Πέμπτη, 23 Μαρτίου 2017

Hepatic transcriptomic alterations for N , N -dimethyl- p -toluidine (DMPT) and p -toluidine after 5-day exposure in rats

Abstract

N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data were used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5 days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5 %). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.



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Optimizing Charge Injection across Transition Metal Dichalcogenide Heterojunctions: Theory and Experiment

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00285
ancac3?d=yIl2AUoC8zA


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Oral Health Education in Medical Curriculum

Objective:

Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum O

Materials (Subjects) and Methods

Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum

Results:

Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum

Conclusion:

Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum Oral Health Education in Medical Curriculum


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New title will be launched on J-STAGE.Journal of Japan Academy of Community Health Nursing



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New title will be launched on J-STAGE.The Southern Hemisphere review



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New title will be launched on J-STAGE.Japan Pension Review



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The new issue is now available.Urban and Regional Planning Review

Vol.4

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The new issue is now available.Archives of Sandplay Therapy

Vol.29 No.2

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The new issue is now available.Journal of the Japan Society for Technology of Plasticity

Vol.58 No.674

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The new issue is now available.Japanese Journal of Infectious Diseases

Vol.70 No.2

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The new issue is now available.The Journal of Agricultural History

Vol.30

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The new issue is now available.The Journal of Agricultural History

Vol.39

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The new issue is now available.The Journal of Agricultural History

Vol.34

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The new issue is now available.Transactions of The Japan Institute of Electronics Packaging

Vol.10

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The new issue is now available.Journal of The Remote Sensing Society of Japan

Vol.36 No.4

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The new issue is now available.SYSTEMS, CONTROL AND INFORMATION

Vol.60 No.8

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The new issue is now available.Root Research

Vol.26 No.1

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The new issue is now available.Japan Journal of Sport Sociology

Vol.25 No.1

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The new issue is now available.Records Management

Vol.70

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The new issue is now available.The Journal of Agricultural History

Vol.38

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The new issue is now available.Records Management

Vol.69

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The new issue is now available.Journal of the Japanese Coronary Association

Vol.23 No.1

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Isolation of nontuberculous mycobacteria from soil using Middlebrook 7H10 agar with increased malachite green concentration

Environmental exposure is considered to be responsible for nontuberculous mycobacterial infections in humans. To facilitate the isolation of mycobacteria from soil, Middlebrook 7H10 agar was optimized as an en...

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Proteomic signature of acute liver failure: from discovery and verification in a pig model to confirmation in humans [Research]

Acute liver failure (ALF) is a fatal condition hallmarked by rapid development. The present study aimed to describe the dynamic alterations of serum proteins associated with ALF development, and to seek for novel biomarkers of ALF. Miniature pigs (n=30) were employed to establish ALF models by infusing D-galactosamine (GALN, 1.3g/kg). A total of 1589 serum proteins were compared in pooled serum samples (n=10) before and 36 hours after GALN administration through label-free quantitation (LFQ) based shotgun proteomics. Functional analysis suggested a significant enrichment of ALF-related proteins involved in energy metabolism. Temporal changes of 20 energy metabolism related proteins were investigated in individual pigs (n=8) via parallel reaction monitoring (PRM) based targeted proteomics. In addition, mitochondrion degeneration and gene expression alteration of aerobic metabolism genes was confirmed in GALN-insulted pig liver. In clinical validation study enrolled 34 ALF patients and 40 healthy controls, fructose-1,6-bisphosphatase 1 (FBP1) showed a prognostic value for short-term survival (30 days) equal to that of the Model of End-stage Liver Disease score (ROC-AUC=0.778). Survival analysis suggested significantly higher death-related hazard in ALF patients with higher FBP1 levels (>16.89 μg/dL) than in those with lower FBP1 levels (p=0.002). Additionally, serum retinol binding protein 4 (RBP4) level was found decreased in prior to ALT elevation in GALN-insulted pig model. We also confirmed that serum level of RBP4 is significantly lower in ALF patients (p<0.001) as compared with healthy controls. In summary, this translational study were displayed by multi-staged proteomics technique unveiled underlying functional changes related to the development of ALF and facilitated the discovery of novel ALF markers.  



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Hypovitaminosis D in patients with heart failure: effects on functional capacity and patients’ survival

Abstract

Chronic heart failure is a major cause of morbidity and mortality, but its prognosis remains poor. Vitamin D hormone has many extra-skeletal functions including a positive impact on the cardiovascular system, and has been proposed for mortality risk evaluation in heart failure patients. The aim of the present study was to evaluate vitamin D status in heart failure patients, measured by high performance liquid chromatography coupled with mass spectrometry and to correlate serum 25 hydroxy-vitamin D (25OHD) levels with functional (peak VO2%) and mortality (Metabolic Exercise Cardiac Kidney Index) heart failure parameters. We enrolled 261 consecutive patients diagnosed with heart failure; all patients underwent a comprehensive clinical and biochemical characterization, and serum 25OHD levels were measured by high performance liquid chromatography coupled with mass spectrometry. Cardiopulmonary test parameters and Metabolic Exercise Cardiac Kidney Index of mortality risk were measured in all patients. Serum 25OHD levels ranged between 2 and 45 ng/ml (mean 17 ± 9 ng/ml); most patients (87%) showed hypovitaminosis D, and 25% showed severe vitamin D deficiency (serum 25OHD < 10 ng/ml). Patients with 25OHD < 10 ng/ml had significantly lower cardiopulmonary test VO2/kg, peak VO2% and significantly higher N-terminalproBrain natriuretic peptide and Metabolic Exercise Cardiac Kidney Index, than patients with 25OHD > 10 ng/ml. Patients with peak VO2% < 50% showed significantly lower 25OHD compared to those with peak VO2% > 50%. There was a significant, positive correlation (r = 0.16, p = 0.008) between 25OHD levels and peak VO2%, and an inverse correlation with Metabolic Exercise Cardiac Kidney Index (r = −0.21, p < 0.001), even when adjusted for age, Body Mass Index, MDRD, N-terminalproBrain natriuretic peptide. In conclusion, our findings show that vitamin D levels are associated with functional and mortality heart failure prognosis parameters.



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In Situ Preparation of Metal Halide Perovskite Nanocrystal Thin Films for Improved Light-Emitting Devices

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00404
ancac3?d=yIl2AUoC8zA


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High-Throughput Survey of Ordering Configurations in MXene Alloys Across Compositions and Temperatures

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b08227
ancac3?d=yIl2AUoC8zA


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Chiral Plasmonic Nanochains via the Self-Assembly of Gold Nanorods and Helical Glutathione Oligomers Facilitated by Cetyltrimethylammonium Bromide Micelles

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.6b07697
ancac3?d=yIl2AUoC8zA


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From Dual-Mode Triboelectric Nanogenerator to Smart Tactile Sensor: A Multiplexing Design

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b00396
ancac3?d=yIl2AUoC8zA


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Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer

Publication date: Available online 23 March 2017
Source:Cancer Cell
Author(s): Xiaoju Wang, Yuanyuan Qiao, Irfan A. Asangani, Bushra Ateeq, Anton Poliakov, Marcin Cieślik, Sethuramasundaram Pitchiaya, Balabhadrapatruni V.S.K. Chakravarthi, Xuhong Cao, Xiaojun Jing, Cynthia X. Wang, Ingrid J. Apel, Rui Wang, Jean Ching-Yi Tien, Kristin M. Juckette, Wei Yan, Hui Jiang, Shaomeng Wang, Sooryanarayana Varambally, Arul M. Chinnaiyan
Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.

Teaser

Wang et al. identify peptides that interact with the DNA binding domain of ERG, thereby attenuating protein-protein interactions and chromatin recruitment of ERG and inducing ERG degradation. These peptides reduce proliferation, invasion, and tumor growth of prostate cancer cells with the TMPRSS2:ERG gene fusion.


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m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

Publication date: Available online 23 March 2017
Source:Cancer Cell
Author(s): Sicong Zhang, Boxuan Simen Zhao, Aidong Zhou, Kangyu Lin, Shaoping Zheng, Zhike Lu, Yaohui Chen, Erik P. Sulman, Keping Xie, Oliver Bögler, Sadhan Majumder, Chuan He, Suyun Huang
The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma.

Graphical abstract

image

Teaser

Zhang et al. reveal that elevated RNA m6A demethylase ALKBH5 in glioblastoma stem-like cells enhances self-renewal and tumorigenesis through regulation of FOXM1. The lncRNA antisense to FOXM1 promotes the interaction of ALKBH5 with FOXM1 nascent RNA, leading to demethylation and elevated expression of FOXM1.


