bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects
Authors: Abdullah L , Crawford F , Langlois H , Tsolaki M , Börjesson-Hanson A , Olde Rikkert M , Pasquier F , Wallin A , Kennelly S , Hendrix S , Blennow K , Lawlor B , Mullan M
Published: June 2018

Background

We explored whether the effects of nilvadipine on cognition were influenced by baseline Alzheimer’s disease (AD) severity.

Methods

Exploratory analyses were performed on the modified intention-to-treat (mITT) dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in very mild, mild and moderate AD subjects. The outcome measures included total and subscale scores of the Alzheimer’s Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS), an outcome measure recently developed to detect treatment responses in subjects with prodromal AD. Cerebrospinal fluid (CSF) biomarkers Aβ38, Aβ40, Aβ42, total tau and P181 tau were measured in a subset of samples (n = 55). Regression analyses were adjusted for potential confounders and effect modifiers in order to examine the interactive effects of nilvadipine and AD severity on cognitive outcomes over 78-weeks.

Results

Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed greater decline on the ADAS-Cog 12. Also in very mild AD, a beneficial effect (as measured by ADCOMS), was detected in the nilvadipine treated group. Therapeutic effects of nilvadipine were also observed for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. CSF Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls.

Conclusion

These data suggest that very mild AD subjects benefited from nilvadipine and that future clinical trials of nilvadipine in this population are required to confirm these findings.

Trial Registration

NCT02017340 Registered 20 December 2013,https://clinicaltrials.gov/ct2/show/NCT02017340

EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013,https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27
MITA couples with PI3K to regulate actin reorganization during BCR activation
Authors: Jing Yukai , Kang Danqing , Yang Lu , Jiang Panpan , Li Na , Cheng Jiali , Li Jingwen , Miller Heather , Ren Boxu , Gong Quan , Yin Wei , Liu Zheng , Mattila Pieta , Yu Bing , Liu Chaohong
Published: June 2018

As an adaptor protein, MITA has been extensively studied in innate immunity. However, its role in adaptive immunity as well as its underlying mechanism are not completely understood. We used MITA KO mice to study the effect of MITA deficiency on B cell development and differentiation, BCR signaling during BCR activation and humoral immune response. We found that MITA deficiency promotes the differentiation of marginal zone B cells, which is linked to the lupus-like autoimmune disease that develops in MITA KO mice. MITA is involved in BCR activation and negatively regulates the activation of CD19 and Btk and positively regulates the activation of SHIP. Interestingly, we found that the activation of WASP and accumulation of F-actin is enhanced in MITA KO B cells upon stimulation. Mechanistically, we found that MITA uses PI3K mediated by the CD19-Btk axis as a central hub to control the actin remodeling that, in turn, offers feedback to BCR signaling. Overall, our study has provided a new mechanism on how MITA regulates BCR signaling via feedback from actin reorganization, which may contribute to the effects of MITA on the humoral immune response.
E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms
Authors: Jolly Mohit Kumar , Ware Kathryn E , Xu Shengnan , Gilja Shivee , Shetler Samantha , Yang Yanjun , Wang Xueyang , Austin Garland , Runyambo Daniella , Hish Alexander J , Bartholf DeWitt Suzanne , George Jason T , Kreulen R. Timothy , Boss Mary-Keara , Lazarides Alexander L , Kerr David L , Gerber Drew G , Sivaraj Dharshan , Armstrong Andrew J , Dewhirst Mark W , Eward William C , Levine Herbert , Somarelli Jason A
Published: June 2018

E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.
Pivoting of microtubules driven by minus end directed motors leads to their alignment to form an interpolar bundle
Authors: Winters Lora , Ban Ivana , Prelogović Marcel , Pavin Nenad , Tolić Iva M.
Published: June 2018

At the beginning of mitosis, the cell forms a spindle made of microtubules and associated proteins to segregate chromosomes. An important part of spindle architecture is a set of antiparallel microtubule bundles connecting the two spindle poles. A key question is how microtubules extending at arbitrary angles form an antiparallel interpolar bundle. Here we show that microtubules meet at an oblique angle and subsequently rotate into antiparallel alignment. By combining experiments with theory, we show that microtubules from each pole search for those from the opposite pole by performing random angular movement. Upon contact of two microtubules, they slide sideways along each other towards the minus end, which we interpret as the action of minus end directed Cut7/kinesin-5 motors. In conclusion, random rotational motion helps microtubules from the opposite poles to find each other and subsequent accumulation of motors allows them to generate forces that drive interpolar bundle formation.
Xylanolytic psychrotrophs from andosolic sedge fens and moss heaths in Iceland
Authors: Rickman Olivia J. , Sigurbjörnsdóttir M. Auður , Vilhelmsson Oddur
Published: June 2018

