PLoS ONE Alerts: New Articles

The Roles of Featural and Configural Face Processing in Snap Judgments of Sexual Orientation

2012-05-16T21:00:00Z

by Joshua A. Tabak, Vivian Zayas

Research has shown that people are able to judge sexual orientation from faces with above-chance accuracy, but little is known about how these judgments are formed. Here, we investigated the importance of well-established face processing mechanisms in such judgments: featural processing (e.g., an eye) and configural processing (e.g., spatial distance between eyes). Participants judged sexual orientation from faces presented for 50 milliseconds either upright, which recruits both configural and featural processing, or upside-down, when configural processing is strongly impaired and featural processing remains relatively intact. Although participants judged women’s and men’s sexual orientation with above-chance accuracy for upright faces and for upside-down faces, accuracy for upside-down faces was significantly reduced. The reduced judgment accuracy for upside-down faces indicates that configural face processing significantly contributes to accurate snap judgments of sexual orientation.

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

2012-05-15T21:00:00Z

by Zixuan Li, Lianyue Qu, Qianze Dong, Bo Huang, Haiying Li, Zhongping Tang, Ying Xu, Wenting Luo, Lifeng Liu, Xueshan Qiu, Enhua Wang

We aimed to investigate the clinical significance of the expression of novel scaffold protein CARMA3 in non-small-cell lung cancer (NSCLC) and the biological function of CARMA3 in NSCLC cell lines. We observed moderate to high CARMA3 staining in 68.8% of 141 NSCLC specimens compared to corresponding normal tissues. The overexpression of CARMA3 was significantly correlated with TNM stage (P = 0.022) and tumor status (P = 0.013). CARMA3 upregulation also correlated with a shorter survival rate of patients of nodal status N0 (P = 0.042)as well as the expression of epidermal growth factor receptor (EGFR) (P = 0.009). In EGFR mutation positive cases, CARMA3 expression was much higher (87.5%) compared to non-mutation cases (66.1%). In addition, we observed that knockdown of CARMA3 inhibits tumor cell proliferation and invasion, and induces cell cycle arrest at the boundary between the G1 and S phase. We further demonstrated a direct link between CARMA3 and NF-κB activation. The change of biological behavior in CARMA3 knockdown cells may be NF-κB-related. Our findings demonstrated, for the first time, that CARMA3 was overexpressed in NSCLC and correlated with lung cancer progression, EGFR expression, and EGFR mutation. CARMA3 could serve as a potential companion drug target, along with NF-kB and EGFR in EGFR-mutant lung cancers.

Small-Molecule Synthetic Compound Norcantharidin Reverses Multi-Drug Resistance by Regulating Sonic Hedgehog Signaling in Human Breast Cancer Cells

2012-05-15T21:00:00Z

by Yu-Jen Chen, Cheng-Deng Kuo, Szu-Han Chen, Wei-Jen Chen, Wen-Chien Huang, K. S. Clifford Chao, Hui-Fen Liao

Multi-drug resistance (MDR), an unfavorable factor compromising treatment efficacy of anticancer drugs, involves upregulated ATP binding cassette (ABC) transporters and activated Sonic hedgehog (Shh) signaling. By preparing human breast cancer MCF-7 cells resistant to doxorubicin (DOX), we examined the effect and mechanism of norcantharidin (NCTD), a small-molecule synthetic compound, on reversing multidrug resistance. The DOX-prepared MCF-7R cells also possessed resistance to vinorelbine, characteristic of MDR. At suboptimal concentration, NCTD significantly inhibited the viability of DOX-sensitive (MCF-7S) and DOX-resistant (MCF-7R) cells and reversed the resistance to DOX and vinorelbine. NCTD increased the intracellular accumulation of DOX in MCF-7R cells and suppressed the upregulated the mdr-1 mRNA, P-gp and BCRP protein expression, but not the MRP-1. The role of P-gp was strengthened by partial reversal of the DOX and vinorelbine resistance by cyclosporine A. NCTD treatment suppressed the upregulation of Shh expression and nuclear translocation of Gli-1, a hallmark of Shh signaling activation in the resistant clone. Furthermore, the Shh ligand upregulated the expression of P-gp and attenuated the growth inhibitory effect of NCTD. The knockdown of mdr-1 mRNA had not altered the expression of Shh and Smoothened in both MCF-7S and MCF-7R cells. This indicates that the role of Shh signaling in MDR might be upstream to mdr-1/P-gp, and similar effect was shown in breast cancer MDA-MB-231 and BT-474 cells. This study demonstrated that NCTD may overcome multidrug resistance through inhibiting Shh signaling and expression of its downstream mdr-1/P-gp expression in human breast cancer cells.

