bluuebunny/crossref_metadata_2025 huggingface dataset:
From root to tips: sporulation evolution and specialization inBacillus subtilisand the intestinal pathogenClostridioides difficile
Authors: Ramos-Silva Paula , Serrano Mónica , Henriques Adriano O.
Published: March 2019

Bacteria of the Firmicutes phylum are able to enter a developmental pathway that culminates with the formation of a highly resistant, dormant spore. Spores allow environmental persistence, dissemination and for pathogens, are infection vehicles. In both the modelBacillus subtilis, an aerobic species, and in the intestinal pathogenClostridioides difficile, an obligate anaerobe, sporulation mobilizes hundreds of genes. Their expression is coordinated between the forespore and the mother cell, the two cells that participate in the process, and is kept in close register with the course of morphogenesis. The evolutionary mechanisms by which sporulation emerged and evolved in these two species, and more broadly across Firmicutes, remain largely unknown. Here, we trace the origin and evolution of sporulation. Using the genes involved in the process inB. subtilisandC. difficile, and estimating their gain-loss dynamics in a comprehensive bacterial macro-evolutionary framework we show that sporulation evolution was driven by two major gene gain events, the first at the base of the Firmicutes and the second at the base of theB. subtilisgroup and within the Peptostreptococcaceae family, which includesC. difficile. We also show that early and late sporulation regulons have been co-evolving and that sporulation genes entail greater innovation inB. subtiliswith many Bacilli-lineage restricted genes. In contrast,C. difficilemore often recruits new sporulation genes by horizontal gene transfer, which reflects both its highly mobile genome, the complexity of the gut microbiota and an adjustment of sporulation to this particular ecosystem.
An Oculometrics-based Biofeedback System to Impede Fatigue Development during Computer Work: a Proof-of-Concept Study
Authors: Marandi Ramtin Zargari , Madeleine Pascal , Omland Øyvind , Vuillerme Nicolas , Samani Afshin
Published: March 2019

A biofeedback system may objectively identify fatigue and provide an individualized timing plan for micro-breaks. We developed and implemented a biofeedback system based on oculometrics using continuous recordings of eye movements and pupil dilations to moderate fatigue development in its early stages. Twenty healthy young participants (10 males and females) performed a cyclic computer task for 31-35 min over two sessions: 1) self-triggered micro-breaks (manual sessions), and 2) biofeedback-triggered micro-breaks (automatic sessions). The sessions were held with one-week inter-session interval and in a counterbalanced order across participants. Each session involved 180 cycles of the computer task and after each 20 cycles (a segment), the task paused for 5-s to acquire perceived fatigue using Karolinska Sleepiness Scale (KSS). Following the pause, a 25-s micro-break involving seated exercises was carried out whether it was triggered by the biofeedback system if the fatigue state (KSS≥5) was detected in automatic sessions or by the participants in manual sessions. National Aeronautics and Space Administration Task Load Index (NASA-TLX) was administered after sessions. The functioning core of the biofeedback system was based on a Decision Tree Ensemble model for fatigue classification, which was developed using an oculometrics dataset previously collected during the same computer task. The biofeedback system identified fatigue states with a mean accuracy of approx. 70% and remained robust against circadian rhythms. Perceived workload obtained from NASA-TLX was significantly lower in the automatic sessions compared with the manual sessions, p=0.01 Cohen’s d=0.89. The results give support to the robustness and effectiveness of integrating oculometrics-based biofeedback in time planning of micro-breaks to impede fatigue development during computer work.
Two pathways of p27Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A
Authors: Sora Richard P. , Ikeda Masato , Longnecker Richard
Published: March 2019

Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt Lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A andMYCtransgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressingMYC(λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1is present at significantly lower levels in LMP2A/λ-MYCmice due to increased post-translational degradation. P27Kip1degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the nucleus via the SCFSkp2complex, which depends on Cks1. We previously demonstrated a S10A knock-in of p27Kip1(p27S10A/S10A), which prevented S10 phosphorylation, failed to significantly delay tumor onset in LMP2A/λ-MYCmice. We also previously demonstrated that aCks1knockout partially delayed tumor onset in LMP2A/λ-MYCmice, but onset was still significantly faster than in λ-MYCmice. Here, we have combined both genetic manipulations in what we call p27Supermice. LMP2A/λ-MYC/p27Supermice and λ-MYC/p27Supermice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Supermice was later than in λ-MYCmice and not significantly different from λ-MYC/p27Supermice. The p27Supergenotype also normalized G1-S phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYCmice. Our results reveal both major pathways of p27Kip1degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A.