Nine xylanolytic bacterial strains were isolated from fen and heath soils in northern Iceland. They were found by 16S rRNA gene sequencing to belong to the generaPaenibacillus,Bacillus,Pseudomonas, andStenotrophomonas. Using a simple, plate-based semiquantitative assay with azo-crosslinked xylan as the substrate, it was determined that although isolated from cold environments, most of the strains displayed greater xylanolytic activity under mesophilic conditions, with only the paenibacilli displaying markedly cold-active xylanolytic activity. Indeed, for one isolate,Paenibacillus castaneaeOV2122, xylanolytic activity was only detected at 15°C and below under the conditions tested. Of the nine strains,Paenibacillus amylolyticusOV2121 displayed the greatest activity at 5°C. Glycohydrolase family-specific PCR indicated that the paenibacilli produced multiple xylanases of families 10 and 11, whereas a family 8 xylanase was detected inPseudomonas kilonensisAL1515, and a family 11 xylanase inStenotrophomonas rhizophilaAL1610.
Gas seepage pockmark microbiomes suggest the presence of sedimentary coal seams in the Öxarfjörður graben of NE-Iceland
Authors: Þorsteinsdóttir Guðný Vala , Blischke Anett , Sigurbjörnsdóttir M. Auður , Óskarsson Finnbogi , Arnarson Þórarinn Sveinn , Magnússon Kristinn P. , Vilhelmsson Oddur
Published: June 2018

Natural gas seepage pockmarks are found off and onshore in the Öxarfjörður graben, NE Iceland. The bacterial communities of two onshore seepage sites were analysed by amplicon sequencing of 16S rDNA, along with determining the geochemical characteristics, hydrocarbon content and the carbon isotope composition of the sites.

While one site was found to be characterised by biogenic origin of methane gas, with carbon isotope ratio δ13C [‰] = −63.2, high content of organic matter and complex hydrocarbons, the other site showed a mixed origin of the methane gas (δ13C [‰] = −26.6) with geothermal characteristics and lower organic matter content. While both sites harbouredProteobacteriaas the most abundant bacterial phyla, theDeltaproteobacteriawere more abundant at the geothermal site, and theAlphaproteobacteriaat the biogenic site. TheDehalococcoidiaclass of theChloroflexiphylum was abundant at the geothermal site while theAnaerolineaeclass was more abundant at the biogenic site. Bacterial strains from the seepage pockmarks were isolated on a variety of selective media targeting bacteria with bioremediation potential. A total of 106 strains were isolated and characterised, including representatives from the phylaProteobacteria, Bacterioidetes, Firmicutes, andActinobacteria. This article describes the first microbial study on gas seepage pockmarks in Iceland.
Planktonic interference and biofilm alliance between aggregation substance and endocarditis and biofilm associated pili inEnterococcus faecalis
Authors: Afonina Irina , Lim Xin Ni , Tan Rosalind , Kline Kimberly A.
Published: June 2018

Like many bacteria,Enterococcus faecalisencodes a number of adhesins involved in colonization or infection of different niches. Two well-studiedE. faecalisadhesins, aggregation substance (AS) and endocarditis and biofilm-associated pili (Ebp), both contribute to biofilm formation on abiotic surfaces and in endocarditis, suggesting they may be expressed at the same time. Because different regulatory pathways have been reported for AS and Ebp, here we examined if they are co-expressed on the same cells and the functional impact of co-expression on individual cells and within a population. We found that while Ebp are only expressed on a subset of cells, when Ebp and AS are expressed on the same cells, pili interfere with AS-mediated clumping and impede AS-mediated conjugative plasmid transfer during planktonic growth. However, when the population density increases, horizontal gene transfer rates normalize and are no longer affected by pilus expression. Instead, at higher cell densities during biofilm formation, Ebp and AS differentially contribute to biofilm development and structure, synergizing to promote maximal biofilm formation.
Pasakbumin A controls the growth of Mycobacterium tuberculosis by enhancing the autophagy and production of antibacterial mediators in mouse macrophages
Authors: Lee Hyo-Ji , Ko Hyun-Jeong , Kim Seung Hyun , Jung Yu-Jin
Published: June 2018

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) and remains a major health problem worldwide. Thus, there is an urgent need to identify new and more effective drugs to treat emerging multidrug-resistant TB (MDR-TB) and to reduce the side effects of anti-TB drugs, such as liver toxicity and other detrimental changes. In this study, to develop a novel candidate drug for effective TB treatment with few side effects in the host, we selected pasakbumin A isolated from Eurycoma longifolia (E. longifolia) Jack, which protected host cells against Mtb infection-induced death. Pasakbumin A significantly inhibited intracellular Mtb growth by inducing autophagy via the ERK1/2-mediated signaling pathway in Mtb-infected macrophages. We further investigated whether pasakbumin A could be used as a potential adjuvant for TB treatment. Treatment with pasakbumin A and the anti-TB drug rifampicin (RMP) potently suppressed intracellular Mtb killing by promoting autophagy as well as TNF-α production via the ERK1/2- and NF-κB-mediated signaling pathways in Mtb-infected cells. Our results suggest that pasakbumin A could be developed as a novel anti-TB drug or host-directed therapeutic (HDT) strategy to protect against host cell death and improve host defense mechanisms against Mtb infection in macrophages.
The effect of a free radical scavenger on oxidation stress in partial bladder outlet obstruction and its relief in a rat model
Authors: Choo Min Soo , Piao SongZhe , Oh Seung-June
Published: June 2018

AIMS

To investigate the effect of a free radical scavenger (tempol) after relief of partial bladder outlet obstruction (pBOO) on bladder function in a rat model.

