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1.  There Is No Joy like Malicious Joy: Schadenfreude in Young Children 
PLoS ONE  2014;9(7):e100233.
Human emotions are strongly shaped by the tendency to compare the relative state of oneself to others. Although social comparison based emotions such as jealousy and schadenfreude (pleasure in the other misfortune) are important social emotions, little is known about their developmental origins. To examine if schadenfreude develops as a response to inequity aversion, we assessed the reactions of children to the termination of unequal and equal triadic situations. We demonstrate that children as early as 24 months show signs of schadenfreude following the termination of an unequal situation. Although both conditions involved the same amount of gains, the children displayed greater positive expressions following the disruption of the unequal as compared to the equal condition, indicating that inequity aversion can be observed earlier than reported before. These results support an early evolutionary origin of inequity aversion and indicate that schadenfreude has evolved as a response to unfairness.
doi:10.1371/journal.pone.0100233
PMCID: PMC4079297  PMID: 24988446
2.  The Potential Wind Power Resource in Australia: A New Perspective 
PLoS ONE  2014;9(7):e99608.
Australia’s wind resource is considered to be very good, and the utilization of this renewable energy resource is increasing rapidly: wind power installed capacity increased by 35% from 2006 to 2011 and is predicted to account for over 12% of Australia’s electricity generation in 2030. Due to this growth in the utilization of the wind resource and the increasing importance of wind power in Australia’s energy mix, this study sets out to analyze and interpret the nature of Australia’s wind resources using robust metrics of the abundance, variability and intermittency of wind power density, and analyzes the variation of these characteristics with current and potential wind turbine hub heights. We also assess the extent to which wind intermittency, on hourly or greater timescales, can potentially be mitigated by the aggregation of geographically dispersed wind farms, and in so doing, lessen the severe impact on wind power economic viability of long lulls in wind and power generated. Our results suggest that over much of Australia, areas that have high wind intermittency coincide with large expanses in which the aggregation of turbine output does not mitigate variability. These areas are also geographically remote, some are disconnected from the east coast’s electricity grid and large population centers, which are factors that could decrease the potential economic viability of wind farms in these locations. However, on the eastern seaboard, even though the wind resource is weaker, it is less variable, much closer to large population centers, and there exists more potential to mitigate it’s intermittency through aggregation. This study forms a necessary precursor to the analysis of the impact of large-scale circulations and oscillations on the wind resource at the mesoscale.
doi:10.1371/journal.pone.0099608
PMCID: PMC4079217  PMID: 24988222
3.  Noninvasive Image Texture Analysis Differentiates K-ras Mutation from Pan-Wildtype NSCLC and Is Prognostic 
PLoS ONE  2014;9(7):e100244.
Background
Non-invasive characterization of a tumor's molecular features could enhance treatment management. Quantitative computed tomography (CT) based texture analysis (QTA) has been used to derive tumor heterogeneity information, and the appearance of the tumors has been shown to relate to patient outcome in non-small cell lung cancer (NSCLC) and other cancers. In this study, we examined the potential of tumoral QTA to differentiate K-ras mutant from pan-wildtype tumors and its prognostic potential using baseline pre-treatment non-contrast CT imaging in NSCLC.
Methods
Tumor DNA from patients with early-stage NSCLC was analyzed on the LungCarta Panel. Cases with a K-ras mutation or pan-wildtype for 26 oncogenes and tumor suppressor genes were selected for QTA. QTA was applied to regions of interest in the primary tumor. Non-parametric Mann Whitney test assessed the ability of the QTA, clinical and patient characteristics to differentiate between K-ras mutation from pan-wildtype. A recursive decision tree was developed to determine whether the differentiation of K-ras mutant from pan-wildtype tumors could be improved by sequential application of QTA parameters. Kaplan-Meier survival analysis assessed the ability of these markers to predict survival.
Results
QTA was applied to 48 cases identified, 27 had a K-ras mutation and 21 cases were pan-wildtype. Positive skewness and lower kurtosis were significantly associated with the presence of a K-ras mutation. A five node decision tree had sensitivity, specificity, and accuracy values (95% CI) of 96.3% (78.1–100), 81.0% (50.5–97.4), and 89.6% (72.9–97.0); respectively. Kurtosis was a significant predictor of OS and DFS, with a lower kurtosis value linked with poorer survival.
Conclusions
Lower kurtosis and positive skewness are significantly associated with K-ras mutations. A QTA feature such as kurtosis is prognostic for OS and DFS. Non-invasive QTA can differentiate the presence of K-ras mutation from pan-wildtype NSCLC and is associated with patient survival.
doi:10.1371/journal.pone.0100244
PMCID: PMC4079229  PMID: 24987838
4.  Phosphorus, Nitrogen and Chlorophyll-a Are Significant Factors Controlling Ciliate Communities in Summer in the Northern Beibu Gulf, South China Sea 
PLoS ONE  2014;9(7):e101121.
