bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous Detection and Genotype Determination of HSV 1 and 2 by Real-time PCR Using Melting Curve Analysis and a Unique Pair of Primers
Authors: Paryan Mahdi , Mohammadi-Yeganeh Samira , Rezvan Houri , Kia Vahid , Mansouri Ardalan , Mirab Samiee Siamak
Published: December 2015

Herpes simplex virus (HSV) is a human pathogen that causes different pathologic manifestations. Rapid and feasible detection and discrimination methods for HSV genotyping is a challenge in clinical laboratories, especially in children suffering from herpetic encephalitis. A quantitative real-time polymerase chain reaction (PCR)-based genotyping assay using SYBR Green I was established. We designed only 1 pair of primer for HSV 1 and 2, targeting thymidine kinase gene conserved region. HSV genotypes were determined by PCR using melting curve analysis with LightCycler®. Different HSV genotypes were successfully detected in all clinical samples. The melting temperature for HSV 1 and 2 was 85.5±0.78°C and 89±0.53°C, respectively. These 2 genotypes were completely distinguished by means of the accurate melting assay. Importantly, detection was reliably performed within only 1 hour. The assay had no cross-reactivity across species, an excellent dynamic range from 10 to 106 copies per reaction, a good intra-assay and interassay reproducibility, and a detection limit of a single copy per reaction. Our homebrew designed and validated quantitative real-time PCR followed by a melting curve analysis provided a rapid and convenient screening test for differential identification of HSV genotypes 1 and 2. We recommend the large-scale application of this method for HSV 1 and 2 detection.
Cancer cells have distinct electrical properties that predict a susceptibility to lipophilic anions; a new cancer drug paradigm
Authors: Forrest Michael D.
Published: December 2015

I use the Nernst equation, parameterised with experimental data, to predict that cancer cells will accumulate more of a lipophilic anion than normal cells. This effect is correlated to charge number. Model cancer cells accumulate *100 more of an anion, *103more di-anion, *106more tri-anion, *108more tetra-anion and *1010more penta-anion (>>1 billion times more). The trend endures, conveying even greater specificity, for higher charge numbers. This effect could be leveraged for cancer therapy. Wherein the lipophilic anion is a toxin that targets some vital cellular process, which normal and cancer cells may even share. It delivers a high, lethal dose to cancer cells but a low, safe dose to normal cells. This mathematical finding conveys the prospect of a broad, powerful new front against cancer.
Recombination Disequilibrium in Ideal and Natural Populations
Authors: Tan Yuan-De
Published: December 2015

Following Hardy-Weinberg disequilibrium (HWD) occurring at a single locus and linkage disequilibrium (LD) between two loci in generations, we here proposed the third genetic disequilibrium in population: recombination disequilibrium (RD). RD is a measurement of crossover interference among multiple loci in a random mating population. In natural populations besides recombination interference, RD may also be due to selection, mutation, gene conversion, drift and/or migration. Therefore, similarly to LD, RD will also reflect the history of natural selection and mutation. In breeding populations, RD purely results from recombination interference and hence can be used to build or evaluate and correct a linkage map. Several practical examples from F2, testcross and human populations indeed demonstrate that RD is useful for measuring recombination interference between two short intervals and evaluating linkage maps. As with LD, RD will be important for studying genetic mapping, association of haplotypes with disease, plant breading and population history.
A mechanistic model of linkage analysis in allohexaploids
Authors: Li Huan , Zhu Xuli , Yan Qin , Mao Ke , Wu Rongling
Published: December 2015

Despite their pivotal role in agriculture and biological research, polyploids, a group of organisms with more than two sets of chromosomes, are very difficult to study. Increasing studies have used high-density genetic linkage maps to investigate the genome structure and function of polyploids and to identify genes underlying polyploid traits. However, although models for linkage analysis have been well established for diploids, with some essential modifications for tetraploids, no models have been available thus far for polyploids at higher ploidy levels. The linkage analysis of polyploids typically requires knowledge about their meiotic mechanisms, depending on the origin of polyplody. Here we describe a computational modeling framework for linkage analysis in allohexaploids by integrating their preferential chromosomal-pairing meiotic feature into a mixture model setting. The framework, implemented with the EM algorithm, allows the simultaneous estimates of preferential pairing factors and the recombination fraction. We investigated statistical properties of the framework through extensive computer simulation and validated its usefulness and utility by analyzing a real data from a full-sib family of allohexaploid persimmon. Our attempt in linkage analysis of allohexaploids by incorporating their meiotic mechanism lays a foundation for allohexaploid genetic mapping and also provides a new horizon to explore allohexaploid parental kinship.
High-throughput pipeline for thede novoviral genome assembly and the identification of minority variants from Next-Generation Sequencing of residual diagnostic samples
Authors: Gallo Cassarino T , Frampton D , Sugar R , Charles E , Kozlakidis Z , Kellam P
Published: December 2015

Motivation

The underlying genomic variation of a large number of pathogenic viruses can give rise to drug resistant mutations resulting in treatment failure. Next generation sequencing (NGS) enables the identification of viral quasi-species and the quantification of minority variants in clinical samples; therefore, it can be of direct benefit by detecting drug resistant mutations and devising optimal treatment strategies for individual patients.