METHODS

pBOO was induced in 50 eight-week-old female Sprague-Dawley rats and relieved 3 weeks later. The rats were divided randomly into 5 groups: sham-operated, tempol-treated for 1 week (Treat-1w) or 3 weeks (Treat-3w), and no treatment for 1 week (nonTreat-1w) or 3 weeks (nonTreat-3w). Awaken cystometrograms were obtained 1 or 3 weeks after relief according to the grouping. The bladders were isolated and weighed. H&E, Masson’s trichrome and TUNEL staining were used to analyze histological changes. The oxidative stress assessed using malondialdehyde. The expression of beta-3 adrenoreceptor was examined by Western blotting.

RESULTS

The tempol-treated groups exhibited a significant decrease in the number of IDCs per voiding cycle (nonTreat-1w vs. Treat-1w, 1.18±0.82 vs. 0.36±0.40, P=0.010; nonTreat-3w vs. Treat-3w, 1.51±0.69 vs. 0.23±0.25, P=0.002). The thickness and collagen fiber deposition of the detrusor muscle layer was significantly decreased in the treated groups. Apoptosis detected was mainly observed in the urothelial cell layer, although the rate of apoptosis was significantly decreased in the treated groups (48.9±3.36% vs. 32.7±11.10%, P=0.024; 25.8±4.67% vs. 15.7±9.83%, P=0.314). The tempol-treated groups showed significant decreases in the MDA concentrations at both 1 and 3 weeks after relief. The expression of the beta-3 adrenoreceptor was increased in the tempol-treated rats.

CONCLUSIONS

Ischemic reperfusion injury after relief of pBOO caused histological and functional changes in the bladder. Free radical scavenger treatment prevented this oxidative stress.
Detecting spatiotemporal pattern of tuberculosis and the relationship between ecological environment and tuberculosis, a spatial panel data analysis in Guangxi, China
Authors: Cui Zhezhe , Lin Dingwen , Chongsuvivatwong Virasakdi , Zhao Jinming , Lin Mei , Ou Jing , Zhao Jinghua
Published: June 2018

Guangxi is one of the provinces having the highest reported incidence of tuberculosis (TB) in China. However, spatial and temporal pattern and causation of the situation are still unclear. In order to detect the spatiotemporal pattern of TB and the association with ecological environment factors in Guangxi Zhuang autonomous region, China, We performed a spatiotemporal analysis with prediction using time series analysis, Moran’s I global and local spatial autocorrelation statistics, and space-time scan statistics, to detect temporal and spatial clusters. Spatial panel models were employed to identify the influence factors. The time series analysis shows that the number of reported cases peaked in spring and summer and decreased in autumn and winter with the annual reported incidence of 113.1/100,000 population. Moran’s I global statistics were greater than 0 (0.363 – 0.536) during the study period. The most significant hot spots were mainly located in the central part. The east part exhibited a low-low relation. By spacetime scanning, the clusters identified were similar to that of the local autocorrelation statistics, and were clustered toward the early of 2016. Duration of sunshine, per capita gross domestic product (PGDP), the recovery rate of TB and participation rate of new cooperative medical care insurance in rural areas had a significant negative association with TB. In conclusion, the reported incidence of TB in Guangxi remains high. The main cluster was located in the central part of Guangxi, a region where promoting the productivity, improving TB treatment pathway and strengthening environmental protective measures (increasing sunshine exposure) are urgently needed.
Netrin-1 plays a role in the effect of 10 weeks moderate exercise on myocardial fibrosis in rats
Authors: Daliang Zhou , Hong Fu , Lifang Yu , Lingling Zhang , Lin Wei , Dapeng Li , Tianshu Zhang , Weimin Li
Published: June 2018

