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1.  Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile 
PLoS ONE  2015;10(6):e0127441.
Dillenia suffruticosa, which is locally known as Simpoh air, has been traditionally used to treat cancerous growth. The ethyl acetate extract of D. suffruticosa (EADs) has been shown to induce apoptosis in MCF-7 breast cancer cells in our previous study. The present study aimed to elucidate the molecular mechanisms involved in EADs-induced apoptosis and to identify the major compounds in the extract. EADs was found to promote oxidative stress in MCF-7 cells that led to cell death because the pre-treatment with antioxidants α-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. Apoptosis induced by EADs was not inhibited by the use of caspase-inhibitor Z-VAD-FMK, suggesting that the cell death is caspase-independent. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. The related molecular pathways involved in EADs-induced apoptosis were determined by GeXP multiplex system and Western blot analysis. EADs is postulated to induce cell cycle arrest that is p53- and p21-dependent based on the upregulated expression of p53 and p21 (P<0.05). The expression of Bax was upregulated with downregulation of Bcl-2 following treatment with EADs. The elevated Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential suggest that EADs-induced apoptosis is mitochondria-dependent. The expression of oxidative stress-related AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK. The data indicate that induction of oxidative-stress related apoptosis by EADs was mediated by inhibition of AKT and ERK, and activation of JNK. The isolation of compounds in EADs was carried out using column chromatography and elucidated using the nuclear resonance magnetic analysis producing a total of six compounds including 3-epimaslinic acid, kaempferol, kaempferide, protocatechuic acid, gallic acid and β-sitosterol-3-O-β-D-glucopyranoside. The cytotoxicity of the isolated compounds was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 ± 1.7 μg/mL (P<0.05). In summary, EADs generated oxidative stress, induced cell cycle arrest and apoptosis in MCF-7 cells by regulating numerous genes and proteins that are involved in the apoptotic signal transduction pathway. Therefore, EADs has the potential to be developed as an anti-cancer agent against breast cancer.
doi:10.1371/journal.pone.0127441
PMCID: PMC4457850  PMID: 26047480
3.  Detecting and Quantifying Forest Change: The Potential of Existing C- and X-Band Radar Datasets 
PLoS ONE  2015;10(6):e0131079.
This paper evaluates the opportunity provided by global interferometric radar datasets for monitoring deforestation, degradation and forest regrowth in tropical and semi-arid environments. The paper describes an easy to implement method for detecting forest spatial changes and estimating their magnitude. The datasets were acquired within space-borne high spatial resolutions radar missions at near-global scales thus being significant for monitoring systems developed under the United Framework Convention on Climate Change (UNFCCC). The approach presented in this paper was tested in two areas located in Indonesia and Australia. Forest change estimation was based on differences between a reference dataset acquired in February 2000 by the Shuttle Radar Topography Mission (SRTM) and TanDEM-X mission (TDM) datasets acquired in 2011 and 2013. The synergy between SRTM and TDM datasets allowed not only identifying changes in forest extent but also estimating their magnitude with respect to the reference through variations in forest height.
doi:10.1371/journal.pone.0131079
PMCID: PMC4482516  PMID: 26111047
4.  Low Serum High Density Lipoprotein Cholesterol Concentration is an Independent Predictor for Enhanced Inflammation and Endothelial Activation 
PLoS ONE  2015;10(1):e0116867.
Background
Inflammation, endothelial activation and oxidative stress have been established as key events in the initiation and progression of atherosclerosis. High-density lipoprotein cholesterol (HDL-c) is protective against atherosclerosis and coronary heart disease, but its association with inflammation, endothelial activation and oxidative stress is not well established.
Objectives
(1) To compare the concentrations of biomarkers of inflammation, endothelial activation and oxidative stress in subjects with low HDL-c compared to normal HDL-c; (2) To examine the association and correlation between HDL-c and these biomarkers and (3) To determine whether HDL-c is an independent predictor of these biomarkers.
Methods
422 subjects (mean age±SD = 43.2±11.9years) of whom 207 had low HDL-c concentrations (HDL-c <1.0mmol/L and <1.3mmol/L for males and females respectively) and 215 normal controls (HDL-c ≥1.0 and ≥1.3mmol/L for males and females respectively) were recruited in this study. The groups were matched for age, gender, ethnicity, smoking status, diabetes mellitus and hypertension. Fasting blood samples were collected for analysis of biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and Interleukin-6 (IL-6)], endothelial activation [soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), soluble Intercellular Adhesion Molecule-1 (sICAM-1) and E-selectin)] and oxidative stress [F2-Isoprostanes, oxidized Low Density Lipoprotein (ox-LDL) and Malondialdehyde (MDA)].
Results
Subjects with low HDL-c had greater concentrations of inflammation, endothelial activation and oxidative stress biomarkers compared to controls. There were negative correlations between HDL-c concentration and biomarkers of inflammation (IL-6, p = 0.02), endothelial activation (sVCAM-1 and E-selectin, p = 0.029 and 0.002, respectively), and oxidative stress (MDA and F2-isoprostane, p = 0.036 and <0.0001, respectively). Multiple linear regression analysis showed HDL-c as an independent predictor of IL-6 (p = 0.02) and sVCAM-1 (p<0.03) after correcting for various confounding factors.