Importance

Burkitt lymphoma (BL) is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain Epstein-Barr virus (EBV) and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression ofMYC. Mice engineered to express an EBV LMP2A along withMYC(LMP2A/λ-MYCmice) develop tumors much more quickly than mice only expressing MYC (λ-MYCmice). Blocking degradation of the cell cycle inhibitor protein p27Kip1in LMP2A/λ-MYCmice causes tumors to develop later than in λ-MYCmice, showing that p27Kip1degradation may play a larger role in EBV-positive BL than EBV-negative. Furthermore, our studies suggest the cell cycle may be an attractive target as a treatment option for LMP2A positive cancers in humans.
A high-resolution pipeline for 16S-sequencing identifies bacterial strains in human microbiome
Authors: Segota Igor , Long Tao
Published: March 2019

We developed a High-resolution Microbial Analysis Pipeline (HiMAP) for 16S amplicon sequencing data analysis, aiming at bacterial species or strain-level identification from human microbiome to enable experimental validation for causal effects of the associated bacterial strains on health and diseases. HiMAP achieved higher accuracy in identifying species in human microbiome mock community than other pipelines. HiMAP identified majority of the species, with strain-level resolution wherever possible, as detected by whole genome shotgun sequencing using MetaPhlAn2 and reported comparable relative abundances. HiMAP is an open-source R package available at https://github.com/taolonglab/himap.
A high-fat high-sugar diet in adolescent rats impairs social memory and alters chemical markers characteristic of atypical neuroplasticity and GABAergic neurodevelopment in the medial prefrontal cortex
Authors: Reichelt Amy C , Gibson Gabrielle D , Abbott Kirsten N , Hare Dominic J
Published: March 2019

Brain plasticity is a multifaceted process that is dependent on both neurons and extracellular matrix (ECM) structures, including perineuronal nets (PNNs). In the medial prefrontal cortex (mPFC) PNNs primarily surround fast-spiking parvalbumin (PV)-containing GABAergic interneurons and are central to regulation of neuroplasticity. In addition to the development of obesity, high-fat and high-sugar (HFHS) diets are also associated with alterations in brain plasticity and emotional behaviours in humans. To examine the underlying involvement of PNNs and cortical plasticity in the mPFC in diet-evoked social behaviour deficits (in this case social recognition), we exposed adolescent (postnatal days P28-P56) rats to a HFHS-supplemented diet. At P56 HFHS-fed animals and age-matched controls fed standard chow were euthanized and co-localization of PNNs with PV neurons in the prelimbic (PrL) and infralimbic (IL) and anterior cingulate (ACC) sub regions of the PFC were examined by dual fluorescence immunohistochemistry. ΔFosB expression was also assessed as a measure of chronic activity and behavioural addiction marker. Consumption of the HFHS diet reduced the number of PV+ neurons and PNNs in the infralimbic (IL) region of the mPFC by −21.9% and −16.5%, respectively. While PV+ neurons and PNNs were not significantly decreased in the ACC or PrL, the percentage of PV+ and PNN co-expressing neurons was increased in all assessed regions of the mPFC in HFHS-fed rats (+33.7% to +41.3%). This shows that the population of PV neurons remaining are those surrounded by PNNs, which may afford some protection against HFHS diet-induced mPFC-dysregulation. ΔFosB expression showed a 5-10-fold increase (p< 0.001) in each mPFC region, supporting the hypothesis that a HFHS diet induces mPFC dysfunction and subsequent behavioural deficits. The data presented shows a potential neurophysiological mechanism and response to specific diet-evoked social recognition deficits as a result of hypercaloric intake in adolescence.
Gene expression profiles and pathway enrichment analysis to identification of differentially expressed gene and signaling pathways in epithelial ovarian cancer based on high-throughput RNA-seq data
Authors: Siavoshi A , Taghizadeh M , Dookhe E , Piran M
Published: March 2019

Epithelial ovarian cancer (EOC) can be considered as a stressful and challenging disease among all women in the world, which has been associated with a poor prognosis and its molecular pathogenesis has remained unclear. In recent years, RNA Sequencing (RNA-seq) has become a functional and amazing technology for profiling gene expression. In the present study, RNA-seq raw data from Sequence Read Archive (SRA) of six tumor and normal ovarian sample was extracted, and then analysis and statistical interpretation was done with Linux and R Packages from the open-source Bioconductor. Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied for the identification of key genes and pathways involved in EOC. We identified 1091 Differential Expression Genes (DEGs) which have been reported in various studies of ovarian cancer as well as other types of cancer. Among them, 333 genes were up-regulated and 273 genes were down-regulated. In addition, Differentially Expressed Genes (DEGs) including RPL41, ALDH3A2, ERBB2, MIEN1, RBM25, ATF4, UPF2, DDIT3, HOXB8 and IL17D as well as Ribosome and Glycolysis/Gluconeogenesis pathway have had the potentiality to be used as targets for EOC diagnosis and treatment. In this study, unlike that of any other studies on various cancers, ALDH3A2 was most down-regulated gene in most KEGG pathways, and ATF4 was most up-regulated gene in leucine zipper domain binding term. In the other hand, RPL41 as a regulatory of cellular ATF4 level was up-regulated in many term and pathways and augmentation of ATF4 could justify the increase of RPL41 in the EOC. Pivotal pathways and significant genes, which were identified in the present study, can be used for adaptation of different EOC study. However, further molecular biological experiments and computational processes are required to confirm the function of the identified genes associated with EOC.
Integrating behaviour and ecology into global biodiversity conservation strategies
Authors: Tobias Joseph A. , Pigot Alex L.
Published: March 2019