Results

The ICONIC (InfeCtion respONse through vIrus genomiCs) project has developed an automated, portable and customisable high-throughput computational pipeline to assemblede novowhole viral genomes, either segmented or non-segmented, and quantify minority variants using residual diagnostic samples. The pipeline has been benchmarked on a dedicated High-Performance Computing cluster using paired-end reads from RSV and Influenza clinical samples. The median length of generated genomes was 96% for the RSV dataset and 100% for each Influenza segment. The analysis of each set lasted less than 12 hours; each sample took around 3 hours and required a maximum memory of 10 GB. The pipeline can be easily ported to a dedicated server or cluster through either an installation script or a docker image. As it enables the subtyping of viral samples and the detection of relevant drug resistance mutations within three days of sample collection, our pipeline could operate within existing clinical reporting time frames and potentially be used as a decision support tool towards more effective personalised patient treatments.

Availability

The software and its documentation are available fromhttps://github.com/ICONIC-UCL/pipeline

Contact

t.cassarino@ucl.ac.uk,pk5@sanger.ac.uk

Supplementary information

Supplementary data are available atBriefings in Bioinformaticsonline.
Reactivation of reward-related patterns from single past episodes supports memory-based decision making
Authors: Wimmer G. Elliott , Buechel Christian
Published: December 2015

Rewarding experiences exert a strong influence on later decision making. While decades of neuroscience research have shown how reinforcement gradually shapes preferences, decisions are often influenced by single past experiences. Surprisingly, relatively little is known about the influence of single learning episodes. While recent work has proposed a role for episodes in decision making, it is largely unknown whether and how episodic experiences contribute to value-based decision making and how the values of single episodes are represented in the brain. In multiple behavioral experiments and an fMRI experiment, we tested whether and how rewarding episodes could support later decision making. Participants experienced episodes of high reward or low reward in conjunction with incidental, trial-unique neutral pictures. In a surprise test phase, we found that participants could indeed remember the associated level of reward, as evidenced by accurate source memory for value and preferences to re-engage with rewarded objects. Further, in a separate experiment, we found that high reward objects shown as primes before a gambling task increased financial risk-taking. Neurally, re-exposure to objects in the test phase led to significant reactivation of reward-related patterns. Importantly, individual variability in the strength of reactivation predicted value memory performance. Further, local searchlight analyses identified significant reactivation in the ventromedial PFC. Our results provide a novel demonstration that affect-related neural patterns are reactivated during later experience. Reactivation of value information represents a mechanism by which memory can guide decision making.
Pain to remember: a single incidental association with pain leads to increased memory for neutral items one year later
Authors: Wimmer G. Elliott , Buechel Christian
Published: December 2015

Negative and positive experiences can exert a strong influence on later memory. Our emotional experiences are composed of many different elements - people, place, things - most of them neutral. Do emotional experiences lead to enhanced long-term for these neutral elements as well? Demonstrating a lasting effect of emotion on memory is particularly important if memory for emotional events is to adaptively guide behavior days, weeks, or years later. We thus tested whether aversive experiences modulate very long-term episodic memory in an fMRI experiment. Participants experienced episodes of high or low pain in conjunction with the presentation of incidental, trial- unique neutral object pictures. In a scanned surprise immediate memory test, we found no effect of pain on recognition strength. Critically, in a follow-up memory test one year later we found that pain significantly enhanced memory. Neurally, we provide a novel demonstration of activity predicting memory one year later, whereby greater insula activity and more unique distributed patterns of insular activity in the initial session correlated with memory for pain-associated objects. Generally, our results suggest that pairing episodes with arousing negative stimuli may lead to very long-lasting memory enhancements.
De novo identification, differential analysis and functional annotation of SNPs from RNA-seq data in non-model species
Authors: Lopez Maestre Hélène , Brinza Lilia , Marchet Camille , Kielbassa Janice , Bastien Sylvère , Boutigny Mathilde , Monnin David , El Filali Adil , Carareto Claudia Marcia , Vieira Cristina , Picard Franck , Kremer Natacha , Vavre Fabrice , Sagot Marie-France , Lacroix Vincent
Published: December 2015

SNPs (Single Nucleotide Polymorphisms) are genetic markers whose precise identification is a prerequisite for association studies. Methods to identify them are currently well developed for model species, but rely on the availability of a (good) reference genome, and therefore cannot be applied to non-model species. They are also mostly tailored for whole genome (re-)sequencing experiments, whereas in many cases, transcriptome sequencing can be used as a cheaper alternative which already enables to identify SNPs located in transcribed regions. In this paper, we propose a method that identifies, quantifies and annotates SNPs without any reference genome, using RNA-seq data only. Individuals can be pooled prior to sequencing, if not enough material is available for sequencing from one individual. Using human RNA-seq data, we first compared the performance of our method with Gatk, a well established method that requires a reference genome. We showed that both methods predict SNPs with similar accuracy. We then validated experimentally the predictions of our method using RNA-seq data from two non-model species. The method can be used for any species to annotate SNPs and predict their impact on proteins. We further enable to test for the association of the identified SNPs with a phenotype of interest.
High-accuracy HLA type inference from whole-genome sequencing data
Authors: Dilthey Alexander , Gourraud Pierre-Antoine , Iqbal Zamin , McVean Gil
Published: December 2015