Long Interspersed Nuclear Element-1 Hypomethylation and Oxidative Stress: Correlation and Bladder Cancer Diagnostic Potential

2012-05-15T21:00:00Z

by Maturada Patchsung, Chanchai Boonla, Passakorn Amnattrakul, Thasinas Dissayabutra, Apiwat Mutirangura, Piyaratana Tosukhowong

Although, increased oxidative stress and hypomethylation of long interspersed nuclear element-1 (LINE-1) associate with bladder cancer (BCa) development, the relationship between these alterations is unknown. We evaluated the oxidative stress and hypomethylation of the LINE-1 in 61 BCa patients and 45 normal individuals. To measure the methylation levels and to differentiate the LINE-1 loci into hypermethylated, partially methylated and hypomethylated, peripheral blood cells, urinary exfoliated cells and cancerous tissues were evaluated by combined bisulfite restriction analysis PCR. The urinary total antioxidant status (TAS) and plasma protein carbonyl content were determined. The LINE-1 methylation levels and patterns, especially hypomethylated loci, in the blood and urine cells of the BCa patients were different from the levels and patterns in the healthy controls. The urinary TAS was decreased, whereas the plasma protein carbonyl content was increased in the BCa patients relative to the controls. A positive correlation between the methylation of LINE-1 in the blood-derived DNA and urinary TAS was found in both the BCa and control groups. The urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content provided the best diagnostic potential for BCa prediction. Based on post-diagnostic samples, the combination test improved the diagnostic power to a sensitivity of 96% and a specificity of 96%. In conclusion, decreased LINE-1 methylation is associated with increased oxidative stress both in healthy and BCa subjects across the various tissue types, implying a dose-response association. Increases in the LINE-1 hypomethylation levels and the number of hypomethylated loci in both the blood- and urine-derived cells and increase in the oxidative stress were found in the BCa patients. The combination test of the urinary hypomethylated LINE-1 loci and the plasma protein carbonyl content may be useful for BCa screening and monitoring of treatment.

Reduced Gray to White Matter Tissue Intensity Contrast in Schizophrenia

2012-05-15T21:00:00Z

by Li Kong, Christina Herold, Bram Stieltjes, Marco Essig, Ulrich Seidl, Robert Christian Wolf, Torsten Wüstenberg, Marc Montgomery Lässer, Lena Anna Schmid, Knut Schnell, Dusan Hirjak, Philipp Arthur Thomann

Background

While numerous structural magnetic resonance imaging (MRI) studies revealed changes of brain volume or density, cortical thickness and fibre integrity in schizophrenia, the effect of tissue alterations on the contrast properties of neural structures has so far remained mostly unexplored.

Methods

Whole brain high-resolution MRI at 3 Tesla was used to investigate tissue contrast and cortical thickness in patients with schizophrenia and healthy controls.

Results

Patients showed significantly decreased gray to white matter contrast in large portions throughout the cortical mantle with preponderance in inferior, middle, superior and medial temporal areas as well as in lateral and medial frontal regions. The extent of these intensity contrast changes exceeded the extent of cortical thinning. Further, contrast changes remained significant after controlling for cortical thickness measurements.

Conclusions

Our findings clearly emphasize the presence of schizophrenia related brain tissue changes that alter the imaging properties of brain structures. Intensity contrast measurements might not only serve as a highly sensitive metric but also as a potential indicator of a distinct pathological process that might be independent from volume or thickness alterations.

Circulating Mesenchymal Stem Cells Microparticles in Patients with Cerebrovascular Disease

2012-05-15T21:00:00Z

by Suk Jae Kim, Gyeong Joon Moon, Yeon Hee Cho, Ho Young Kang, Na Kyum Hyung, Donghee Kim, Ji Hyun Lee, Ji Yoon Nam, Oh Young Bang

Preclinical and clinical studies have shown that the application of CD105⁺ mesenchymal stem cells (MSCs) is feasible and may lead to recovery after stroke. In addition, circulating microparticles are reportedly functional in various disease conditions. We tested the levels of circulating CD105⁺ microparticles in patients with acute ischemic stroke. The expression of CD105 (a surface marker of MSCs) and CXCR4 (a CXC chemokine receptor for MSC homing) on circulating microparticles was evaluated by flow cytometry of samples from 111 patients and 50 healthy subjects. The percentage of apoptotic CD105 microparticles was determined based on annexin V (AV) expression. The relationship between serum levels of CD105⁺/AV⁻ microparticles, stromal cells derived factor-1α (SDF-1α), and the extensiveness of cerebral infarcts was also evaluated. CD105⁺/AV⁻ microparticles were higher in stroke patients than control subjects. Correlation analysis showed that the levels of CD105⁺/AV⁻ microparticles increased as the baseline stroke severity increased. Multivariate testing showed that the initial severity of stroke was independently associated with circulating CD105⁺/AV⁻ microparticles (OR, 1.103 for 1 point increase in the NIHSS score on admission; 95% CI, 1.032–1.178) after adjusting for other variables. The levels of CD105⁺/CXCR4⁺/AV⁻ microparticles were also increased in patients with severe disability (r = 0.192, p = 0.046 for NIHSS score on admission), but were decreased with time after stroke onset (r = −0.204, p = 0.036). Risk factor profiles were not associated with the levels of circulating microparticles or SDF-1α. In conclusion, our data showed that stroke triggers the mobilization of MSC-derived microparticles, especially in patients with extensive ischemic stroke.

Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis

2012-05-15T21:00:00Z

by Navid Shiee, Pierre-Louis Bazin, Kathleen M. Zackowski, Sheena K. Farrell, Daniel M. Harrison, Scott D. Newsome, John N. Ratchford, Brian S. Caffo, Peter A. Calabresi, Dzung L. Pham, Daniel S. Reich

Background

Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment.

Methodology/Principal Findings

Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ∼0.3–0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = −0.36, p<0.005).

Conclusion

The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability.