Ciliates (protozoa) are ubiquitous components of plankton community and play important roles in aquatic ecosystems in regards of their abundance, biomass, diversity and energy turnover. Based on the stratified samples collected from the northern Beibu Gulf in August 2011, species composition, abundance, biomass, diversity and spatial pattern of planktonic ciliates were studied. Furthermore the main environmental factors controlling ciliate communities were determined. A total of 101 species belonging to 44 genera and 7 orders (i.e., Oligotrichida, Haptorida, Euplotida, Sessilida, Pleurostomatida, Scuticociliatida and Tintinnida) were identified. The variation of ciliate communities was significant at horizontal level, but that was not at vertical level. Based on cluster analysis, ciliate communities were divided into three main groups. Redundancy analysis (RDA) revealed that Group A, existing in the waters with higher concentration of phosphorus and nitrogen, was dominated by Tintinnidium primitivum. Group B in the waters with lower temperature and chlorophyll-a concentration, was dominated by Leegaardiella ovalis. Group C, existing in the waters with higher temperature and chlorophyll-a concentration, was dominated by large Strombidium spp. and Mesodinium rubrum. Combining multiple analytic methods, our results strongly supported that phosphorus, nitrogen and chlorophyll-a were the most significant factors affecting the ciliate communities in the northern Beibu Gulf in summer. Concentration of phosphorus and nitrogen primarily influenced ciliate biomass, implying a potential impact of eutrophication on ciliate growth. The correlation with chlorophyll-a concentration, on one hand indicate the response of ciliates to the food availability, and on the other hand, the ciliates containing chloroplasts or endosymbionts may contribute greatly to the chlorophyll-a.
doi:10.1371/journal.pone.0101121
PMCID: PMC4079230  PMID: 24987960
5.  Are Iron-Phosphate Minerals a Sink for Phosphorus in Anoxic Black Sea Sediments? 
PLoS ONE  2014;9(7):e101139.
Phosphorus (P) is a key nutrient for marine organisms. The only long-term removal pathway for P in the marine realm is burial in sediments. Iron (Fe) bound P accounts for a significant proportion of this burial at the global scale. In sediments underlying anoxic bottom waters, burial of Fe-bound P is generally assumed to be negligible because of reductive dissolution of Fe(III) (oxyhydr)oxides and release of the associated P. However, recent work suggests that Fe-bound P is an important burial phase in euxinic (i.e. anoxic and sulfidic) basin sediments in the Baltic Sea. In this study, we investigate the role of Fe-bound P as a potential sink for P in Black Sea sediments overlain by oxic and euxinic bottom waters. Sequential P extractions performed on sediments from six multicores along two shelf-to-basin transects provide evidence for the burial of Fe-bound P at all sites, including those in the euxinic deep basin. In the latter sediments, Fe-bound P accounts for more than 20% of the total sedimentary P pool. We suggest that this P is present in the form of reduced Fe-P minerals. We hypothesize that these minerals may be formed as inclusions in sulfur-disproportionating Deltaproteobacteria. Further research is required to elucidate the exact mineral form and formation mechanism of this P burial phase, as well as its role as a sink for P in sulfide-rich marine sediments.
doi:10.1371/journal.pone.0101139
PMCID: PMC4079231  PMID: 24988389
6.  An Objective Approach to Determining the Weight Ranges of Prey Preferred by and Accessible to the Five Large African Carnivores 
PLoS ONE  2014;9(7):e101054.
Broad-scale models describing predator prey preferences serve as useful departure points for understanding predator-prey interactions at finer scales. Previous analyses used a subjective approach to identify prey weight preferences of the five large African carnivores, hence their accuracy is questionable. This study uses a segmented model of prey weight versus prey preference to objectively quantify the prey weight preferences of the five large African carnivores. Based on simulations of known predator prey preference, for prey species sample sizes above 32 the segmented model approach detects up to four known changes in prey weight preference (represented by model break-points) with high rates of detection (75% to 100% of simulations, depending on number of break-points) and accuracy (within 1.3±4.0 to 2.7±4.4 of known break-point). When applied to the five large African carnivores, using carnivore diet information from across Africa, the model detected weight ranges of prey that are preferred, killed relative to their abundance, and avoided by each carnivore. Prey in the weight ranges preferred and killed relative to their abundance are together termed “accessible prey”. Accessible prey weight ranges were found to be 14–135 kg for cheetah Acinonyx jubatus, 1–45 kg for leopard Panthera pardus, 32–632 kg for lion Panthera leo, 15–1600 kg for spotted hyaena Crocuta crocuta and 10–289 kg for wild dog Lycaon pictus. An assessment of carnivore diets throughout Africa found these accessible prey weight ranges include 88±2% (cheetah), 82±3% (leopard), 81±2% (lion), 97±2% (spotted hyaena) and 96±2% (wild dog) of kills. These descriptions of prey weight preferences therefore contribute to our understanding of the diet spectrum of the five large African carnivores. Where datasets meet the minimum sample size requirements, the segmented model approach provides a means of determining, and comparing, the prey weight range preferences of any carnivore species.
doi:10.1371/journal.pone.0101054
PMCID: PMC4079238  PMID: 24988433
7.  Merging Fargesia dracocephala into Fargesia decurvata (Bambusoideae, Poaceae): Implications from Morphological and ITS Sequence Analyses 
PLoS ONE  2014;9(7):e101362.