Conclusion
Low serum HDL-c concentration is strongly correlated with enhanced status of inflammation, endothelial activation and oxidative stress. It is also an independent predictor for enhanced inflammation and endothelial activation, which are pivotal in the pathogenesis of atherosclerosis and atherosclerosis-related complications.
doi:10.1371/journal.pone.0116867
PMCID: PMC4304817  PMID: 25614985
5.  Parasitism Performance and Fitness of Cotesia vestalis (Hymenoptera: Braconidae) Infected with Nosema sp. (Microsporidia: Nosematidae): Implications in Integrated Pest Management Strategy 
PLoS ONE  2014;9(6):e100671.
The diamondback moth (DBM) Plutella xylostella (L.) has traditionally been managed using synthetic insecticides. However, the increasing resistance of DBM to insecticides offers an impetus to practice integrated pest management (IPM) strategies by exploiting its natural enemies such as pathogens, parasitoids, and predators. Nevertheless, the interactions between pathogens and parasitoids and/or predators might affect the effectiveness of the parasitoids in regulating the host population. Thus, the parasitism rate of Nosema-infected DBM by Cotesia vestalis (Haliday) (Hym., Braconidae) can be negatively influenced by such interactions. In this study, we investigated the effects of Nosema infection in DBM on the parasitism performance of C. vestalis. The results of no-choice test showed that C. vestalis had a higher parasitism rate on non-infected host larvae than on Nosema-treated host larvae. The C. vestalis individuals that emerged from Nosema-infected DBM (F1) and their progeny (F2) had smaller pupae, a decreased rate of emergence, lowered fecundity, and a prolonged development period compared to those of the control group. DBM infection by Nosema sp. also negatively affected the morphometrics of C. vestalis. The eggs of female C. vestalis that developed in Nosema-infected DBM were larger than those of females that developed in non-infected DBM. These detrimental effects on the F1 and F2 generations of C. vestalis might severely impact the effectiveness of combining pathogens and parasitoids as parts of an IPM strategy for DBM control.
doi:10.1371/journal.pone.0100671
PMCID: PMC4072679  PMID: 24968125
6.  Statistical Methods Used to Test for Agreement of Medical Instruments Measuring Continuous Variables in Method Comparison Studies: A Systematic Review 
PLoS ONE  2012;7(5):e37908.
Background
Accurate values are a must in medicine. An important parameter in determining the quality of a medical instrument is agreement with a gold standard. Various statistical methods have been used to test for agreement. Some of these methods have been shown to be inappropriate. This can result in misleading conclusions about the validity of an instrument. The Bland-Altman method is the most popular method judging by the many citations of the article proposing this method. However, the number of citations does not necessarily mean that this method has been applied in agreement research. No previous study has been conducted to look into this. This is the first systematic review to identify statistical methods used to test for agreement of medical instruments. The proportion of various statistical methods found in this review will also reflect the proportion of medical instruments that have been validated using those particular methods in current clinical practice.
Methodology/Findings
Five electronic databases were searched between 2007 and 2009 to look for agreement studies. A total of 3,260 titles were initially identified. Only 412 titles were potentially related, and finally 210 fitted the inclusion criteria. The Bland-Altman method is the most popular method with 178 (85%) studies having used this method, followed by the correlation coefficient (27%) and means comparison (18%). Some of the inappropriate methods highlighted by Altman and Bland since the 1980s are still in use.
Conclusions
This study finds that the Bland-Altman method is the most popular method used in agreement research. There are still inappropriate applications of statistical methods in some studies. It is important for a clinician or medical researcher to be aware of this issue because misleading conclusions from inappropriate analyses will jeopardize the quality of the evidence, which in turn will influence quality of care given to patients in the future.
doi:10.1371/journal.pone.0037908
PMCID: PMC3360667  PMID: 22662248
7.  Effects of a Community-Based Healthy Lifestyle Intervention Program (Co-HELP) among Adults with Prediabetes in a Developing Country: A Quasi-Experimental Study 
PLoS ONE  2016;11(12):e0167123.
Background
The prevalence of type 2 diabetes among Malaysian adults has increased by more than two folds over the past two decades. Strategies to collaborate with the existing community partners may become a promising channel for wide-scale dissemination of diabetes prevention in the country. The objectives of this study were to determine the effects of community-based lifestyle interventions delivered to adults with prediabetes and their health-related quality of life as compared to the usual care group.