Extensive hyperpolymorphism and sequence similarity between the HLA genes make HLA type inference from whole-genome sequencing data a challenging problem. We address these by representing sequences from over 10,000 known alleles in a reference graph structure, enabling accurate read mapping. HLA*PRG, our algorithm, outperforms existing methods by a wide margin and for the first time consistently achieves the accuracy of gold-standard reference methods with one error across 158 alleles tested.
Rail-dbGaP: analyzing dbGaP-protected data in the cloud with Amazon Elastic MapReduce
Authors: Nellore Abhinav , Wilks Christopher , Hansen Kasper D , Leek Jeffrey T , Langmead Ben
Published: December 2015

Motivation: Public archives contain thousands of trillions of bases of valuable sequencing data. More than 40% of the Sequence Read Archive is human data protected by provisions such as dbGaP To analyze dbGaP-protected data, researchers must typically work with IT administrators and signing officials to ensure all levels of security are implemented at their institution. This is a major obstacle, impeding reproducibility and reducing the utility of archived data.

Results: We present a protocol and software tool for analyzing protected data in a commercial cloud. The protocol, Rail-dbGaP, is applicable to any tool running on Amazon Web Services Elastic MapReduce. The tool, Rail-RNA v0.2, is a spliced aligner for RNA- seq data, which we demonstrate by running on 9,662 samples from the dbGaP-protected GTEx consortium dataset. The Rail-dbGaP protocol makes explicit for the first time the steps an investigator must take to develop Elastic MapReduce pipelines that analyze dbGaP-protected data in a manner compliant with NIH guidelines. Rail-RNA automates implementation of the protocol, making it easy for typical biomedical investigators to study protected RNA-seq data, regardless of their local IT resources or expertise.

Availability: Rail-RNA is available fromhttp://rail.bio. Technical details on the Rail-dbGaP protocol as well as an implementation walkthrough are available athttps://github.com/nellore/rail-dbgap. Detailed instructions on running Rail-RNA on dbGaP-protected data using Amazon Web Services are available athttp://docs.rail.bio/dbgap/.

Contact:anellore@gmail.com,langmea@cs.jhu.edu
Interactive Analytics for Very Large Scale Genomic Data
Authors: Pan Cuiping , Deflaux Nicole , McInnes Gregory , Snyder Michael , Bingham Jonathan , Datta Somalee , Tsao Philip
Published: December 2015

Large scale genomic sequencing is now widely used to decipher questions in diverse realms such as biological function, human diseases, evolution, ecosystems, and agriculture. With the quantity and diversity these data harbor, a robust and scalable data handling and analysis solution is desired. Here we present interactive analytics using public cloud infrastructure and distributed computing database Dremel and developed according to the standards of Global Alliance for Genomics and Health, to perform information compression, comprehensive quality controls, and biological information retrieval in large volumes of genomic data. We demonstrate that such computing paradigms can provide orders of magnitude faster turnaround for common analyses, transforming long-running batch jobs submitted via a Linux shell into questions that can be asked from a web browser in seconds.
Integration of mobile sequencers in an academic classroom
Authors: Zaaijer Sophie , Erlich Yaniv ,   Columbia University Ubiquitous Genomics 2015 class
Published: December 2015

The rapid development of DNA sequencing technologies creates new educational opportunities for hands-on training. We report our experience in integrating handheld DNA sequencers (Oxford Nanopore Technologies’ MinION) as part of an academic class. This manuscript describes lessons learned to facilitate successful integration and provides educational resources for the benefit of the community.
GWIS: Genome Wide Inferred Statistics for non-linear functions of multiple phenotypes
Authors: Nieuwboer H. A. , Pool R. , Dolan C. V. , Boomsma D. I. , Nivard M. G.
Published: December 2015

Here we present a method of genome wide inferred study (GWIS) that provides an approximation of genome wide association study (GWAS) summary statistics for a variable that is a function of phenotypes for which GWAS summary statistics, phenotypic means and covariances are available. GWIS can be performed regardless of sample overlap between the GWAS of the phenotypes on which the function depends. As GWIS provides association estimates and their standard errors for each SNP, GWIS can form the basis for polygenic risk scoring, LD score regression1, Mendelian randomization studies, biological annotation and other analyses. Here, we replicate a body mass index (BMI) GWAS using GWIS based on a height GWAS and a weight GWAS. We proceed to use a GWIS to further our understanding of the genetic architecture of schizophrenia and bipolar disorder.
A mechanistic first–passage time framework for bacterial cell-division timing
Authors: Ghusinga Khem Raj , Vargas-García Cesar A. , Singh Abhyudai
Published: December 2015