The Impact of Human Conflict on the Genetics of Mastomys natalensis and Lassa Virus in West Africa

2012-05-15T21:00:00Z

by Aude Lalis, Raphaël Leblois, Emilie Lecompte, Christiane Denys, Jan ter Meulen, Thierry Wirth

Environmental changes have been shown to play an important role in the emergence of new human diseases of zoonotic origin. The contribution of social factors to their spread, especially conflicts followed by mass movement of populations, has not been extensively investigated. Here we reveal the effects of civil war on the phylogeography of a zoonotic emerging infectious disease by concomitantly studying the population structure, evolution and demography of Lassa virus and its natural reservoir, the rodent Mastomys natalensis, in Guinea, West Africa. Analysis of nucleoprotein gene sequences enabled us to reconstruct the evolutionary history of Lassa virus, which appeared 750 to 900 years ago in Nigeria and only recently spread across western Africa (170 years ago). Bayesian demographic inferences revealed that both the host and the virus populations have gone recently through severe genetic bottlenecks. The timing of these events matches civil war-related mass movements of refugees and accompanying environmental degradation. Forest and habitat destruction and human predation of the natural reservoir are likely explanations for the sharp decline observed in the rodent populations, the consequent virus population decline, and the coincident increased incidence of Lassa fever in these regions. Interestingly, we were also able to detect a similar pattern in Nigeria coinciding with the Biafra war. Our findings show that anthropogenic factors may profoundly impact the population genetics of a virus and its reservoir within the context of an emerging infectious disease.

Increased Expression of PITX2 Transcription Factor Contributes to Ovarian Cancer Progression

2012-05-15T21:00:00Z

by Frederic K. C. Fung, David W. Chan, Vincent W. S. Liu, Thomas H. Y. Leung, Annie N. Y. Cheung, Hextan Y. S. Ngan

Background

Paired-like homeodomain 2 (PITX2) is a bicoid homeodomain transcription factor which plays an essential role in maintaining embryonic left-right asymmetry during vertebrate embryogenesis. However, emerging evidence suggests that the aberrant upregulation of PITX2 may be associated with tumor progression, yet the functional role that PITX2 plays in tumorigenesis remains unknown.

Principal Findings

Using real-time quantitative RT-PCR (Q-PCR), Western blot and immunohistochemical (IHC) analyses, we demonstrated that PITX2 was frequently overexpressed in ovarian cancer samples and cell lines. Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (P<0.001) ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect.

Conclusion

Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.

A Comprehensive Breath Plume Model for Disease Transmission via Expiratory Aerosols

2012-05-15T21:00:00Z

by Siobhan K. Halloran, Anthony S. Wexler, William D. Ristenpart

The peak in influenza incidence during wintertime in temperate regions represents a longstanding, unresolved scientific question. One hypothesis is that the efficacy of airborne transmission via aerosols is increased at lower humidities and temperatures, conditions that prevail in wintertime. Recent work with a guinea pig model by Lowen et al. indicated that humidity and temperature do modulate airborne influenza virus transmission, and several investigators have interpreted the observed humidity dependence in terms of airborne virus survivability. This interpretation, however, neglects two key observations: the effect of ambient temperature on the viral growth kinetics within the animals, and the strong influence of the background airflow on transmission. Here we provide a comprehensive theoretical framework for assessing the probability of disease transmission via expiratory aerosols between test animals in laboratory conditions. The spread of aerosols emitted from an infected animal is modeled using dispersion theory for a homogeneous turbulent airflow. The concentration and size distribution of the evaporating droplets in the resulting “Gaussian breath plume” are calculated as functions of position, humidity, and temperature. The overall transmission probability is modeled with a combination of the time-dependent viral concentration in the infected animal and the probability of droplet inhalation by the exposed animal downstream. We demonstrate that the breath plume model is broadly consistent with the results of Lowen et al., without invoking airborne virus survivability. The results also suggest that, at least for guinea pigs, variation in viral kinetics within the infected animals is the dominant factor explaining the increased transmission probability observed at lower temperatures.

Ammonium Is Toxic for Aging Yeast Cells, Inducing Death and Shortening of the Chronological Lifespan

2012-05-15T21:00:00Z

by Júlia Santos, Maria João Sousa, Cecília Leão

Here we show that in aging Saccharomyces cerevisiae (budding yeast) cells, NH₄⁺ induces cell death associated with shortening of chronological life span. This effect is positively correlated with the concentration of NH₄⁺ added to the culture medium and is particularly evident when cells are starved for auxotrophy-complementing amino acids. NH₄⁺-induced cell death is accompanied by an initial small increase of apoptotic cells followed by extensive necrosis. Autophagy is inhibited by NH₄⁺, but this does not cause a decrease in cell viability. We propose that the toxic effects of NH₄⁺ are mediated by activation of PKA and TOR and inhibition of Sch9p. Our data show that NH₄⁺ induces cell death in aging cultures through the regulation of evolutionary conserved pathways. They may also provide new insights into longevity regulation in multicellular organisms and increase our understanding of human disorders such as hyperammonemia as well as effects of amino acid deprivation employed as a therapeutic strategy.