Methods
This was a quasi-experimental study conducted in two sub-urban communities in Seremban, Malaysia. A total of 268 participants with prediabetes aged between 18 to 65 years old were assigned to either the community-based lifestyle intervention (Co-HELP) (n = 122) or the usual care (n = 146) groups. The Co-HELP program was delivered in partnership with the existing community volunteers to incorporate diet, physical activity, and behaviour modification strategies. Participants in the Co-HELP group received twelve group-based sessions and two individual counselling to reinforce behavioural change. Participants in the usual care group received standard health education from primary health providers in the clinic setting. Primary outcomes were fasting blood glucose, 2-hour plasma glucose, and HbA1C. Secondary outcomes included weight, BMI, waist circumference, total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, systolic and diastolic blood pressure, physical activity, diet, and health-related quality of life (HRQOL).
Results
An intention-to-treat analysis of between-groups at 12-month (mean difference, 95% CI) revealed that the Co-HELP participants’ mean fasting plasma glucose reduced by -0.40 mmol/l (-0.51 to -0.28, p<0.001), 2-hour post glucose by -0.58 mmol/l (-0.91 to -0.24, p<0.001), HbA1C by -0.24% (-0.34 to -0.15, p<0.001), diastolic blood pressure by -2.63 mmHg (-3.79 to -1.48, p<0.01), and waist circumference by -2.44 cm (-4.75 to -0.12, p<0.05) whereas HDL cholesterol increased by 0.12 mmol/l (0.05 to 0.13, p<0.01), compared to the usual care group. Significant improvements were also found in HRQOL for both physical component (PCS) by 6.51 points (5.21 to 7.80, p<0.001) and mental component (MCS) by 7.79 points (6.44 to 9.14, p<0.001). Greater proportion of participants from the Co-HELP group met the clinical recommended target of 5% or more weight loss from the initial weight (24.6% vs 3.4%, p<0.001) and physical activity of >600 METS/min/wk (60.7% vs 32.2%, p<0.001) compared to the usual care group.
Conclusions
This study provides evidence that a culturally adapted diabetes prevention program can be implemented in the community setting, with reduction of several diabetes risk factors and improvement of HRQOL. Collaboration with existing community partners demonstrated a promising channel for the wide-scale dissemination of diabetes prevention at the community level. Further studies are required to determine whether similar outcomes could be achieved in communities with different socioeconomic backgrounds and geographical areas.
Trial Registration
IRCT201104106163N1
doi:10.1371/journal.pone.0167123
PMCID: PMC5147835  PMID: 27935988
8.  Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells 
PLoS ONE  2016;11(12):e0167650.
Background
Despite the remarkable progress to fight against breast cancer, metastasis remains the dominant cause of treatment failure and recurrence. Therefore, control of invasiveness potential of breast cancer cells is crucial. Accumulating evidences suggest Aryl hydrocarbon receptor (Ahr), a helix-loop-helix transcription factor, as a promising target to control migration and invasion in breast cancer cells. Thus, an Ahr-based exploration was performed to identify a new Ahr agonist with inhibitory potentials on cancer cell motility.
Methods
For prediction of potential interactions between Ahr and candidate molecules, bioinformatics analysis was carried out. The interaction of the selected ligand with Ahr and its effects on migration and invasion were examined in vitro using the MDA-MB-231 and T47D cell lines. The silencing RNAs were transfected into cells by electroporation. Expressions of microRNAs (miRNAs) and coding genes were quantified by real-time PCR, and the protein levels were detected by western blot.
Results
The in silico and in vitro results identified Flavipin as a novel Ahr agonist. It induces formation of Ahr/Ahr nuclear translocator (Arnt) heterodimer to promote the expression of cytochrome P450 family 1 subfamily A member 1 (Cyp1a1). Migration and invasion of MDA-MB-231 and T47D cells were inhibited with Flavipin treatment in an Ahr-dependent fashion. Interestingly, Flavipin suppressed the pro-metastatic factor SRY-related HMG-box4 (Sox4) by inducing miR-212/132 cluster. Moreover, Flavipin inhibited growth and adhesion of both cell lines by suppressing gene expressions of B-cell lymphoma 2 (Bcl2) and integrinα4 (ITGA4).
Conclusion
Taken together, the results introduce Flavipin as a novel Ahr agonist, and provide first evidences on its inhibitory effects on cancer cell motility, suggesting Flavipin as a candidate to control cell invasiveness in breast cancer patients.
doi:10.1371/journal.pone.0167650
PMCID: PMC5132326  PMID: 27907195
9.  Immune Activation at Sites of HIV/TB Co-Infection Contributes to the Pathogenesis of HIV-1 Disease 
PLoS ONE  2016;11(11):e0166954.