How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells on average, add a fixed size (volume) from birth to division. Interestingly, this added volume differs considerably among genetically-identical newborn cells with similar sizes suggesting a stochastic component in the timing of cell-division. To mechanistically explain the adder principle, we consider a time-keeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that while the mean cell-division time decreases with increasing size of newborns, the noise in timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distributions of the added volume and the cell-division time when scaled by their respective means become invariant of the growth rate. Finally, we discuss various modifications to the proposed model that lead to deviations from the adder principle. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for size control.
solarius: an R interface to SOLAR for variance component analysis in pedigrees
Authors: Ziyatdinov Andrey , Brunel Helena , Martinez-Perez Angel , Buil Alfonso , Perera Alexandre , Soria Jose Manuel
Published: December 2015

The open source environment R is one of the most widely used software for statistical computing. It provides a variety of applications including statistical genetics. Most of the powerful tools for quantitative genetic analyses are stand-alone free programs developed by researchers in academia. SOLAR is the standard software program to perform linkage and association mappings of the quantitative trait loci (QTLs) in pedigrees of arbitrary size and complexity.solariusallows the user to exploit the variance component methods implemented in SOLAR. It automates such routine operations as formatting pedigree and phenotype data. It also parses the model output and contains summary and plotting functions for exploration of the results. In addition,solariusenables parallel computing of the linkage and association analyses, that makes the calculation of genome-wide scans more efficient.

Availability and implementation

solariusis available on CRANhttps://cran.r-project.org/package=solariusand on GitHubhttps://github.com/ugcd/solarius. Seehttp://solar.txbiomedgenetics.org/for more information about SOLAR.

Contact

aziyatdinov@santpau.cat
Gene body H2B monoubiquitylation regulates gene-selective RNA Polymerase II pause release and is not rate limiting for transcription elongation
Authors: Fuchs Gilad , Rosenthal Eran , Bublik Debora-Rosa , Kaplan Tommy , Oren Moshe
Published: December 2015

Histone H2B monoubiquitylation (H2Bub1) is localized preferentially to transcribed regions of genes and spreads concomitantly with the progression of RNA polymerase II (Pol II). In mammalian cells, H2Bub1 levels are highly correlated with transcription elongation rates, consistent with the general belief that H2Bub1 facilitates the elongation process. Yet, a causative role of H2Bub1 in regulating elongation rates within live cells remains to be proven. Using our recently developed 4sUDRB-seq method, we examined the impact of H2Bub1 downregulation, through silencing of its cognate E3 ubiquitin ligase RNF20, on genomewide transcription elongation rates. Surprisingly, H2Bub1 downregulation had no measurable effect on global elongation rates. Instead, it led to upregulation of over 1,000 genes by altering their Pol II pause release times; notably, those genes are characterized by the presence of H2Bub1 in relatively close proximity to the paused Pol II. Conversely, another set of genes was downregulated upon partial H2Bub1 depletion, and in those genes H2Bub1 appeared to be required for efficient recruitment of Pol II to the promoter region. Overall, our data shed new light on the molecular mechanisms by which H2Bub1 regulates gene expression and imply that the role of H2Bub1 in transcription elongation should be reconsidered.

AUTHOR SUMMARY

Transcription elongation is an important component of the gene expression process. Numerous factors and chromatin modifications, including some that are misregulated in various human diseases, have been suggested to regulate transcription elongation. New methods to measure genomewide transcription elongation rates now enable, for the first time, to determine how a specific factor affects transcription elongation and what is the outcome of its misregulation. Using such method, we examined the role of one specific chromatin modification, histone H2B monoubiquitination (H2Bub1), in regulating transcription. Strikingly, although H2Bub1 is widely believed to serve as a regulator of transcription elongation, its downregulation did not affect genomewide elongation rates. Instead, we found that H2Bub1 regulates the expression of distinct subsets of genes by either promoting recruitment of the transcription machinery or, conversely, favoring the pausing of this machinery shortly after initiation of transcription. Our findings demonstrate that the use of genomewide elongation rate measurements can redefine the true roles of putative transcription elongation factors. Furthermore, they provide a new understanding of the functions of H2Bub1 and its impact on gene expression patterns, which is of particular interest because H2Bub1 is often downregulated in human cancer.
Pharmacokinetics and bio‐distribution of novel super paramagnetic iron oxide nanoparticles (SPIONs) in the anaesthetized pig
Authors: Edge Deirdre , Shortt Christine M , Gobbo Oliviero L , Teughels Stephanie , Prina‐Mello Adriele , Volkov Yuri , MacEneaney Peter , Radomski Marek W , Markos Farouk
Published: December 2015

Manufactured nanomaterials have a variety of medical applications, including diagnosis and targeted treatment of cancer. A series of experiments were conducted to determine the pharmacokinetic, biodistribution and biocompatibility of two novel magnetic nanoparticles (MNPs) in the anaesthetized pig. Dimercaptosuccinic acid (DMSA) coated superparamagnetic iron oxide nanoparticles (MF66‐labelled 12 nm, core nominal diameter and OD15 15 nm); at 0.5, or 2.0 mg/kg) were injected intravenously. Particles induced a dose‐dependent decrease in blood pressure following administration which recovered to control levels several minutes after injection. Blood samples were collected for a 5‐h period and stored for determination of particle concentration using particle electron paramagnetic resonance (pEPR). Organs were harvested post‐mortem for magnetic resonance imaging (MRI at 1.5 T field strength) and histology. OD15 (2.0 mg/kg) MNP had a plasma half‐life of approximately 15 min. Both doses of the MF66 (0.5 and 2.0 mg/kg) MNP were below detection limits. MNP accumulation was observed primarily in the liver and spleen with MRI scans which was confirmed by histology. MRI also showed that both MNPs were present in the lungs. The results show that further modifications may be required to improve the biocompatibility of these particles for use as diagnostic and therapeutic agents.
Serous and mucinous borderline ovarian tumours: differences in clinical presentation, high‐risk histopathological features, and lethal recurrence rates
Authors: Vasconcelos I , Darb‐Esfahani S , Sehouli J
Published: December 2015

Background

Mucinous and serous borderline ovarian tumours (mBOTs and sBOTs) are controversial diseases.