Insights into animal behaviour play an increasingly central role in species-focused conservation practice. However, progress towards incorporating behaviour into regional or global conservation strategies has been far more limited, not least because standardised datasets of behavioural traits are generally lacking at wider taxonomic or spatial scales. Here we make use of the recent expansion of global datasets for birds to assess the prospects for including behavioural traits in systematic conservation priority-setting and monitoring programmes. Using IUCN Red List classification for >9500 bird species, we show that the incidence of threat can vary substantially across different behavioural syndromes, and that some types of behaviour—including particular foraging, mating and migration strategies—are significantly more threatened than others. When all factors are included in a combined model, behavioural traits have a weaker effect than well-established geographical and ecological factors, including range size, body mass and human population pressures. We also show that the association between behavior and extinction risk is partly driven by correlations with these underlying factors. Overall, these results suggest that a multi-species approach at the scale of communities, continents and ecosystems can be used to identify and monitor threatened behaviours, and to flag up cases of latent extinction risk, where threatened status may currently be underestimated. Our findings also highlight the importance of comprehensive standardized descriptive data for ecological and behavioural traits, and point the way forward to a deeper integration of behaviour into quantitative conservation assessments.
Functional dissection of TADs reveals non-essential and instructive roles in regulating gene expression
Authors: Despang Alexandra , Schöpflin Robert , Franke Martin , Ali Salaheddine , Jerkovic Ivana , Paliou Christina , Chan Wing-Lee , Timmermann Bernd , Wittler Lars , Vingron Martin , Mundlos Stefan , Ibrahim Daniel M.
Published: March 2019

The genome is organized in megabase-sized three-dimensional units, called Topologically Associated Domains (TADs), that are separated by boundaries. TADs bring distant cis-regulatory elements into proximity, a process dependent on the cooperative action of cohesin and the DNA binding factor CTCF. Surprisingly, genome-wide depletion of CTCF has little effect on transcription, yet structural variations affecting TADs have been shown to cause gene misexpression and congenital disease. Here, we investigate TAD functionin vivoin mice by systematically editing components of TAD organization at theSox9/Kcnjlocus. We find that TADs are formed by a redundant system of CTCF sites requiring the removal of all major sites within the TAD and at the boundary for two neighboring TADs to fuse. TAD fusion resulted in leakage of regulatory activity from theSox9to theKcnjTAD, but no major changes in gene expression. This indicates that TAD structures provide robustness and precision, but are not essential for developmental gene regulation. Gene misexpression and resulting disease phenotypes, however, were attained by re-directing regulatory activity through inversions and/or the re-positioning of boundaries. Thus, efficient re-wiring of enhancer promoter interaction and aberrant disease causing gene activation is not induced by a mere loss of insulation but requires the re-direction of contacts.
Reconstructing the ecology of a Jurassic pseudoplanktonic megaraft colony
Authors: Hunter Aaron W. , Casenove David , Mitchell Emily G. , Mayers Celia
Published: March 2019

Pseudoplanktonic crinoid megaraft colonies are an enigma of the Jurassic. They are among the largest in-situ invertebrate accumulations ever to exist in the Phanerozoic fossil record. These megaraft colonies and are thought to have developed as floating filter-feeding communities due to an exceptionally rich relatively predator free oceanic niche, high in the water column enabling them to reach high densities on these log rafts. However, this pseudoplanktonic hypothesis has never actually been quantitatively tested and some researchers have cast doubt that this mode of life was even possible. The ecological structure of the crinoid colony is resolved using spatial point process techniques and its longevity using moisture diffusion models. Using spatial analysis we found that the crinoids would have trailed preferentially positioned at the back of migrating structures in the regions of least resistance, consistent with a floating, not benthic ecology. Additionally, we found using a series of moisture diffusion models at different log densities and sizes that ecosystem collapse did not take place solely due to colonies becoming overladen as previously assumed. We have found that these crinoid colonies studied could have existed for greater than 10 years, even up to 20 years exceeding the life expectancy of modern documented megaraft systems with implications for the role of modern raft communities in the biotic colonisation of oceanic islands and intercontinental dispersal of marine and terrestrial species.

Significance statement

Transoceanic rafting is the principle mechanism for the biotic colonisation of oceanic island ecosystems. However, no historic records exist of how long such biotic systems lasted. Here, we use a deep-time example from the Early Jurassic to test the viability of these pseudoplanktonic systems, resolving for the first time whether these systems were truly free floating planktonic and viable for long enough to allow its inhabitants to grow to maturity. Using spatial methods we show that these colonies have a comparable structure to modern marine pesudoplankton on maritime structures, whilst the application of methods normally used in commercial logging is used to demonstrate the viability of the system which was capable of lasting up to 20 years.
A robust and efficient method for Mendelian randomization with hundreds of genetic variants: unravelling mechanisms linking HDL-cholesterol and coronary heart disease
Authors: Burgess Stephen , Foley Christopher N , Allara Elias , Staley James R , Howson Joanna MM
Published: March 2019