Systemic immune activation is critical to the pathogenesis of HIV-1 disease, and is accentuated in HIV/TB co-infected patients. The contribution of immune activation at sites of HIV/TB co-infection to viral activity, CD4 T cell count, and productive HIV-1 infection remain unclear. In this study, we measured markers of immune activation both in pleural fluid and plasma, and in T cells in pleural fluid mononuclear cell (PFMC) and peripheral blood mononuclear cell (PBMC) in HIV/TB co-infected subjects. The relationship between soluble and T cell activation markers with viral load in pleural fluid and blood CD4 T cell count were assessed. The T cell phenotype and activation status of HIV-1 p24 + T cells in PFMC and PBMC from HIV/TB patients were determined. We found that T cell and macrophage-specific and non-specific soluble markers of immune activation, sCD27, sCD163, IL1Ra, and sCD14, were higher in pleural fluid as compared to plasma from HIV/TB co-infected subjects, and higher as compared to pleural fluid from TB mono-infected subjects. Intestinal fatty acid-binding protein, a marker of intestinal tract damage, in plasma from HIV/TB co-infected patients was not different than that in HIV+ subjects. Expression of HLADR and CD38 double positive (HLADR/CD38) on CD4 T cells, and CD69+ on CD8 T cells correlated with pleural fluid viral load, and inversely with blood CD4 T cell count. Higher expression of HLADR/CD38 and CCR5 on CD4 T cells, and HLADR/CD38 and CD69 on CD8 T cells in PFMC were limited to effector memory populations. HIV-1 p24+ CD8 negative (includes CD4 + and double negative T cells) effector memory T cells in PFMC had higher expression of HLADR/CD38, Ki67, and CCR5 compared to HIV-1 p24- CD8 negative PFMC. Cumulatively, these data indicate that sites of HIV/TB co-infection are the source of intense immune activation.
doi:10.1371/journal.pone.0166954
PMCID: PMC5117743  PMID: 27870882
10.  Efficient and Stable Routing Algorithm Based on User Mobility and Node Density in Urban Vehicular Network 
PLoS ONE  2016;11(11):e0165966.
Vehicular ad hoc networks (VANETs) are considered an emerging technology in the industrial and educational fields. This technology is essential in the deployment of the intelligent transportation system, which is targeted to improve safety and efficiency of traffic. The implementation of VANETs can be effectively executed by transmitting data among vehicles with the use of multiple hops. However, the intrinsic characteristics of VANETs, such as its dynamic network topology and intermittent connectivity, limit data delivery. One particular challenge of this network is the possibility that the contributing node may only remain in the network for a limited time. Hence, to prevent data loss from that node, the information must reach the destination node via multi-hop routing techniques. An appropriate, efficient, and stable routing algorithm must be developed for various VANET applications to address the issues of dynamic topology and intermittent connectivity. Therefore, this paper proposes a novel routing algorithm called efficient and stable routing algorithm based on user mobility and node density (ESRA-MD). The proposed algorithm can adapt to significant changes that may occur in the urban vehicular environment. This algorithm works by selecting an optimal route on the basis of hop count and link duration for delivering data from source to destination, thereby satisfying various quality of service considerations. The validity of the proposed algorithm is investigated by its comparison with ARP-QD protocol, which works on the mechanism of optimal route finding in VANETs in urban environments. Simulation results reveal that the proposed ESRA-MD algorithm shows remarkable improvement in terms of delivery ratio, delivery delay, and communication overhead.
doi:10.1371/journal.pone.0165966
PMCID: PMC5113918  PMID: 27855165
11.  A Framework for Assessing High School Students' Statistical Reasoning 
PLoS ONE  2016;11(11):e0163846.
Based on a synthesis of literature, earlier studies, analyses and observations on high school students, this study developed an initial framework for assessing students’ statistical reasoning about descriptive statistics. Framework descriptors were established across five levels of statistical reasoning and four key constructs. The former consisted of idiosyncratic reasoning, verbal reasoning, transitional reasoning, procedural reasoning, and integrated process reasoning. The latter include describing data, organizing and reducing data, representing data, and analyzing and interpreting data. In contrast to earlier studies, this initial framework formulated a complete and coherent statistical reasoning framework. A statistical reasoning assessment tool was then constructed from this initial framework. The tool was administered to 10 tenth-grade students in a task-based interview. The initial framework was refined, and the statistical reasoning assessment tool was revised. The ten students then participated in the second task-based interview, and the data obtained were used to validate the framework. The findings showed that the students’ statistical reasoning levels were consistent across the four constructs, and this result confirmed the framework’s cohesion. Developed to contribute to statistics education, this newly developed statistical reasoning framework provides a guide for planning learning goals and designing instruction and assessments.
doi:10.1371/journal.pone.0163846
PMCID: PMC5094664  PMID: 27812091
12.  Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data 
PLoS ONE  2016;11(10):e0164169.
The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme’s activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.
doi:10.1371/journal.pone.0164169
PMCID: PMC5087908  PMID: 27798644
13.  Fluoxetine Increases the Expression of miR-572 and miR-663a in Human Neuroblastoma Cell Lines 
PLoS ONE  2016;11(10):e0164425.
