bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive transcriptional changes in the aphid speciesMyzus cerasiunder different host environments associated with detoxification genes
Authors: Thorpe Peter , Escudero-Martinez Carmen M. , den Akker Sebastian Eves-van , Bos Jorunn I.B.
Published: July 2018

Aphids are phloem-feeding insects that cause yield losses to crops globally. These insects feature complex life cycles, which in the case of many agriculturally important species involves the use of primary and secondary host plant species. Whilst host alternation between primary and secondary host can occur in the field depending on host availability and the environment, aphid populations maintained as laboratory stocks generally are kept under conditions that allow asexual reproduction by parthenogenesis on secondary hosts. Here, we usedMyzus cerasi(black cherry aphid) to assess aphid transcriptional differences between populations collected from primary hosts in the field and those adapted to secondary hosts under controlled environment conditions. Adaptation experiments ofM. cerasicollected from local cherry tress to reported secondary host species resulted in low survival rates. Moreover, aphids were unable to survive on secondary host Land cress, unless first adapted to another secondary host, cleavers. Transcriptome analyses of populations collected from primary host cherry in the field and the two secondary host plant species in a controlled environment showed extensive transcriptional plasticity to a change in host environment, with predominantly genes involved in redox reactions differentially regulated. Most of the differentially expressed genes across theM. cerasipopulations from the different host environments were duplicated and we found evidence for differential exon usage. In contrast, we observed only limited transcriptional to a change in secondary host plant species.
Exploring the effects of BCG vaccination in patients diagnosed with tuberculosis: observational study using the Enhanced Tuberculosis Surveillance system
Authors: Abbott Sam , Christensen Hannah , Lalor Maeve K , Zenner Dominik , Campbell Colin , Ramsay Mary , Brooks-Pollock Ellen
Published: July 2018

Background

Bacillus Calmette–Guérin (BCG) is one of the most widely-used vaccines worldwide. BCG primarily reduces the progression from infection to disease, however there is evidence that BCG may provide additional benefits. We aimed to investigate whether there is evidence in routinely-collected surveillance data that BCG vaccination impacts outcomes for tuberculosis (TB) cases in England.

Methods

We obtained all TB notifications for 2009–2015 in England from the Enhanced Tuberculosis surveillance system. We considered five outcomes: All-cause mortality, death due to TB (in those who died), recurrent TB, pulmonary disease, and sputum smear status. We used logistic regression, with complete case analysis, to investigate each outcome with BCG vaccination, years since vaccination and age at vaccination, adjusting for potential confounders. All analyses were repeated using multiply imputed data.

Results

We found evidence of an association between BCG vaccination and reduced all-cause mortality (aOR:0.76 (95%CI 0.64 to 0.89), P:0.001) and weak evidence of an association with reduced recurrent TB (aOR:0.90 (95%CI 0.81 to 1.00), P:0.056). Analyses using multiple imputation suggested that the benefits of vaccination for all-cause mortality were reduced after 10 years.

Conclusions

We found that BCG vaccination was associated with reduced all-cause mortality in people with TB although this benefit was less pronounced more than 10 years after vaccination. There was weak evidence of an association with reduced recurrent TB.

Highlights

Found evidence of an association between BCG vaccination and reduced all-cause mortality in TB cases.

Weaker evidence of an association between BCG vaccination and reduced repeat TB episodes in TB cases.

There was little evidence of an association with other TB outcomes.

We explored the identified associations by age and time since vaccination.
Interspecies interactions mediated by conductive minerals in the sediments of the ferruginous Lake La Cruz, Spain
Authors: Rotaru Amelia-Elena , Posth Nicole R. , Löscher Carolin R. , Miracle Maria R. , Vicente Eduardo , Cox Raymond P. , Thompson Jennifer , Poulton Simon W. , Thamdrup Bo
Published: July 2018

Lake La Cruz is considered a biogeochemical analogue to early Earth marine environments because its water column is depleted in sulfate, but rich in methane and iron, similar to conditions envisaged for much of the Precambrian. In this early Earth analogue environment, we show that conductive particles establish a tight metabolic coupling between electroactive microbial clades. We propose that mineral-based syntrophy is of potential relevance for the evolution of Earth’s earliest complex life forms. We show that the anoxic sediment of Lake La Cruz, which is rich in biogeochemically ‘reactive’ iron minerals, harbors known electroactive species such asGeobacterandMethanothrix,in addition to other groups which have not been previously associated with an electroactive lifestyle. Slurry incubations on various substrates in the presence of conductive particles showed significant methanogenic activity, whereas incubations with non-conductive glass beads resulted in low methanogenic rates similar to slurries without added particles. In the absence of conductive particles, all tested substrates were metabolized to acetate, which accumulated to ∼10 mM. Similar to a previous study on iron-rich Baltic Sea sediments, we observed that conductive mineral additions to La Cruz slurries enabled acetate oxidation, thus preventing acetate accumulation. Acetate oxidation coupled to high methanogenic activity was only maintained in successive mud-free enrichments when these were amended with conductive minerals. In serial mud-free transfers, conductive particles conserved a consortium ofYoungiibacter-Methanothrix,whereasYoungiibacterspp. died off in the absence of conductive particles. In contrast, mud-free enrichments without conductive particles ceased any metabolic activity during the second transfers. Syntrophic consortia from this early Earth analogue environment only survived in the presence of conductive particles. Mineral-mediated syntrophy could be one of the earliest evolutionary interspecies associations. Conductive minerals might have fueled metabolic exchange between cells via intercellular electron transfer prompting tight cell-to-cell associations and possibly eukaryogenesis.
Attack and defence in cellular decision-making: lessons from machine learning
Authors: Rademaker Thomas J. , Bengio Emmanuel , François Paul
Published: July 2018

