in L. lactis, in response to acid stress during exponential phase. Subsequently, more significant flux ratio differences were seen through the oxidative and non-oxidative pentose phosphate (PP) pathways, malic enzyme, and serine and C1 metabolism, suggesting NADPH requirements in response to environmental stimuli. These reactions could play an important role in optimization strategies for metabolic engineering in L. lactis. Overall, the integration of systematic analysis of amino acids and flux ratio analysis provides a systems-level understanding of how L. lactis regulates central metabolism under various conditions.
Fulltext Characterization and toxicity of citral incorporated with nanostructured lipid carrier

Nordin N, Yeap SK, Zamberi NR, Abu N, Mohamad NE, Rahman HS, et al.

PeerJ, 2018;6:e3916.
PMID: 29312812 DOI: 10.7717/peerj.3916

The nanoparticle as a cancer drug delivery vehicle is rapidly under investigation due to its promising applicability as a novel drug delivery system for anticancer agents. This study describes the development, characterization and toxicity studies of a nanostructured lipid carrier (NLC) system for citral. Citral was loaded into the NLC using high pressure homogenization methods. The characterizations of NLC-citral were then determined through various methods. Based on Transmission Electron Microscope (TEM) analysis, NLC-Citral showed a spherical shape with an average diameter size of 54.12 ± 0.30 nm and a polydipersity index of 0.224 ± 0.005. The zeta potential of NLC-Citral was -12.73 ± 0.34 mV with an entrapment efficiency of 98.9 ± 0.124%, and drug loading of 9.84 ± 0.041%. Safety profile of the formulation was examined via in vitro and in vivo routes to study its effects toward normal cells. NLC-Citral exhibited no toxic effects towards the proliferation of mice splenocytes. Moreover, no mortality and toxic signs were observed in the treated groups after 28 days of treatment. There were also no significant alterations in serum biochemical analysis for all treatments. Increase in immunomodulatory effects of treated NLC-Citral and Citral groups was verified from the increase in CD4/CD3 and CD8/CD3 T cell population in both NLC-citral and citral treated splenocytes. This study suggests that NLC is a promising drug delivery system for citral as it has the potential in sustaining drug release without inducing any toxicity.
Occurrence of Blastocystis sp. in water catchments at Malay villages and Aboriginal settlement during wet and dry seasons in Peninsular Malaysia

Noradilah SA, Lee IL, Anuar TS, Salleh FM, Abdul Manap SN, Mohd Mohtar NS, et al.

PeerJ, 2016;4:e2541.
PMID: 27761331

In the tropics, there are too few studies on isolation of Blastocystis sp. subtypes from water sources; in addition, there is also an absence of reported studies on the occurrence of Blastocystis sp. subtypes in water during different seasons. Therefore, this study was aimed to determine the occurrence of Blastocystis sp. subtypes in river water and other water sources that drained aboriginal vicinity of highly endemic intestinal parasitic infections during wet and dry seasons. Water samples were collected from six sampling points of Sungai Krau (K1-K6) and a point at Sungai Lompat (K7) and other water sources around the aboriginal villages. The water samples were collected during both seasons, wet and dry seasons. Filtration of the water samples were carried out using a flatbed membrane filtration system. The extracted DNA from concentrated water sediment was subjected to single round polymerase chain reaction and positive PCR products were subjected to sequencing. All samples were also subjected to filtration and cultured on membrane lactose glucuronide agar for the detection of faecal coliforms. During wet season, Blastocystis sp. ST1, ST2 and ST3 were detected in river water samples. Blastocystis sp. ST3 occurrence was sustained in the river water samples during dry season. However Blastocystis sp. ST1 and ST2 were absent during dry season. Water samples collected from various water sources showed contaminations of Blastocystis sp. ST1, ST2, ST3 and ST4, during wet season and Blastocystis sp. ST1, ST3, ST8 and ST10 during dry season. Water collected from all river sampling points during both seasons showed growth of Escherichia coli and Enterobacter aerogenes, indicating faecal contamination. In this study, Blastocystis sp. ST3 is suggested as the most robust and resistant subtype able to survive in any adverse environmental condition. Restriction and control of human and animal faecal contaminations to the river and other water sources shall prevent the transmission of Blastocystis sp. to humans and animals in this aboriginal community.
Fulltext Tracking the virus-like particles of Macrobrachium rosenbergii nodavirus in insect cells