Evidence suggests neuroprotective effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on the developed neurons in the adult brain. In contrast, the drug may be deleterious to immature or undifferentiated neural cells, although the mechanism is unclear. Recent investigations have suggested that microRNAs (miRNA) may be critical for effectiveness of psychotropic drugs including SSRI. We investigated whether fluoxetine could modulate expressions of neurologically relevant miRNAs in two neuroblastoma SK-N-SH and SH-SY5Y cell lines. Initial screening results revealed that three (miR-489, miR-572 and miR-663a) and four (miR-320a, miR-489, miR-572 and miR-663a) miRNAs were up-regulated in SK-N-SH cells and SH-SY5Y cells, respectively, after 24 hours treatment of fluoxetine (1–25 μM). Cell viability was reduced according to the dose of fluoxetine. The upregulation of miR-572 and miR-663a was consistent in both the SH-SY5Y and SK-N-SH cells, confirmed by a larger scale culture condition. Our data is the first in vitro evidence that fluoxetine could increase the expression of miRNAs in undifferentiated neural cells, and that putative target genes of those miRNAs have been shown to be involved in fundamental neurodevelopmental processes.
doi:10.1371/journal.pone.0164425
PMCID: PMC5055328  PMID: 27716787
14.  The Epidemiology of Meningitis among Adults in a South African Province with a High HIV Prevalence, 2009-2012 
PLoS ONE  2016;11(9):e0163036.
Introduction
Meningitis is a major cause of mortality in southern Africa. We aimed to describe the aetiologies and frequencies of laboratory-confirmed fungal and bacterial meningitis among adults in a South African province with an 11% HIV prevalence, over 4 years.
Methods
We conducted a retrospective, observational study of secondary laboratory data, extracted on all cerebrospinal fluid (CSF) specimens submitted to public-sector laboratories in Gauteng province from 2009 through 2012. We calculated cause-specific incidence rates in the general and HIV-infected populations and used Poisson regression to determine if trends were significant.
Results
We identified 11,891 (10.7%) incident cases of meningitis from 110,885 CSF specimens. Cryptococcal meningitis, tuberculous meningitis and pneumococcal meningitis accounted for 62.3% (n = 7,406), 24.6% (n = 2,928) and 10.1% (n = 1,197) of cases over the four-year period. The overall incidence (cases per 100,000 persons) of cryptococcal meningitis declined by 23% from 24.4 in 2009 to 18.7 in 2012 (p <0.001) and decreased by 19% among HIV-infected persons from 178.2 to 144.7 (p <0.001). Tuberculous meningitis decreased by 40% from 11.3 in 2009 to 6.8 in 2012 (p <0.001) and decreased by 36% among HIV-infected persons from 54.4 to 34.9 (p <0.001). Pneumococcal meningitis decreased by 41% from 4.2 in 2009 to 2.5 in 2012 (p <0.001) and decreased by 38% among HIV-infected persons from 28.0 to 17.5 (p <0.001). Among cases of other bacterial meningitis (248/11,891, 2.1%), Neisseria meningitidis (n = 93), Escherichia coli (n = 72) and Haemophilus influenzae (n = 20) were the most common organisms identified.
Conclusions
In this high HIV-prevalence province, cryptococcal meningitis was the leading cause of laboratory-confirmed meningitis among adults. Over a 4-year period, there was a significant decrease in incidence of cryptococcal, tuberculous and pneumococcal meningitis. This coincided with expansion of the national antiretroviral treatment programme, enhanced tuberculosis control programme and routine childhood immunisation with pneumococcal conjugate vaccines.
doi:10.1371/journal.pone.0163036
PMCID: PMC5036788  PMID: 27669564
15.  Physicochemical Properties Influencing Presence of Burkholderia pseudomallei in Soil from Small Ruminant Farms in Peninsular Malaysia 
PLoS ONE  2016;11(9):e0162348.
Soil is considered to be a major reservoir of Burkholderia pseudomallei in the environment. This paper investigates soil physicochemical properties that may influence presence of B. pseudomallei in soil samples from small ruminant farms in Peninsular Malaysia. Soil samples were collected from the farms and cultured for B. pseudomallei. The texture, organic matter and water contents, pH, elemental contents, cation exchange capacities, carbon, sulfur and nitrogen contents were determined. Analysis of soil samples that were positive and negative for B. pseudomallei using multivariable logistic regression found that the odds of bacterial isolation from soil was significantly higher for samples with higher contents of iron (OR = 1.01, 95%CI = 1.00–1.02, p = 0.03), water (OR = 1.28, 95%CI = 1.05–1.55, p = 0.01) and clay (OR = 1.54, 95%CI = 1.15–2.06, p = 0.004) compared to the odds of isolation in samples with lower contents of the above variables. These three factors may have favored the survival of B. pseudomallei because iron regulates expression of respiratory enzymes, while water is essential for soil ecology and agent’s biological processes and clay retains water and nutrients.
doi:10.1371/journal.pone.0162348
PMCID: PMC5026356  PMID: 27635652
16.  Enhancing the Quality of Service for Real Time Traffic over Optical Burst Switching (OBS) Networks with Ensuring the Fairness for Other Traffics 
PLoS ONE  2016;11(9):e0161873.