Machine learning algorithms can be fooled by small well-designed adversarial perturbations. This is reminiscent of cellular decision-making where ligands (called antagonists) prevent correct signalling, like in early immune recognition. We draw a formal analogy between neural networks used in machine learning and models of cellular decision-making (adaptive proofreading). We apply attacks from machine learning to simple decision-making models, and show explicitly the correspondence to antagonism by weakly bound ligands. Such antagonism is absent in more nonlinear models, which inspired us to implement a biomimetic defence in neural networks filtering out adversarial perturbations. We then apply a gradient-descent approach from machine learning to different cellular decision-making models, and we reveal the existence of two regimes characterized by the presence or absence of a critical point for the gradient. This critical point causes the strongest antagonists to lie close to the decision boundary. This is validated in the loss landscapes of robust neural networks and cellular decision-making models, and observed experimentally for immune cells. For both regimes, we explain how associated defence mechanisms shape the geometry of the loss landscape, and why different adversarial attacks are effective in different regimes. Our work connects evolved cellular decision-making to machine learning, and motivates the design of a general theory of adversarial perturbations, both forin vivoandin silicosystems.
Processivity, velocity and universal characteristics of nucleic acid unwinding by helicases
Authors: Chakrabarti Shaon , Jarzynski Christopher , Thirumalai D.
Published: July 2018

Helicases that act as motors and unwind double stranded nucleic acids are broadly classified as either active or passive, depending on whether or not they directly destabilize the double strand. By using this description in a mathematical framework, we derive analytic expressions for the velocity and run-length of a general model of finitely processive helicases. We show that, in contrast to the helicase unwinding velocity, the processivity exhibits a universal increase in response to external force. We use our results to analyze velocity and processivity data from single molecule experiments on the superfamily-4 ring helicase T7, and establish quantitatively that T7 is a weakly active helicase. We predict that compared to single-strand translocation, there is almost a two orders-of-magnitude increase in the back-stepping probability of T7 while unwinding double-stranded DNA. Our quantitative analysis of T7 suggests that the tendency of helicases to take frequent back-steps may be more common than previously anticipated, as was recently shown for the XPD helicase. Finally, our results suggest the intriguing possibility of a single underlying physical principle governing the experimentally observed increase in unwinding efficiencies of helicases in the presence of force, oligomerization or partner proteins like single strand binding proteins. The clear implication is that helicases may have evolved to maximize processivity rather than speed.
Feasibility of Functional MRI at Ultralow Magnetic Field via Changes in Cerebral Blood Volume
Authors: Buckenmaier Kai , Pedersen Anders , SanGiorgio Paul , Scheffler Klaus , Clarke John , Inglis Ben
Published: July 2018

We investigate the feasibility of performing functional MRI (fMRI) at ultralow field (ULF) with a Superconducting QUantum Interference Device (SQUID), as used for detecting magnetoencephalography (MEG) signals from the human head. While there is negligible magnetic susceptibility variation to produce blood oxygenation level-dependent (BOLD) contrast at ULF, changes in cerebral blood volume (CBV) may be a sensitive mechanism for fMRI given the five-fold spread in spin-lattice relaxation time (T1) values across the constituents of the human brain. We undertook simulations of functional signal strength for a simplified brain model involving activation of a primary cortical region in a manner consistent with a blocked task experiment. Our simulations involve measured values of T1 at ULF and experimental parameters for the performance of an upgraded ULFMRI scanner. Under ideal experimental conditions we predict a functional signal-to-noise ratio of between 3.1 and 7.1 for an imaging time of 30 minutes, or between 1.5 and 3.5 for a blocked task experiment lasting 7.5 minutes. Our simulations suggest it may be feasible to perform fMRI using a ULFMRI system designed to perform MRI and MEG in situ.
The many nuanced evolutionary consequences of duplicated genes
Authors: Teufel Ashley I. , Johnson Mackenzie M. , Laurent Jon M. , Kachroo Aashiq H. , Marcotte Edward M. , Wilke Claus O.
Published: July 2018