Objectives

With this systematic review we aim to evaluate the different high‐risk histopathological features and recurrence rates.

Search strategy

The PubMed database was searched using two terms: {serous AND [(borderline) OR (low malignant potential)] AND ovarian AND tumour} and {mucinous AND [(borderline) OR (low malignant potential)] AND ovarian AND tumour}.

Selection criteria

Cohorts of either sBOT or mBOT, peer‐reviewed, retrospective, or prospective.

Data collection and analysis

Lethal recurrence data for micropapillary patterns (MPs), microinvasion, non‐invasive and invasive implants, and intraepithelial carcinoma (IECA). The primary measure of effect was the odds ratio of lethal recurrence reduction.

Results

Data from patients in 42 studies including 4414 sBOTs and 12 studies including 894 mBOTs were pooled. Of these, 53.3% presented early‐stage typical sBOTs, 24.4% presented with MPs, 22.3% presented with microinvasion, 34.4% presented with non‐invasive implants, and 7.3% presented with invasive implants. The pooled lethal recurrence rates were, respectively: 18.3, 16.8, 10.7, 16.2, and 33.8%. Patients with MPs were more likely to suffer lethal recurrence when compared with high‐stage sBOTs (odds ratio, OR 0.501; P = 0.003), whereas the trend in microinvasive sBOTs did not reach statistical significance. Regarding mBOTs, 61.6% presented with early‐stage typical mBOTs, 19.6% presented with microinvasion, 34.8% presented with IECA, and six patients presented with non‐invasive implants; none presented with invasive implants. The lethal recurrence rates were, respectively: 3.6, 0, 3.7, and 0%.

Conclusion

Micropapillary patterns (MPs) showed a higher risk for lethal recurrence when compared with high‐stage sBOTs. Regarding mBOTs, IECA and microinvasion do not play a role in the lethal recurrence rate.

Tweetable abstract

Micropapillary pattern confirmed as high‐risk in BOT. IECA and microinvasion don't play a role in mucinous BOT.
Effects of chlorpyrifos on enzymatic systems of Cydia pomonella (Lepidoptera: Tortricidae) adults
Authors: Parra Morales Laura Beatriz , Alzogaray Raúl Adolfo , Cichón Liliana , Garrido Silvina , Soleño Jimena , Montagna Cristina Mónica
Published: December 2015

The control program of codling moth (Cydia pomonella L.) in the Río Negro and Neuquén Valley is intended to neonate larvae. However, adults may be subjected to sublethal pesticide concentrations generating stress which might enhance both mutation rates and activity of the detoxification system. This study assessed the exposure effects of chlorpyrifos on target enzyme and, both detoxifying and antioxidant systems of surviving adults from both a laboratory susceptible strain (LSS) and a field population (FP). The results showed that the FP was as susceptible to chlorpyrifos as the LSS and, both exhibited a similar chlorpyrifos‐inhibitory concentration 50 (IC50) of acetylcholinesterase (AChE). The FP displayed higher carboxylesterase (CarE) and 7‐ethoxycoumarine O‐deethylase (ECOD) activities than LSS. Both LSS and FP showed an increase on CarE activity after the exposure to low‐chlorpyrifos concentrations, followed by enzyme inhibition at higher concentrations. There were no significant differences neither in the activities of glutathione S‐transferases (GST), catalase (CAT) and superoxide dismutase (SOD) nor in the reduced glutathione (GSH) content between LSS and FP. Moreover, these enzymes were unaffected by chlorpyrifos. In conclusion, control adults from the FP exhibited higher CarE and ECOD activities than control adults from the LSS. AChE and CarE activities were the most affected by chlorpyrifos. Control strategies used for C. pomonella, such as rotations of insecticides with different modes of action, will probably delay the evolution of insecticide resistance in FPs from the study area.
Specific protein homeostatic functions of small heat‐shock proteins increase lifespan
Authors: Vos Michel J. , Carra Serena , Kanon Bart , Bosveld Floris , Klauke Karin , Sibon Ody C. M. , Kampinga Harm H.
Published: December 2015