Optical burst switching (OBS) networks have been attracting much consideration as a promising approach to build the next generation optical Internet. A solution for enhancing the Quality of Service (QoS) for high priority real time traffic over OBS with the fairness among the traffic types is absent in current OBS’ QoS schemes. In this paper we present a novel Real Time Quality of Service with Fairness Ratio (RT-QoSFR) scheme that can adapt the burst assembly parameters according to the traffic QoS needs in order to enhance the real time traffic QoS requirements and to ensure the fairness for other traffic. The results show that RT-QoSFR scheme is able to fulfill the real time traffic requirements (end to end delay, and loss rate) ensuring the fairness for other traffics under various conditions such as the type of real time traffic and traffic load. RT-QoSFR can guarantee that the delay of the real time traffic packets does not exceed the maximum packets transfer delay value. Furthermore, it can reduce the real time traffic packets loss, at the same time guarantee the fairness for non real time traffic packets by determining the ratio of real time traffic inside the burst to be 50–60%, 30–40%, and 10–20% for high, normal, and low traffic loads respectively.
doi:10.1371/journal.pone.0161873
PMCID: PMC5008841  PMID: 27583557
17.  Human Exposure to Anaplasma phagocytophilum in Two Cities of Northwestern Morocco 
PLoS ONE  2016;11(8):e0160880.
Anaplasma phagocytophilum is an emerging tick-borne zoonosis with extensive increased interest. Epidemiological data are available in several regions of the USA, Europe and Asia in contrast to other parts of the world such as North Africa. Blood samples of 261 healthy individuals divided in two groups i.e., dog handlers and blood donors were analysed. Indirect immunofluorescent assay using a commercial kit was performed to detect specific A. phagocytophilum IgG. Two dilutions were used to assess the prevalence of seroreactive samples. Demographic variables were assessed as potential risk factors using exact logistic regression. Seropositivity rates reached 37% and 27% in dog handlers and 36% and 22% in blood donors. No statistically significant differences were found in the prevalence rates between the two groups. Analysis of risk factors such as gender, age groups, outdoor activities, self-reported previous exposure to ticks, or contact with domestic animals (dogs, cats, ruminants and horses) did not shown any significant difference. A. phagocytophilum exposure was common in both high-risk population and blood donors in Morocco.
doi:10.1371/journal.pone.0160880
PMCID: PMC4988626  PMID: 27532208
18.  ‘Robot’ Hand Illusion under Delayed Visual Feedback: Relationship between the Senses of Ownership and Agency 
PLoS ONE  2016;11(7):e0159619.
The rubber hand illusion (RHI) is an illusion of the self-ownership of a rubber hand that is touched synchronously with one’s own hand. While the RHI relates to visual and tactile integration, we can also consider a similar illusion with visual and motor integration on a fake hand. We call this a “robot hand illusion” (RoHI), which relates to both the senses of ownership and agency. Here we investigate the effect of delayed visual feedback on the RoHI. Participants viewed a virtual computer graphic hand controlled by their hand movement recorded using a data glove device. We inserted delays of various lengths between the participant’s hand and the virtual hand movements (90–590 ms), and the RoHI effects for each delay condition were systematically tested using a questionnaire. The results showed that the participants felt significantly greater RoHI effects with temporal discrepancies of less than 190 ms compared with longer temporal discrepancies, both in the senses of ownership and agency. Additionally, participants felt significant, but weaker, RoHI effects with temporal discrepancies of 290–490 ms in the sense of agency, but not in the sense of ownership. The participants did not feel a RoHI with temporal discrepancies of 590 ms in either the senses of agency or ownership. Our results suggest that a time window of less than 200 ms is critical for multi-sensory integration processes constituting self-body image.
doi:10.1371/journal.pone.0159619
PMCID: PMC4959734  PMID: 27454579
19.  A Cross-Sectional Study of the Prevalence of Metabolic Syndrome among Young Female Emirati Adults 
PLoS ONE  2016;11(7):e0159378.
Introduction
Metabolic syndrome (MetS) is a growing problem in the United Arab Emirates (UAE). Moreover, the prevalence of overweight and obesity is rapidly increasing in the UAE especially among young females. However, few studies have evaluated the prevalence of MetS among young female adults in the UAE. This study determined the prevalence of MetS in Emirati females aged 17–25 years and its relation to overweight and obesity.
Methods
In total, 555 Emirati female college students were enrolled in a cross-sectional study, conducted during 2013–2014 at United Arab Emirates University in Al Ain, UAE. Anthropometric measurements, blood pressure and biochemical measurements were collected. MetS was defined according to the harmonised International Diabetes Federation criteria.
Results
Of the 555 participants enrolled, 23.1% were overweight and 10.4% were classified as obese. The overall prevalence of MetS was 6.8%. MetS prevalence was highest among obese participants (34.5%), as compared with normal-weight (1.7%) and overweight (10.1%) participants. MetS was significantly associated with overweight (adjusted odds ratio [aOR] = 3.8, 95% confidence interval [CI]; 1.15–12.52) and obesity (aOR = 11.2, 95% CI; 3.1–40.9), as compared with normal-weight. Waist-hip ratio ≥ 0.8 (aOR = 3.04, 95% CI; 1.10–8.44) was significantly associated with MetS, as compared with waist-hip ratio <0.8. The odds of MetS were 22 fold higher in participants with glycated haemoglobin (HbA1c) ≥ 6.5% (aOR = 22.5, 95% CI; 6.37–79.42) compared to HbA1c <6.5%. This difference was 9 fold higher when HbA1c between 5.6%–6.4% was compared to HbA1c <5.6% (aOR = 8.9, 95% CI; 3.4–23.5).