Gene duplication is seen as a major source of structural and functional divergence in genome evolution. Under the conventional models of sub- or neofunctionalizaton, functional changes arise in one of the duplicates after duplication. However, we suggest here that the presence of a duplicated gene can result in functional changes to its interacting partners. We explore this hypothesis byin-silicoevolution of a heterodimer when one member of the interacting pair is duplicated. We examine how a range of selection pressures and protein structures leads to differential patterns of evolutionary divergence. We find that a surprising number of distinct evolutionary trajectories can be observed even in a simple three member system. Further, we observe that selection to correct dosage imbalance can affect the evolution of the initial function in several unexpected ways. For example, if a duplicate is under selective pressure to avoid binding its original binding partner, this can lead to changes in the binding interface of a non-duplicated interacting partner to exclude the duplicate. Hence, independent of the fate of the duplicate, its presence can impact how the original function operates. Additionally, we introduce a conceptual framework to describe how interacting partners cope with dosage imbalance after duplication. Contextualizing our results within this framework reveals that the evolutionary path taken by a duplicate’s interacting partners is highly stochastic in nature. Consequently, the fate of duplicate genes may not only be controlled by their own ability to accumulate mutations but also by how interacting partners cope with them.
Acinetobacter baumanniidetected on mCCDA medium in a waste stabilisation pond
Authors: Sheludchenko Maxim , Padovan Anna , Katouli Mohammad , Roiko Anne , Stratton Helen
Published: July 2018

Acinetobacter baumanniisurvives for prolonged periods under a wide range of environmental conditions. In a larger study investigating the efficacy of pathogen removal in a waste stabilization ponds (WSP), we cultivated microbes from wastewater samples on mCCDA agar containing selective and recommended supplements for the growth ofCampylobacter. This bacterium is a recommended reference pathogen for the verification and validation of water recycling schemes in Australia and other parts of the world. A high number of colonies characteristic ofCampylobactergrew on the selective media but this did not correlate with qPCR data. Using primers targeting the16S rRNA gene, and additional confirmatory tests such as detection of VS1,ompA, blaOXA-51-like, blaOXA-23-likegenes, we tested eight random colonies from eight samples (64 colonies in total) and identified them asA. baumannii. Wastewater grab samples taken three times over 6 months throughout the WSP system showed removal ofA. baumanniiin the WSP atrates similar toE. coli. In contrast, further intensive sampling from the inlet and the outlet of the WSP using a refrigerated auto-sampler showed that the number ofA. baumanniiin most sampling rounds did not differ significantly between the inlet and outlet of the WSP and that there was high variation between replicates at the outlet only. Resistance genes were detected in mostA. baumanniiisolated from the waste stabilisation pond and may potentially be a source of antibiotic resistance for environmental strains.
Lineage tracing using a Cas9-deaminase barcoding system targeting endogenous L1 elements
Authors: Hwang Byungjin , Lee Wookjae , Yum Soo-Young , Jeon Yujin , Cho Namjin , Jang Goo , Bang Duhee
Published: July 2018

Determining cell lineage and function is critical to understanding human physiology and pathology. Although advances in lineage tracing methods have provided new insight into cell fate, defining cellular diversity at the mammalian level remains a challenge. Here, we developed a genome editing strategy using a cytidine deaminase fused with inactive Cas9 (dCas9) to specifically target endogenous interspersed repeat regions in mammalian cells. The resulting mutation patterns served as a genetic barcode, which was induced by targeted mutagenesis with single-guide RNA (sgRNA), leveraging substitution events, and subsequent read out by a single primer pair. By analyzing interspersed mutation signatures, we show the accurate reconstruction of cell lineage using both bulk cell and single-cell data. We envision that our genetic barcode system will enable fine-resolution mapping of organismal development in healthy and diseased mammalian states.
The Biological Basis of Mathematical Beauty
Authors: Zeki Semir , Chén Oliver Y. , Romaya John Paul
Published: July 2018

Through our past studies of the neurobiology of beauty, we have come to divide aesthetic experiences into two broad categories: biological and artifactual. The aesthetic experience of biological beauty is dictated by inherited brain concepts, which are resistant to change even in spite of extensive experience. The experience of artifactual beauty on the other hand is determined by post-natally acquired concepts, which are modifiable throughout life by exposure to different experiences (Zeki, 2009). Hence, in terms of aesthetic rating, biological beauty (in which we include the experience of beautiful faces or human bodies) is characterized by less variability between individuals belonging to different ethnic origins and cultural backgrounds or the same individual at different times. Artifactual beauty (in which we include the aesthetic experience of human artifacts such as buildings and cars) is characterized by greater variability between individuals belonging to different ethnic and cultural groupings and by the same individual at different times. In this paper, we present results to show that the experience of mathematical beauty (Zeki et al 2014), even though it constitutes an extreme example of beauty that is dependent upon (mathematical) culture and learning, belongs to the biological category and obeys one of its characteristics, namely a lesser variability in terms of the aesthetic ratings given to mathematical formulae experienced as beautiful.
The creation of sexual dimorphism in Drosophila gonad stem cell niches
Authors: Camara Nicole , Whitworth Cale , Van Doren Mark
Published: July 2018