Hanapi UF, Yong CY, Goh ZH, Alitheen NB, Yeap SK, Tan WS

PeerJ, 2017;5:e2947.
PMID: 28194311 DOI: 10.7717/peerj.2947

Macrobrachium rosenbergii nodavirus (MrNv) poses a major threat to the prawn industry. Currently, no effective vaccine and treatment are available to prevent the spread of MrNv. Its infection mechanism and localisation in a host cell are also not well characterised. The MrNv capsid protein (MrNvc) produced in Escherichia coli self-assembled into virus-like particles (VLPs) resembling the native virus. Thus, fluorescein labelled MrNvc VLPs were employed as a model to study the virus entry and localisation in Spodoptera frugiperda, Sf9 cells. Through fluorescence microscopy and sub-cellular fractionation, the MrNvc was shown to enter Sf9 cells, and eventually arrived at the nucleus. The presence of MrNvc within the cytoplasm and nucleus of Sf9 cells was further confirmed by the Z-stack imaging. The presence of ammonium chloride (NH4Cl), genistein, methyl-β-cyclodextrin or chlorpromazine (CPZ) inhibited the entry of MrNvc into Sf9 cells, but cytochalasin D did not inhibit this process. This suggests that the internalisation of MrNvc VLPs is facilitated by caveolae- and clathrin-mediated endocytosis. The whole internalisation process of MrNvc VLPs into a Sf9 cell was recorded with live cell imaging. We have also identified a potential nuclear localisation signal (NLS) of MrNvc through deletion mutagenesis and verified by classical-NLS mapping. Overall, this study provides an insight into the journey of MrNvc VLPs in insect cells.
Fulltext Genetic variation and DNA fingerprinting of durian types in Malaysia using simple sequence repeat (SSR) markers

Siew GY, Ng WL, Tan SW, Alitheen NB, Tan SG, Yeap SK

PeerJ, 2018;6:e4266.
PMID: 29511604 DOI: 10.7717/peerj.4266

Durian (Durio zibethinus) is one of the most popular tropical fruits in Asia. To date, 126 durian types have been registered with the Department of Agriculture in Malaysia based on phenotypic characteristics. Classification based on morphology is convenient, easy, and fast but it suffers from phenotypic plasticity as a direct result of environmental factors and age. To overcome the limitation of morphological classification, there is a need to carry out genetic characterization of the various durian types. Such data is important for the evaluation and management of durian genetic resources in producing countries. In this study, simple sequence repeat (SSR) markers were used to study the genetic variation in 27 durian types from the germplasm collection of Universiti Putra Malaysia. Based on DNA sequences deposited in Genbank, seven pairs of primers were successfully designed to amplify SSR regions in the durian DNA samples. High levels of variation among the 27 durian types were observed (expected heterozygosity,H
E
= 0.35). The DNA fingerprinting power of SSR markers revealed by the combined probability of identity (PI) of all loci was 2.3×10-3. Unique DNA fingerprints were generated for 21 out of 27 durian types using five polymorphic SSR markers (the other two SSR markers were monomorphic). We further tested the utility of these markers by evaluating the clonal status of shared durian types from different germplasm collection sites, and found that some were not clones. The findings in this preliminary study not only shows the feasibility of using SSR markers for DNA fingerprinting of durian types, but also challenges the current classification of durian types, e.g., on whether the different types should be called "clones", "varieties", or "cultivars". Such matters have a direct impact on the regulation and management of durian genetic resources in the region.
Fulltext Cellular prion protein and γ-synuclein overexpression in LS 174T colorectal cancer cell drives endothelial proliferation-to-differentiation switch

Ong SH, Goh KW, Chieng CK, Say YH

PeerJ, 2018;6:e4506.
PMID: 29527422 DOI: 10.7717/peerj.4506

Background: Tumor-induced angiogenesis is an imperative event in pledging new vasculature for tumor metastasis. Since overexpression of neuronal proteins gamma-synuclein (γ-Syn) and cellular prion protein (PrPC) is always detected in advanced stages of cancer diseases which involve metastasis, this study aimed to investigate whether γ-Syn or PrPCoverexpression in colorectal adenocarcinoma, LS 174T cells affects angiogenesis of endothelial cells, EA.hy 926 (EA).
Methods: EA cells were treated with conditioned media (CM) of LS 174T-γ-Syn or LS 174T-PrP, and their proliferation, invasion, migration, adhesion and ability to form angiogenic tubes were assessed using a range of biological assays. To investigate plausible background mechanisms in conferring the properties of EA cells above, nitrite oxide (NO) levels were measured and the expression of angiogenesis-related factors was assessed using a human angiogenesis antibody array.
Results: EA proliferation was significantly inhibited by LS 174T-PrP CM whereas its telomerase activity was reduced by CM of LS 174T-γ-Syn or LS 174T-PrP, as compared to EA incubated with LS 174T CM. Besides, LS 174T-γ-Syn CM or LS 174T-PrP CM inhibited EA invasion and migration in Boyden chamber assay. Furthermore, LS 174T-γ-Syn CM significantly inhibited EA migration in scratch wound assay. Gelatin zymography revealed reduced secretion of MMP-2 and MMP-9 by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM. In addition, cell adhesion assay showed lesser LS 174T-γ-Syn or LS 174T-PrP cells adhered onto EA, as compared to LS 174T. In tube formation assay, LS 174T-γ-Syn CM or LS 174T-PrP CM induced EA tube formation. Increased NO secretion by EA treated with LS 174T-γ-Syn CM or LS 174T-PrP CM was also detected. Lastly, decreased expression of pro-angiogenic factors like CXCL16, IGFBP-2 and amphiregulin in LS 174T-γ-Syn CM or LS 174T-PrP CM was detected using the angiogenesis antibody array.
Discussion: These results suggest that overexpression of γ-Syn or PrPCcould possibly be involved in colorectal cancer-induced angiogenesis by inducing an endothelial proliferation-differentiation switch. NO could be the main factor in governing this switch, and modulation on the secretion patterns of angiogenesis-related proteins could be the strategy of colorectal cancer cells overexpressing γ-Syn or PrPCin ensuring this transition.

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