Aims
Fargesia decurvata is closely allied with F. dracocephala and differs in 5 major characters (i.e. the culm sheath blade base shape, the width of the culm sheath blade base, the auricle shape, and the lower surface of leaf blade) in Fargesia. It is difficult to distinguish these two species because of existing of transitional statements of characters. The aims of this paper are to (i) investigate whether the variation of the characters is continuous or not; (ii) reveal whether the publishment of F. dracocephala was the result of discontinuous sampling of F. decurvata or not.
Methods
Ten populations of F. decurvata and F. dracocephala were investigated in their entire distribution (including type localities). The statements of 5 major characters were measured from 693 annual and 693 perennial culms of 231 individuals in 10 populations, and analyzed at population, individual and culm levels. UPGMA cluster analysis was carried out based on 29 characters from 10 populations of F. decurvata and F. dracocephala and 2 populations of F. qinlingensis as outgroup. The ITS sequences were also sequenced and analyzed.
Important Findings
Five major characters exhibited great variation not only at population level, but at individual level within a population, even the culm level within an individual and in different parts of the same culm. Cluster analyses showed that 10 populations of F. decurvata and F. dracocephala were not divided into two species, but they were well separated with outgroup. There was no difference in floral organ between F. decurvata and F. dracocephala. MP and NJ trees based on ITS sequences showed the same results with the cluster analysis on morphological characters. All the facts indicated that the publishment of F. dracocephala was the result of discontinuous sampling of F. decurvata, and F. dracocephala should be treated as the synonym of F. decurvata.
doi:10.1371/journal.pone.0101362
PMCID: PMC4079244  PMID: 24988081
8.  The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(7):e100239.
Background
The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke.
Methods
Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models.
Findings
A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05).
Conclusions
The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.
doi:10.1371/journal.pone.0100239
PMCID: PMC4079245  PMID: 24988537
9.  Alzheimer's Associated β-Amyloid Protein Inhibits Influenza A Virus and Modulates Viral Interactions with Phagocytes 
PLoS ONE  2014;9(7):e101364.
Accumulation of β-Amyloid (βA) is a key pathogenetic factor in Alzheimer's disease; however, the normal function of βA is unknown. Recent studies have shown that βA can inhibit growth of bacteria and fungi. In this paper we show that βA also inhibits replication of seasonal and pandemic strains of H3N2 and H1N1 influenza A virus (IAV) in vitro. The 42 amino acid fragment of βA (βA42) had greater activity than the 40 amino acid fragment. Direct incubation of the virus with βA42 was needed to achieve optimal inhibition. Using quantitative PCR assays βA42 was shown to reduce viral uptake by epithelial cells after 45 minutes and to reduce supernatant virus at 24 hours post infection. βA42 caused aggregation of IAV particles as detected by light transmission assays and electron and confocal microscopy. βA42 did not stimulate neutrophil H2O2 production or extracellular trap formation on its own, but it increased both responses stimulated by IAV. In addition, βA42 increased uptake of IAV by neutrophils. βA42 reduced viral protein synthesis in monocytes and reduced IAV-induced interleukin-6 production by these cells. Hence, we demonstrate for the first time that βA has antiviral activity and modulates viral interactions with phagocytes.
doi:10.1371/journal.pone.0101364
PMCID: PMC4079246  PMID: 24988208
10.  Prospective Study of Police Officer Spouse/Partners: A New Pathway to Secondary Trauma and Relationship Violence? 
PLoS ONE  2014;9(7):e100663.
Introduction
It has been reported that posttraumatic stress disorder (PTSD) is associated with secondary spouse/partner (S/P) emotional distress and relationship violence.
Objective
To investigate the relationships between PTSD, S/P emotional distress and relationship violence among police recruits using a prospective design.
Methods
Two hypotheses were tested in 71 S/Ps: (1) Police officer reports of greater PTSD symptoms after 12 months of police service will be associated with greater secondary trauma symptoms among S/Ps; (2) Greater secondary trauma symptoms among S/Ps at 12 months will be associated with S/P reports of greater relationship violence.
Methods
71 police recruits and their S/Ps were assessed at baseline and 12 months after the start of police officer duty. Using linear and logistic regression, we analyzed explanatory variables for 12 month S/P secondary traumatic stress symptoms and couple violence, including baseline S/P variables and couple violence, as well as exposure and PTSD reports from both S/P and officer.