Sex-specific development of the gonads is a key aspect of sexual dimorphism that is regulated by Doublesex/Mab3 Related Transcription Factors (DMRTs) in diverse animals species. We find that in mutants forDrosophila dsx, important components of the male and female gonad stem cell niches (hubs and terminal filaments/cap cells, respectively) still form. Initially, gonads in alldsxmutants (both XX and XY) initiate the male program of development, but later half of these gonads switch to form female stem cell niche structures. One individual can have both male-type and female-type gonad niches, however male and female niches are usually not observed in the same gonad, indicating that cells make a “group decision” about which program to follow. We conclude thatdsxdoes not act in an instructive manner to regulate male vs. female niche formation, as these structures form in the absence ofdsxfunction. Instead,dsxacts to “tip the balance” between the male or female programs, which are then executed independent ofdsx. We show thatbric a bracacts downstream ofdsxto control the male vs. female niche decision. These results indicate that, in both flies and mammals, the sexual fate of the somatic gonad is remarkably plastic and is controlled by a combination of autonomous and non-autonomous cues.
Differential metabolic activity and discovery of therapeutic targets using summarized metabolic pathway models
Authors: Çubuk Cankut , Hidalgo Marta R. , Amadoz Alicia , Rian Kinza , Salavert Francisco , Pujana Miguel A. , Mateo Francesca , Herranz Carmen , Carbonell-Caballero Jose , Dopazo Joaquín
Published: July 2018

Background

in spite of the increasing availability of genomic and transcriptomic data, there is still a gap between the detection of perturbations in gene expression and the understanding of their contribution to the molecular mechanisms that ultimately account for the phenotype studied. Alterations in the metabolism are behind the initiation and progression of many diseases, including cancer. The wealth of available knowledge on metabolic processes can therefore be used to derive mechanistic models that link gene expression perturbations to changes in metabolic activity that provide relevant clues on molecular mechanisms of disease and drug modes of action (MoA). In particular, pathway modules, which recapitulate the main aspects of metabolism, are especially suitable for this type of modeling.

Results

we present Metabolizer, a web-based application that offers an intuitive, easy-to-use interactive interface to analyze differences in pathway module metabolic activities that can also be used for class prediction and in silico prediction of Knock-Out (KO) effects. Moreover, Metabolizer can automatically predict the optimal KO intervention for restoring a diseased phenotype. We provide different types of validations of some of the predictions made by Metabolizer.

Conclusions

Metabolizer is a web tool that allows understanding molecular mechanisms of disease or the MoA of drugs within the context of the metabolism by using gene expression measurements. In addition, this tool automatically suggests potential therapeutic targets for individualized therapeutic interventions.

Metabolizer can be found at:http://metabolizer.babelomics.org.
Olive fruit fly rearing procedures affect the vertical transmission of the bacterial symbiontCandidatusErwinia dacicola
Authors: Sacchetti Patrizia , Pastorelli Roberta , Bigiotti Gaia , Guidi Roberto , Ruschioni Sara , Viti Carlo , Belcari Antonio
Published: July 2018

Background: The symbiosis between the olive fruit fly,Bactrocera oleae, andCandidatusErwinia dacicola has been demonstrated as essential for the fly’s larval development and adult physiology. The mass rearing of the olive fruit fly has been hindered by several issues, including problems which could be related to the lack of the symbiont, presumably due to preservatives and antibiotics currently used in the laboratory. To better understand the mechanisms underlying symbiont removal or loss during the rearing of lab colonies of the olive fruit fly, we performed experiments that focused on bacterial transfer from wild female flies to their eggs. In this research, eggs laid by wild females were treated with propionic acid solution, which is often used as an antifungal agent, a mixture of sodium hypochlorite and Triton X, or water (as a control). The presence of the bacterial symbiont on eggs was evaluated by real-time PCR and scanning electron microscopy.

Results: DGGE analysis showed a clear band with the same migration behavior present in all DGGE profiles but with a decreasing intensity. Molecular analyses performed by real-time PCR showed a significant reduction inCa. E. dacicola abundance in eggs treated with propionic acid solution or a mixture of sodium hypochlorite and Triton X compared to those treated with water. In addition, the removal of bacteria from the surfaces of treated eggs was highlighted by scanning electron microscopy.