This study aimed to determine the effect of Netrin-1 and its receptor on acute myocardial infarction in rats after aerobic exercise.METHODS:Twenty-four rats were randomly divided into three groups: the sham group (n = 8); acute myocardial infarction model group (AMI)(n = 8); and aerobic exercise treatment after acute myocardial infarction group(ET) (n = 8). After 10 weeks, the levels of netrin-1, tumor necrosis factor alpha α(TNF-α), and interleukin 6(IL-6) in the serum were measured. The expression of matrix metalloproteinases 2 and 9(MMP2,9), and their inhibitor, tissue inhibitor of metalloproteinases 2(TIMP2), myocardial netrin-1, Deleted in colorectal cancer(DCC) receptor were evaluated. Histopathological were evaluated. The collagen volume fraction of myocardial tissues was also calculated.RESULTS:Compared to the sham group, the AMI group and ET groups showed increased levels of serum TNF-α, IL-6 and significantly reduced levels of netrin-1. Levels of TNF-α and IL-6 were significantly reduced in the ET group compared to the AMI group, whereas the level of netrin-1 was increased. The expression of myocardial MMP2,9 was significantly increased in the AMI group compared to the sham group, whereas that of myocardial netrin-1, inhibitor of TIMP2 and DCC receptor, was significantly reduced. Compared to AMI group, the ET group showed reduced expression of myocardial MMP2,9 proteins, whereas expression of myocardial netrin-1, inhibitor of TIMP2 and DCC receptor, was significantly increased. The collagen volume fraction of myocardial tissues was significantly increased in the AMI group and ET group compared to the sham group, with the greater increase being noted in the AMI group.CONCLUSIONS: Aerobic exercise could increase levels of serum netrin-1 myocardial netrin-1, and DCC receptor and reduced expression of myocardial MMP2,9 proteins, to improve the degree of fibrosis following myocardial infarction in rats.
Spatial transcriptomics ofC. elegansmales and hermaphrodites identifies novel fertility genes
Authors: Ebbing Annabel , Vertesy Abel , Betist Marco , Spanjaard Bastiaan , Junker Jan Philipp , Berezikov Eugene , van Oudenaarden Alexander , Korswagen Hendrik C.
Published: June 2018

To advance our understanding of the genetic programs that drive cell and tissue specialization, it is necessary to obtain a comprehensive overview of gene expression patterns. Here, we have used RNA tomography to generate the first high-resolution, anteroposterior gene expression maps ofC. elegansmales and hermaphrodites. To explore these maps, we have developed computational methods for discovering region and tissue-specific genes. Moreover, by combining pattern-based analysis with differential gene expression analysis, we have found extensive sex-specific gene expression differences in the germline and sperm. We have also identified genes that are specifically expressed in the male reproductive tract, including a group of uncharacterized genes that encode small secreted proteins that are required for male fertility. We conclude that spatial gene expression maps provide a powerful resource for identifying novel tissue-specific gene functions inC. elegans. Importantly, we found that expression maps from different animals can be precisely aligned, which opens up new possibilities for transcriptome-wide comparisons of gene expression patterns.
Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy
Authors: Vasiliauskaité-Brooks Ieva , Healey Robert D. , Rochaix Pascal , Sounier Rémy , Grison Claire , Waltrich-Augusto Thierry , Fortier Mathieu , Hoh François , Saied Essa M. , Arenz Christoph , Basu Shibom , Leyrat Cédric , Granier Sébastien
Published: June 2018

Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients.
Argininosuccinic aciduria fosters neuronal nitrosative stress reversed byAslgene transfer
Authors: Baruteau Julien , Perocheau Dany P. , Hanley Joanna , Rocha-Ferreira Eridan , Karda Rajvinder , Ng Joanne , Suff Nattalie , Rahim Ahad A. , Hughes Michael P. , Banushi Blerida , Prunty Helen , Hristova Mariya , Ridout Deborah A. , Virasami Alex , Heales Simon , Howe Stewen J. , Buckley Suzy M. , Mills Philippa B. , Gissen Paul , Waddington Simon N.
Published: June 2018

Argininosuccinate lyase (ASL) belongs to the liver-based urea cycle detoxifying ammonia, and the citrulline-nitric oxide cycle synthesising nitric oxide (NO). ASL-deficient patients present argininosuccinic aciduria characterised by hyperammonaemia and a multi-organ disease with neurocognitive impairment. Current therapeutic guidelines aim to control ammonaemia without considering the systemic NO imbalance. Here, we observed a neuronal disease with oxidative/nitrosative stress in ASL-deficient mouse brains. A single systemic injection of gene therapy mediated by an adeno-associated viral vector serotype 8 (AAV8) in adult or neonatal mice demonstrated the long-term correction of the urea cycle and the citrulline-NO cycle in the brain, respectively. The neuronal disease persisted if ammonaemia only was normalised but was dramatically reduced after correction of both ammonaemia and neuronal ASL activity. This was correlated with behavioural improvement and a decrease of the cortical cell death rate. Thus, the cerebral disease in argininosuccinic aciduria involves neuronal oxidative/nitrosative stress not mediated by hyperammonaemia, which is reversed by AAV gene transfer targeting the brain and the liver, acting on two different metabolic pathwaysviaa single vector delivered systemically. This approach provides new hope for hepatocerebral metabolic diseases.
Regulation of spatial and temporal gene expression in an animal germline
Authors: Diag Asija , Schilling Marcel , Klironomos Filippos , Ayoub Salah , Rajewsky Nikolaus
Published: June 2018