The Viral TRAF Protein (ORF111L) from Infectious Spleen and Kidney Necrosis Virus Interacts with TRADD and Induces Caspase 8-mediated Apoptosis

2012-05-15T21:00:00Z

by Bai-Liang He, Ji-Min Yuan, Lu-Yun Yang, Jun-Feng Xie, Shao-Ping Weng, Xiao-Qiang Yu, Jian-Guo He

Infectious spleen and kidney necrosis virus (ISKNV) is the type species of the Megalocytivirus genus of the Iridoviridae family. It causes a serious and potentially pandemic disease in wild and cultured fishes. ISKNV infection induces evident apoptosis in mandarin fish (Siniperca chuatsi) and zebrafish (Danio renio). However, the mechanism is still unknown. After a genome-wide bioinformatics analysis of ISKNV-encoded proteins, the ISKNV open reading frame 111L (ORF111L) shows a high similarity to the tumour necrosis factor receptor-associated factor (TRAF) encoded by fish, mice and mammals, which is essential for apoptotic signal transduction. Moreover, ORF111L was verified to directly interact with the zebrafish TNF receptor type 1 associated death domain protein (TRADD). A recombinant plasmid containing the DNA sequence of ORF111L was constructed and microinjected into zebrafish embryos at the 1–2 cell stage to investigate its biological function in vivo. ORF111L overexpression in the embryos resulted in increased apoptosis. ORF111L-induced apoptosis was clearly associated with significant caspase 8 upregulation and activation. The knockdown of zebrafish caspase 8 expression effectively blocked the apoptosis induced by ORF111L overexpression. Significantly, ORF111L overexpression resulted in much stronger effect on caspase 8 and caspase 3 upregulation compared to zebrafish TRAF2. This is the first report of a viral protein similar to TRAF that interacts with TRADD and induces caspase 8-mediated apoptosis, which may provide novel insights into the pathogenesis of ISKNV infection.

Decoding the Folding of Burkholderia glumae Lipase: Folding Intermediates En Route to Kinetic Stability

2012-05-15T21:00:00Z

by Kris Pauwels, Manuel M. Sanchez del Pino, Georges Feller, Patrick Van Gelder

The lipase produced by Burkholderia glumae folds spontaneously into an inactive near-native state and requires a periplasmic chaperone to reach its final active and secretion-competent fold. The B. glumae lipase-specific foldase (Lif) is classified as a member of the steric-chaperone family of which the propeptides of α-lytic protease and subtilisin are the best known representatives. Steric chaperones play a key role in conferring kinetic stability to proteins. However, until present there was no solid experimental evidence that Lif-dependent lipases are kinetically trapped enzymes. By combining thermal denaturation studies with proteolytic resistance experiments and the description of distinct folding intermediates, we demonstrate that the native lipase has a kinetically stable conformation. We show that a newly discovered molten globule-like conformation has distinct properties that clearly differ from those of the near-native intermediate state. The folding fingerprint of Lif-dependent lipases is put in the context of the protease-prodomain system and the comparison reveals clear differences that render the lipase-Lif systems unique. Limited proteolysis unveils structural differences between the near-native intermediate and the native conformation and sets the stage to shed light onto the nature of the kinetic barrier.

Introduced Pathogens and Native Freshwater Biodiversity: A Case Study of Sphaerothecum destruens

2012-05-15T21:00:00Z

by Demetra Andreou, Kristen D. Arkush, Jean-François Guégan, Rodolphe E. Gozlan

A recent threat to European fish diversity was attributed to the association between an intracellular parasite, Sphaerothecum destruens, and a healthy freshwater fish carrier, the invasive Pseudorasbora parva originating from China. The pathogen was found to be responsible for the decline and local extinction of the European endangered cyprinid Leucaspius delineatus and high mortalities in stocks of Chinook and Atlantic salmon in the USA. Here, we show that the emerging S. destruens is also a threat to a wider range of freshwater fish than originally suspected such as bream, common carp, and roach. This is a true generalist as an analysis of susceptible hosts shows that S. destruens is not limited to a phylogenetically narrow host spectrum. This disease agent is a threat to fish biodiversity as it can amplify within multiple hosts and cause high mortalities.

Tailored vs. Standardized Internet-Based Cognitive Behavior Therapy for Depression and Comorbid Symptoms: A Randomized Controlled Trial

2012-05-15T21:00:00Z

by Robert Johansson, Elin Sjöberg, Magnus Sjögren, Erik Johnsson, Per Carlbring, Therese Andersson, Andréas Rousseau, Gerhard Andersson

Background and Aims

Major depression can be treated by means of cognitive behavior therapy, delivered via the Internet as guided self-help. Individually tailored guided self-help treatments have shown promising results in the treatment of anxiety disorders. This randomized controlled trial tested the efficacy of an Internet-based individually tailored guided self-help treatment which specifically targeted depression with comorbid symptoms. The treatment was compared both to standardized (non-tailored) Internet-based treatment and to an active control group in the form of a monitored online discussion group. Both guided self-help treatments were based on cognitive behavior therapy and lasted for 10 weeks. The discussion group consisted of weekly discussion themes related to depression and the treatment of depression.

Methods

A total of 121 participants with diagnosed major depressive disorder and with a range of comorbid symptoms were randomized to three groups. The tailored treatment consisted of a prescribed set of modules targeting depression as well as comorbid problems. The standardized treatment was a previously tested guided self-help program for depression.

Results

From pre-treatment to post-treatment, both treatment groups improved on measures of depression, anxiety and quality of life. The results were maintained at a 6-month follow-up. Subgroup analyses showed that the tailored treatment was more effective than the standardized treatment among participants with higher levels of depression at baseline and more comorbidity, both in terms of reduction of depressive symptoms and on recovery rates. In the subgroup with lower baseline scores of depression, few differences were seen between treatments and the discussion group.

Conclusions

This study shows that tailored Internet-based treatment for depression is effective and that addressing comorbidity by tailoring may be one way of making guided self-help treatments more effective than standardized approaches in the treatment of more severe depression.