Conclusions: The results clearly indicate how the first phases of the colony-establishment process are important in maintaining the symbiont load in laboratory populations and suggest that the use of products with antimicrobial activity should be avoided. The results also suggest that alternative rearing procedures for the olive fruit fly should be investigated.
Does gender influence cardiovascular remodeling in C57BL/6J mice fed a high-fat, high-sucrose, high-salt diet?
Authors: Pereira-Silva Debora Cristina , Machado-Silva Rayane Paula , Castro-Pinheiro Camila , Fernandes-Santos Caroline
Published: July 2018

Animal models are widely used to study the physiopathology of human diseases. However, the influence of gender on modern society diet style-induced cardiovascular disease was not exploited so far. Thus, this study investigated cardiovascular remodeling in C57BL/6J mice fed a diet rich in saturated fat, sucrose, and salt, evaluating gender effect on this process. Male and female C57BL/6J mice were fed AIN93M diet or a modified AIN93M rich in fat, sucrose, and salt (HFSS) for 12 weeks. Body mass, water and food intake and cardiovascular remodeling were assessed. The HFSS diet did not lead to body mass gain or glucose metabolism disturbance assessed by serum glucose, insulin, and oral glucose tolerance test. However, female mice on a HFSS diet had increased visceral and subcutaneous adiposity. Only male mice displayed heart hypertrophy. The left ventricle was not hypertrophied in male and female mice, but its lumen was dilated. Intramyocardial arteries and the thoracic aorta had intima-media thickening in male mice, but in the female, it was only noticed in the thoracic aorta. Finally, intramyocardial artery dilation was present in both genders, but not in the aorta. Changes in LV dimensions and the arterial remodeling were influenced by both gender and the HFSS diet. In conclusion, male and female C57BL/6J mice suffered cardiovascular remodeling after 12 weeks of high-fat, high-sucrose, high-salt feeding, although they did not develop obesity or diabetes. Sexual dimorphism occurred in response to diet for body adiposity, heart hypertrophy, and intramyocardial artery remodeling.
Corticospinal neuroplasticity and sensorimotor recovery in rats treated by infusion of neurotrophin-3 into disabled forelimb muscles started 24 h after stroke
Authors: Duricki Denise A. , Drndarski Svetlana , Bernanos Michel , Wood Tobias , Bosch Karen , Chen Qin , Shine H. David , Simmons Camilla , Williams Steven C.R. , McMahon Stephen B. , Begley David J. , Cash Diana , Moon Lawrence D.F.
Published: July 2018

Stroke often leads to arm disability and reduced responsiveness to stimuli on the other side of the body. Neurotrophin-3 (NT3) is made by skeletal muscle during infancy but levels drop postnatally and into adulthood. It is essential for the survival and wiring-up of sensory afferents from muscle. We have previously shown that gene therapy delivery of human NT3 into the affected triceps brachii forelimb muscle improves sensorimotor recovery after ischemic stroke in adult and elderly rats. Here, to move this therapy one step nearer to the clinic, we set out to test the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after ischemic cortical stroke in adult rats. To simulate a clinically-feasible time-to-treat, twenty-four hours later rats were randomized to receive NT3 or vehicle by infusion into triceps brachii for four weeks using implanted minipumps. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory deficits on the affected forearm. There was no evidence of forepaw sensitivity to cold stimuli after stroke or NT3 treatment. MRI confirmed that treatment did not induce neuroprotection. Functional MRI during low threshold electrical stimulation of the affected forearm showed an increase in peri-infarct BOLD signal with time in both stroke groups and indicated that neurotrophin-3 did not further increase peri-infarct BOLD signal. Rather, NT3 induced spinal neuroplasticity including sprouting of the spared corticospinal and serotonergic pathways. Neurophysiology showed that NT3 treatment increased functional connectivity between the corticospinal tracts and spinal circuits controlling muscles on the treated side. After intravenous injection, radiolabelled NT3 crossed from bloodstream into the brain and spinal cord in adult mice with or without strokes. Our results show that delayed, peripheral infusion of neurotrophin-3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke.
Triflic acid treatment enables LC-MS/MS analysis of insoluble bacterial biomass
Authors: Wang Ana Y. , Thuy-Boun Peter S. , Stupp Gregory S. , Su Andrew I. , Wolan Dennis W.
Published: July 2018

The lysis and extraction of soluble bacterial proteins from cells is a common practice for proteomics analyses, but insoluble bacterial biomasses are often left behind. Here, we show that with triflic acid treatment, the insoluble bacterial biomass of Gram- and Gram+ bacteria can be rendered soluble. We use LC-MS/MS shotgun proteomics to show that bacterial proteins in the soluble and insoluble post-lysis fractions differ significantly. Additionally, in the case of Gram-Pseudomonas aeruginosa, triflic acid treatment enables the enrichment of cell envelope-associated proteins. Finally, we apply triflic acid to a human microbiome sample to show that this treatment is robust and enables the identification of a new, complementary subset of proteins from a complex microbial mixture.
Genetic data and cognitively-defined late-onset Alzheimer’s disease subgroups
Authors: Mukherjee Shubhabrata , Mez Jesse , Trittschuh Emily , Saykin Andrew J. , Gibbons Laura E. , Fardo David W. , Wessels Madeline , Bauman Julianna , Moore Mackenzie , Choi Seo-Eun , Gross Alden L. , Rich Joanne , Louden Diana K.N. , Sanders R. Elizabeth , Grabowski Thomas J. , Bird Thomas D. , McCurry Susan M. , Snitz Beth E. , Kamboh M. Ilyas , Lopez Oscar L. , De Jager Philip L. , Bennett David A. , Keene C. Dirk , Larson Eric B. , Crane Paul K.
Published: July 2018