Results
S/P perception of officer PTSD symptoms predicted S/P secondary traumatic stress. OS/P secondary trauma was significantly associated with both total couple violence (.34, p = .004) and S/P to officer violence (.35, p = .003).
Conclusions
Although results from this relatively small study of young police officers and their S/Ps must be confirmed by larger studies in general populations, findings suggest that S/P perception of PTSD symptoms may play a key role in the spread of traumatic stress symptoms across intimate partner relationships and intimate partner violence in the context of PTSD.
doi:10.1371/journal.pone.0100663
PMCID: PMC4079247  PMID: 24987848
11.  Ethanol-Induced Effects on Sting Extension Response and Punishment Learning in the Western Honey Bee (Apis mellifera) 
PLoS ONE  2014;9(7):e100894.
Acute ethanol administration is associated with sedation and analgesia as well as behavioral disinhibition and memory loss but the mechanisms underlying these effects remain to be elucidated. During the past decade, insects have emerged as important model systems to understand the neural and genetic bases of alcohol effects. However, novel assays to assess ethanol's effects on complex behaviors in social or isolated contexts are necessary. Here we used the honey bee as an especially relevant model system since bees are typically exposed to ethanol in nature when collecting standing nectar crop of flowers, and there is recent evidence for independent biological significance of this exposure for social behavior. Bee's inhibitory control of the sting extension response (SER) and a conditioned-place aversion assay were used to study ethanol effects on analgesia, behavioral disinhibition, and associative learning. Our findings indicate that although ethanol, in a dose-dependent manner, increases SER thresholds (analgesic effects), it disrupts the ability of honey bees to inhibit SER and to associate aversive stimuli with their environment. These results suggest that ethanol's effects on analgesia, behavioral disinhibition and associative learning are common across vertebrates and invertebrates. These results add to the use of honey bees as an ethanol model to understand ethanol's effects on complex, socially relevant behaviors.
doi:10.1371/journal.pone.0100894
PMCID: PMC4079248  PMID: 24988309
12.  The Role of Canine Distemper Virus and Persistent Organic Pollutants in Mortality Patterns of Caspian Seals (Pusa caspica) 
PLoS ONE  2014;9(7):e99265.
Persistent organic pollutants are a concern for species occupying high trophic levels since they can cause immunosuppression and impair reproduction. Mass mortalities due to canine distemper virus (CDV) occurred in Caspian seals (Pusa caspica), in spring of 1997, 2000 and 2001, but the potential role of organochlorine exposure in these epizootics remains undetermined. Here we integrate Caspian seal mortality data spanning 1971–2008, with data on age, body condition, pathology and blubber organochlorine concentration for carcases stranded between 1997 and 2002. We test the hypothesis that summed PCB and DDT concentrations contributed to CDV associated mortality during epizootics. We show that age is the primary factor explaining variation in blubber organochlorine concentrations, and that organochlorine burden, age, sex, and body condition do not account for CDV infection status (positive/negative) of animals dying in epizootics. Most animals (57%, n = 67) had PCB concentrations below proposed thresholds for toxic effects in marine mammals (17 µg/g lipid weight), and only 3 of 67 animals had predicted TEQ values exceeding levels seen to be associated with immune suppression in harbour seals (200 pg/g lipid weight). Mean organonchlorine levels were higher in CDV-negative animals indicating that organochlorines did not contribute significantly to CDV mortality in epizootics. Mortality monitoring in Azerbaijan 1971–2008 revealed bi-annual stranding peaks in late spring, following the annual moult and during autumn migrations northwards. Mortality peaks comparable to epizootic years were also recorded in the 1970s–1980s, consistent with previous undocumented CDV outbreaks. Gompertz growth curves show that Caspian seals achieve an asymptotic standard body length of 126–129 cm (n = 111). Males may continue to grow slowly throughout life. Mortality during epizootics may exceed the potential biological removal level (PBR) for the population, but the low frequency of epizootics suggest they are of secondary importance compared to anthropogenic sources of mortality such as fishing by-catch.
doi:10.1371/journal.pone.0099265
PMCID: PMC4079250  PMID: 24987857
13.  Expression of the Genetic Suppressor Element 24.2 (GSE24.2) Decreases DNA Damage and Oxidative Stress in X-Linked Dyskeratosis Congenita Cells 
PLoS ONE  2014;9(7):e101424.
The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of GSE24.2 was able to diminish it. Altogether our data indicated that supplying GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach.
doi:10.1371/journal.pone.0101424
PMCID: PMC4079255  PMID: 24987982
14.  Applicability of Single-Camera Photogrammetry to Determine Body Dimensions of Pinnipeds: Galapagos Sea Lions as an Example 
PLoS ONE  2014;9(7):e101197.