During aging, oxidized, misfolded, and aggregated proteins accumulate in cells, while the capacity to deal with protein damage declines severely. To cope with the toxicity of damaged proteins, cells rely on protein quality control networks, in particular proteins belonging to the family of heat‐shock proteins (HSPs). As safeguards of the cellular proteome, HSPs assist in protein folding and prevent accumulation of damaged, misfolded proteins. Here, we compared the capacity of all Drosophila melanogaster small HSP family members for their ability to assist in refolding stress‐denatured substrates and/or to prevent aggregation of disease‐associated misfolded proteins. We identified CG14207 as a novel and potent small HSP member that exclusively assisted in HSP70‐dependent refolding of stress‐denatured proteins. Furthermore, we report that HSP67BC, which has no role in protein refolding, was the most effective small HSP preventing toxic protein aggregation in an HSP70‐independent manner. Importantly, overexpression of both CG14207 and HSP67BC in Drosophila leads to a mild increase in lifespan, demonstrating that increased levels of functionally diverse small HSPs can promote longevity in vivo.
Role of Paternal Antigen‐Specific Treg Cells in Successful Implantation
Authors: Saito Shigeru , Shima Tomoko , Nakashima Akitoshi , Inada Kumiko , Yoshino Osamu
Published: December 2015

Maternal lymphocytes recognize fetal antigens, so tolerance is necessary to prevent rejection. Seminal plasma is important for induction of paternal antigen‐specific Treg cells in the uterine draining lymph nodes and the pregnant uterus. Elimination of Treg cells during implantation or early pregnancy induces implantation failure or fetal resorption in mice. Immunosuppressive therapy with an anti‐TNF antibody or the immunosuppressive agent tacrolimus improves the pregnancy rate in women with repeated implantation failure and recurrent pregnancy loss of unknown etiology, suggesting that Treg cells play an essential role in successful implantation and pregnancy in humans.
Longitudinal evaluation of functional connectivity variation in the monkey sensorimotor network induced by spinal cord injury
Authors: Rao J.S. , Liu Z. , Zhao C. , Wei R.H. , Zhao W. , Yang Z.Y. , Li X.G.
Published: December 2015

Aim

Given the unclear pattern of cerebral function reorganization induced by spinal cord injury (SCI), this study aimed to longitudinally evaluate the changes in resting‐state functional connectivity (FC) in the sensorimotor network after SCI and explore their relationship with gait performance.

Methods

Four adult female rhesus monkeys were examined using resting‐state functional magnetic resonance imaging during their healthy stage and after hemitransected SCI (4, 8 and 12 weeks after SCI), and the gait characteristics of their hindlimbs were recorded (except 4 weeks after SCI). Twenty sensorimotor‐related cortical areas were adopted in the FC analysis to evaluate the functional network reorganization. Correlation analyses were then used to explore the relationship between functional network variations and gait characteristic changes.

Results

Compared with that during the healthy stage, the FC strength during post‐SCI period was significantly increased in multiple areas of the motor control network, including the primary sensorimotor cortex, supplementary motor area (SMA) and putamen (Pu). However, the FC strength was remarkably reduced in the thalamus and parieto‐occipital association cortex of the sensory network 8 weeks after SCI. Most FC intensities gradually approached the normal level 12 weeks after the SCI. Correlation analyses revealed that the enhanced FC strength between Pu and SMA in the left hemisphere, which regulates motor functions of the right side, was negatively correlated with the gait height of the right hindlimb.

Conclusion

The cerebral functional network presents an adjust–recover pattern after SCI, which may help us further understand the cerebral function reorganization after SCI.
Mechanisms Involved in Thromboxane A2‐induced Vasoconstriction of Rat Intracavernous Small Penile Arteries
Authors: Grann Martin , Comerma‐Steffensen Simon , Arcanjo Daniel D. R. , Simonsen Ulf
Published: December 2015

Diabetes is associated with erectile dysfunction and with hypercontractility in erectile tissue and this is in part ascribed to increased formation of thromboxane. Rho kinase (ROCK) is a key regulator of calcium sensitization and contraction in vascular smooth muscle. This study investigated the role of calcium and ROCK in contraction evoked by activation of the thromboxane receptors. Rat intracavernous penile arteries were mounted for isometric tension and intracellular calcium ([Ca2+]i) recording and corpus cavernosum for measurements of MYPT1 phosphorylation. In penile arteries, U46619 by activation of thromboxane receptors concentration dependently increased calcium and contraction. U46619‐induced calcium influx was blocked by nifedipine, a blocker of L‐type calcium channels, and by 2‐aminoethoxydiphenyl borate, a blocker of transient receptor potential (TRP) channels. Inhibitors of ROCK, Y27632 and glycyl‐H1152P, concentration dependently reduced U46619‐induced contraction, but only Y27632 reduced [Ca2+]i levels in the penile arteries activated with either high extracellular potassium or U46619. MYPT‐Thr850 phosphorylation in corpus cavernous strips was increased in response to U46619 through activation of TP receptors and was found to be a direct result of phosphorylation by ROCK. Y27632 induced less relaxation in mesenteric arteries, H1152P induced equipotent relaxations, and a protein kinase C inhibitor, Ro‐318220, failed to relax intracavernous penile arteries, but induced full relaxation in rat mesenteric arteries. Our findings suggest that U46619 contraction depends on Ca2+ influx through L‐type and TRP channels, and ROCK‐dependent mechanisms in penile arteries. Inhibition of the ROCK pathway is a potential approach for the treatment of erectile dysfunction associated with hypertension and diabetes.
Sydnone 1: A Mesoionic Compound with Antitumoral and Haematological Effects In Vivo
Authors: Galuppo Larissa Favaretto , dos Reis Lívero Francislaine Aparecida , Martins Gracianny Gomes , Cardoso Cibele Campos , Beltrame Olair Carlos , Klassen Liliane Maria Bacaro , Canuto André Vinicius dos Santos , Echevarria Aurea , Telles José Ederaldo Queiroz , Klassen Giseli , Acco Alexandra
Published: December 2015