Conclusion
The prevalence of MetS among obese Emirati female students was significantly higher than overweight and normal weight students. The high prevalence of MetS highlights the importance of regular screening and intervention programmes targeting weight reduction.
doi:10.1371/journal.pone.0159378
PMCID: PMC4944977  PMID: 27414402
20.  Pineal Gland Calcification in Kurdistan: A Cross-Sectional Study of 480 Roentgenograms 
PLoS ONE  2016;11(7):e0159239.
Objective
The goal of this study was to compare the incidence of Pineal Gland Calcification (PGC) by age group and gender among the populations living in the Kurdistan Region-Iraq.
Methods
This prospective study examined skull X-rays of 480 patients between the ages of 3 and 89 years who sought care at a large teaching public hospital in Duhok, Iraq from June 2014 to November 2014. Descriptive statistics and a binary logistic regression were used for analysis.
Results
The overall incidence rate of PGC among the study population was 26.9% with the 51–60 age group and males having the highest incidence. PGC incidence increased after the first decade and remained steady until the age of 60. Thereafter the incidence began to decrease. Logistic regression analysis revealed that both age and gender significantly affected the risk of PGC. After adjusting for age, males were 1.94 (95% CI, 1.26–2.99) times more likely to have PGC compared to females. In addition, a one year increase in age increases the odds of developing PGC by 1.02 (95% CI, 1.01–1.03) units after controlling for the effects of gender.
Conclusion
Our analysis demonstrated a close relationship between PGC and age and gender, supporting a link between the development of PGC and these factors. This study provides a basis for future researchers to further investigate the nature and mechanisms underlying pineal gland calcification.
doi:10.1371/journal.pone.0159239
PMCID: PMC4945046  PMID: 27415622
21.  Rickettsia australis Activates Inflammasome in Human and Murine Macrophages 
PLoS ONE  2016;11(6):e0157231.
Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8–12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.
doi:10.1371/journal.pone.0157231
PMCID: PMC4928923  PMID: 27362650
22.  Cost-Effectiveness of Automated Digital Microscopy for Diagnosis of Active Tuberculosis 
PLoS ONE  2016;11(6):e0157554.
Background
Automated digital microscopy has the potential to improve the diagnosis of tuberculosis (TB), particularly in settings where molecular testing is too expensive to perform routinely. The cost-effectiveness of TB diagnostic algorithms using automated digital microscopy remains uncertain.
Methods
Using data from a demonstration study of an automated digital microscopy system (TBDx, Applied Visual Systems, Inc.), we performed an economic evaluation of TB diagnosis in South Africa from the health system perspective. The primary outcome was the incremental cost per new TB diagnosis made. We considered costs and effectiveness of different algorithms for automated digital microscopy, including as a stand-alone test and with confirmation of positive results with Xpert MTB/RIF (‘Xpert’, Cepheid, Inc.). Results were compared against both manual microscopy and universal Xpert testing.
Results
In settings willing to pay $2000 per incremental TB diagnosis, universal Xpert was the preferred strategy. However, where resources were not sufficient to support universal Xpert, and a testing volume of at least 30 specimens per day could be ensured, automated digital microscopy with Xpert confirmation of low-positive results could facilitate the diagnosis of 79–84% of all Xpert-positive TB cases, at 50–60% of the total cost. The cost-effectiveness of this strategy was $1280 per incremental TB diagnosis (95% uncertainty range, UR: $340-$3440) in the base case, but improved under conditions likely reflective of many settings in sub-Saharan Africa: $677 per diagnosis (95% UR: $450-$935) when sensitivity of manual smear microscopy was lowered to 0.5, and $956 per diagnosis (95% UR: $40-$2910) when the prevalence of multidrug-resistant TB was lowered to 1%.
Conclusions
Although universal Xpert testing is the preferred algorithm for TB diagnosis when resources are sufficient, automated digital microscopy can identify the majority of cases and halve the cost of diagnosis and treatment when resources are more scarce and multidrug-resistant TB is not common.
doi:10.1371/journal.pone.0157554
PMCID: PMC4913947  PMID: 27322162
23.  Maternal Pregnancy Intention and Professional Antenatal Care Utilization in Bangladesh: A Nationwide Population-Based Survey 
PLoS ONE  2016;11(6):e0157760.
Objective
To investigate the association between maternal pregnancy intention and professional antenatal and delivery care utilization.
Methods
Our data were derived from the 2011 nationally representative Bangladesh Demographic Health Survey. We included antenatal and delivery care utilization data of the most recent live births for women for the previous three years (n = 4672). We used multilevel logistic regression models to assess the relationship between pregnancy intention and use of professional antenatal and delivery care, with adjustment for potential confounding variables.