Morphological features correlate with many life history traits and are therefore of high interest to behavioral and evolutionary biologists. Photogrammetry provides a useful tool to collect morphological data from species for which measurements are otherwise difficult to obtain. This method reduces disturbance and avoids capture stress. Using the Galapagos sea lion (Zalophus wollebaeki) as a model system, we tested the applicability of single-camera photogrammetry in combination with laser distance measurement to estimate morphological traits which may vary with an animal’s body position. We assessed whether linear morphological traits estimated by photogrammetry can be used to estimate body length and mass. We show that accurate estimates of body length (males: ±2.0%, females: ±2.6%) and reliable estimates of body mass are possible (males: ±6.8%, females: 14.5%). Furthermore, we developed correction factors that allow the use of animal photos that diverge somewhat from a flat-out position. The product of estimated body length and girth produced sufficiently reliable estimates of mass to categorize individuals into 10 kg-classes of body mass. Data of individuals repeatedly photographed within one season suggested relatively low measurement errors (body length: 2.9%, body mass: 8.1%). In order to develop accurate sex- and age-specific correction factors, a sufficient number of individuals from both sexes and from all desired age classes have to be captured for baseline measurements. Given proper validation, this method provides an excellent opportunity to collect morphological data for large numbers of individuals with minimal disturbance.
doi:10.1371/journal.pone.0101197
PMCID: PMC4079256  PMID: 24987983
15.  Knowing Right From Wrong In Mental Arithmetic Judgments: Calibration Of Confidence Predicts The Development Of Accuracy 
PLoS ONE  2014;9(7):e98663.
Does knowing when mental arithmetic judgments are right—and when they are wrong—lead to more accurate judgments over time? We hypothesize that the successful detection of errors (and avoidance of false alarms) may contribute to the development of mental arithmetic performance. Insight into error detection abilities can be gained by examining the “calibration” of mental arithmetic judgments—that is, the alignment between confidence in judgments and the accuracy of those judgments. Calibration may be viewed as a measure of metacognitive monitoring ability. We conducted a developmental longitudinal investigation of the relationship between the calibration of children's mental arithmetic judgments and their performance on a mental arithmetic task. Annually between Grades 5 and 8, children completed a problem verification task in which they rapidly judged the accuracy of arithmetic expressions (e.g., 25+50 = 75) and rated their confidence in each judgment. Results showed that calibration was strongly related to concurrent mental arithmetic performance, that calibration continued to develop even as mental arithmetic accuracy approached ceiling, that poor calibration distinguished children with mathematics learning disability from both low and typically achieving children, and that better calibration in Grade 5 predicted larger gains in mental arithmetic accuracy between Grades 5 and 8. We propose that good calibration supports the implementation of cognitive control, leading to long-term improvement in mental arithmetic accuracy. Because mental arithmetic “fluency” is critical for higher-level mathematics competence, calibration of confidence in mental arithmetic judgments may represent a novel and important developmental predictor of future mathematics performance.
doi:10.1371/journal.pone.0098663
PMCID: PMC4079261  PMID: 24988539
16.  Discovery of a Dicer-Independent, Cell-Type Dependent Alternate Targeting Sequence Generator: Implications in Gene Silencing & Pooled RNAi Screens 
PLoS ONE  2014;9(7):e100676.
There is an acceptance that plasmid-based delivery of interfering RNA always generates the intended targeting sequences in cells, making it as specific as its synthetic counterpart. However, recent studies have reported on cellular inefficiencies of the former, especially in light of emerging gene discordance at inter-screen level and across formats. Focusing primarily on the TRC plasmid-based shRNA hairpins, we reasoned that alleged specificities were perhaps compromised due to altered processing; resulting in a multitude of random interfering sequences. For this purpose, we opted to study the processing of hairpin TRCN#40273 targeting CTTN; which showed activity in a miRNA-21 gain-of-function shRNA screen, but inactive when used as an siRNA duplex. Using a previously described walk-through method, we identified 36 theoretical cleavage variants resulting in 78 potential siRNA duplexes targeting 53 genes. We synthesized and tested all of them. Surprisingly, six duplexes targeting ASH1L, DROSHA, GNG7, PRKCH, THEM4, and WDR92 scored as active. QRT-PCR analysis on hairpin transduced reporter cells confirmed knockdown of all six genes, besides CTTN; revealing a surprising 7 gene-signature perturbation by this one single hairpin. We expanded our qRT-PCR studies to 26 additional cell lines and observed unique knockdown profiles associated with each cell line tested; even for those lacking functional DICER1 gene suggesting no obvious dependence on dicer for shRNA hairpin processing; contrary to published models. Taken together, we report on a novel dicer independent, cell-type dependent mechanism for non-specific RNAi gene silencing we coin Alternate Targeting Sequence Generator (ATSG). In summary, ATSG adds another dimension to the already complex interpretation of RNAi screening data, and provides for the first time strong evidence in support of arrayed screening, and questions the scientific merits of performing pooled RNAi screens, where deconvolution of up to genome-scale pools is indispensable for target identification.
doi:10.1371/journal.pone.0100676
PMCID: PMC4079264  PMID: 24987961
17.  Impulsive Social Influence Increases Impulsive Choices on a Temporal Discounting Task in Young Adults 
PLoS ONE  2014;9(7):e101570.