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Latest in @JAMAOnc : mothers who are #cancer #survivors face higher risk of preterm births. Read more at… https://t.co/a2qje2ctMu

Latest in @JAMAOnc : mothers who are #cancer #survivors face higher risk of preterm births. Read more at… https://t.co/a2qje2ctMu

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Ten simple rules for forming a scientific professional society

by Bruno A. Gaëta, Javier De Las Rivas, Paul Horton, Pieter Meysman, Nicola Mulder, Paolo Romano, Lonnie Welch



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Understanding health policy leaders’ training needs

by Carey Roth Bayer, L. Lerissa Smith, Renée Volny Darko, Marissa McKool, Fengxia Yan, Harry Heiman

Purpose

We assessed the training needs of health policy leaders and practitioners across career stages; identified areas of core content for health policy training programs; and, identified training modalities for health policy leaders.

Methods

We convened a focus group of health policy leaders at varying career stages to inform the development of the Health Policy Leaders’ Training Needs Assessment tool. We piloted and distributed the tool electronically. We used descriptive statistics and thematic coding for analysis.

Results

Seventy participants varying in age and stage of career completed the tool. “Cost implications of health policies” ranked highest for personal knowledge development and “intersection of policy and politics” ranked highest for health policy leaders in general. “Effective communication skills” ranked as the highest skill element and “integrity” as the highest attribute element. Format for training varied based on age and career stage.

Conclusions

This study highlighted the training needs of health policy leaders personally as well as their perceptions of the needs for training health policy leaders in general. The findings are applicable for current health policy leadership training programs as well as those in development.



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Quantitative shotgun proteomics unveils candidate novel oesophageal adenocarcinoma-specific proteins [Research]

Oesophageal cancer is the eighth most common cancer worldwide and the majority of patients have systemic disease at presentation. Oesophageal adenocarcinoma (OAC), the predominant subtype in western countries, is largely resistant to current chemotherapy regimens. Selective markers are needed to enhance clinical staging and to allow targeted therapies yet there are minimal proteomic data on this cancer type. After histological review, lysates from OAC and matched normal oesophageal and gastric samples from seven patients were subjected to LC MS/MS after tandem mass tag labelling and OFFGEL fractionation. Patient matched samples of OAC, normal oesophagus, normal stomach, lymph node metastases and uninvolved lymph nodes were used from an additional 115 patients for verification of expression by immunohistochemistry (IHC). Over six thousand proteins were identified and quantified across samples. Quantitative reproducibility was excellent between technical replicates and a moderate correlation was seen across samples with the same histology. The quantitative accuracy was verified across the dynamic range for seven proteins by immunohistochemistry (IHC) on the originating tissues. Multiple novel tumour-specific candidates are proposed and EPCAM was verified by IHC. This shotgun proteomic study of OAC used a comparative quantitative approach to reveal proteins highly expressed in specific tissue types. Novel tumour-specific proteins are proposed and EPCAM was demonstrated to be specifically over-expressed in primary tumours and lymph node metastases compared to surrounding normal tissues. This candidate and others proposed in this study could be developed as tumour-specific targets for novel clinical staging and therapeutic approaches.



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Quantitative age-specific variability of plasma proteins in healthy neonates, children and adults. [Research]

Human blood plasma is a complex biological fluid containing soluble proteins, sugars, hormones, electrolytes, and dissolved gasses. As plasma interacts with a wide array of bodily systems, changes in protein expression, or the presence or absence of specific proteins are regularly used in the clinic as a molecular biomarker tool. A large body of literature exists detailing proteomic changes in pathologic contexts, however little research has been conducted on the quantitation of the plasma proteome in age-specific, healthy subjects, especially in pediatrics. In this study, we utilized SWATH-MS to identify and quantify proteins in the blood plasma of healthy neonates, infants under 1 year of age, children between 1-5 years, and adults. We identified more than 100 proteins that showed significant differential expression levels across these age groups, and we analyzed variation in protein expression across the age spectrum. The plasma proteomic profiles of neonates were strikingly dissimilar to the older children and adults. By extracting the SWATH data against a large human spectral library we increased protein identification more than 6-fold (940 proteins) and confirmed the concentrations of several of these using ELISA. The results of this study map the variation in expression of proteins and pathways often implicated in disease, and so have significant clinical implication.



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FDG-PET/CT scoring system aids in cervical cancer prognosis

2017_03_23_09_13_42_115_2017_03_23_PET_CWith the help of an established five-point scoring system to assess metabolic...


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New study finds that most cancer mutations are due to random DNA copying 'mistakes'

Johns Hopkins Kimmel Cancer Center scientists report data from a new study providing evidence that random, unpredictable DNA copying "mistakes" account for nearly two-thirds of the mutations that cause cancer. Their research is grounded on a novel...

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Macrophage origin limits functional plasticity in helminth-bacterial co-infection

journal.ppat.1006233.g001

by Dominik Rückerl, Sharon M. Campbell, Sheelagh Duncan, Tara E. Sutherland, Stephen J. Jenkins, James P. Hewitson, Tom A. Barr, Lucy H. Jackson-Jones, Rick M. Maizels, Judith E. Allen

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.

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Delayed Otolith Development Does Not Impair Vestibular Circuit Formation in Zebrafish

Abstract

What is the role of normally patterned sensory signaling in development of vestibular circuits? For technical reasons, including the difficulty in depriving animals of vestibular inputs, this has been a challenging question to address. Here we take advantage of a vestibular-deficient zebrafish mutant, rock solo AN66 , in order to examine whether normal sensory input is required for formation of vestibular-driven postural circuitry. We show that the rock solo AN66 mutant is a splice site mutation in the secreted glycoprotein otogelin (otog), which we confirm through both whole genome sequencing and complementation with an otog early termination mutant. Using confocal microscopy, we find that elements of postural circuits are anatomically normal in rock solo AN66 mutants, including hair cells, vestibular ganglion neurons, and vestibulospinal neurons. Surprisingly, the balance and postural deficits that are readily apparent in younger larvae disappear around 2 weeks of age. We demonstrate that this behavioral recovery follows the delayed development of the anterior (utricular) otolith, which appears around 14 days post-fertilization (dpf), compared to 1 dpf in WT. These findings indicate that utricular signaling is not required for normal structural development of the inner ear and vestibular nucleus neurons. Furthermore, despite the otolith’s developmental delay until well after postural behaviors normally appear, downstream circuits can drive righting reflexes within ∼1–2 days of its arrival, indicating that vestibular circuit wiring is not impaired by a delay in patterned activity. The functional recovery of postural behaviors may shed light on why humans with mutations in otog exhibit only subclinical vestibular deficits.



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Correction: Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization

by Milad Adibi, Saiko Yoshida, Dolf Weijers, Christian Fleck



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Challenges of developing a cardiovascular risk calculator for patients with rheumatoid arthritis

by Cynthia S. Crowson, Silvia Rollefstad, George D. Kitas, Piet L. C. M. van Riel, Sherine E. Gabriel, Anne Grete Semb, On behalf of A Trans-Atlantic Cardiovascular Risk Consortium for Rheumatoid Arthritis (ATACC-RA)

Objective

Cardiovascular disease (CVD) risk calculators designed for use in the general population do not accurately predict the risk of CVD among patients with rheumatoid arthritis (RA), who are at increased risk of CVD. The process of developing risk prediction models involves numerous issues. Our goal was to develop a CVD risk calculator for patients with RA.

Methods

Thirteen cohorts of patients with RA originating from 10 different countries (UK, Norway, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico) were combined. CVD risk factors and RA characteristics at baseline, in addition to information on CVD outcomes were collected. Cox models were used to develop a CVD risk calculator, considering traditional CVD risk factors and RA characteristics. Model performance was assessed using measures of discrimination and calibration with 10-fold cross-validation.

Results

A total of 5638 RA patients without prior CVD were included (mean age: 55 [SD: 14] years, 76% female). During a mean follow-up of 5.8 years (30139 person years), 389 patients developed a CVD event. Event rates varied between cohorts, necessitating inclusion of high and low risk strata in the models. The multivariable analyses revealed 2 risk prediction models including either a disease activity score including a 28 joint count and erythrocyte sedimentation rate (DAS28ESR) or a health assessment questionnaire (HAQ) along with age, sex, presence of hypertension, current smoking and ratio of total cholesterol to high-density lipoprotein cholesterol. Unfortunately, performance of these models was similar to general population CVD risk calculators.

Conclusion

Efforts to develop a specific CVD risk calculator for patients with RA yielded 2 potential models including RA disease characteristics, but neither demonstrated improved performance compared to risk calculators designed for use in the general population. Challenges encountered and lessons learned are discussed in detail.