Results
Approximately 13% and 16% of children were reported by their mothers as unwanted and mistimed at the time of conception, respectively. Among the women, 55% received at least one professional antenatal care service; 21% received four or more professional antenatal services, while 32% were attended by professionals during deliveries. Mothers of children whose pregnancies had been unwanted had a greater risk for not seeking professional antenatal and professional delivery care than those whose pregnancies had been wanted [1≥ ANC from professionals: AOR: 0.66; 95% CI:0.51–0.93; 4≥ ANC from professionals: AOR:0.56; 95% CI:0.37–0.84; and delivery care from professionals: AOR: 0.70; 95% CI:0.50–0.97]. Women who were married after age 18, had secondary or higher level of education, and were from the wealthiest households were more likely to utilize antenatal and delivery care.
Conclusion
Unwanted pregnancy is significantly associated with lower utilization of professional antenatal and delivery care services in Bangladesh. Reducing unwanted births and promoting access to professional antenatal and delivery care are crucial for achieving the Sustainable Development Goals (SDGs) 3 in Bangladesh.
doi:10.1371/journal.pone.0157760
PMCID: PMC4911017  PMID: 27309727
24.  Fibulin-5 Regulates Angiopoietin-1/Tie-2 Receptor Signaling in Endothelial Cells 
PLoS ONE  2016;11(6):e0156994.
Background
Fibulin-5 is an extracellular matrix glycoprotein that plays critical roles in vasculogenesis and embryonic development. Deletion of Fibulin-5 in mice results in enhanced skin vascularization and upregulation of the angiogenesis factor angiopoietin-1 (Ang-1), suggesting that Fibulin-5 functions as an angiogenesis inhibitor. In this study, we investigate the inhibitory effects of Fibulin-5 on Ang-1/TIE-2 receptor pathway signaling and cell survival in human endothelial cells.
Methodology/Principal Findings
Recombinant wild-type and RGE-mutant Fibulin-5 proteins were generated through stable transfection of HEK293 and CHO cells, respectively. In vitro solid phase binding assays using pure proteins revealed that wild-type Fibulin-5 does not bind to Ang-1 or TIE-2 proteins but strongly binds to heparin. Binding assays using human umbilical vein endothelial cells (HUVECs) indicated that wild-type Fibulin-5 strongly binds to cells but RGE-mutant Fibulin-5, which is incapable of binding to integrins, does not. Pre-incubation of HUVECs for 1 hr with Fibulin-5 significantly increased caspase 3/7 activity, ERK1/2 phosphorylation, and expressions of the transcription factor early growth response 1 (EGR1) and the dual-specificity phosphatase 5 (DUSP5). Fibulin-5 also strongly attenuated Ang-1-induced TIE-2 and AKT phosphorylation, decreased Ang-1-induced expressions of the transcription factors Inhibitor of DNA Binding 1 (ID1) and Kruppel-like Factor 2 (KLF2), and reversed the inhibitory effect of Ang-1 on serum deprivation-induced cytotoxicity and caspase 3/7 activity.
Conclusion/Significance
We conclude that Fibulin-5 strongly binds to the endothelial cell surface through heparin-sulfate proteoglycans and possibly integrins and that it exerts strong anti-angiogenic effects by reducing endothelial cell viability and interfering with the signaling pathways of the Ang-1/TIE-2 receptor axis.
doi:10.1371/journal.pone.0156994
PMCID: PMC4909301  PMID: 27304216
25.  Isolation and Characterization of an Atypical Metschnikowia sp. Strain from the Skin Scraping of a Dermatitis Patient 
PLoS ONE  2016;11(6):e0156119.
A yeast-like organism was isolated from the skin scraping sample of a stasis dermatitis patient in the Mycology Unit Department of Medical Microbiology, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia. The isolate produced no pigment and was not identifiable using chromogenic agar and API 20C AUX. The fungus was identified as Metschnikowia sp. strain UM 1034, which is close to that of Metschnikowia drosophilae based on ITS- and D1/D2 domain-based phylogenetic analysis. However, the physiology of the strain was not associated to M. drosophilae. This pathogen exhibited low sensitivity to all tested azoles, echinocandins, 5-flucytosine and amphotericin B. This study provided insight into Metschnikowia sp. strain UM 1034 phenotype profiles using a Biolog phenotypic microarray (PM). The isolate utilized 373 nutrients of 760 nutrient sources and could adapt to a broad range of osmotic and pH environments. To our knowledge, this is the first report of the isolation of Metschnikowia non-pulcherrima sp. from skin scraping, revealing this rare yeast species as a potential human pathogen that may be misidentified as Candida sp. using conventional methods. Metschnikowia sp. strain UM 1034 can survive in flexible and diverse environments with a generalist lifestyle.
doi:10.1371/journal.pone.0156119
PMCID: PMC4900598  PMID: 27280438

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