Trial Registration

Clinicaltrials.gov NCT01181583

HBsAg Inhibits the Translocation of JTB into Mitochondria in HepG2 Cells and Potentially Plays a Role in HCC Progression

2012-05-15T21:00:00Z

by Yun-Peng Liu, Xiao-Ning Yang, Amarsanaa Jazag, Jin-Shui Pan, Tian-Hui Hu, Jing-Jing Liu, Bayasi Guleng, Jian-Lin Ren

Background and Aims

The expression of the jumping translocation breakpoint (JTB) gene is upregulated in malignant liver tissues; however, JTB is associated with unbalanced translocations in many other types of cancer that suppress JTB expression. No comprehensive analysis on its function in human hepatocellular carcinoma (HCC) has been performed to date. We aimed to define the biological consequences for interaction between JTB and HBsAg in HCC cell lines.

Methods

We employed the stable transfection to establish small HBsAg expressing HepG2 cell line, and stably silenced the JTB expression using short hairpin RNA in HepG2 cell line. The effects of JTB and small HBsAg in vitro were determined by assessing cell apoptosis and motility.

Results

Silencing of JTB expression promoted cancer cell motility and reduced cell apoptosis, which was significantly enhanced by HBs expression. Expression of HBsAg inhibited the translocation of JTB to the mitochondria. Furthermore, silencing of the JTB resulted in an increase in the phosphorylation of p65 in HepG2 cells and HepG2-HBs cells, whereas HBsAg expression decreased the phosphorylation of p65. The silencing of JTB in HepG2-HBs cells conferred increased advantages in cell motility and anti-apoptosis.

Conclusion

HBsAg inhibited the translocation of JTB to the mitochondria and decreased the phosphorylation of p65 through the interaction with JTB, After JTB knockdown, HBsAg exhibited a stronger potential to promote tumor progression. Our data suggested that JTB act as a tumor suppressor gene in regards to HBV infection and its activation might be applied as a therapeutic strategy for in control of HBV related HCC development.

Transcriptome Characterization by RNA-seq Unravels the Mechanisms of Butyrate-Induced Epigenomic Regulation in Bovine Cells

2012-05-15T21:00:00Z

by Sitao Wu, Robert W. Li, Weizhong Li, Cong-jun Li

Short-chain fatty acids (SCFAs), especially butyrate, affect cell differentiation, proliferation, and motility. Butyrate also induces cell cycle arrest and apoptosis through its inhibition of histone deacetylases (HDACs). In addition, butyrate is a potent inducer of histone hyper-acetylation in cells. Therefore, this SCFA provides an excellent in vitro model for studying the epigenomic regulation of gene expression induced by histone acetylation. In this study, we analyzed the differential in vitro expression of genes induced by butyrate in bovine epithelial cells by using deep RNA-sequencing technology (RNA-seq). The number of sequences read, ranging from 57,303,693 to 78,933,744, were generated per sample. Approximately 11,408 genes were significantly impacted by butyrate, with a false discovery rate (FDR) <0.05. The predominant cellular processes affected by butyrate included cell morphological changes, cell cycle arrest, and apoptosis. Our results provided insight into the transcriptome alterations induced by butyrate, which will undoubtedly facilitate our understanding of the molecular mechanisms underlying butyrate-induced epigenomic regulation in bovine cells.

The Sound of Feelings: Electrophysiological Responses to Emotional Speech in Alexithymia

2012-05-15T21:00:00Z

by Katharina Sophia Goerlich, André Aleman, Sander Martens

Background

Alexithymia is a personality trait characterized by difficulties in the cognitive processing of emotions (cognitive dimension) and in the experience of emotions (affective dimension). Previous research focused mainly on visual emotional processing in the cognitive alexithymia dimension. We investigated the impact of both alexithymia dimensions on electrophysiological responses to emotional speech in 60 female subjects.

Methodology

During unattended processing, subjects watched a movie while an emotional prosody oddball paradigm was presented in the background. During attended processing, subjects detected deviants in emotional prosody. The cognitive alexithymia dimension was associated with a left-hemisphere bias during early stages of unattended emotional speech processing, and with generally reduced amplitudes of the late P3 component during attended processing. In contrast, the affective dimension did not modulate unattended emotional prosody perception, but was associated with reduced P3 amplitudes during attended processing particularly to emotional prosody spoken in high intensity.

Conclusions

Our results provide evidence for a dissociable impact of the two alexithymia dimensions on electrophysiological responses during the attended and unattended processing of emotional prosody. The observed electrophysiological modulations are indicative of a reduced sensitivity to the emotional qualities of speech, which may be a contributing factor to problems in interpersonal communication associated with alexithymia.