In animal germlines, regulation of cell proliferation and differentiation is particularly important but poorly understood. Here, using a cryo-cut approach, we mapped RNA expression along theCaenorhabditis elegansgermline and, using mutants, dissected gene regulatory mechanisms that control spatio-temporal expression. We detected, at near single-cell resolution, > 10,000 mRNAs, > 300 miRNAs and numerous novel miRNAs. Most RNAs were organized in distinct spatial patterns. Germline-specific miRNAs and their targets were co-localized. Moreover, we observed differential 3’ UTR isoform usage for hundreds of mRNAs. In tumorousgld-2 gld-1mutants, gene expression was strongly perturbed. In particular, differential 3’ UTR usage was significantly impaired. We propose that PIE-1, a transcriptional repressor, functions to maintain spatial gene expression. Our data also suggest thatcpsf-4andfipp-1control differential 3’ UTR usage for hundreds of genes. Finally, we constructed a “virtual gonad” enabling “virtualin situhybridizations” and access to all data (https://shiny.mdc-berlin.de/spacegerm/).
Base pair editing of goat embryos: nonsense codon introgression into FGF5 to improve cashmere yield
Authors: Li Guanwei , Zhou Shiwei , Li Chao , Cai Bei , Yu Honghao , Ma Baohua , Huang Yu , Ding Yige , Liu Yao , Ding Qiang , He Chong , Zhou Jiankui , Wang Ying , Zhou Guangxian , Li Yan , Yan Yuan , Hua Jinlian , Petersen Bjoern , Jiang Yu , Sonstegard Tad , Huang Xingxu , Chen Yulin , Wang Xiaolong
Published: June 2018

The ability to alter single bases without DNA double strand breaks provides a potential solution for multiplex editing of livestock genomes for quantitative traits. Here, we report using a single base editing system, Base Editor 3 (BE3), to induce nonsense codons (C-to-T transitions) at four target sites in caprine FGF5. All five progenies produced from microinjected single-cell embryos had alleles with a targeted nonsense mutation and yielded expected phenotypes. The effectiveness of BE3 to make single base changes varied considerably based on sgRNA design. Also, the rate of mosaicism differed between animals, target sites, and tissue type. PCR amplicon and whole genome resequencing analyses for off-target changes caused by BE3 were low at a genome-wide scale. This study provides first evidence of base editing in livestock, thus presenting a potentially better method to introgress complex human disease alleles into large animal models and provide genetic improvement of complex health and production traits in a single generation.
Design and assessment of species-level qPCR primers targeting comammox
Authors: Keene-Beach Natalie , Noguera Daniel R.
Published: June 2018

Published PCR primers targeting the ammonia monooxygenase gene (amoA) were applied to samples from activated sludge systems operated with low dissolved oxygen (DO) to quantify total and clade-levelNitrospirathat perform complete ammonium oxidation (comammox); however, we found these existing primers resulted in significant artifact-associated non-target amplification. This not only overestimated comammoxamoAcopies but also resulted in numerous false positive detections in the environmental samples tested, as confirmed by gel electrophoresis. Therefore, to more accurately quantify known comammox, we designed specific and sensitive primers targeting three candidate species:Candidatus(Ca.) Nitrospira nitrosa,Ca.N. inopinata, andCa.N. nitrificans. The primers were tested withamoAtemplates of these candidate species, and used to quantify comammox at the species level in low DO activated sludge systems. We found that comammox related toCa.N. nitrosa were present and abundant in the majority of samples from low DO bioreactors and were not detected in samples from a high DO system. In addition, the greatest abundance ofCa.N. nitrosa was found in bioreactors operated with a long solids retention time.Ca.N. inopinata andCa.N. nitrificans were only detected sporadically in these samples, indicating a minor role of these comammox in nitrification under low DO conditions.

Abstract art
JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias
Authors: Kim Sang-Kyu , Knight Deborah A. , Jones Lisa R. , Vervoort Stephin , Ng Ashley P. , Seymour John F. , Bradner James E. , Waibel Michaela , Kats Lev , Johnstone Ricky W.
Published: June 2018

Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
PARD3 dysfunction in conjunction with dynamic HIPPO signaling drives cortical enlargement with massive heterotopia
Authors: Liu Wenying Angela , Chen She , Li Zhizhong , Lee Choong Heon , Mirzaa Ghayda , Dobyns William B. , Ross M. Elizabeth , Zhang Jiangyang , Shi Song-Hai
Published: June 2018

Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons. Ectopically localized RGPs subsequently undergo accelerated and excessive neurogenesis, leading to the formation of an enlarged cortex with massive heterotopia and increased seizure susceptibility. Simultaneous removal of HIPPO pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) suppresses cortical enlargement and heterotopia formation. These results define a dynamic regulatory program of mammalian cortical development and highlight a progenitor origin of megalencephaly with ribbon heterotopia and epilepsy.
A modular dCas9-SunTag DNMT3A epigenome editing system overcomes pervasive off-target activity of direct fusion dCas9-DNMT3A constructs
Authors: Pflueger Christian , Tan Dennis , Swain Tessa , Nguyen Trung , Pflueger Jahnvi , Nefzger Christian , Polo Jose M. , Ford Ethan , Lister Ryan
Published: June 2018