This study evaluated the antitumour activity of the mesoionic compound sydnone 1 (Syd‐1) against Walker‐256 carcinosarcoma. Tumour cells were subcutaneously inoculated in the hind limb in male Wistar rats. The animals were orally treated for 12 days with Syd‐1 (75 mg/kg) or vehicle. At the end of treatment, considerable decreases in tumour volume and tumour weight were observed in treated animals. Samples of these tumours presented increases in apoptotic bodies and pro‐apoptotic protein expression (Bax and p53), while the expression of the anti‐apoptotic protein Bcl‐2 was reduced. A decrease in reduced glutathione levels and an increase in glutathione peroxidase activity were observed in tumour after Syd‐1 treatment. However, significant splenomegaly was evident in animals that received Syd‐1, most likely attributable to the induction of haemolysis. This study demonstrated the antitumour activity of Syd‐1 against Walker‐256 carcinosarcoma. Its mechanism of action is linked to the activation of apoptotic pathways that lead to tumour cell death.
Physiology and Pharmacology of Ejaculation
Authors: Clement Pierre , Giuliano François
Published: December 2015

Ejaculation is the final stage of coitus in mammalian male and is mandatory for natural procreation. Two synchronized phases, emission and expulsion, form the ejaculatory response and involve specific organs and anatomical structures. The peripheral events leading to ejaculation are commanded by autonomic (sympathetic and parasympathetic) and somatic divisions of the nervous system. The autonomic and somatic motor efferents originate in spinal nuclei located in thoracolumbar and lumbosacral segments. Co‐ordinated activation of autonomic and somatic spinal nuclei is orchestrated by a group of lumbar spinal interneurons defined as the spinal generator of ejaculation. The generator of ejaculation together with the autonomic and somatic spinal nuclei constitutes a spinal network that is under the strong influence of stimulating or inhibiting genital sensory and supraspinal inputs. A brain circuitry dedicated to ejaculation has been delineated that is part of a more global network controlling other aspects of the sexual response. This circuitry includes discrete neuronal populations distributed in all divisions of the brain. The corollary to the expanded CNS network is the variety of neurotransmitter systems participating in the ejaculatory process. Among them, serotonin neurotransmission plays a key role and its targeting led to the development of the first registered pharmacological treatment of premature ejaculation in human beings. Critical gaps remain in the understanding of neurophysiopharmacology of ejaculation and management of ejaculatory disorders in human beings needs improvement. Because the ejaculatory response in laboratory animals and in human beings shares many similarities, the use of animal models will certainly provide further advances in the field.
Systematic Review and Meta‐Analysis: Macrolides‐ and Amoxicillin/Clavulanate‐induced Acute Liver Injury
Authors: Ferrer Pili , Amelio Justyna , Ballarín Elena , Sabaté Mònica , Vidal Xavi , Rottenkolber Marietta , Schmiedl Sven , Laporte Joan‐Ramon , Ibáñez Luisa ,   the PROTECT Work Package 2
Published: December 2015

Antibacterials are frequently associated with idiosyncratic drug‐induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta‐analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980–2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non‐user comparator. We summarized the evidence with a random‐effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case–control, one cohort and one case–population studies) and 9 (case–population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81–4.47], p < 0.0001, I2 = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65–135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.
BERTRAND Vs. COURNOT COMPETITION WITH UPSTREAM FIRM INVESTMENT
Authors: Lee DongJoon , Choi Kangsik
Published: December 2015

This paper compares Bertrand and Cournot competition in a vertical structure in which the upstream firm sets the input price and makes R&D investments. We show that from the downstream firms’ point of view, Cournot competition has the advantage of a more monopolistic effect, leading to the setting of a higher price, but has the disadvantage of inducing a lower incentive for the upstream firm to invest. On the other hand, Bertrand competition has the advantage of providing a greater incentive for the upstream firm to invest but has the disadvantage of a more competitive effect, leading to the setting of a lower price. Our main findings are as follows. First, R&D investment level is greater under Bertrand competition than under Cournot competition. Second, from the standpoint of the upstream firm and industry, Bertrand competition is more efficient than Cournot competition. Third, from the standpoint of the downstream firms, Bertrand competition is more efficient than Cournot when investment is sufficiently efficient and products are sufficiently differentiated.
COGNITIVE SKILLS AND CONFIDENCE: INTERRELATIONS WITH OVERESTIMATION, OVERPLACEMENT AND OVERPRECISION
Authors: Duttle Kai
Published: December 2015