Mendelian randomization (MR) investigations with large numbers of genetic variants are becoming increasingly common. However, the reliability of findings from a MR investigation is dependent on the validity of the genetic variants as instrumental variables. We developed a method to identify groups of genetic variants with similar causal effect estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Our contamination mixture method is a robust and efficient method for valid MR in the presence of invalid IVs. Compared to other robust methods, our method had the lowest mean squared error across a range of realistic scenarios. The method is fast and efficient, and can perform analysis with hundreds of variants in a fraction of a second. In a MR analysis for high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) risk, the method identified 11 variants associated with increased HDL-cholesterol, decreased triglyceride levels, and decreased CHD risk that had the same directions of associations with platelet distribution width and other blood cell traits, suggesting a shared mechanism linking lipids and CHD risk relating to platelet aggregation.
Nanopore sequencing of full-length circRNAs in human and mouse brains reveals circRNA-specific exon usage and intron retention
Authors: Rahimi Karim , Venø Morten T. , Dupont Daniel M. , Kjems Jørgen
Published: March 2019

Circular RNA (circRNA) is a poorly understood class of non-coding RNAs, some of which have been shown to be functional important for cell proliferation and development. CircRNAs mainly derive from back splicing events of coding mRNAs, making it difficult to distinguish the internal exon composition of circRNA from the linearly spliced mRNA. To examine the global exon composition of circRNAs, we performed long-read sequencing of single molecules using nanopore technology for human and mouse brain-derived RNA. By applying an optimized circRNA enrichment protocol prior to sequencing, we were able to detect 7,834 and 10,975 circRNAs in human and mouse brain, respectively, of which 2,945 and 7,052 are not currently found in circBase. Alternative splicing was more prevalent in circRNAs than in linear spliced transcripts, and notably >200 not previously annotated exons were used in circRNAs. This suggests that properties associated with circRNA- specific features, e.g. the unusual back-splicing step during biogenesis, increased stability and /or their lack of translation, alter the general exon usage at steady state. We conclude that the nanopore sequencing technology provides a fast and reliable method to map the specific exon composition of circRNA.
Insights into an alternative pathway for glycerol metabolism in a glycerol kinase deficientPseudomonas putidaKT2440
Authors: Walsh Meg , Casey William , Kenny Shane T. , Narancic Tanja , Blank Lars M. , Wierckx Nick , Ballerstedt Hendrik , Connor Kevin E O
Published: March 2019

Pseudomonas putidaKT2440 is known to metabolise glycerol via glycerol-3-phosphate using glycerol kinase an enzyme previously described as critical for glycerol metabolism (1). However, when glycerol kinase was knocked out inP. putidaKT2440 it retained the ability to use glycerol as the sole carbon source, albeit with a much-extended lag period and 2 fold lower final biomass compared to the wild type strain. A metabolomic study identified glycerate as a major and the most abundant intermediate in glycerol metabolism in this mutated strain with levels 21-fold higher than wild type. Erythrose-4-phosphate was detected in the mutant strain, but not in the wild type strain. Glyceraldehyde and glycraldehyde-3-phosphate were detected at similar levels in the mutant strain and the wild type. Transcriptomic studies identified 191 genes that were more than 2-fold upregulated in the mutant compared to the wild type and 175 that were down regulated. The genes involved in short chain length fatty acid metabolism were highly upregulated in the mutant strain. The genes encoding 3-hydroxybutyrate dehydrogenase were 5.8-fold upregulated and thus the gene was cloned, expressed and purified to reveal it can act on glyceraldehyde but not glycerol as a substrate.
Application of Global Metabolomics to the Identification of Complex Counterfeit Medicinal Products
Authors: Jenkins Conor , Orsburn Ben
Published: March 2019

Food fraud and drug counterfeiting are of increasingly large concern to both global economics and to public health and safety. Simple medicinal products consisting of single synthesized or purified compounds can be tested for purity and authenticity rapidly with established assays such as chromatography and UV absorbance. Drugs derived from natural sources may contain hundreds or thousands of distinct chemical compounds and require correspondingly complex analytical methods. In this study we explore the use of methods developed for global metabolic profiling toward the identification of unknown complex medicinal products. By utilizing rapid solvent extraction followed by ultrahigh pressure high performance liquid chromatography (UHPLC) coupled to high resolution accurate mass spectrometry (HRAM-MS/MS), we can reliably obtain a profile of the sample’s molecular makeup. After profiling plant material to the depth of over 1,000 distinct molecules identified and quantified, we utilize these profiles to identify separately prepared and individually assayed blinded samples. We conclude that once a comprehensive library of small molecules has been acquired for each sample, identical preparations of products of unknown origin may be identified using simple statistical tools such as principal component analysis. We also conclude that these tools will be a valuable resource in affordably identified contaminated, adulterated and counterfeit products.