Categorizing people with late-onset Alzheimer’s disease into biologically coherent subgroups is important for personalized medicine. We evaluated data from five studies (total n=4 050, of whom 2 431 had genome-wide single nucleotide polymorphism (SNP) data). We assigned people to cognitively-defined subgroups on the basis of relative performance in memory, executive functioning, visuospatial functioning, and language at the time of Alzheimer’s disease diagnosis. We compared genotype frequencies for each subgroup to those from cognitively normal elderly controls. We focused on APOE and on SNPs with p<10-5 and odds ratios more extreme than those previously reported for Alzheimer’s disease (<0.77 or >1.30). There was substantial variation across studies in the proportions of people in each subgroup. In each study, higher proportions of people with isolated substantial relative memory impairment had ≥1 APOE e4 allele than any other subgroup (overall p= 1.5 × 10-27). Across subgroups, there were 33 novel suggestive loci across the genome with p<10-5 and an extreme OR compared to controls, of which none had statistical evidence of heterogeneity and 30 had ORs in the same direction across all datasets. These data support the biological coherence of cognitively-defined subgroups and nominate novel genetic loci.
Ubiquitin-dependent and -independent roles of E3 ligase RIPLET in innate immunity
Authors: Cadena Cristhian , Ahmad Sadeem , Xavier Audrey , Willemsen Joschka , Park Sehoon , Park Ji Woo , Oh Seong-Wook , Fujita Takashi , Hou Fajian , Binder Marco , Hur Sun
Published: July 2018

The conventional view posits that E3 ligases function primarily through conjugating ubiquitin (Ub) to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET uses its dimeric structure and a bivalent binding mode to preferentially recognize and ubiquitinate RIG-I pre-oligomerized on dsRNA. In addition, RIPLET can cross-bridge RIG-I filaments on longer dsRNAs, inducing aggregate-like RIG-I assemblies. The consequent receptor clustering synergizes with the Ub-dependent mechanism to amplify RIG-I-mediated antiviral signaling in an RNA-length dependent manner. These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. It also highlights a previously unrecognized mechanism by which the innate immune system measures foreign nucleic acid length, a common criterion for self vs. non-self nucleic acid discrimination.
Enhancing microRNA activity through increased endosomal release mediated by nigericin
Authors: Orellana Esteban A. , Rangasamy Loganathan , Tenneti Srinivasarao , Abdelaal Ahmed M. , Low Philip S. , Kasinski Andrea L.
Published: July 2018

The therapeutic promise of small RNA therapeutics (siRNAs, miRNAs) is not only limited by the lack of delivery vehicles, but also by the inability of the small RNAs to reach intracellular compartments where they can be biologically active. We previously reported successful delivery of functionally active miRNAs via receptor-mediated endocytosis1. This type of targeted therapy still faces one of the major challenges in the delivery field, endosomal sequestration. Here, a new method has been developed to promote endosomal escape of delivered miRNA. The strategy relies on the difference in solute contents between nascent endosomes and the cytoplasm: early endosomes are rich in sodium ions (Na+) while the intracellular fluid is rich is potassium ions (K+). Exploiting this difference through favoring the influx of K+into the endosomes without the exchange for a osmotically active ion (Na+), results in an osmotic differential leading to endosome swelling and bursting. One molecule that is able to exchange K+for an osmotically inactive hydrogen ion is the ionophore nigericin. Via generating an intramolecular miRNA delivery vehicle, containing a ligand, in this case folate, and nigericin we achieve escape of folate-RNA conjugates (e.g. FolamiRs) from their entrapping endosomes into the cytoplasm where they bind the RNA Induced Silencing complex (RISC) and activate the RNAi response.
A bacterial display system for effective selection of protein-biotin ligase BirA variants with novel peptide specificity
Authors: Granhøj Jeff , Dimke Henrik , Svenningsen Per
Published: July 2018

Biotinylation creates a sensitive and specific tag for purification and detection of target proteins. TheE. coliprotein-biotin ligase BirA biotinylates a lysine within a synthetic biotin acceptor peptide (AP) and allow for specific tagging of proteins fused to the AP. The approach is not applicable to unmodified proteins, and we sought to develop an effective selection system that could form the basis for directed evolution of novel BirA variants with specificity towards unmodified proteins. The system was based on bacterial display of a target peptide sequence, which could be biotinylated by cytosolic BirA variants before being displayed on the surface. In a model selection, the bacterial display system accomplished >1.000.000 enrichment in a single selection step. A randomly mutated BirA library was used to identify novel variants. Bacteria displaying peptide sequences from 13 out of 14 tested proteins were strongly enriched after 3–5 selection rounds. Moreover, a clone selected for biotinylation of a C-terminal peptide from red-fluorescent protein TagRFP showed site-specific biotinylation. Thus, active BirA variants with novel specificity are effectively isolated with our bacterial display system and provides a basis for the development of BirA variants for site-selective biotinylation.
(Al,Mg)3La: a new phase in the Mg–Al–La system
Authors: Wong Charlotte , Styles Mark J. , Zhu Suming , Qiu Dong , McDonald Stuart D. , Zhu Yuman , Gibson Mark A. , Abbott Trevor B. , Easton Mark A.
Published: July 2018