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Temperature and food quantity effects on the harpacticoid copepod Nitocra spinipes: Combining in vivo bioassays with population modeling

by Josef Koch, Thuy T. Bui, Elin Lundström Belleza, Markus Brinkmann, Henner Hollert, Magnus Breitholtz

The harpacticoid copepod Nitocra spinipes has become a popular model species for toxicity testing over the past few decades. However, the combined influence of temperature and food shortage, two climate change-related stressors, has never been assessed in this species. Consequently, effects of three temperatures (15, 20 and 25°C) and six food regimes (between 0 and 5 × 105 algal cells/mL) on the life cycle of N. spinipes were examined in this study. Similarly to other copepod species, development times and brood sizes decreased with rising temperatures. Mortality was lowest in the 20°C temperature setup, indicating a close-by temperature optimum for this species. Decreasing food concentrations led to increased development times, higher mortality and a reduction in brood size. A sex ratio shift toward more females per male was observed for increasing temperatures, while no significant relationship with food concentration was found. Temperature and food functions for each endpoint were integrated into an existing individual-based population model for N. spinipes which in the future may serve as an extrapolation tool in environmental risk assessment. The model was able to accurately reproduce the experimental data in subsequent verification simulations. We suggest that temperature, food shortage, and potentially other climate change-related stressors should be considered in environmental risk assessment of chemicals to account for non-optimal exposure conditions that may occur in the field. Furthermore, we advocate combining in vivo bioassays with population modeling as a cost effective higher tier approach to assess such considerations.

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Does shoe heel design influence ground reaction forces and knee moments during maximum lunges in elite and intermediate badminton players?

by Wing-Kai Lam, Jaejin Ryue, Ki-Kwang Lee, Sang-Kyoon Park, Jason Tak-Man Cheung, Jiseon Ryu

Background

Lunge is one frequently executed movement in badminton and involves a unique sagittal footstrike angle of more than 40 degrees at initial ground contact compared with other manoeuvres. This study examined if the shoe heel curvature design of a badminton shoe would influence shoe-ground kinematics, ground reaction forces, and knee moments during lunge.

Methods

Eleven elite and fifteen intermediate players performed five left-forward maximum lunge trials with Rounded Heel Shoe (RHS), Flattened Heel Shoe (FHS), and Standard Heel Shoes (SHS). Shoe-ground kinematics, ground reaction forces, and knee moments were measured by using synchronized force platform and motion analysis system. A 2 (Group) x 3 (Shoe) ANOVA with repeated measures was performed to determine the effects of different shoes and different playing levels, as well as the interaction of two factors on all variables.

Results

Shoe effect indicated that players demonstrated lower maximum vertical loading rate in RHS than the other two shoes (P P P P Conclusions

These findings indicate that shoe heel curvature would play some role in altering ground reaction force impact during badminton lunge. The differences in impact loads and knee moments between elite and intermediate players may be useful in optimizing footwear design and training strategy to minimize the potential risks for impact related injuries in badminton.



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Evaluating alignment and variant-calling software for mutation identification in C. elegans by whole-genome sequencing

by Harold E. Smith, Sijung Yun

Whole-genome sequencing is a powerful tool for analyzing genetic variation on a global scale. One particularly useful application is the identification of mutations obtained by classical phenotypic screens in model species. Sequence data from the mutant strain is aligned to the reference genome, and then variants are called to generate a list of candidate alleles. A number of software pipelines for mutation identification have been targeted to C. elegans, with particular emphasis on ease of use, incorporation of mapping strain data, subtraction of background variants, and similar criteria. Although success is predicated upon the sensitive and accurate detection of candidate alleles, relatively little effort has been invested in evaluating the underlying software components that are required for mutation identification. Therefore, we have benchmarked a number of commonly used tools for sequence alignment and variant calling, in all pair-wise combinations, against both simulated and actual datasets. We compared the accuracy of those pipelines for mutation identification in C. elegans, and found that the combination of BBMap for alignment plus FreeBayes for variant calling offers the most robust performance.

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Assessing various Infrared (IR) microscopic imaging techniques for post-mortem interval evaluation of human skeletal remains

by Claudia Woess, Seraphin Hubert Unterberger, Clemens Roider, Monika Ritsch-Marte, Nadin Pemberger, Jan Cemper-Kiesslich, Petra Hatzer-Grubwieser, Walther Parson, Johannes Dominikus Pallua

Due to the influence of many environmental processes, a precise determination of the post-mortem interval (PMI) of skeletal remains is known to be very complicated. Although methods for the investigation of the PMI exist, there still remains much room for improvement. In this study the applicability of infrared (IR) microscopic imaging techniques such as reflection-, ATR- and Raman- microscopic imaging for the estimation of the PMI of human skeletal remains was tested. PMI specific features were identified and visualized by overlaying IR imaging data with morphological tissue structures obtained using light microscopy to differentiate between forensic and archaeological bone samples. ATR and reflection spectra revealed that a more prominent peak at 1042 cm-1 (an indicator for bone mineralization) was observable in archeological bone material when compared with forensic samples. Moreover, in the case of the archaeological bone material, a reduction in the levels of phospholipids, proteins, nucleic acid sugars, complex carbohydrates as well as amorphous or fully hydrated sugars was detectable at (reciprocal wavelengths/energies) between 3000 cm-1 to 2800 cm-1. Raman spectra illustrated a similar picture with less ν2PO43−at 450 cm-1 and ν4PO43− from 590 cm-1 to 584 cm-1, amide III at 1272 cm-1 and protein CH2 deformation at 1446 cm-1 in archeological bone material/samples/sources. A semi-quantitative determination of various distributions of biomolecules by chemi-maps of reflection- and ATR- methods revealed that there were less carbohydrates and complex carbohydrates as well as amorphous or fully hydrated sugars in archaeological samples compared with forensic bone samples. Raman- microscopic imaging data showed a reduction in B-type carbonate and protein α-helices after a PMI of 3 years. The calculated mineral content ratio and the organic to mineral ratio displayed that the mineral content ratio increases, while the organic to mineral ratio decreases with time. Cluster-analyses of data from Raman microscopic imaging reconstructed histo-anatomical features in comparison to the light microscopic image and finally, by application of principal component analyses (PCA), it was possible to see a clear distinction between forensic and archaeological bone samples. Hence, the spectral characterization of inorganic and organic compounds by the afore mentioned techniques, followed by analyses such as multivariate imaging analysis (MIAs) and principal component analyses (PCA), appear to be suitable for the post mortem interval (PMI) estimation of human skeletal remains.

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Multidrug resistant tuberculosis in prisons located in former Soviet countries: A systematic review

by Maxwell Droznin, Allen Johnson, Asal Mohamadi Johnson

Background

A systematic literature review was performed to investigate the occurrence of multidrug-resistant tuberculosis (MDR TB) in prisons located in countries formerly part of the Soviet Union.

Methods

A systematic search of published studies reporting MDR TB occurrence in prisons located in former Soviet countries was conducted by probing PubMed and Cumulative Index Nursing and Allied Health Literature for articles that met predetermined inclusion criteria.

Results

Seventeen studies were identified for systematic review. Studies were conducted in six different countries. Overall, prevalence of MDR TB among prisoners varied greatly between studies. Our findings suggest a high prevalence of MDR TB in prisons of Post-Soviet states with percentages as high as 16 times more than the worldwide prevalence estimated by the WHO in 2014.

Conclusion

All studies suggested a high prevalence of MDR TB in prison populations in Post-Soviet states.



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Lateral cephalometric analysis for treatment planning in orthodontics based on MRI compared with radiographs: A feasibility study in children and adolescents

by Alexander Heil, Eduardo Lazo Gonzalez, Tim Hilgenfeld, Philipp Kickingereder, Martin Bendszus, Sabine Heiland, Ann-Kathrin Ozga, Andreas Sommer, Christopher J. Lux, Sebastian Zingler

Objective

The objective of this prospective study was to evaluate whether magnetic resonance imaging (MRI) is equivalent to lateral cephalometric radiographs (LCR, “gold standard”) in cephalometric analysis.

Methods

The applied MRI technique was optimized for short scanning time, high resolution, high contrast and geometric accuracy. Prior to orthodontic treatment, 20 patients (mean age ± SD, 13.95 years ± 5.34) received MRI and LCR. MRI datasets were postprocessed into lateral cephalograms. Cephalometric analysis was performed twice by two independent observers for both modalities with an interval of 4 weeks. Eight bilateral and 10 midsagittal landmarks were identified, and 24 widely used measurements (14 angles, 10 distances) were calculated. Statistical analysis was performed by using intraclass correlation coefficient (ICC), Bland-Altman analysis and two one-sided tests (TOST) within the predefined equivalence margin of ± 2°/mm.

Results

Geometric accuracy of the MRI technique was confirmed by phantom measurements. Mean intraobserver ICC were 0.977/0.975 for MRI and 0.975/0.961 for LCR. Average interobserver ICC were 0.980 for MRI and 0.929 for LCR. Bland-Altman analysis showed high levels of agreement between the two modalities, bias range (mean ± SD) was -0.66 to 0.61 mm (0.06 ± 0.44) for distances and -1.33 to 1.14° (0.06 ± 0.71) for angles. Except for the interincisal angle (p = 0.17) all measurements were statistically equivalent (p Conclusions

This study demonstrates feasibility of orthodontic treatment planning without radiation exposure based on MRI. High-resolution isotropic MRI datasets can be transformed into lateral cephalograms allowing reliable measurements as applied in orthodontic routine with high concordance to the corresponding measurements on LCR.