Abstract Graphic
The Paf1 complex broadly impacts the transcriptome ofSaccharomyces cerevisiae
Authors: Ellison Mitchell A. , Lederer Alex R. , Warner Marcie H. , Mavrich Travis , Raupach Elizabeth A. , Heisler Lawrence E. , Nislow Corey , Lee Miler T. , Arndt Karen M.
Published: March 2019

The Polymerase Associated Factor 1 complex (Paf1C) is a multifunctional regulator of eukaryotic gene expression important for the coordination of transcription with chromatin modification and post-transcriptional processes. In this study, we investigated the extent to which the functions of Paf1C combine to regulate theSaccharomyces cerevisiaetranscriptome. While previous studies focused on the roles of Paf1C in controlling mRNA levels, here we took advantage of a genetic background that enriches for unstable transcripts and demonstrate that deletion ofPAF1affects all classes of Pol II transcripts including multiple classes of noncoding RNAs. By conducting ade novodifferential expression analysis independent of gene annotations, we found that Paf1 positively and negatively regulates antisense transcription at multiple loci. Comparisons with nascent transcript data revealed that many, but not all, changes in RNA levels detected by our analysis are due to changes in transcription instead of post-transcriptional events. To investigate the mechanisms by which Paf1 regulates protein-coding genes, we focused on genes involved in iron and phosphate homeostasis, which were differentially affected byPAF1deletion. Our results indicate that Paf1 stimulates phosphate gene expression through a mechanism that is independent of any individual Paf1C-dependent histone modification. In contrast, the inhibition of iron gene expression by Paf1 correlates with a defect in H3 K36 tri-methylation. Finally, we showed that one iron regulon gene,FET4, is coordinately controlled by Paf1 and transcription of upstream noncoding DNA. Together these data identify roles for Paf1C in controlling both coding and noncoding regions of the yeast genome.
A Comparison of Non-human Primate and Deep Reinforcement Learning Agent Performance in a Virtual Pursuit-Avoidance Task
Authors: Willke Theodore L. , Yoo Seng Bum M. , Capotă Mihai , Musslick Sebastian , Hayden Benjamin Y. , Cohen Jonathan D.
Published: March 2019

We compare the performance of non-human primates and deep reinforcement learning agents in a virtual pursuit-avoidance task, as part of an effort to understand the role that cognitive control plays in the deeply evolved skill of chase and escape behavior. Here we train two agents, a deep Q network and an actor-critic model, on a video game in which the player must capture a prey while avoiding a predator. A previously trained rhesus macaque performed well on this task, and in a manner that obeyed basic principles of Newtonian physics. We sought to compare the principles learned by artificial agents with those followed by the animal, as determined by the ability of one to predict the other. Our findings suggest that the agents learn primarily 1st order physics of motion, while the animal exhibited abilities consistent with the 2nd order physics of motion. We identify scenarios in which the actions taken by the animal and agents were consistent as well as ones in which they differed, including some surprising strategies exhibited by the agents. Finally, we remark on how the differences between how the agents and the macaque learn the task may affect their peak performance as well as their ability to generalize to other tasks.
MRI and cognitive scores complement each other to accurately predict Alzheimer’s dementia 2 to 7 years before clinical onset
Authors: Zandifar Azar , Fonov Vladimir S. , Ducharme Simon , Belleville Sylvie , Collins D. Louis ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: March 2019

Background

Predicting cognitive decline and the eventual onset of dementia in patients with Mild Cognitive Impairment (MCI) is of high value for patient management and potential cohort enrichment in pharmaceutical trials. We used cognitive scores and MRI biomarkers from a single baseline visit to predict the onset of dementia in an MCI population over a nine-year follow-up period.

Method

All MCI subjects from ADNI1, ADNI2, and ADNI-GO with available baseline cognitive scores and T1w MRI were included in the study (n=756). We built a Naïve Bayes classifier for every year over a 9-year follow-up period and tested each one with Leave one out cross validation.

Results

We reached 87% prediction accuracy at five years follow-up with an AUC>0.85 from two to seven years (peaking at 0.92 at five years). Both cognitive test scores and MR biomarkers were needed to make the prognostic models highly sensitive and specific, especially for longer follow-ups. MRI features are more sensitive, while cognitive features bring specificity to the prediction.

Conclusion

Combining cognitive scores and MR biomarkers yield accurate prediction years before onset of dementia. Such a tool may be helpful in selecting patients that would most benefit from lifestyle changes, and eventually early treatments that would slow cognitive decline and delay the onset of dementia.
Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle
Authors: Han X. , Møller L. L. V. , De Groote Estelle , Bojsen-Møller K.N. , Davey J. , Henríquez-Olguin C. , Li Z. , Knudsen J.R. , Jensen T. E. , Madsbad S. , Gregorevic P. , Richter E. A. , Sylow L.
Published: March 2019

Background

Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor β (TGF-β) superfamily, including activin A, which causes atrophy. TGF-β superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.

Methods

To elucidate if TGF-β superfamily ligands regulate insulin action we used an adeno-associated virus gene editing approach to overexpress the activin A inhibitor, follistatin (Fst288) in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2 deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB).