Adolescents and young adults who affiliate with friends who engage in impulsive behavior are more likely to engage in impulsive behaviors themselves, and those who associate with prosocial (i.e. more prudent, future oriented) peers are more likely to engage in prosocial behavior. However, it is difficult to disentangle the contribution of peer influence vs. peer selection (i.e., whether individuals choose friends with similar traits) when interpreting social behaviors. In this study, we combined a novel social manipulation with a well-validated delay discounting task assessing impulsive behavior to create a social influence delay discounting task, in which participants were exposed to both impulsive (smaller, sooner or SS payment) and non-impulsive (larger, later or LL payment) choices from their peers. Young adults in this sample, n = 51, aged 18–25 had a higher rate of SS choices after exposure to impulsive peer influence than after exposure to non-impulsive peer influence. Interestingly, in highly susceptible individuals, the rate of non-impulsive choices did not increase after exposure to non-impulsive influence. There was a positive correlation between self-reported suggestibility and degree of peer influence on SS choices. These results suggest that, in young adults, SS choices appear to be influenced by the choices of same-aged peers, especially for individuals who are highly susceptible to influence.
doi:10.1371/journal.pone.0101570
PMCID: PMC4079280  PMID: 24988440
18.  Morphological and Volumetric Analysis of Left Atrial Appendage and Left Atrium: Cardiac Computed Tomography-Based Reproducibility Assessment 
PLoS ONE  2014;9(7):e101580.
Objectives
Left atrial appendage (LAA) dilatation and morphology may influence an individual's risk for intracardiac thrombi and ischemic stroke. LAA size and morphology can be evaluated using cardiac computed tomography (cCT). The present study evaluated the reproducibility of LAA volume and morphology assessments.
Methods
A total of 149 patients (47 females; mean age 60.9±10.6 years) with suspected cardioembolic stroke/transient ischemic attack underwent cCT. Image quality was rated based on four categories. Ten patients were selected from each image quality category (N = 40) for volumetric reproducibility analysis by two individual readers. LAA and left atrium (LA) volume were measured in both two-chamber (2CV) and transversal view (TV) orientation. Intertechnique reproducibility was assessed between 2CV and TV (200 measurement pairs). LAA morphology (A = Cactus, B = ChickenWing, C = WindSock, D = CauliFlower), LAA opening height, number of LAA lobes, trabeculation, and orientation of the LAA tip was analysed in all study subjects by three individual readers (447 interobserver measurement pairs). The reproducibility of volume measurements was assessed by intra-class correlation (ICC) and the reproducibility of LAA morphology assessments by Cohen's kappa.
Results
The intra-observer and interobserver reproducibility of LAA and LA volume measurements was excellent (ICCs>0.9). The LAA (ICC = 0.954) and LA (ICC = 0.945) volume measurements were comparable between 2CV and TV. Morphological classification (ĸ = 0.24) and assessments of LAA opening height (ĸ = 0.1), number of LAA lobes (ĸ = 0.16), trabeculation (ĸ = 0.15), and orientation of the LAA tip (ĸ = 0.37) was only slightly to fairly reproducible.
Conclusions
LA and LAA volume measurements on cCT provide excellent reproducibility, whereas visual assessment of LAA morphological features is challenging and results in unsatisfactory agreement between readers.
doi:10.1371/journal.pone.0101580
PMCID: PMC4079282  PMID: 24988467
19.  Infra-Population and -Community Dynamics of the Parasites Nosema apis and Nosema ceranae, and Consequences for Honey Bee (Apis mellifera) Hosts 
PLoS ONE  2014;9(7):e99465.
Nosema spp. fungal gut parasites are among myriad possible explanations for contemporary increased mortality of western honey bees (Apis mellifera, hereafter honey bee) in many regions of the world. Invasive Nosema ceranae is particularly worrisome because some evidence suggests it has greater virulence than its congener N. apis. N. ceranae appears to have recently switched hosts from Asian honey bees (Apis cerana) and now has a nearly global distribution in honey bees, apparently displacing N. apis. We examined parasite reproduction and effects of N. apis, N. ceranae, and mixed Nosema infections on honey bee hosts in laboratory experiments. Both infection intensity and honey bee mortality were significantly greater for N. ceranae than for N. apis or mixed infections; mixed infection resulted in mortality similar to N. apis parasitism and reduced spore intensity, possibly due to inter-specific competition. This is the first long-term laboratory study to demonstrate lethal consequences of N. apis and N. ceranae and mixed Nosema parasitism in honey bees, and suggests that differences in reproduction and intra-host competition may explain apparent heterogeneous exclusion of the historic parasite by the invasive species.
doi:10.1371/journal.pone.0099465
PMCID: PMC4079283  PMID: 24987989
20.  Movement-Based Estimation and Visualization of Space Use in 3D for Wildlife Ecology and Conservation 
PLoS ONE  2014;9(7):e101205.