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HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients

by Luke B. Fletcher, Rianne N. Veenstra, Eric Y. Loo, Amie E. Hwang, Imran N. Siddiqi, Lydia Visser, Bouke G. Hepkema, Ilja M. Nolte, Anke van den Berg, Wendy Cozen, Arjan Diepstra

A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000–2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations.

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Dissecting the relationships of IgG subclasses and complements in membranous lupus nephritis and idiopathic membranous nephropathy

by Woong Na, Kijong Yi, Young Soo Song, Moon Hyang Park

Membranous lupus nephritis (MLN) and idiopathic membranous nephropathy (IMN) are kidney diseases with similar morphology, but distinct etiologies, both producing glomeruli with immune deposits. Immunoglobulins and complements, the main components of the deposits, can be detected by immunofluorescence (IF) microscopy. Previous researches characterized the immune deposits only individually, but not the interactions between them. To study these relationships we analyzed an IF profile of IgG subclasses and complements (IgG1, IgG2, IgG3, IgG4, C3, C1q, and C4) in 53 and 95 cases of biopsy-confirmed MLNs and IMNs, respectively, mainly using information theory and Bayesian networks. We identified significant entropy differences between MLN and IMN for all markers except C3 and IgG1, but mutual information (a measure of mutual dependence) were not significantly different for all the pairs of markers. The entropy differences between MLN and IMN, therefore, were not attributable to the mutual information. These findings suggest that disease type directly and/or indirectly influences the glomerular deposits of most of IgG subclasses and complements, and that the interactions between any pair of the markers were similar between the two diseases. A Markov chain of IgG subclasses was derived from the mutual information about each pair of IgG subclass. Finally we developed an integrated disease model, consistent with the previous findings, describing the glomerular immune deposits of the IgG subclasses and complements based on a Bayesian network using the Markov chain of IgG subclasses as seed. The relationships between the markers were effectively explored by information theory and Bayesian network. Although deposits of IgG subclasses and complements depended on both disease type and the other markers, the interaction between the markers appears conserved, independent from the disease type. The disease model provided an integrated and intuitive representation of the relationships of the IgG subclasses and complements in MLN and IMN.

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L-arginine attenuates Interleukin-1β (IL-1β) induced Nuclear Factor Kappa-Beta (NF-κB) activation in Caco-2 cells

by Qinghe Meng, Mitchell Cooney, Natesh Yepuri, Robert N. Cooney

Background

Specific nutrients like L-arginine (L-Arg) ameliorate intestinal inflammation, however the exact mechanisms of this effect are unclear. We hypothesized the anti-inflammatory effects of L-Arg require active transport and metabolism by inducible nitric oxide synthase (iNOS) to generate nitric oxide (NO). To test this hypothesis we examined the effects of L-Arg, L-Arg transport activity, NO production and iNOS inhibitor on IL-1β-mediated NF-κB-activation in Caco-2 cells.

Methods

Caco-2 cells were cultured, transfected with a NF-κB promoter luciferase vector, incubated ± L-Arg, ± IL-1β and luciferase activity was measured. Using siRNA we inhibited the L-Arg cationic amino acid transporter system y+ (CAT1) expression and examined its effects on L-Arg transport activity and IL-1β-mediated NF-κB-activation. Finally, the effects of sodium nitroprusside (SNP, a NO donor) and Nω-nitro-L-arginine (NNA, an iNOS inhibitor) on IL-1β-mediated NF-κB-activation were examined.

Results

IL-1β increased NF-κB luciferase activity (8-fold) and NF-κB expression (mRNA and protein), both of these were significantly decreased by L-Arg. System y+ CAT1 siRNA decreased CAT1 expression, L-Arg transport activity and attenuated the inhibitory effects of L-Arg on NF- κB activity. SNP attenuated the IL-1β-induced increase in NF-κB luciferase activity and expression, whereas NNA diminished the inhibitory effects of L-Arg on IL-1β-inducible NF- κB luciferase activity.

Conclusion

The inhibitory effects of L-Arg on IL-1β-mediated NF-κB-activation in Caco-2 cells involve L-Arg transport activity by CAT1, regulation of IL-1β-mediated increases in NF-κB expression, changes in iNOS expression and NO production. Our data suggest the inhibitory effects of L-Arg on NF-κB activation are mediated in part by iNOS since SNP preserves and NNA attenuates the effects of L-Arg on IL-1β-mediated NF-κB-activation and expression.



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MMP1 expression is activated by Slug and enhances multi-drug resistance (MDR) in breast cancer

by Ching-Ju Shen, Yu-Ling Kuo, Chien-Chung Chen, Ming-Jenn Chen, Ya-Min Cheng

High matrix metalloproteinase 1 (MMP1) expression is associated with enhanced breast cancer growth and metastasis and also might predict poor prognosis. In this study, we further investigated the functional role of MMP1 and how it is upregulated in multi-drug resistant (MDR) breast cancer cells. By retrieving microarray data in GEO datasets and the survival data in the Kaplan Meier plotter, we observed that MMP1 is significantly upregulated in MCF-7/ADR cells compared to the parental MCF-7 cells, while high MMP1 expression is associated with worse overall survival (OS) and recurrence free survival (RFS) in breast cancer patients after systematic therapy. Functional studies showed that MMP1 overexpression significantly reduced the drug sensitivity in MCF-7 cells, while MMP1 knockdown substantially enhanced the sensitivity in MCF-7/ADR cells. By performing western blotting and immunofluorescent staining, we confirmed that MCF-7/ADR cells had enhanced mesenchymal properties than MCF-7 cells. In MCF-7 cells, enforced Slug expression resulted in significant MMP1 upregulation, while in MCF-7/ADR cells, Slug knockdown led to reduced MMP1 expression. By performing bioinformatic analysis, we observed that the promoter of MMP1 has three putative Slug binding sites. The following dual luciferase assay and ChIP-qPCR verified these three binding sites. Therefore, we infer that Slug enhances MMP1 transcription via directly binding to the promoter region in breast cancer cells, which is a previously unrecognized mechanism in the development of MDR.

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The role of above-ground competition and nitrogen vs. phosphorus enrichment in seedling survival of common European plant species of semi-natural grasslands

by Tobias Ceulemans, Eva Hulsmans, Sigi Berwaers, Kasper Van Acker, Olivier Honnay

Anthropogenic activities have severely altered fluxes of nitrogen and phosphorus in ecosystems worldwide. In grasslands, subsequent negative effects are commonly attributed to competitive exclusion of plant species following increased above-ground biomass production. However, some studies have shown that this does not fully account for nutrient enrichment effects, questioning whether lowering competition by reducing grassland productivity through mowing or herbivory can mitigate the environmental impact of nutrient pollution. Furthermore, few studies so far discriminate between nitrogen and phosphorus pollution. We performed a full factorial experiment in greenhouse mesocosms combining nitrogen and phosphorus addition with two clipping regimes designed to relax above-ground competition. Next, we studied the survival and growth of seedlings of eight common European grassland species and found that five out of eight species showed higher survival under the clipping regime with the lowest above-ground competition. Phosphorus addition negatively affected seven plant species and nitrogen addition negatively affected four plant species. Importantly, the negative effects of nutrient addition and higher above-ground competition were independent of each other for all but one species. Our results suggest that at any given level of soil nutrients, relaxation of above-ground competition allows for higher seedling survival in grasslands. At the same time, even at low levels of above-ground competition, nutrient enrichment negatively affects survival as compared to nutrient-poor conditions. Therefore, although maintaining low above-ground competition appears essential for species’ recruitment, for instance through mowing or herbivory, these management efforts are likely to be insufficient and we conclude that environmental policies aimed to reduce both excess nitrogen and particularly phosphorus inputs are also necessary.

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Validation of questionnaire-reported hearing with medical records: A report from the Swiss Childhood Cancer Survivor Study

by Annette Weiss, Grit Sommer, Rahel Kuonen, Katrin Scheinemann, Michael Grotzer, Martin Kompis, Claudia E. Kuehni, on behalf of the Swiss Paediatric Oncology Group (SPOG)

Background

Hearing loss is a potential late effect after childhood cancer. Questionnaires are often used to assess hearing in large cohorts of childhood cancer survivors and it is important to know if they can provide valid measures of hearing loss. We therefore assessed agreement and validity of questionnaire-reported hearing in childhood cancer survivors using medical records as reference.

Procedure

In this validation study, we studied 361 survivors of childhood cancer from the Swiss Childhood Cancer Survivor Study (SCCSS) who had been diagnosed after 1989 and had been exposed to ototoxic cancer treatment. Questionnaire-reported hearing was compared to the information in medical records. Hearing loss was defined as ≥ grade 1 according to the SIOP Boston Ototoxicity Scale. We assessed agreement and validity of questionnaire-reported hearing overall and stratified by questionnaire respondents (survivor or parent), sociodemographic characteristics, time between follow-up and questionnaire and severity of hearing loss.