A Neuromorphic Architecture for Object Recognition and Motion Anticipation Using Burst-STDP

2012-05-15T21:00:00Z

by Andrew Nere, Umberto Olcese, David Balduzzi, Giulio Tononi

In this work we investigate the possibilities offered by a minimal framework of artificial spiking neurons to be deployed in silico. Here we introduce a hierarchical network architecture of spiking neurons which learns to recognize moving objects in a visual environment and determine the correct motor output for each object. These tasks are learned through both supervised and unsupervised spike timing dependent plasticity (STDP). STDP is responsible for the strengthening (or weakening) of synapses in relation to pre- and post-synaptic spike times and has been described as a Hebbian paradigm taking place both in vitro and in vivo. We utilize a variation of STDP learning, called burst-STDP, which is based on the notion that, since spikes are expensive in terms of energy consumption, then strong bursting activity carries more information than single (sparse) spikes. Furthermore, this learning algorithm takes advantage of homeostatic renormalization, which has been hypothesized to promote memory consolidation during NREM sleep. Using this learning rule, we design a spiking neural network architecture capable of object recognition, motion detection, attention towards important objects, and motor control outputs. We demonstrate the abilities of our design in a simple environment with distractor objects, multiple objects moving concurrently, and in the presence of noise. Most importantly, we show how this neural network is capable of performing these tasks using a simple leaky-integrate-and-fire (LIF) neuron model with binary synapses, making it fully compatible with state-of-the-art digital neuromorphic hardware designs. As such, the building blocks and learning rules presented in this paper appear promising for scalable fully neuromorphic systems to be implemented in hardware chips.

Optic Nerve Head Quantification in Idiopathic Intracranial Hypertension by Spectral Domain OCT

2012-05-15T21:00:00Z

by Falko Kaufhold, Ella Maria Kadas, Christoph Schmidt, Hagen Kunte, Jan Hoffmann, Hanna Zimmermann, Timm Oberwahrenbrock, Lutz Harms, Konrad Polthier, Alexander U. Brandt, Friedemann Paul

Objective

To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH).

Design and Patients

Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans.

Results

Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP).

Conclusion

Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumbar punctures and could therefore ease monitoring of treatment or disease progression.

The Fanconi Anaemia Components UBE2T and FANCM Are Functionally Linked to Nucleotide Excision Repair

2012-05-15T21:00:00Z

by Ian R. Kelsall, Judith Langenick, Craig MacKay, Ketan J. Patel, Arno F. Alpi

The many proteins that function in the Fanconi anaemia (FA) monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes – UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair.

The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

2012-05-15T21:00:00Z

by Hongen Wei, Carl Dobkin, Ashfaq M. Sheikh, Mazhar Malik, W. Ted Brown, Xiaohong Li

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

Characterization of Modular Bacteriophage Endolysins from Myoviridae Phages OBP, 201φ2-1 and PVP-SE1

2012-05-15T21:00:00Z

by Maarten Walmagh, Yves Briers, Silvio Branco dos Santos, Joana Azeredo, Rob Lavigne

Peptidoglycan lytic enzymes (endolysins) induce bacterial host cell lysis in the late phase of the lytic bacteriophage replication cycle. Endolysins OBPgp279 (from Pseudomonas fluorescens phage OBP), PVP-SE1gp146 (Salmonella enterica serovar Enteritidis phage PVP-SE1) and 201φ2-1gp229 (Pseudomonas chlororaphis phage 201φ2-1) all possess a modular structure with an N-terminal cell wall binding domain and a C-terminal catalytic domain, a unique property for endolysins with a Gram-negative background. All three modular endolysins showed strong muralytic activity on the peptidoglycan of a broad range of Gram-negative bacteria, partly due to the presence of the cell wall binding domain. In the case of PVP-SE1gp146, this domain shows a binding affinity for Salmonella peptidoglycan that falls within the range of typical cell adhesion molecules (K_aff = 1.26×10⁶ M⁻¹). Remarkably, PVP-SE1gp146 turns out to be thermoresistant up to temperatures of 90°C, making it a potential candidate as antibacterial component in hurdle technology for food preservation. OBPgp279, on the other hand, is suggested to intrinsically destabilize the outer membrane of Pseudomonas species, thereby gaining access to their peptidoglycan and exerts an antibacterial activity of 1 logarithmic unit reduction. Addition of 0.5 mM EDTA significantly increases the antibacterial activity of the three modular endolysins up to 2–3 logarithmic units reduction. This research work offers perspectives towards elucidation of the structural differences explaining the unique biochemical and antibacterial properties of OBPgp279, PVP-SE1gp146 and 201φ2-1gp229. Furthermore, these endolysins extensively enlarge the pool of potential antibacterial compounds used against multi-drug resistant Gram-negative bacterial infections.

Phenotypic and Functional Changes in Blood Monocytes Following Adherence to Endothelium

2012-05-15T21:00:00Z

by Colin Tso, Kerry-Anne Rye, Philip Barter

Objective

Blood monocytes are known to express endothelial-like genes during co-culture with endothelium. In this study, the time-dependent change in the phenotype pattern of primary blood monocytes after adhering to endothelium is reported using a novel HLA-A2 mistyped co-culture model.

Methods and Results

Freshly isolated human PBMCs were co-cultured with human umbilical vein endothelial cells or human coronary arterial endothelial cells of converse human leukocyte antigen A2 (HLA-A2) status. This allows the tracking of the PBMC-derived cells by HLA-A2 expression and assessment of their phenotype pattern over time. PBMCs that adhered to the endothelium at the start of the co-culture were predominantly CD11b+ blood monocytes. After 24 to 72 hours in co-culture, the endothelium-adherent monocytes acquired endothelial-like properties including the expression of endothelial nitric oxide synthase, CD105, CD144 and vascular endothelial growth factor receptor 2. The expression of monocyte/macrophage lineage antigens CD14, CD11b and CD36 were down regulated concomitantly. The adherent monocytes did not express CD115 after 1 day of co-culture. By day 6, the monocyte-derived cells expressed vascular cell adhesion molecule 1 in response to tumour necrosis factor alpha. Up to 10% of the PBMCs adhered to the endothelium. These monocyte-derived cells contributed up to 30% of the co-cultured cell layer and this was dose-dependent on the PBMC seeding density.