Results

Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, p<0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, PDH-E1α, and p70S6K (p<0.05). No correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake but Fst288 increased basal and insulin-stimulated protein synthesis. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced Activin A (−24%, p<0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.

Conclusions

We here present evidence that Fst is a potent regulator of insulin action in muscle and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4 and PAK1 as Fst targets. A possible role for Fst in regulating glycemic control is suggested because circulating Fst more than doubled post RYGB surgery, a treatment that markedly improved insulin sensitivity. These findings demonstrate the therapeutic potential of inhibiting TGF-β superfamily ligands to improve insulin action and Fst’s relevance to muscle wasting associated insulin resistant conditions in mice and humans.
The Arabian camel,Camelus dromedariusinterferon epsilon: functional expression,in vitrorefolding, purification and cytotoxicity on breast cancer cell lines MDA-MB-231 and MCF-7
Authors: Abdel-Fattah Manal , Saeed Hesham , El-Shennawy Lamiaa , Shalaby Manal , Embaby Amira M. , Ataya Farid , E.Mahmoud Hoda , Hussein Ahmed
Published: March 2019

The current study highlights for the first time cloning, overexpression, purification, and assessing the cytotxcity of the novel interferon epsilon (IFNε), from the Arabian camelCamelus dromedarius, against two human breast cancer cell lines MDA-MB-231 and MCF-7. Full-length cDNA encoding interferon epsilon (IFNε) was isolated and cloned from the liver of the Arabian camel,C. dromedariususing reverse transcription-polymerase chain reaction. The sequence analysis of the camel IFNε cDNA showed a 582-bp open reading frame encoding a protein of 193 amino acids with an estimated molecular weight of 22.953 kDa. A BLAST search analysis revealed that theC. dromedariusIFNε shared high sequence identity with the IFN genes of other species, such asCamelus ferus,Vicugna pacos, andHomo sapiens. Expression of the camel IFNε cDNA inEscherichia coligave a fusion protein band of 22.73 kDa after induction with either isopropyl β-D-1-thiogalactopyranoside or lactose for 5 h. Recombinant IFNε protein was overexpressed in the form of inclusion bodies that were easily solubilized and refolded using SDS and KCl. The solubilized inclusion bodies were purified to apparent homogeneity using nickel affinity chromatography. We examined the effect of IFNε on two breast cancer cell lines MDA-MB-231 and MCF-7. In both cell lines, IFNε inhibited cell survival in a dose dependent manner as observed by MTT assay, morphological changes and apoptosis assay. Caspase-3 expression level was found to be increased in MDA-MB-231 treated cells as compared to untreated cells.
Niche partitioning and coexistence of two spiders of the genusPeucetia(Araneae, Oxyopidae) inhabitingTrichogoniopsis adenanthaplants (Asterales, Asteraceae): a population approach
Authors: Villanueva-Bonilla German Antonio , Safuan-Naide Suyen , Pires Mathias Mistretta , Vasconcellos-Neto João
Published: March 2019

Niche theory suggests that the coexistence of ecologically similar species at the same site requires some form of resource partitioning that reduces or avoids interspecific competition. Here, we investigated the temporal and spatial niche differentiation of two sympatric congeneric spiders,Peucetia rubrolineataandP. flava, inhabitingTrichogoniopsis adenantha(Asteraceae) plants along an altitudinal gradient in various shaded and open areas in an Atlantic forest in Serra do Japi, SP, Brazil. In theory, the coexistence of twoPeucetiaspecies could be explained by: (1) temporal segregation; (2) differential use of the branches of the plant; (3) differential use of specific parts of the branches of the plant; (4) differential distribution in shaded and open areas; and (5) differential altitudinal distribution of the twoPeucetiaspecies. With respect to temporal niche, we observed that the two spider species had a similar age structure and similar fluctuation in abundance throughout the year. With respect to micro-habitat use, in both species, different instars used different plant parts, while the same instars of both species used the same type of substrate. However, the twoPeucetiaspecies segregated by meso-habitat type, withP. rubrolineatapreferringT. adenanthaplants in shaded areas andP. flavapreferring those in open areas. Our results support the hypothesis of niche partitioning begetting diversity, and highlight the importance of analysing habitat use at multiple scales to understand mechanisms related to coexistence.
An Integrated Chemical Proteomics Approach for Quantitative Profiling of Intracellular ADP-Ribosylation
Authors: Kalesh Karunakaran , Lukauskas Saulius , Borg Aaron J. , Snijders Ambrosius P. , Leung Anthony K. L. , Haskard Dorian O. , DiMaggio Peter A.
Published: March 2019