Detection of DNA methylation in the genome has been possible for decades; however, the ability to deliberately and specifically manipulate local DNA methylation states in the genome has been extremely limited. Consequently, this has impeded our understanding of the direct effect of DNA methylation on transcriptional regulation and transcription factor binding in the native chromatin context. Thus, highly specific targeted epigenome editing tools are needed to address this. Recent adaptations of genome editing technologies, including fusion of the DNMT3A DNA methyltransferase catalytic domain to catalytically inactive Cas9 (dC9-D3A), have aimed to alter DNA methylation at desired loci. Here, we show that these tools exhibit consistent off-target DNA methylation deposition in the genome, limiting their capabilities to unambiguously assess the functional consequences of DNA methylation. To address this, we developed a modular dCas9-SunTag (dC9Sun-D3A) system that can recruit multiple DNMT3A catalytic domains to a target site for editing DNA methylation. dC9Sun-D3A is tunable, specific, and exhibits much higher induction of DNA methylation at target sites than the dC9-D3A direct fusion protein. Importantly, genome-wide characterization of dC9Sun-D3A binding sites and DNA methylation revealed minimal off-target protein binding and induction of DNA methylation with dC9Sun-D3A, compared to pervasive off-target methylation by dC9-D3A. Furthermore, we used dC9Sun-D3A to demonstrate the binding sensitivity to DNA methylation for CTCF and NRF1 in situ. Overall, this modular dC9Sun-D3A system enables precise DNA methylation deposition with the lowest off-target DNA methylation levels reported to date, allowing accurate functional determination of the role of DNA methylation at single loci.
Crystal structure of (2,2′-bipyridine-κ2
N,N′)-trans-bis(tert-butyldimethylsilyloxy)-cis-dioxidomolybdenum(VI)
Authors: Minyaev Mikhail E. , Vinogradov Alexander A. , Nifant'ev Ilya E. , Churakov Andrei V.
Published: June 2018

In the title compound, [(
t
BuSiMe2O)2MoO2(2,2′-bipyridine)] or [Mo(C6H15OSi)2O2(C10H8N2)], the MoVI atom has a distorted octahedral environment with the siloxy substituents occupying the trans positions. The complex contains a rare (R
3SiO)2
MO2 (M = Mo, W) structural motif and was formed in a reaction between sodium molybdate and tert-butyldimethylsilyl chloride in the presence of 2,2-bipyridine. In the crystal, neighbouring molecules are linked by C—H...O=Mo hydrogen bonds, forming chains propagating along the a-axis direction.
(E)-1-[5-Methyl-1-(4-methylphenyl)-1H-1,2,3-triazol-4-yl]-3-(4-nitrophenyl)prop-2-en-1-one
Authors: El-Hiti Gamal A. , Abdel-Wahab Bakr F. , Mostafa Mohamed S. , Khidre Rizk E. , Hegazy Amany S. , Kariuki Benson M.
Published: June 2018

The title compound, C19H16N4O3, crystallizes with two molecules (A and B) in the asymmetric unit. In molecule A, the dihedral angles between the triazole ring and the toluyl and nitrobenzene rings are 62.68 (16) and 10.77 (15)°, respectively. The corresponding data for molecule B are 68.61 (17) and 15.59 (15)°, respectively. In the crystal, the B molecules are linked by C—H...N hydrogen bonds to generate [001] chains. Weak C—H...π(benzene) and N—O...π(triazole) contacts are also present.
fac-Triaqua(2,2′-bipyridine-κ2
N,N′)(nitrato-κO)cobalt(II) chloride
Authors: Diop Mouhamadou Birame , Diop Libasse , Bernès Sylvain
Published: June 2018

The asymmetric unit of the title complex, [Co(NO3)(C10H8N2)(H2O)3]Cl, consists of a chloride anion and a complex cation, which is built on a monodentate nitrate anion, three water molecules and one bidentate 2,2′-bipyridine molecule, coordinated to a CoII cation, in a distorted octahedral geometry. The water molecules are arranged in a facial geometry, and serve as donors for hydrogen bonding. Acceptor sites in the crystal are chloride ions and one O atom of the coordinating nitrate ion. A three-dimensional framework is formed, based on O—H...O and O—H...Cl contacts.
Impression management in annual report narratives: the case of the UK private finance initiative
Authors: C. Edgar Victoria , Beck Matthias , Brennan Niamh M.
Published: June 2018

Purpose

The UK private finance initiative (PFI) public policy is heavily criticised. PFI contracts are highly profitable leading to incentives for PFI private-sector companies to support PFI public policy. This contested nature of PFIs requires legitimation by PFI private-sector companies, by means of impression management, in terms of the attention to and framing of PFI in PFI private-sector company annual reports. The paper aims to discuss this issue.