Conclusions

Human blood monocytes undergo rapid phenotype change to resemble endothelial cells after adhering to endothelium.

A Dual-Color Luciferase Assay System Reveals Circadian Resetting of Cultured Fibroblasts by Co-Cultured Adrenal Glands

2012-05-15T21:00:00Z

by Takako Noguchi, Masaaki Ikeda, Yoshihiro Ohmiya, Yoshihiro Nakajima

In mammals, circadian rhythms of various organs and tissues are synchronized by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. Glucocorticoids released from the adrenal glands can synchronize circadian rhythms in other tissues. Many hormones show circadian rhythms in their plasma concentrations; however, whether organs outside the SCN can serve as master synchronizers to entrain circadian rhythms in target tissues is not well understood. To further delineate the function of the adrenal glands and the interactions of circadian rhythms in putative master synchronizing organs and their target tissues, here we report a simple co-culture system using a dual-color luciferase assay to monitor circadian rhythms separately in various explanted tissues and fibroblasts. In this system, circadian rhythms of organs and target cells were simultaneously tracked by the green-emitting beetle luciferase from Pyrearinus termitilluminans (ELuc) and the red-emitting beetle luciferase from Phrixothrix hirtus (SLR), respectively. We obtained tissues from the adrenal glands, thyroid glands, and lungs of transgenic mice that expressed ELuc under control of the promoter from a canonical clock gene, mBmal1. The tissues were co-cultured with Rat-1 fibroblasts as representative target cells expressing SLR under control of the mBmal1 promoter. Amplitudes of the circadian rhythms of Rat-1 fibroblasts were potentiated when the fibroblasts were co-cultured with adrenal gland tissue, but not when co-cultured with thyroid gland or lung tissue. The phases of Rat-1 fibroblasts were reset by application of adrenal gland tissue, whereas the phases of adrenal gland tissue were not influenced by Rat-1 fibroblasts. Furthermore, the effect of the adrenal gland tissue on the fibroblasts was blocked by application of a glucocorticoid receptor (GR) antagonist. These results demonstrate that glucocorticoids are strong circadian synchronizers for fibroblasts and that this co-culture system is a useful tool to analyze humoral communication between different tissues or cell populations.

Concurrent Word Generation and Motor Performance: Further Evidence for Language-Motor Interaction

2012-05-15T21:00:00Z

by Amy D. Rodriguez, Matthew L. McCabe, Joe R. Nocera, Jamie Reilly

Embodied/modality-specific theories of semantic memory propose that sensorimotor representations play an important role in perception and action. A large body of evidence supports the notion that concepts involving human motor action (i.e., semantic-motor representations) are processed in both language and motor regions of the brain. However, most studies have focused on perceptual tasks, leaving unanswered questions about language-motor interaction during production tasks. Thus, we investigated the effects of shared semantic-motor representations on concurrent language and motor production tasks in healthy young adults, manipulating the semantic task (motor-related vs. nonmotor-related words) and the motor task (i.e., standing still and finger-tapping). In Experiment 1 (n = 20), we demonstrated that motor-related word generation was sufficient to affect postural control. In Experiment 2 (n = 40), we demonstrated that motor-related word generation was sufficient to facilitate word generation and finger tapping. We conclude that engaging semantic-motor representations can have a reciprocal influence on motor and language production. Our study provides additional support for functional language-motor interaction, as well as embodied/modality-specific theories.

High-Resolution Positional Tracking for Long-Term Analysis of Drosophila Sleep and Locomotion Using the “Tracker” Program

2012-05-15T21:00:00Z

by Nathan Donelson, Eugene Z. Kim, Justin B. Slawson, Christopher G. Vecsey, Robert Huber, Leslie C. Griffith

Drosophila melanogaster has been used for decades in the study of circadian behavior, and more recently has become a popular model for the study of sleep. The classic method for monitoring fly activity involves counting the number of infrared beam crosses in individual small glass tubes. Incident recording methods such as this can measure gross locomotor activity, but they are unable to provide details about where the fly is located in space and do not detect small movements (i.e. anything less than half the enclosure size), which could lead to an overestimation of sleep and an inaccurate report of the behavior of the fly. This is especially problematic if the fly is awake, but is not moving distances that span the enclosure. Similarly, locomotor deficiencies could be incorrectly classified as sleep phenotypes. To address these issues, we have developed a locomotor tracking technique (the “Tracker” program) that records the exact location of a fly in real time. This allows for the detection of very small movements at any location within the tube. In addition to circadian locomotor activity, we are able to collect other information, such as distance, speed, food proximity, place preference, and multiple additional parameters that relate to sleep structure. Direct comparisons of incident recording and our motion tracking application using wild type and locomotor-deficient (CASK-β null) flies show that the increased temporal resolution in the data from the Tracker program can greatly affect the interpretation of the state of the fly. This is especially evident when a particular condition or genotype has strong effects on the behavior, and can provide a wealth of information previously unavailable to the investigator. The interaction of sleep with other behaviors can also be assessed directly in many cases with this method.