During an investigation of the Mg-rich end of the Mg–Al–La system, a new ternary phase with the composition of (Al,Mg)3La was identified. The crystal structure of this phase was determined by conventional X-ray powder diffraction and transmission electron microscopy analysis and refined using high-resolution X-ray powder diffraction. The (Al,Mg)3La phase is found to have an orthorhombic structure with a space group of C2221 and lattice parameters of a = 4.3365 (1) Å, b = 18.8674 (4) Å and c = 4.4242 (1) Å, which is distinctly different from the binary Al3La phase (P63/mmc). The resolved structure of the (Al,Mg)3La phase is further verified by high-angle annular dark-field scanning transmission electron microscopy.
Supply chain – marketing integration
Authors: Alon Ilan , Chen Shan , Mandolfo Marco
Published: July 2018

Purpose

The purpose of this paper is to discuss China’s New Silk Road initiative as an opportunity for European small and medium-sized enterprises (SMEs) to export to Chinese market. It offers research propositions on redefining the business process of European SMEs and Chinese importers in light of the initiative.

Design/methodology/approach

SMEs’ export barriers, particularly in SCM and marketing, are identified through literature review. Then they are discussed in accordance with the measures that New Silk Road proposed.

Findings

Logistic infrastructure development under the New Silk Road significantly lowers the supply chain barrier. Marketing remains a challenge for European SMEs to export to China. This paper argues that the European SMEs and the Chinese importers should create closer collaboration, expand their relationship beyond SCM, and integrate their marketing efforts for mutual benefits.

Research limitations/implications

Several future research areas are proposed in this paper. The authors invite researchers and practitioners to deepen the discussion with empirical evidence.

Practical implications

The New Silk Road has already become a high stake project for many countries involved. Many measures are yet to be defined and the stakeholders, including industries and businesses, should have an influence on their definition. This paper provides the authors’ viewpoints on how businesses should act in this initiative.

Originality/value

Despite being an important topic of the world’s economy in the recent years, the New Silk Road initiative has rarely been studied in management research, possibly due to lack of evidence. As its development significantly sped up since 2017, it is high time that the research community starts to contribute to the knowledge building in this project. This paper is among the firsts to call for and to propose avenues for future research efforts.
Spatial analysis of dairy yields response to intensive farming in New Zealand
Authors: Yang Wei , Sharp Basil
Published: July 2018

Purpose

The New Zealand (NZ) dairy industry faces the challenge of increasing productivity and dealing with public concerns over nutrient pollution. The effective policy needs to address regional differences in productivity and fertilizer use. The purpose of this paper is to investigate how spatial effects influence the relationship between dairy yields and intensive farming practices across regions in NZ.

Design/methodology/approach

This paper employs spatial panel data models to establish whether unobserved spatial effects exist in the relationship between dairy yields and nutrient inputs regionally and nationally using 2002, 2007 and 2012 data from Statistics NZ and DairyNZ.

Findings

The results show positive spatial spillovers for most intensive inputs. The high level of effluent use and estimated negative yield response to nitrogen suggests that an opportunity exists for greater use of effluent as a substitute for nitrogenous fertilizer. Substitution has the potential to reduce dependence on fertilizer and contribute to a reduction in the nutrient pollution.

Originality/value

This paper is the first empirical application of spatial econometric methods to examine the spatial relevance of dairy yields and intensive farming in NZ. In particular, the spatial panel data model accounts for cross-sectional dependence and controls for heterogeneity. The results contribute to an understanding of how farmers can improve their management of intensive inputs and contribute to the formation of regional environmental policy that recognizes regional heterogeneity.
Towards well-being: role of diversity and nature of work
Authors: Jaiswal Akanksha , Dyaram Lata
Published: July 2018

Purpose

Literature highlights diversity to facilitate cognitive outcomes; nevertheless, there is limited scholarly attention on affective diversity effects. The purpose of this paper is to examine the impact of perceived diversity on employee well-being (EWB) and contend different types of diversity to yield differential impact. Further, the authors explore how nature of employee work can moderate these relationships.

Design/methodology/approach

With 311 full-time employees representing large manufacturing organizations in India, the authors test the hypothesized relationships using PROCESS macro.

Findings

Results indicate perception of surface and knowledge diversity having a significant positive impact on EWB. Further, the authors found nature of employee work to moderate the link between knowledge diversity and well-being such that perception of knowledge diversity under complex tasks enhanced well-being; no impact of work complexity was observed on the link between surface diversity and well-being.