Results

Questionnaire reports agreed with medical records in 85% of respondents (kappa 0.62), normal hearing was correctly assessed in 92% of those with normal hearing (n = 249), and hearing loss was correctly assessed in 69% of those with hearing loss (n = 112). Sensitivity of the questionnaires was 92%, 74%, and 39% for assessment of severe, moderate and mild bilateral hearing loss; and 50%, 33% and 10% for severe, moderate and mild unilateral hearing loss, respectively. Results did not differ by sociodemographic characteristics of the respondents, and survivor- and parent-reports were equally valid.

Conclusions

Questionnaires are a useful tool to assess hearing in large cohorts of childhood cancer survivors, but underestimate mild and unilateral hearing loss. Further research should investigate whether the addition of questions with higher sensitivity for mild degrees of hearing loss could improve the results.



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Evaluating erroneous offside calls in soccer

by Stefanie Hüttermann, Benjamin Noël, Daniel Memmert

The ability to simultaneously attend to multiple objects declines with increases in the visual angle separating distant objects. We explored whether these laboratory-measured limits on visual attentional spread generalize to a real life context: offside calls by soccer assistant referees. We coded all offside calls from a full year of first division German soccer matches. By determining the x-y coordinates of the relevant players and assistant referee on the soccer field we were able to calculate how far assistant referees had to spread their visual attention to perform well. Counterintuitively, assistant referees made fewer errors when they were farther away from the action due to an advantageous (smaller) visual angle on the game action. The pattern held even when we accounted for individual differences in a laboratory-based attentional spread measure of ten of the assistant referees. Our finding that errors are linked to smaller visual angles may explain the complaints of fans in some situations: Those seated directly behind the assistant referee, further from the players, might actually have it easier to make the right call because the relevant players would form a smaller visual angle.

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Synergistic effect of divalent cations in improving technological properties of cross-linked alginate beads

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Andrea Cerciello, Pasquale Del Gaudio, Veronica Granata, Marina Sala, Rita P. Aquino, Paola Russo
Gelling solution parameters are some of the most important variables in ionotropic gelation and consequently influence the technological characteristics of the product. To date, only a few studies have focused on the simultaneous use of multiple cations as gelling agents. With the aim to deeply explore this possibility, in this research we investigated the effect of two divalent cations (Ca2+ and Zn2+) on alginate beads formation and properties. Alginate beads containing prednisolone (P) as model drug were prepared by prilling technique. The main critical variables of the ionotropic gelation process i.e. composition of the aqueous feed solutions (sodium alginate and prednisolone concentration) and cross-linking conditions (Ca2+, Zn2+ or Ca2++Zn2+), were studied. The obtained beads were characterized and their in vitro release performances were assessed in conditions simulating the gastrointestinal environment. Results evidenced a synergistic effect of the two cations, affecting positively both the encapsulation efficiency and the ability of the alginate polymeric matrix to control the drug release. A Ca2+/Zn2+ ratio of 4:1, in fact, exploited the Ca2+ ability of establish quicker electrostatic interactions with guluronic groups of alginate and the Zn2+ ability to establish covalent-like bonds with carboxylate groups of both guluronic and mannuronic moieties of alginate.



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Regulating dyslipidemia effect of polysaccharides from Pleurotus ostreatus on fat-emulsion-induced hyperlipidemia rats

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Yan Zhang, Zhuowei Wang, Gang Jin, Xiudong Yang, Hongli Zhou
This study was conducted to evaluate the regulating dyslipidemia effect of polysaccharides from Pleurotus ostreatus (POP) on fat-emulsion-induced hyperlipidemia rats. A plasma metabonomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to analyze the holistic mechanism of POP in a hyperlipidemia rat model. Multivariate statistical approaches such as principal component analysis and orthogonal projection to latent structure square-discriminant analysis revealed distinctions among the control, hyperlipidemia model, and POP groups.The results demonstrated that POP had an effect on regulating dyslipidemia. The mechanism of POP on regulating dyslipidemia was partially relevant with correcting the abnormal levels of fifteen potential biomarkers towards their normal levels. These biomarkers were belong to glycerophospholipids, fatty acids, prenol lipids, sphingolipids metabolism.



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Initiating fibro-proliferation through interfacial interactions of myoglobin colloids with collagen in solution

Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Madhumitha Dhanasekaran, Aruna Dhathathreyan
This work examines fibro-proliferation through interaction of myoglobin (Mb), a globular protein with collagen, an extracellular matrix fibrous protein. Designed colloids of Mb at pH 4.5 and 7.5 have been mixed with collagen solution at pH 7.5 and 4.5 in different concentrations altering their surface charges. For the Mb colloids, 100–200nm sizes have been measured from Transmission electron micrographs and zeta sizer. CD spectra shows a shift to beta sheet like structure for the protein in the colloids. Interaction at Mb/Collagen interface studied using Dilational rheology, Quartz crystal microbalance with dissipation and Differential Scanning calorimetry show that the perturbation is not only by the charge compensation arising from the difference in pH of the colloids and collagen, but also by the organized assembly of collagen at that particular pH. Results demonstrate that positive Mb colloids at pH 4.5, having more% of entrained water stabilize the collagen fibrils (pH 7.5) around them. Ensuing dehydration leads to effective cross-linking and inherently anisotropic growth of fibrils/fibres of collagen. In the case of Mb colloids at pH 7.5, the fibril formation seems to supersede the clustering of Mb suggesting that the fibro-proliferation is both pH and hydrophilic-hydrophobic balance dependent at the interface.

Graphical abstract

image


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Induction of mitochondrial-dependent apoptosis in T24 cells by a selenium (Se)-containing polysaccharide from Ginkgo biloba L. leaves

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Dong Chen, Shaopeng Sun, Dawei Cai, Guangqi Kong
In the present study, a selenium (Se)-containing polysaccharide (Se-GBLP) was isolated and purified from the leaves of Ginkgo biloba L. Se-GBLP was further evaluated for its antitumor activity against human bladder cancer T24 cells together with the possible mechanism of action. Our results showed that treatment of T24 cells with Se-GBLP (50, 100 and 200μg/ml) for 48h significantly inhibited cell viability and induced apoptosis in a dose- dependent manner. This Se-GBLP-induced apoptosis is associated with an increased protein expression of pro-apoptotic Bax, decreased expression of anti-apoptotic Bcl-2, loss of mitochondrial membrane potential, and cleavage of caspase-9, caspase-3 and PARP, suggesting that Se-GBLP-induced apoptosis occurs through the mitochondria-dependent pathway. Se-GBLP therefore merits further investigation as a promising preventive and/or therapeutic agent against human bladder cancer.



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Protein–drug nanoconjugates: Finding the alternative proteins as drug carrier

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Iqra Munir, Sadia Ajmal, Muhammad Raza Shah, Aftab Ahmad, Abdul Hameed, Syed Abid Ali
Present study was conducted to establish the interaction of bovine fetuin-A to validate its binding modalities with doxorubicin (Dox). Fetuin-A was purified to highest purity and monodispersity. Green synthesis of fetuin-A conjugated gold nanoparticles (F-GNPs) has been performed giving typical UV-maxima with subtle variation in fourier transform infrared spectroscopy (FTIR). Atomic force microscopy (AFM) revealed spherical shaped, polydisperse F-GNPs of varying sizes, complementing the radius of hydration (19.5–62.4nm) by dynamic light scattering (DLS). Circular dichroism (CD) analysis of fetuin-A with respect to Dox interaction shows remarkable reduction in ellipticity with increasing concentrations of Dox (20–120μM). Fetuin-A:Dox and F-GNPs:Dox at variable concentrations revealed significantly enhanced absorption spectra, while a continuous decrease in florescence (560nm). This effect was more drastic when Dox interact with fetuin-A as compared to F-GNPs. Some known antimicrobial drugs were also investigated under similar conditions, giving strong quenching effect in a dose dependent manner suggesting the significant yet differential interactions. In cytotoxicity assay, fetuin-A:Dox conjugates revealed less toxicity as compared to F-GNPs:Dox and Dox alone. In-silico studies of the fetuin-A:Dox complex suggest that the drug binds in the major grove between beta-sheet and long loop region of D1 domain and stabilized by several hydrogen bonds.



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Cacao pod husks as a source of low-methoxyl, highly acetylated pectins able to gel in acidic media

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Lúcia Cristina Vriesmann, Carmen Lúcia de Oliveira Petkowicz
Cacao pod husks, the main by-product from cocoa production, have been investigated for pectin isolation. In the present study, the rheological properties of two low-methoxyl (LM) pectins isolated from cacao pod husks using different extraction conditions were evaluated. One pectin was obtained from optimized conditions employing aqueous nitric acid as an extractant, and the other one was extracted with boiling water. Pectin gels (0.99% galacturonic acid equivalent, w/w) were prepared at pH 2.5–3.0 in the presence of 60% sucrose (w/w) and subjected to rheological analysis. Dynamic oscillatory experiments at 25°C indicated that better gels were obtained at the lowest pH (2.5). Steady shear measurements revealed a shear-thinning behavior. The apparent viscosities of the samples increased as pH decreased. Gelation with calcium ions was not observed for either of the highly acetylated LM pectins analyzed. The rheological analysis results showed that despite their high acetyl content, LM pectins extracted by different methods from cacao pod husks were able to form gels at low pH under reduced water activity, suggesting a possible application in acidic products.