ADP-ribosylation is integral to a diverse range of cellular processes such as DNA repair, chromatin regulation and RNA processing. However, proteome-wide investigation of its cellular functions has been limited due to numerous technical challenges including the complexity of the poly(ADP-ribose) (PAR) chains, low abundance of the modification and lack of sensitive enrichment methods. To facilitate live-cell profiling of ADP-ribosylated proteins, we show that 2-alkyne-adenosine (2YnAd) is metabolically incorporated in mammalian cells and enables fluorescent detection and robust affinity enrichment of the modified proteins. We then present an integrated chemical biology approach that involves simultaneous metabolic incorporation of 2YnAd and the previously reported 6-alkyne-adenosine (6YnAd) in live cells followed by click chemistry with a capture reagent to facilitate highly sensitive and comprehensive enrichment of the modified proteins. By combining this dual metabolic labelling strategy with the tandem mass tag (TMT) isobaric mass spectrometry, we have quantified the responses of thousands of endogenous proteins to clinical PARP inhibitors Olaparib and Rucaparib. Our study provides insight into the wider scope of PARP targets and will help to advance further characterisation of their functional roles.
A new method of calculating interatomic spacing: the equal-ratio method
Authors: Fan Quncheng
Published: March 2019

Based on a simple principle of analytical geometry, a new equal-ratio method has been developed to calculate the interatomic spacing of crystal structures. If an atom (x
2, y
2, z
2) or its equi-position atom (e + x
2, f + y
2, g + z
2) (e, f and g are integers) is located at the 1/r ≤ 1 of one interatomic spacing period d′[uvw] on the [uvw] atomic row passing through the atom (x
1, y
1, z
1), the distance between the two atoms can be calculated by the formula d
[uvw]
(1/r) = d′[uvw]/r, where d′[uvw] = (u
2
a
2 + v
2
b
2 + w
2
c
2 + 2uvabcosγ + 2vwbccosα + 2uwaccosβ)1/2 is the interlattice point spacing of the corresponding primary lattice of the crystal structure, 1/r is the interatomic spacing coefficient, and r is equal to the reciprocal of the common factor of (x
2 − x
1), (y
2 − y
1) and (z
2 − z
1). The reliability and advantages (no auxiliary view is required, suitable for arbitrary directions and for all crystal structures) of the equal-ratio method have been examined by calculations for the β-cristobalite SiO2 structure and Cu3Au I superstructure as well as face-centred cubic, body-centred cubic and hexagonal close-packed structures.
Crystal structure, morphology and formation mechanism of a novel polymorph of lead dioxide, γ-PbO2
Authors: Kabbara Hiba , Ghanbaja Jaafar , Redjaïmia Abdelkrim , Belmonte Thierry
Published: March 2019

Nanosecond-pulsed spark discharge between two lead electrodes in liquid nitrogen has been used to synthesize hexagonal lead nanosheets. These original nanostructures are collected on a substrate located under the electrodes. After the full evaporation of the liquid nitrogen, the nanosheets are oxidized in air and transform into a lead dioxide. The resulting hexagonal sheets have typical widths of around 1 µm and typical thicknesses of around 10 nm. Investigations by energy dispersive spectroscopy microanalysis, transmission electron microscopy, high-angle annular dark-field scanning transmission electron microscopy and electron microdiffraction were performed in order to identify the crystal structure in which these hexagonal nanosheets crystallize. An analysis of the chemical composition pointed to a stoichiometric lead dioxide, PbO2. This PbO2lead dioxide crystallizes in the hexagonal system (a= 0.912 nm andc= 1.265 nm) and belongs to the space groupP6/m2/m2/m. On the basis of group theory (symmetry analysis), the nanosheets develop a hexagonal-prismatic shape in liquid nitrogen, assumed to be an isotropic medium. From the energetic point of view, this shape, dictated by the 6/m2/m2/mpoint group, corresponds to an absolute extremum, an indicator of the stability of this lead dioxide. A mechanism similar to that of the ledge mechanism explaining the formation of thin plates in a metallic matrix has been adapted and proposed for the formation of the lead nanosheets in the liquid nitrogen. When the liquid nitrogen is removed, the lead nanosheet is oxidized, leading to a lead dioxide, inheriting the nanosheet morphology. As far as the authors are aware, this is the first time that such a lead dioxide has been synthesized by spark discharge in liquid nitrogen followed by oxidation in air. The crystallographic structure is determined and the morphology is explained. A mechanism for the development of the lead nanosheets and their oxidation is proposed. This hexagonal phase, designated γ-PbO2, is thought to be the third polymorph after the α-PbO2and β-PbO2phases of lead dioxide, the former being orthorhombic and the latter being tetragonal.
Structures of rhenium(I) complexes with 3-hydroxyflavone and benzhydroxamic acid as O,O′-bidentate ligands and confirmation of π-stacking by solid-state NMR spectroscopy
Authors: Schutte-Smith Marietjie , Roodt Andreas , Alberto Roger , Twigge Linette , Visser Hendrik Gideon , Kirsten Leo , Koen Renier
Published: March 2019