This experimental study measures the three major types of judgmental overconfidence in a within‐subjects design. Performance‐based overestimation and overplacement are elicited in a Raven Progressive Matrices test for general intelligence. Calibration‐based overprecision is evaluated in a forecasting by confidence intervals task. This study takes a closer look at the interrelations of these different types. Moreover, as the main focus, it considers the effect of cognitive abilities on overconfidence. These are quantified in a cognitive reflection test. I find that cognitive skills are substantially interrelated with subjects’ confidence levels. Although overconfidence in absolute terms (overestimation) is not affected by cognitive abilities, the effect on overconfidence in relative terms (overplacement) is positive and significant. Overprecision, the calibration‐based type of overconfidence, is found to be significantly affected by cognitive capacity as well. Interval forecasts of cognitively more able subjects were much better calibrated than those of their peers who displayed substantial overconfidence in the precision of their forecasts.
Design, Synthesis and Pharmacological Evaluation of Novel Piperlongumine derivatives as Potential Antiplatelet Aggregation Candidate
Authors: Wang Yujun , Wang Jie , Li Jiaming , Zhang Yanchun , Huang Weijun , Zuo Jian , Liu Huicai , Xie Di , Zhu Panhu
Published: December 2015

A series of novel piperlongumine derivatives (4a‐i, 6a‐i) were designed and synthesized. The inhibitory activities of platelet aggregation induced by ADP and AA in vitro have been evaluated by bron turbidimetry and liver microsomal incubated assay. The assay results show that compounds 4e and 6e exhibited remarkable potency to that of the positive control piplartine and aspirin.
Synthesis and Protective Effects of Kaempferol‐3′‐sulfonate on Hydrogen Peroxide‐induced injury in Vascular Smooth Muscle Cells
Authors: Yang Xinbin , Wang Qin , Wang Chunmei , Qin Xiaolin , Huang Yu , Zeng Renquan
Published: December 2015

A novel water‐soluble sulfated derivative, kaempferol‐3′‐sulfonate acid sodium (KS) with the composition of [C15H9O9SNa]·2.5H2O, was synthesized and characterized by elemental analysis, IR, 1H NMR, 13C NMR, and HRMS. Its protective effects on human vascular smooth muscle cells injured by hydrogen peroxide were evaluated by CCK‐8 method, flow cytometry, and Western blotting. The experimental results indicated that the KS can significantly increase cell viability and reduce apoptosis on H2O2‐injured VSMCs, as well as reverse the effects of H2O2 on Bcl‐2, Bad, and caspase‐3 expressions. In addition, LDH leakage, MDA levels, and SOD and GSH activities were also measured with spectrophotometry. The results indicated that the KS acted as antioxidant preventing LDH leakage and MDA production, while increasing intracellular SOD and GSH activities. These findings revealed that KS might potentially serve as an effective antioxidant agent for prevention and treatment of vascular disease caused by H2O2‐injured VSMCs.
Synthetic Zeolites as Controlled‐Release Delivery Systems for Anti‐Inflammatory Drugs
Authors: Khodaverdi Elham , Soleimani Hossein Ali , Mohammadpour Fatemeh , Hadizadeh Farzin
Published: December 2015

Scientists have always been trying to use artificial zeolites to make modified‐release drug delivery systems in the gastrointestinal tract. An ideal carrier should have the capability to release the drug in the intestine, which is the main area of absorption. Zeolites are mineral aluminosilicate compounds with regular structure and huge porosity, which are available in natural and artificial forms. In this study, soaking, filtration and solvent evaporation methods were used to load the drugs after activation of the zeolites. Weight measurement, spectroscopy FTIR, thermogravimetry and scanning electronic microscope were used to determine drug loading on the systems. Finally, consideration of drug release was made in a simulated gastric fluid and a simulated intestinal fluid for all matrixes (zeolites containing drugs) and drugs without zeolites. Diclofenac sodium (D) and piroxicam (P) were used as the drug models, and zeolites X and Y as the carriers. Drug loading percentage showed that over 90% of drugs were loaded on zeolites. Dissolution tests in stomach pH environment showed that the control samples (drug without zeolite) released considerable amount of drugs (about 90%) within first 15 min when it was about 10–20% for the matrixes. These results are favorable as NSAIDs irritate the stomach wall and it is ideal not to release much drugs in the stomach. Furthermore, release rate of drugs from matrixes has shown slower rate in comparison with control samples in intestine pH environment.
Design, Synthesis, and Potential Antidepressant‐like Activity of 7‐prenyloxy‐2,3‐dihydroflavanone Derivatives
Authors: Zhen Xing‐Hua , Quan Ying‐Chun , Peng Zhou , Han Yan , Zheng Zhou‐Jun , Guan Li‐Ping
Published: December 2015

A series of 7‐prenyloxy‐2, 3‐dihydroflavanone derivatives were synthesized and screened for their antidepressant‐like activity. Among them, it was observed that compounds 5j and 5k were found to be the most antidepressant‐like activity. In addition, it was found that compounds 5j and 5k significantly increased the concentrations of the main neurotransmitters 5‐HT and NE in the hippocampus, hypothalamus, and cortex. Compounds 5j and 5k also significantly increased the contents of 5‐HIAA in the hippocampus and cortex, shut down 5‐HT metabolism compared with mice treated with stress vehicle. These results suggested that compounds 5j and 5k displayed potent antidepressant‐like properties that were mediated via neurochemical systems.