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Polysaccharide based bionanocomposite hydrogels reinforced with cellulose nanocrystals: Drug release and biocompatibility analyses

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Kummara Madhusudana Rao, Anuj Kumar, Sung Soo Han
Cellulose nanocrystals (CNCs) reinforced, bionanocomposite (BNC) has shown great potential in tissue engineering and drug delivery applications due to the low toxicity, low density, and high aspect ratio. In this work, BNC hydrogels reinforced with CNCs were fabricated from xanthan (XG) solutions and chitosan (CS) in presence of green acidifying agent through electrostatic and hydrogen bonding interactions. As developed BNC hydrogels were characterized for complex formation, morphology, and mechanical behavior. The mechanical performance of BNC hydrogels was improved significantly as increased CNC content (from 2 to 10wt%). 5-Flurouracil as model chemotherapeutic agent was loaded into these BNC hydrogels for evaluating their drug release properties. The BNC hydrogels showed excellent cytocompatability and ability to release of chemotherapeutic agent that shows the suitability to be used in tissue engineering as well as drug delivery applications.



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Understanding the link between antimicrobial properties of dietary olive phenolics and bacterial ATP synthase

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Publication date: August 2017
Source:International Journal of Biological Macromolecules, Volume 101
Author(s): Amon Amini, Mason Liu, Zulfiqar Ahmad
The naturally occurring olive phenolics tyrosol, hydroxytyrosol, dihydroxyphenylglycol (DHPG), and oleuropein are known to have antioxidant, antitumor, and antibacterial properties. In the current study, we examined whether the antimicrobial properties of tyrosol, hydroxytyrosol, DHPG, and oleuropein were linked to the inhibition of bacterial ATP synthase. Tyrosol, hydroxytyrosol, DHPG, and oleuropein inhibited Escherichia coli wild-type and mutant membrane-bound F1Fo ATP synthase to variable degrees. The growth properties of wild-type, null, and mutant strains in presence of above olive phenolics were also abrogated to variable degrees on limiting glucose and succinate. Tyrosol and oleuropein synergistically inhibited the wild-type enzyme. Comparative wild-type and mutant F1Fo ATP synthase inhibitory profiles suggested that αArg-283 is an important residue and olive phenolics bind at the polyphenol binding pocket of ATP synthase. Growth patterns of wild-type, null, and mutant strains in the presence of tyrosol, hydroxytyrosol, DHPG, and oleuropein also hint at the possibility of additional molecular targets. Our results demonstrated that ATP synthase can be used as a molecular target and the antimicrobial properties of olive phenolics in general and tyrosol in particular can be linked to the binding and inhibition of bacterial ATP synthase.



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Genome-wide RNAi selection identifies a regulator of transmission stage-enriched gene families and cell-type differentiation in Trypanosoma brucei

journal.ppat.1006279.g001

by Eva Rico, Alasdair Ivens, Lucy Glover, David Horn, Keith R. Matthews

Trypanosoma brucei, causing African sleeping-sickness, exploits quorum-sensing (QS) to generate the ‘stumpy forms’ necessary for the parasite’s transmission to tsetse-flies. These quiescent cells are generated by differentiation in the bloodstream from proliferative slender forms. Using genome-wide RNAi selection we screened for repressors of transmission stage-enriched mRNAs in slender forms, using the stumpy-elevated ESAG9 transcript as a model. This identified REG9.1, whose RNAi-silencing alleviated ESAG9 repression in slender forms and tsetse-midgut procyclic forms. Interestingly, trypanosome surface protein Family 5 and Family 7 mRNAs were also elevated, which, like ESAG9, are T. brucei specific and stumpy-enriched. We suggest these contribute to the distinct transmission biology and vector tropism of T. brucei from other African trypanosome species. As well as surface family regulation, REG9.1-depletion generated QS-independent development to stumpy forms in vivo, whereas REG9.1 overexpression in bloodstream forms potentiated spontaneous differentiation to procyclic forms in the absence of an external signal. Combined, this identifies REG9.1 as a regulator of developmental cell fate, controlling the expression of Trypanosoma brucei-specific molecules elevated during transmission.

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Virus-mediated suppression of host non-self recognition facilitates horizontal transmission of heterologous viruses

journal.ppat.1006234.g001

by Songsong Wu, Jiasen Cheng, Yanping Fu, Tao Chen, Daohong Jiang, Said A. Ghabrial, Jiatao Xie

Non-self recognition is a common phenomenon among organisms; it often leads to innate immunity to prevent the invasion of parasites and maintain the genetic polymorphism of organisms. Fungal vegetative incompatibility is a type of non-self recognition which often induces programmed cell death (PCD) and restricts the spread of molecular parasites. It is not clearly known whether virus infection could attenuate non-self recognition among host individuals to facilitate its spread. Here, we report that a hypovirulence-associated mycoreovirus, named Sclerotinia sclerotiorum mycoreovirus 4 (SsMYRV4), could suppress host non-self recognition and facilitate horizontal transmission of heterologous viruses. We found that cell death in intermingled colony regions between SsMYRV4-infected Sclerotinia sclerotiorum strain and other tested vegetatively incompatible strains was markedly reduced and inhibition barrage lines were not clearly observed. Vegetative incompatibility, which involves Heterotrimeric guanine nucleotide-binding proteins (G proteins) signaling pathway, is controlled by specific loci termed het (heterokaryon incompatibility) loci. Reactive oxygen species (ROS) plays a key role in vegetative incompatibility-mediated PCD. The expression of G protein subunit genes, het genes, and ROS-related genes were significantly down-regulated, and cellular production of ROS was suppressed in the presence of SsMYRV4. Furthermore, SsMYRV4-infected strain could easily accept other viruses through hyphal contact and these viruses could be efficiently transmitted from SsMYRV4-infected strain to other vegetatively incompatible individuals. Thus, we concluded that SsMYRV4 is capable of suppressing host non-self recognition and facilitating heterologous viruses transmission among host individuals. These findings may enhance our understanding of virus ecology, and provide a potential strategy to utilize hypovirulence-associated mycoviruses to control fungal diseases.

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Immune correlates of HIV-associated cryptococcal meningitis

by Mark W. Tenforde, James E. Scriven, Thomas S. Harrison, Joseph N. Jarvis



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How free speech can become censorship – and how to solve it

gettyimages-557608477.jpg

The more free speech, the better – or so we thought. But in a world of bots and misinformation, the online free-for-all is ruining debate

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CSL encodes a leucine-rich-repeat protein implicated in red/violet light signaling to the circadian clock in Chlamydomonas

journal.pgen.1006645.g001

by Ayumi Kinoshita, Yoshimi Niwa, Kiyoshi Onai, Takashi Yamano, Hideya Fukuzawa, Masahiro Ishiura, Takuya Matsuo

The green alga Chlamydomonas reinhardtii shows various light responses in behavior and physiology. One such photoresponse is the circadian clock, which can be reset by external light signals to entrain its oscillation to daily environmental cycles. In a previous report, we suggested that a light-induced degradation of the clock protein ROC15 is a trigger to reset the circadian clock in Chlamydomonas. However, light signaling pathways of this process remained unclear. Here, we screened for mutants that show abnormal ROC15 diurnal rhythms, including the light-induced protein degradation at dawn, using a luciferase fusion reporter. In one mutant, ROC15 degradation and phase resetting of the circadian clock by light were impaired. Interestingly, the impairments were observed in response to red and violet light, but not to blue light. We revealed that an uncharacterized gene encoding a protein similar to RAS-signaling-related leucine-rich repeat (LRR) proteins is responsible for the mutant phenotypes. Our results indicate that a previously uncharacterized red/violet light signaling pathway is involved in the phase resetting of circadian clock in Chlamydomonas.

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Visualizing the structure of RNA-seq expression data using grade of membership models

journal.pgen.1006599.e001

by Kushal K. Dey, Chiaowen Joyce Hsiao, Matthew Stephens

Grade of membership models, also known as “admixture models”, “topic models” or “Latent Dirichlet Allocation”, are a generalization of cluster models that allow each sample to have membership in multiple clusters. These models are widely used in population genetics to model admixed individuals who have ancestry from multiple “populations”, and in natural language processing to model documents having words from multiple “topics”. Here we illustrate the potential for these models to cluster samples of RNA-seq gene expression data, measured on either bulk samples or single cells. We also provide methods to help interpret the clusters, by identifying genes that are distinctively expressed in each cluster. By applying these methods to several example RNA-seq applications we demonstrate their utility in identifying and summarizing structure and heterogeneity. Applied to data from the GTEx project on 53 human tissues, the approach highlights similarities among biologically-related tissues and identifies distinctively-expressed genes that recapitulate known biology. Applied to single-cell expression data from mouse preimplantation embryos, the approach highlights both discrete and continuous variation through early embryonic development stages, and highlights genes involved in a variety of relevant processes—from germ cell development, through compaction and morula formation, to the formation of inner cell mass and trophoblast at the blastocyst stage. The methods are implemented in the Bioconductor package CountClust.