The synthesis and crystal structures of two new rhenium(I) complexes obtained utilizing benzhydroxamic acid (BHAH) and 3-hydroxyflavone (2-phenylchromen-4-one, FlavH) as bidentate ligands, namely tetraethylammonium fac-(benzhydroxamato-κ2
O,O′)bromidotricarbonylrhenate(I), (C8H20N)[ReBr(C7H6NO2)(CO)3], 1, and fac-aquatricarbonyl(4-oxo-2-phenylchromen-3-olato-κ2
O,O′)rhenium(I)–3-hydroxyflavone (1/1), [Re(C15H9O3)(CO)3(H2O)]·C15H10O3, 3, are reported. Furthermore, the crystal structure of free 3-hydroxyflavone, C15H10O3, 4, was redetermined at 100 K in order to compare the packing trends and solid-state NMR spectroscopy with that of the solvate flavone molecule in 3. The compounds were characterized in solution by 1H and 13C NMR spectroscopy, and in the solid state by 13C NMR spectroscopy using the cross-polarization magic angle spinning (CP/MAS) technique. Compounds 1 and 3 both crystallize in the triclinic space group P\overline{1} with one molecule in the asymmetric unit, while 4 crystallizes in the orthorhombic space group P212121. Molecules of 1 and 3 generate one-dimensional chains formed through intermolecular interactions. A comparison of the coordinated 3-hydroxyflavone ligand with the uncoordinated solvate molecule and free molecule 4 shows that the last two are virtually completely planar due to hydrogen-bonding interactions, as opposed to the former, which is able to rotate more freely. The differences between the solid- and solution-state 13C NMR spectra of 3 and 4 are ascribed to inter- and intramolecular interactions. The study also investigated the potential labelling of both bidentate ligands with the corresponding fac-99mTc-tricarbonyl synthon. All attempts were unsuccessful and reasons for this are provided.
Social responsibility and event-sponsor portfolio fit
Authors: Close Scheinbaum Angeline , Lacey Russell , Drumwright Minnette
Published: March 2019

Purpose

This study aims to examine the outcomes of consumer perceptions of event social responsibility (ESR) for a sponsored community event and its sponsor portfolio (i.e. group of sponsoring companies). It integrates a new antecedent and new moderators of ESR with extant findings to provide a comprehensive model that is theoretically grounded in social identity theory, congruency theory and image and affect transfer.

Design/methodology/approach

The authors test the theoretical framework via a field study of attendees (n = 879) at a sponsored, large-scale sporting event that provided ESR through health and wellness education and activities. A field study is especially appropriate because of the experiential nature of sponsored events and ESR.

Findings

Fan identification with the sport is an antecedent of ESR, and motivation to attend the event’s supporting activities moderates the relationship between fan identification and ESR. High event-sponsor fit strengthens the relationship between ESR and word-of-mouth and between ESR and sponsor patronage.

Research limitations/implications

This study illuminates the role of ESR as a key driver of outcomes for events and for their sponsor portfolio. Future research should investigate ESR in contexts other than sport and use longitudinal data that include actual purchases. It should further examine the construct of sponsor portfolio because so many events have multiple sponsors

Practical implications

Event sponsorship offers an attractive platform for brands to demonstrate good corporate citizenship; therefore, marketers should consider ESR as a key criterion when selecting events to sponsor. Marketers should sponsor events with high event-sponsor portfolio fit to enhance the outcomes related to ESR for both sponsors and events. This research generally underscores the importance of creating auxiliary, interactive experiences for event attendees.

Social implications

ESR entails that events should contribute or give back to the local communities and organizations in a charitable way to both help give back socially and to maximize success as measured by electronic word-of-mouth (eWOM) and sponsor patronage toward brands sponsoring the event.

Originality/value

This research identifies a new antecedent and new moderators of ESR and integrates them with extant findings to create a comprehensive, theoretically grounded model. It investigates outcomes for both the event and its sponsor portfolio, in contrast to the scholarship that tends to focus on the (title) sponsor.
Interpersonal practice in project marketing: how institutional logics condition and change them
Authors: Cova Bernard , Skålén Per , Pace Stefano
Published: March 2019

Purpose

Project marketing is the specific activity of companies selling projects-to-order. Interpersonal practice is known to be important in this type of marketing. While this interpersonal practice has been little studied, some previous research suggests that changes in the institutional macro environment have affected it. Therefore, the purpose of this paper is to study today’s interpersonal practice in project business and how the institutional environment conditions it.

Design/methodology/approach

Semi-structured interviews were conducted with marketing managers at project-based firms in different business sectors in France and Sweden. Data collection and analysis was informed by grounded theory.

Findings

The paper identifies three types of interpersonal practice in project marketing, referred to as the transactional, the work-based and the socializing. Changes in these are explained in relation to the three institutional logics identified in the data: the market institutional logic of business ethics, the corporate institutional logic of rationalization and the family institutional logic of gender equality.

Research limitations/implications

Future studies can continue and broaden this work as it regards how the institutional conditioning of interpersonal practice varies with context.

Practical implications

By clearly categorizing the three types of interpersonal practice and their relative role today, companies can orient the activities of salespeople, business developers and other project marketers.

Social implications

The paper highlights how business ethics and gender equality have changed interpersonal practices in project marketing.

Originality/value

The paper contributes to the current debate on project marketing by identifying three types of interpersonal practice and by illustrating how institutional logics condition and change these. The paper shows that extra-business activities are needed less than previous research has argued with regard to maintaining customer relationships in-between projects.