Design/methodology/approach

PFI-related annual report narratives of three UK PFI private-sector companies, over seven years and across two periods of significant change in the development of the PFI public policy, are analysed using manual content analysis.

Findings

Results suggest that PFI private-sector companies use impression management to legitimise during periods of uncertainty for PFI public policy, to alleviate concerns, to provide credibility for the policy and to legitimise the private sector’s own involvement in PFI.

Research limitations/implications

While based on a sizeable database, the research is limited to the study of three PFI private-sector companies.

Originality/value

The portrayal of public policy in annual report narratives has not been subject to prior research. The research demonstrates how managers of PFI private-sector companies present PFI narratives in support of public policy direction that, in turn, benefits PFI private-sector companies.
The right word for the right crowd: an attempt to recognize the influence of emotions
Authors: Wuillaume Amélie , Jacquemin Amélie , Janssen Frank
Published: June 2018

Purpose

The purpose of this paper is to propose a better understanding of how entrepreneurial narrative influences resource acquisition in the fundraising context.

Design/methodology/approach

The paper combines the literature on emotion as information theory from psychology with behavioral finance findings to develop a conceptual framework with research proposals highlighting the use of narratives in the crowdfunding process.

Findings

The proposition of the paper advocates that entrepreneurial narrative may influence crowdfunders’ attitude and decision to fund a project. It theorizes how emotions in narratives shape the funders’ attitude toward a project and, in turn, their decision to support it. This potential influence is qualified by taking into account the funders’ primary motivations. These motivations affect the degree to which funders rely on affect or cognition to form their attitude and to which they are influenced by more emotional or cognitive narratives.

Originality/value

This framework is the result of an effort to achieve the recognition of emotions in entrepreneurial funding. The paper creates a bridge between the narrative emotional content and the often neglected emotional arousal of funders (considered as traditional investors) to provide a framework for explaining crowdfunders’ decision making. The paper also offers nuances by taking into account the different audiences’ motivations to fund a project.
Lean Six Sigma and the Australian business excellence framework
Authors: Price Oriana M. , Pepper Matthew , Stewart Matthew
Published: June 2018

Purpose

The purpose of this paper is to examine a contextualized local government case study of the application of Lean Six Sigma (LSS) in conjunction with the Australian Business Excellence Framework (ABEF) to highlight the importance of a good strategic fit between LSS and organizational objectives before implementation.

Design/methodology/approach

A local government council is used in a case study-based approach. Organizational artefacts and documents were used for data collection in conjunction with interviews from senior executives within the organization.

Findings

Results indicate that when used in conjunction with the ABEF, LSS provides focus on organizational learning practices embedded within the implementation of continuous improvement.

Research limitations/implications

The purpose of this paper is to contribute to discourse regarding the effective application and implementation of LLS in local government.

Practical implications

LSS tools and techniques are known to local government, but are applied in isolation of the overarching LSS framework. This paper emphasizes the importance of comprehensive implementation of these tools, guided by the inclusion of an external contextualized framework (ABEF) in conjunction with the LSS to achieve sustainable continuous improvement.

Originality/value

Business excellence frameworks are widely used in the public sector as a reference/means for improvement. This paper highlights the importance of LSS in operationalizing strategic direction provided by such frameworks and providing the focus on learning practices critical for sustainable improvements.
Relative supervisor education and worker well-being
Authors: Artz Benjamin
Published: June 2018

Purpose

Less educated supervisors create worker status incongruence, a violation of social norms that signals advancement uncertainty and job ambiguity for workers, and leads to negative behavioral and well-being outcomes. The purpose of this paper is to compare education levels of supervisors with their workers and measure the correlation between relative supervisor education and worker job satisfaction.

Design/methodology/approach

Using the only wave of the 1979 National Longitudinal Survey of Youth that identifies education levels of both supervisor and worker, a series of ordered probit estimates describe the relationship between supervisor education levels and subordinate worker well-being. Extensive controls, sub-sample estimates and a control for sorting confirm the estimates.

Findings

Worker well-being is negatively correlated with having a less educated supervisor and positively correlated with having a more educated supervisor. This result is robust to a number of alternative specifications. In sub-sample estimates, workers highly placed in an organization’s hierarchy do not exhibit reduced well-being with less educated supervisors.

Research limitations/implications

A limitation is the inability to control for worker fixed effects, which may introduce omitted variable bias into the estimates.

Originality/value

The paper is the first to introduce relative supervisor–worker education level as a determinant of worker well-being.
Career stages and occupations impacts on workers motivations
Authors: Duarte Henrique , Lopes Diniz
Published: June 2018

Purpose

The career concept has become fuzzier due to changing work patterns, the ageing workforce and the environmental changes occurring during workers lifespans. Together this requires a renewed and broader reaching contextualization of this concept. The purpose of this paper is to set out an integrative approach arguing that the integration of career stage models with occupational groups proves more explanative of intrinsic and extrinsic worker motivations.