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Involvement of β- and γ-actin isoforms in actin cytoskeleton organization and migration abilities of bleb-forming human colon cancer cells

by Aleksandra Simiczyjew, Antonina Joanna Mazur, Ewelina Dratkiewicz, Dorota Nowak

Amoeboid movement is characteristic for rounded cells, which do not form strong adhesion contacts with the ECM and use blebs as migratory protrusions. It is well known that actin is the main component of mature forms of these structures, but the exact role fulfilled by non-muscle actin isoforms β- and γ- in bleb formation and migration of these cells is still not fully understood. The aim of this study was to establish the role of β- and γ-actin in migration of bleb-forming cancer cells using isoform-specific antibodies and expression of fluorescently tagged actin isoforms. We observed, after staining with monoclonal antibodies, that both actins are present in these cells in the form of a cortical ring as well as in the area of blebs. Additionally, using simultaneous expression of differentially tagged β- and γ-actin in cells, we observed that the actin isoforms are present together in a single bleb. They were involved during bleb expansion as well as retraction. Also present in the area of these protrusions formed by both isoforms were the bleb markers–ezrin and myosin II. The overexpression of β- or γ-actin led to actin cytoskeletal rearrangement followed by the growth of migration and invasion abilities of examined human colon cancer cells, LS174T line. In summary these data prove that both actin isoforms have an impact on motility of bleb-forming cancer cells. Moreover, we conclude that monoclonal antibodies directed against actin isoforms in combination with the tagged actins are good tools to study their role in important biological processes.

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Surgical interventions to treat humerus shaft fractures: A network meta-analysis of randomized controlled trials

by Jia-Guo Zhao, Jia Wang, Xiao-Hui Meng, Xian-Tie Zeng, Shi-Lian Kan

Background

There are three main surgical techniques to treat humeral shaft fractures: open reduction and plate fixation (ORPF), intramedullary nail (IMN) fixation, and minimally invasive percutaneous osteosynthesis (MIPO). We performed a network meta-analysis to compare three surgical procedures, including ORPF, IMN fixation, and MIPO, to provide the optimum treatment for humerus shaft fractures.

Methods

MEDLINE, EMBASE, Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, and Cochrane library were researched for reports published up to May 2016. We only included randomized controlled trials (RCTs) comparing two or more of the three surgical procedures, including the ORPF, IMN, and MIPO techniques, for humeral shaft fractures in adults. The methodological quality was evaluated based on the Cochrane risk of bias tool. We used WinBUGS1.4 to conduct this Bayesian network meta-analysis. We used the odd ratios (ORs) with 95% confidence intervals (CIs) to calculate the dichotomous outcomes and analyzed the percentages of the surface under the cumulative ranking curve.

Results

Seventeen eligible publications reporting 16 RCTs were included in this study. Eight hundred and thirty-two participants were randomized to receive one of three surgical procedures. The results showed that shoulder impingement occurred more commonly in the IMN group than with either ORPF (OR, 0.13; 95% CI, 0.03–0.37) or MIPO fixation (OR, 0.08; 95% CI, 0.00–0.69). Iatrogenic radial nerve injury occurred more commonly in the ORPF group than in the MIPO group (OR, 11.09; 95% CI, 1.80–124.20). There were no significant differences among the three procedures in nonunion, delayed union, and infection.

Conclusion

Compared with IMN and ORPF, MIPO technique is the preferred treatment method for humeral shaft fractures.



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Metabolic syndrome and its components among rheumatoid arthritis patients: A comprehensive updated systematic review and meta-analysis

by Jamal Hallajzadeh, Saeid Safiri, Mohammad Ali Mansournia, Maliheh Khoramdad, Neda Izadi, Amir Almasi-Hashiani, Reza Pakzad, Erfan Ayubi, Mark J. M. Sullman, Nahid Karamzad

Background

Estimating the current global prevalence of metabolic syndrome (MetS), and its components, among rheumatoid arthritis (RA) patients is necessary in order to formulate preventative strategies and to ensure there are adequate community resources available for these patients. Furthermore, the association between RA and MetS is controversial and has not previously been comprehensively assessed. Therefore, the present study aimed to: 1) determine the prevalence of MetS, and its components, among RA patients across the world 2) update the odds ratio of MetS in RA patients, compared to healthy controls, using a comprehensive systematic review and meta-analysis.

Methods

International databases, including: the Web of Science, PubMed, Scopus, Embase, CINAHL and other relevant databases were searched to identify English language articles which reported the prevalence and risk of MetS in RA patients between January 2000 and August 2016. The meta-analysis only included studies which clearly described the time and location of the study, utilised adequate sampling strategies, and appropriate statistical analyses.

Results

The meta-analyses of prevalence (70 studies [n = 12612]) and risk (43 studies [n = 35220]) of MetS in RA patients were undertaken separately. The overall pooled prevalence of MetS was 30.65% (95% CI: 27.87–33.43), but this varied from 14.32% (95% CI: 10.59–18.05) to 37.83% (95% CI: 31.05–44.61), based upon the diagnostic criteria used. The prevalence of MetS also varied slightly between males (31.94%, 95% CI: 24.37–39.51) and females (33.03%, 95% CI: 28.09–37.97), but this was not statistically significant. The overall pooled odds ratio (OR) of MetS in RA patients, compared to healthy controls, was 1.44 (95% CI: 1.20–1.74), but this ranged from 0.70 (95% CI: 0.27–1.76) to 4.09 (95% CI: 2.03–8.25), depending on the criteria used. The mean age and diagnostic criteria of MetS were identified as sources of heterogeneity in the estimated odds ratios between studies (P Conclusions

According to the high prevalence of MetS in RA patients, and high risk of MetS, measuring metabolic syndrome in RA patients is strongly recommended. Furthermore, as high waist circumference (WC) is the most common metabolic syndrome component, more attention must be paid to nutrition and weight loss among those with RA.



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Prognostic value of plasma EGFR ctDNA in NSCLC patients treated with EGFR-TKIs

by Chengjuan Zhang, Bing Wei, Peng Li, Ke Yang, Zhizhong Wang, Jie Ma, Yongjun Guo

Objective

Epidermal growth factor receptor (EGFR) specific mutations have been known to improve survival of patients with non-small-cell lung carcinoma (NSCLC). However, whether there are any changes of EGFR mutations after targeted therapy and its clinical significance is unclear. This study was to identify the status of EGFR mutations after targeted therapy and predict the prognostic significance for NSCLC patients.

Methods

A total of forty-five (45) NSCLC patients who received EGFR-TKI therapy were enrolled. We identified the changes of EGFR mutations in plasma ctDNA by Amplification Refractory Mutation System (ARMS) PCR technology.

Results

In the 45 cases of NSCLC with EGFR mutations, the EGFR mutation status changed in 26 cases, in which, 12 cases (26.7%) from positive to negative, and 14 cases (31.1%) from T790M mutation negative to positive after TKI targeted therapy. The T790M occurance group had a shorter Progression -Free-Survival (PFS) than the groups of EGFR mutation undetected and EGFR mutation turned out to have no change after EGFR-TKI therapy (p Conclusions

According to this study, it’s necessary to closely monitor EGFR mutations during follow-up to predict the prognosis of NSCLC patients who are to receive the TKI targeted therapy.



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Geometry-dependent functional changes in iPSC-derived cardiomyocytes probed by functional imaging and RNA sequencing

by Christopher A. Werley, Miao-Ping Chien, Jellert Gaublomme, Karthik Shekhar, Vincent Butty, B. Alexander Yi, Joel M. Kralj, William Bloxham, Laurie A. Boyer, Aviv Regev, Adam E. Cohen

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a promising platform for cardiac studies in vitro, and possibly for tissue repair in humans. However, hiPSC-CM cells tend to retain morphology, metabolism, patterns of gene expression, and electrophysiology similar to that of embryonic cardiomyocytes. We grew hiPSC-CM in patterned islands of different sizes and shapes, and measured the effect of island geometry on action potential waveform and calcium dynamics using optical recordings of voltage and calcium from 970 islands of different sizes. hiPSC-CM in larger islands showed electrical and calcium dynamics indicative of greater functional maturity. We then compared transcriptional signatures of the small and large islands against a developmental time course of cardiac differentiation. Although island size had little effect on expression of most genes whose levels differed between hiPSC-CM and adult primary CM, we identified a subset of genes for which island size drove the majority (58%) of the changes associated with functional maturation. Finally, we patterned hiPSC-CM on islands with a variety of shapes to probe the relative contributions of soluble factors, electrical coupling, and direct cell-cell contacts to the functional maturation. Collectively, our data show that optical electrophysiology is a powerful tool for assaying hiPSC-CM maturation, and that island size powerfully drives activation of a subset of genes involved in cardiac maturation.