Advances in digital biotelemetry technologies are enabling the collection of bigger and more accurate data on the movements of free-ranging wildlife in space and time. Although many biotelemetry devices record 3D location data with x, y, and z coordinates from tracked animals, the third z coordinate is typically not integrated into studies of animal spatial use. Disregarding the vertical component may seriously limit understanding of animal habitat use and niche separation. We present novel movement-based kernel density estimators and computer visualization tools for generating and exploring 3D home ranges based on location data. We use case studies of three wildlife species – giant panda, dugong, and California condor – to demonstrate the ecological insights and conservation management benefits provided by 3D home range estimation and visualization for terrestrial, aquatic, and avian wildlife research.
doi:10.1371/journal.pone.0101205
PMCID: PMC4079284  PMID: 24988114
21.  Household Crowding, Social Mixing Patterns and Respiratory Symptoms in Seven Countries of the African Meningitis Belt 
PLoS ONE  2014;9(7):e101129.
Objectives
To describe the variation in household crowding and social mixing patterns in the African meningitis belt and to assess any association with self-reported recent respiratory symptoms.
Methods
In 2010, the African Meningococcal Carriage Consortium (MenAfriCar) conducted cross-sectional surveys in urban and rural areas of seven countries. The number of household members, rooms per household, attendance at social gatherings and meeting places were recorded. Associations with self-reported recent respiratory symptoms were analysed by univariate and multivariate regression models.
Results
The geometric mean people per room ranged from 1.9 to 2.8 between Ghana and Ethiopia respectively. Attendance at different types of social gatherings was variable by country, ranging from 0.5 to 1.5 per week. Those who attended 3 or more different types of social gatherings a week (frequent mixers) were more likely to be older, male (OR 1.27, p<0.001) and live in urban areas (OR 1.45, p<0.001). Frequent mixing and young age, but not increased household crowding, were associated with higher odds of self-reported respiratory symptoms (aOR 2.2, p<0.001 and OR 2.8, p<0.001 respectively). A limitation is that we did not measure school and workplace attendance.
Conclusion
There are substantial variations in household crowding and social mixing patterns across the African meningitis belt. This study finds a clear association between age, increased social mixing and respiratory symptoms. It lays the foundation for designing and implementing more detailed studies of social contact patterns in this region.
doi:10.1371/journal.pone.0101129
PMCID: PMC4079295  PMID: 24988195
22.  Detecting DNA Depurination with Solid-State Nanopores 
PLoS ONE  2014;9(7):e101632.
Among the different types of DNA damage that occur endogenously in the cell, depurination is especially prevalent. These lesions can initiate mutagenesis and have been implicated in a variety of diseases, including cancer. Here, we demonstrate a new approach for the detection of depurination at the single-molecule scale using solid-state nanopores. We induce depurination in short duplex DNA using acidic conditions and observe that the presence of apurinic sites results in significantly slower dynamics during electrokinetic translocation. This procedure may be valuable as a diagnostic for in situ quantification of DNA depurination.
doi:10.1371/journal.pone.0101632
PMCID: PMC4079296  PMID: 24988437
23.  Differences in Epidemiological and Molecular Characteristics of Nasal Colonization with Staphylococcus aureus (MSSA-MRSA) in Children from a University Hospital and Day Care Centers 
PLoS ONE  2014;9(7):e101417.
Background
Clinical significance of Staphylococcus aureus colonization has been demonstrated in hospital settings; however, studies in the community have shown contrasting results regarding the relevance of colonization in infection by community-associated MRSA (CA-MRSA). In Colombia there are few studies on S. aureus colonization. The aim of this study was to determine the molecular and epidemiological characteristics of nasal colonization by S. aureus (MSSA-MRSA) in children from a university hospital and day care centers (DCCs) of Medellin, Colombia.
Methods
An observational cross-sectional study was conducted in 400 children (200 in each setting), aged 0 months to 5 years, during 2011. Samples were collected from each nostril and epidemiological information was obtained from the parents. Genotypic analysis included spa typing, PFGE, MLST, SCCmec typing, detection of genes for virulence factors and agr groups.