Diabetes and Pre-Diabetes as Determined by Glycated Haemoglobin A1c and Glucose Levels in a Developing Southern Chinese Population

2012-05-15T21:00:00Z

by Yong Hui Zhang, Wen Jun Ma, G. Neil Thomas, Yan Jun Xu, Xiang Qian Lao, Xiao Jun Xu, Xiu Ling Song, Hao Feng Xu, Qiu Mao Cai, Liang Xia, Shao Ping Nie, Hui Hong Deng, Ignatius Tak Sun Yu

Background

The American Diabetes Association and World Health Organization have recently adopted the HbA1c measurement as one method of diagnostic criteria for diabetes. The change in diagnostic criteria has important implications for diabetes treatment and prevention. We therefore investigate diabetes using HbA1c and glucose criteria together, and assess the prevalent trend in a developing southern Chinese population with 85 million residents.

Methods

A stratified multistage random sampling method was applied and a representative sample of 3590 residents 18 years of age or above was obtained in 2010. Each participant received a full medical check-up, including measurement of fasting plasma glucose, 2-hour post-load plasma glucose, and HbA1c. Information on history of diagnosis and treatment of diabetes was collected. The prevalence of diabetes obtained from the present survey was compared with the data from the survey in 2002.

Results

The prevalence of diabetes based on both glucose and HbA1c measurements was 21.7% (95% CI: 17.4%–26.1%) in 2010, which suggests that more than 1 in 5 adult residents were suffering from diabetes in this developing population. Only 12.9% (95% CI: 8.3%–17.6%) of diabetic residents were aware of their condition. The prevalence of pre-diabetes was 66.3% (95% CI: 62.7%–69.8%). The prevalence of diabetes and pre-diabetes which met all the three diagnostic thresholds (fast plasma glucose, 2 hour post-load plasma glucose, and HbA1c) was 3.1% and 5.2%, respectively. Diabetes and pre-diabetes as determined by HbA1c measurement had higher vascular risk than those determined by glucose levels. The prevalence of diabetes increased from 2.9% (95% CI: 2.0%–3.7%) in 2002 to 13.8% (95% CI: 10.2%–17.3%) in 2010 based on the same glucose criteria.

Conclusions

Our results show that the diabetes epidemic is accelerating in China. The awareness of diabetes is extremely low. The glucose test and HbA1c measurement should be used together to increase detection of diabetes and pre-diabetes.

Insufficient Radiofrequency Ablation Promotes Angiogenesis of Residual Hepatocellular Carcinoma via HIF-1α/VEGFA

2012-05-15T21:00:00Z

by Jian Kong, Jinge Kong, Bing Pan, Shan Ke, Shuying Dong, Xiuli Li, Aimin Zhou, Lemin Zheng, Wen-bing Sun

Background

The mechanism of rapid growth of the residual tumor after radiofrequency (RF) ablation is poorly understood. In this study, we investigated the effect of hyperthermia on HepG2 cells and generated a subline with enhanced viability and dys-regulated angiogenesis in vivo, which was used as a model to further determine the molecular mechanism of the rapid growth of residual HCC after RF ablation.

Methodology/Principal Findings

Heat treatment was used to establish sublines of HepG2 cells. A subline (HepG2 k) with a relatively higher viability and significant heat tolerance was selected. The cellular protein levels of VEGFA, HIF-1α and p-Akt, VEGFA mRNA and secreted VEGFA were measured, and all of these were up-regulated in this subline compared to parental HepG2 cells. HIF-1α inhibitor YC-1 and VEGFA siRNA inhibited the high viability of the subline. The conditioned media from the subline exerted stronger pro-angiogenic effects. Bevacizumab, VEGFA siRNA and YC-1 inhibited proangiogenic effects of the conditioned media of HepG2 k cells and abolished the difference between parental HepG2 cells and HepG2 k cells. For in vivo studies, a nude mouse model was used, and the efficacy of bavacizumab was determined. HepG2 k tumor had stronger pro-angiogenic effects than parental HepG2 tumor. Bevacizumab could inhibit the tumor growth and angiogenesis, and also eliminate the difference in tumor growth and angiogenesis between parental HepG2 tumor and HepG2 k tumor in vivo.

Conclusions/Significance

The angiogenesis induced by HIF1α/VEGFA produced by altered cells after hyperthermia treatment may play an important role in the rapid growth of residual HCC after RF ablation. Bevacizumab may be a good candidate drug for preventing and treating the process.

Slip-Flow and Heat Transfer of a Non-Newtonian Nanofluid in a Microtube

2012-05-15T21:00:00Z

by Jun Niu, Ceji Fu, Wenchang Tan

The slip-flow and heat transfer of a non-Newtonian nanofluid in a microtube is theoretically studied. The power-law rheology is adopted to describe the non-Newtonian characteristics of the flow, in which the fluid consistency coefficient and the flow behavior index depend on the nanoparticle volume fraction. The velocity profile, volumetric flow rate and local Nusselt number are calculated for different values of nanoparticle volume fraction and slip length. The results show that the influence of nanoparticle volume fraction on the flow of the nanofluid depends on the pressure gradient, which is quite different from that of the Newtonian nanofluid. Increase of the nanoparticle volume fraction has the effect to impede the flow at a small pressure gradient, but it changes to facilitate the flow when the pressure gradient is large enough. This remarkable phenomenon is observed when the tube radius shrinks to micrometer scale. On the other hand, we find that increase of the slip length always results in larger flow rate of the nanofluid. Furthermore, the heat transfer rate of the nanofluid in the microtube can be enhanced due to the non-Newtonian rheology and slip boundary effects. The thermally fully developed heat transfer rate under constant wall temperature and constant heat flux boundary conditions is also compared.