Design/methodology/approach

Secondary data from 23 European countries were drawn from the European Social Survey 2006. The construct validity and reliability of indicators was analyzed. Hypotheses were tested using discriminant analysis.

Findings

Results showed that neither occupations nor career stages are determinants per se of intrinsic motivations, but are better explained by their mutual integration. Career stages were shown to predict per se extrinsic motivations.

Research limitations/implications

The recourse to the European Social Survey pre-determined scales and the application of age ranges as proxies for careers stages suggested the usage of more specific measures in future studies.

Practical implications

Career management and compensation policies might be better tailored to worker motivations by considering the age ranges (as proxies of career stages) and workers’ occupations.

Originality/value

Findings evidenced the explanatory value of occupations for worker motivations and allowed putting into perspective the contextualization of not only boundaryless and protean career concepts, but also career stage theories. Data support the ecological validity of applying a career stages and occupations framework to a highly diversified and representative sample of European countries.
How does labour market history influence the access to hiring interviews?
Authors: Duguet Emmanuel , Le Gall Rémi , L’Horty Yannick , Petit Pascale
Published: June 2018

Purpose

The purpose of this paper is to provide evidence of the effect of labour market status on the current probability to be invited to a hiring interview. The authors compare the effect of periods of unemployment, part-time job and short-term contracts (STCs).

Design/methodology/approach

Correspondence tests were conducted for accountants and sales assistants. The authors estimate the discrimination components from the response rate of each candidate by the asymptotic least squares method.

Findings

The authors find that men with a part-time profile suffer discrimination in both professions. Other differences of treatment are specific: for accountants, the authors find that the probability of success decreases with the time spent in unemployment, while for sales assistants the probability of success is smaller with a history of STCs.

Originality/value

This study compares the effect of different dimensions of career history (part-time versus full-time, permanent versus short-term, unemployment versus employment) for experienced job candidates. It also proposes an alternative way to exploit the design of a correspondence experiment.
Neighborhood signaling effects, commuting time, and employment
Authors: Carlsson Magnus , Reshid Abdulaziz Abrar , Rooth Dan-Olof
Published: June 2018

Purpose

The purpose of this paper is to investigate whether there is unequal treatment in hiring depending on whether a job applicant signals living in a bad (deprived) neighborhood or in a good (affluent) neighborhood.

Design/methodology/approach

The authors conducted a field experiment where fictitious job applications were sent to employers with an advertised vacancy. Each job application was randomly assigned a residential address in either a bad or a good neighborhood. The measured outcome is the fraction of invitations for a job interview (the callback rate).

Findings

The authors find no evidence of general neighborhood signaling effects. However, job applicants with a foreign background have callback rates that are 42 percent lower if they signal living in a bad neighborhood rather than in a good neighborhood. In addition, the authors find that applicants with commuting times longer than 90 minutes have lower callback rates, and this is unrelated to the neighborhood signaling effect.

Originality/value

Empirical evidence of causal neighborhood effects on labor market outcomes is scant, and causal evidence on the mechanisms involved is even more scant. The paper provides such evidence.
Robust adaptive sliding mode control for a human-driven knee joint orthosis
Authors: Bkekri Rihab , Benamor Anouar , Alouane Mohamed Amine , Fried Georges , Messaoud Hassani
Published: June 2018

Purpose

Assistive technology products are designed to provide additional accessibility to individuals who have physical or cognitive difficulties, impairments and disabilities. The purpose of this paper is to deal with the control of a knee joint orthosis intended to be used for rehabilitation and assistive purpose; this control aims to reduce the influence of the uncertainties and eliminating the external disturbances in the system.

Design/methodology/approach

This paper deals with the robust adaptive sliding mode controller (ASMC) of human-driven knee joint orthosis system with mismatched uncertainties and external disturbances. The shank-orthosis system has been modeled and its parameters have been identified. This control reduces the effect of parameter uncertainties and external disturbances on the system performance and improves the system robustness as results. The ASMC was designed to offer the possibility to track the state of the reference model. Moreover, the Lyapunov stability theory was used to study the asymptotical stability of the ASMC.

Findings

The advantage of the robust ASMC method is the tracking precision and reducing the required time for eliminating external disturbances and uncertainties. The experimental results show in real-time in terms of stability and present that the advantages of this control approach are the position tracking and robustness.

Originality/value

In this paper, to deal with the parameter uncertainties of the human-driven knee joint orthosis, an ASMC was successfully applied based on sliding mode and Lyapunov stability theory. It has good dynamic response and tracking performance. Besides, the adaptive algorithm is simple, easy to achieve and has good adaptability and robustness against the parameter variations and external disturbances. The design technique is simple and efficient. The development of this control takes into consideration the perturbation, allowing to track a desired trajectory.