Results
Frequency of S. aureus colonization was 39.8% (n = 159) (hospital 44.5% and DCCs 35.0%) and by MRSA, 5.3% (n = 21) (hospital 7.0% and DCCs 3.5%). Most S. aureus colonized children were older than two years (p = 0.005), the majority of them boys (59.1%), shared a bedroom with a large number of people (p = 0.028), with history of β-Lactamase inhibitors usage (p = 0.020). MSSA strains presented the greatest genotypic diversity with 15 clonal complexes (CC). MRSA isolates presented 6 CC, most of them (47.6%) belonged to CC8-SCCmec IVc and were genetically related to previously reported infectious MRSA strains.
Conclusion
Differences in epidemiological and molecular characteristics between populations may be useful for the understanding of S. aureus nasal colonization dynamics and for the design of strategies to prevent S. aureus infection and dissemination. The finding of colonizing MRSA with similar molecular characteristics of those causing infection demonstrates the dissemination capacity of S. aureus and the risk of infection among the child population.
doi:10.1371/journal.pone.0101417
PMCID: PMC4079298  PMID: 24987854
24.  Human Endogenous Retrovirus-K(II) Envelope Induction Protects Neurons during HIV/AIDS 
PLoS ONE  2014;9(7):e97984.
Human endogenous retroviruses (HERVs) are differentially expressed depending on the cell type and physiological circumstances. HERV-K has been implicated in the pathogenesis of several diseases although the functional consequences of its expression remain unknown. Human immunodeficiency virus (HIV) infection causes neuroinflammation with neuronal damage and death. Herein, we investigated HERV-K(II)/(HML-2) envelope (Env) expression and its actions in the brain during HIV/AIDS. HERV-K(II) Env expression was assessed in healthy brain tissues, autopsied HIV HIV− infected (HIV+) and uninfected (HIV−) brains and in neural cell cultures by real time RT-PCR, massively parallel (deep) sequencing, immunoblotting and immunohistochemistry. Neuronal and neural stem cells expressing HERV-K(II) Env were analyzed in assays of host responses including cellular viability, immune responses and neurobehavioral outcomes. Deep sequencing of human brain transcriptomes disclosed that RNA sequences encoded by HERV-K were among the most abundant HERV sequences detected in human brain. Comparison of different cell types revealed that HERV-K(II) env RNA abundance was highest in cultured human neurons but was suppressed by epidermal growth factor exposure. HERV-K(II) Env immunoreactivity was increased in the cerebral cortex from persons with HIV/AIDS, principally localized in neurons. Human neuronal cells transfected with HERV-K(II) Env exhibited increased NGF and BDNF expression. Expression of HERV-K(II) Env in neuronal cells increased cellular viability and prevented neurotoxicity mediated by HIV-1 Vpr. Intracerebral delivery of HERV-K(II) Env expressed by neural stem cells suppressed TNF-α expression and microglial activation while also improving neurobehavioral deficits in vpr/RAG1−/− mice. HERV-K(II) Env was highly expressed in human neurons, especially during HIV/AIDS, but in addition exerted neuroprotective effects. These findings imply that HERV gene products might exert adaptive effects in circumstances of pathophysiological stress, perhaps underlying the conservation of HERVs within the human genome.
doi:10.1371/journal.pone.0097984
PMCID: PMC4079299  PMID: 24988390
25.  Phase 1 Study of the E-Selectin Inhibitor GMI 1070 in Patients with Sickle Cell Anemia 
PLoS ONE  2014;9(7):e101301.
Background
Sickle cell anemia is an inherited disorder of hemoglobin that leads to a variety of acute and chronic complications. Abnormal cellular adhesion, mediated in part by selectins, has been implicated in the pathophysiology of the vaso-occlusion seen in sickle cell anemia, and selectin inhibition was able to restore blood flow in a mouse model of sickle cell disease.
Methods
We performed a Phase 1 study of the selectin inhibitor GMI 1070 in patients with sickle cell anemia. Fifteen patients who were clinically stable received GMI 1070 in two infusions.
Results
The drug was well tolerated without significant adverse events. There was a modest increase in total peripheral white blood cell count without clinical symptoms. Plasma concentrations were well-described by a two-compartment model with an elimination T1/2 of 7.7 hours and CLr of 19.6 mL/hour/kg. Computer-assisted intravital microscopy showed transient increases in red blood cell velocity in 3 of the 4 patients studied.
Conclusions
GMI 1070 was safe in stable patients with sickle cell anemia, and there was suggestion of increased blood flow in a subset of patients. At some time points between 4 and 48 hours after treatment with GMI 1070, there were significant decreases in biomarkers of endothelial activation (sE-selectin, sP-selectin, sICAM), leukocyte activation (MAC-1, LFA-1, PM aggregates) and the coagulation cascade (tissue factor, thrombin-antithrombin complexes). Development of GMI 1070 for the treatment of acute vaso-occlusive crisis is ongoing.
Trial Registration
ClinicalTrials.gov NCT00911495
doi:10.1371/journal.pone.0101301
PMCID: PMC4079300  PMID: 24988449

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