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Adenosine for postoperative analgesia: A systematic review and meta-analysis

by Xin Jin, Weidong Mi

Purpose

Perioperative infusion of adenosine has been suggested to reduce the requirement for inhalation anesthetics, without causing serious adverse effects in humans. We conducted a meta-analysis of randomized controlled trials evaluating the effect of adenosine on postoperative analgesia.

Methods

We retrieved articles in computerized searches of Scopus, Web of Science, PubMed, EMBASE, and Cochrane Library databases, up to July 2016. We used adenosine, postoperative analgesia, and postoperative pain(s) as key words, with humans, RCT, and CCT as filters. Data of eligible studies were extracted, which included pain scores, cumulative opioid consumption, adverse reactions, and vital signs. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed-effects or random-effects models, depending on the heterogeneity of the included trials.

Results

In total, 757 patients from 9 studies were included. The overall effect of adenosine on postoperative VAS/VRS scores and postoperative opioid consumption was not significantly different from that of controls (P >0.1). The occurrence of PONV and pruritus was not statistically significantly different between an adenosine and nonremifentanil subgroup (P >0.1), but the rate of PONV occurrence was greater in the remifentanil subgroup (P 0.1).

Conclusion

Adenosine has no analgesic effect or prophylactic effect against PONV, but reduce systolic blood pressure and heart rates. Adenosine may benefit patients with hypertension, ischemic heart disease, and tachyarrhythmia, thereby improving cardiac function.



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Dengue seroprevalence, seroconversion and risk factors in Dhaka, Bangladesh

by Parnali Dhar-Chowdhury, Kishor Kumar Paul, C. Emdad Haque, Shakhawat Hossain, L. Robbin Lindsay, Antonia Dibernardo, W. Abdullah Brooks, Michael A. Drebot

Background

Dengue virus (DENV) activity has been reported in Dhaka, Bangladesh since the early 1960s with the greatest burden of dengue fever and dengue hemorrhagic fever cases observed in 2000. Since this time, the intensity of dengue activity has varied from year to year, and its determining factors remained relatively unknown. In light of such gaps in knowledge, the main objectives of this study were to determine the magnitude of seroprevalence and seroconversion among the surveyed population, and establish the individual/household level risk factors for the presence of DENV antibodies among all age groups of target populations in the city of Dhaka.

Methodology/Principal findings

Considering the lack of fine scale investigations on the factors driving dengue activity in Bangladesh, a prospective cohort study involving serological surveys was undertaken with participant interviews and blood donation across the city of Dhaka in 2012. Study participants were recruited from 12 of 90 wards and blood samples were collected during both the pre-monsoon (n = 1125) and post-monsoon (n = 600) seasons of 2012. The findings revealed that the seroprevalence in all pre-monsoon samples was 80.0% (900/1125) while the seropositivity in the pre-monsoon samples that had paired post-monsoon samples was 83.3% (503/600). Of the 97 paired samples that were negative at the pre-monsoon time point, 56 were positive at the post-monsoon time point. This resulted in a seroprevalence of 93.2% (559/600) among individuals tested during the post-monsoon period. Seroprevalence trended higher with age with children exhibiting a lower seropositivity as compared to adults. Results from this study also indicated that DENV strains were the only flaviviruses circulating in Dhaka in 2012. A multivariate analysis revealed that age, possession of indoor potted plants, and types of mosquito control measures were significant factors associated with dengue seroprevalence; while attendance in public/mass gatherings, and use of mosquito control measures were significantly associated with DENV seroconversion after adjusting for all other variables.

Conclusions/Significance

Our study suggests that there is a high level of endemic dengue virus circulation in the city of Dhaka which has resulted in significant DENV seroprevalence among its residents. Seropositivity increased with age, however, a substantial proportion of children are at risk for DENV infections. Our serological analysis also documents considerable DENV seroconversions among study participants which indicates that a large proportion of the population in the city of Dhaka were newly exposed to DENV during the study period (pre-and post-monsoon 2012). High levels of seroconversion suggest that there was an intense circulation of DENV in 2012 and this may have resulted in a significant risk for viral associated illness. Findings of our study further indicated that home-based interventions, such as removing indoor potted plants and increased bed net use, in addition to vector control measures in public parks, would reduce exposure to DENV and further decrease risk of viral associated disease.



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Improving transcriptome de novo assembly by using a reference genome of a related species: Translational genomics from oil palm to coconut

by Alix Armero, Luc Baudouin, Stéphanie Bocs, Dominique This

The palms are a family of tropical origin and one of the main constituents of the ecosystems of these regions around the world. The two main species of palm represent different challenges: coconut (Cocos nucifera L.) is a source of multiple goods and services in tropical communities, while oil palm (Elaeis guineensis Jacq) is the main protagonist of the oil market. In this study, we present a workflow that exploits the comparative genomics between a target species (coconut) and a reference species (oil palm) to improve the transcriptomic data, providing a proteome useful to answer functional or evolutionary questions. This workflow reduces redundancy and fragmentation, two inherent problems of transcriptomic data, while preserving the functional representation of the target species. Our approach was validated in Arabidopsis thaliana using Arabidopsis lyrata and Capsella rubella as references species. This analysis showed the high sensitivity and specificity of our strategy, relatively independent of the reference proteome. The workflow increased the length of proteins products in A. thaliana by 13%, allowing, often, to recover 100% of the protein sequence length. In addition redundancy was reduced by a factor greater than 3. In coconut, the approach generated 29,366 proteins, 1,246 of these proteins deriving from new contigs obtained with the BRANCH software. The coconut proteome presented a functional profile similar to that observed in rice and an important number of metabolic pathways related to secondary metabolism. The new sequences found with BRANCH software were enriched in functions related to biotic stress. Our strategy can be used as a complementary step to de novo transcriptome assembly to get a representative proteome of a target species. The results of the current analysis are available on the website PalmComparomics (http://ift.tt/2mV7dAY).

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Differential gene expression in patients with subsyndromal symptomatic depression and major depressive disorder

by Chengqing Yang, Guoqin Hu, Zezhi Li, Qingzhong Wang, Xuemei Wang, Chengmei Yuan, Zuowei Wang, Wu Hong, Weihong Lu, Lan Cao, Jun Chen, Yong Wang, Shunying Yu, Yimin Zhou, Zhenghui Yi, Yiru Fang

Background

Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and can lead to significant psychosocial functional impairment. Although the pathogenesis of major depressive disorder (MDD) and SSD still remains poorly understood, a set of studies have found that many same genetic factors play important roles in the etiology of these two disorders. Nowadays, the differential gene expression between MDD and SSD is still unknown. In our previous study, we compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD and matched healthy controls (8 subjects in each group), and finally determined 48 gene expression signatures. Based on these findings, we further clarify whether these genes mRNA was different expressed in peripheral blood in patients with SSD, MDD and healthy controls (60 subjects respectively)

Method

With the help of the quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR), we gained gene relative expression levels among the three groups.

Results

We found that there are three of the forty eight co-regulated genes had differential expression in peripheral blood among the three groups, which are CD84, STRN, CTNS gene (F = 3.528, p = 0.034; F = 3.382, p = 0.039; F = 3.801, p = 0.026, respectively) while there were no significant differences for other genes.

Conclusion

CD84, STRN, CTNS gene may have significant value for performing diagnostic functions and classifying SSD, MDD and healthy controls.



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CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo

by Zichen Xie, Jiqin Wang, Mei Liu, Deshan Chen, Chao Qiu, Keyu Sun

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related human mortalities. Over-activation of mammalian target of rapamycin (mTOR) is important for HCC tumorigenesis and progression. The current study assessed the potential anti-HCC activity by a novel mTOR kinase inhibitor, CC-223. We demonstrate that CC-223, at nM concentrations, induced profound cytotoxic and anti-proliferative activities against established HCC cell lines (HepG2, KYN-2 and Huh-7) and primary human HCC cells. Meanwhile, CC-223 activated caspase-3/-9 and apoptosis in the above HCC cells. CC-223 concurrently blocked mTORC1 and mTORC2 activation, and its cytotoxicity against HCC cells was much more potent than the traditional mTORC1 inhibitors (RAD001 and rapamycin). Further studies demonstrated that CC-223 disrupted mitochondrial function, and induced mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. On the other hand, ROS scavengers and mPTP blockers (cyclosporin A or sanglifehrin A) largely attenuated CC-223-induced HepG2 cell apoptosis. In vivo studies showed that oral administration of CC-223 dramatically inhibited growth of HepG2 xenografts in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation was also blocked in xenografts with CC-223 administration. Together, CC-223 simultaneously blocks mTORC1/2 and efficiently inhibits human HCC cells.

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