Research limitations/implications

Perceived diversity is malleable lending itself to longitudinal work in this field. Besides nature of work, future research may explore other key contextual factors in diversity dynamics.

Practical implications

Contrary to the longstanding theories such as social categorization/similarity attraction, the authors found surface diversity to positively influence EWB. This indicates firms’ effective diversity management strategies in creating inclusive workplace. Further, the authors draw implications around team design and workforce composition.

Originality/value

While the scholarly attention to perceived diversity is gradually growing, in a first, the authors empirically examine the impact of diversity perceptions on employee affect in the context of Indian manufacturing firms.
Managing hazards of the make-buy decision in the face of radical technological change
Authors: Park Woo-Yong
Published: July 2018

Purpose

The purpose of this paper is to consider the management of hazards arising from the make-buy choice in the face of radical technological change. This sourcing choice can lead to distinctive exchange and hierarchical hazards. This study’s main interest is in investigating the research question “How can firms reduce those distinctive exchange and hierarchical hazards arising from the make-buy sourcing strategy when dealing with radical technological change?”

Design/methodology/approach

The author develops hypotheses that the in-house retention of outsourced component knowledge will likely reduce exchange hazards arising from the buy strategy choice. And prior exploratory technological experience will likely reduce hierarchical hazards arising from the make strategy choice. The author explores the US mountain bicycle industry from 1980 to 1992 to test the developed hypotheses. For endogeneity arising from the make-buy sourcing decision, the author uses Heckman’s two-stage switching regression model.

Findings

The major findings are that the in-house retention of outsourced component knowledge and prior exploratory technological experience is distinctive moderating factors improving performance of a buy strategy and a make strategy, respectively.

Originality/value

Since the extant literature tends to focus on which of the two sourcing strategies provides the greatest performance advantages in the face of radical technological change, there is a strong implication to suggest that if a firm performs poorly with one sourcing decision, the firm should switch to an alternative one. Different from the expositions of the literature, this study elevates the understanding regarding how firms can improve the performance of their current sourcing orientation rather than whether they should switch from one sourcing strategy to another.
External auditor type, discretionary accruals and investors’ reactions
Authors: Abdallah Sara
Published: July 2018

Purpose

The purpose of this paper is to investigate, in an Egyptian context, the external auditor type (Big 4 vs local) implications on reporting quality proxied by discretionary accruals (DA) and also examine whether auditor type impacts the market’s pricing of DA, where pricing is considered a proxy for the perceived DA quality.

Design/methodology/approach

The sample period is 2012–2015, that is meant to be post the Egyptian revolution financial crisis; all Egyptian stock exchange (EGX) listed firms (except banks and financial institutions) are considered. DA are estimated using modified Dichev and Dechow’s (2002) model (McNicholas, 2002). Ordinary least squares regression tests are used to investigate the external auditor type implications on DA level and the related EGX investors’ pricing.

Findings

The findings generally show the external auditor’s minimal role in mitigating DA. Moreover, the findings reflect the EGX investors’ negligence and/or lack of confidence in regards to DA and external auditor type factors in stock pricing.

Practical implications

The paper findings highlight to regulators the need for effective monitoring of audit firms earnings management mitigation performance to help reinforce investor confidence in financial reporting quality.

Originality/value

This paper is the first that investigates the external auditor monitoring mechanism implications on investors’ perceptions of earnings quality in Egypt. The paper findings would provide important contributions, particularly post the Egyptian revolution crisis, where the EGX market is trying to restore the investors’ confidence.
The course of recognition and the emergence of change initiatives
Authors: Niess Alexander , Duhamel Francois B.
Published: July 2018

Purpose

The purpose of this paper is to study the status of the individual self in the emergence of change initiatives in organizations.

Design/methodology/approach

This theoretical paper examines the emergence of change initiatives through the building of agents’ capacity to act, based on a theory of action inspired by Paul Ricœur.

Findings

This paper identifies the “course of recognition” to favor the emergence of change initiatives and the building of the capacity to act of agents, respecting the autonomy at the individual level, a sense of care at the group level and justice at the institutional level.

Research limitations/implications

The theoretical research can be extended with empirical studies dealing with the role of agents’ capacities in conflict management, the role of the “narrative self´” in change processes in organizations and the conjoint operationalization of autonomy care and justice to determine the agents’ capacity to act for initiatives to emerge.

Practical implications

It is important to develop a sense of shared leadership to nurture the capacity to act of agents to make change initiatives emerge in organizations, increasing organizational members’ feelings of being recognized.

Originality/value

So far, research has not provided satisfactory answers to the question about how to best initiate organizational change. The use of Ricœur’s theory of action adds value to the existing approaches as it addresses the source of the emergence of initiatives from agents’ feelings of their capacity to act, and integrates individual, group and institutional levels, which are rarely contemplated together.