bluuebunny/crossref_metadata_2025 huggingface dataset:
Creation of a novel trigeminal tractography atlas for automated trigeminal nerve identification
Authors: Zhang Fan , Xie Guoqiang , Leung Laura , Mooney Michael A. , Epprecht Lorenz , Norton Isaiah , Rathi Yogesh , Kikinis Ron , Al-Mefty Ossama , Makris Nikos , Golby Alexandra J. , O’Donnell Lauren J.
Published: January 2020

Diffusion MRI (dMRI) tractography has been successfully used to study the trigeminal nerves (TGNs) in many clinical and research applications. Currently, identification of the TGN in tractography data requires expert nerve selection using manually drawn regions of interest (ROIs), which is prone to inter-observer variability, time-consuming and carries high clinical and labor costs. To overcome these issues, we propose to create a novel anatomically curated TGN tractography atlas that enables automated identification of the TGN from dMRI tractography. In this paper, we first illustrate the creation of a trigeminal tractography atlas. Leveraging a well-established computational pipeline and expert neuroanatomical knowledge, we generate a data-driven TGN fiber clustering atlas using tractography data from 50 subjects from the Human Connectome Project. Then, we demonstrate the application of the proposed atlas for automated TGN identification in new subjects, without relying on expert ROI placement. Quantitative and visual experiments are performed with comparison to expert TGN identification using dMRI data from two different acquisition sites. We show highly comparable results between the automatically and manually identified TGNs in terms of spatial overlap and visualization, while our proposed method has several advantages. First, our method performs automated TGN identification, and thus it provides an efficient tool to reduce expert labor costs and inter-operator bias relative to expert manual selection. Second, our method is robust to potential imaging artifacts and/or noise that can prevent successful manual ROI placement for TGN selection and hence yields a higher successful TGN identification rate.
ATF4 mediates fetal globin upregulation in response to reduced β-globin
Authors: Boontanrart Mandy , Stehli Gautier , Banovic Marija , Schröder Markus S. , Wyman Stacia , Lew Rachel , Bordi Matteo , Gowen Benjamin , DeWitt Mark , Corn Jacob E.
Published: January 2020

Fetal development and anemias such as β-hemoglobinopathies trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin, which has suggested strategies to treat hemoglobinopathies such as thalassemia and sickle cell disease. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here we use CRISPR-Cas genome editing and CRISPRi transcriptional repression to model the stress caused by reduced levels of adult β-globin. We find that loss of β-globin is sufficient to induce widespread globin compensation, including robust re-expression of γ-globin. Time-course RNA-seq of differentiating isogenic erythroid precursors identified the ATF4 transcription factor as a causal regulator of this response. ChIP-seq of multiple erythroid precursor genotypes and differentiation states revealed that β-globin knockout leads to reduced engagement of ATF4 targets involved in the unfolded protein response. This ATF4 program indirectly regulates the levels of BCL11A, a key repressor of γ-globin. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could be relevant for proposed gene editing strategies to treat hemoglobinopathies.
Individual yeast cells signal at different levels but each with good precision
Authors: Andrews Steven S. , Brent Roger
Published: January 2020

Different isogenic cells have been shown to exhibit widely varying responses to the same extracellular signal. Based on the assumption that this variation arises from noise in the signaling pathways that cells use to transmit information from surface to nucleus, recent publications asserted that single cells cannot detect their surroundings accurately. Here, we analyze existing data on gene expression induced by theSaccharomyces cerevisiaepheromone response system, finding that individual cells signal consistently over time, implying that response variation arises primarily from stable cell-to-cell differences rather than signaling noise. Individual cells transmit at least 2.7 bits of information through the pheromone response system, enabling each cell to distinguish between at least 6 pheromone concentrations. In principle, cells can gain further precision by internally referencing these responses with measurements of constitutively expressed genes. Combination with prior results shows that only about 6% of total response variation arises from signaling pathway noise.

One-sentence summary

Single yeast cells signal consistently over time, indicating that their signaling pathways transmit information precisely.
Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome
Authors: Garcia Jesse A. , Lohmueller Kirk E.
Published: January 2020

While there has been extensive work on patterns of linkage disequilibrium (LD) for neutral loci, the extent to which negative selection impacts LD is less clear. Forces like Hill-Robertson interference and negative epistasis are expected to lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of LD in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to generate predictions as to how selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes, generating an excess of negative LD relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect r2decay. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived nonsynonymous SNPs is more negative compared to pairs of derived synonymous variants. This result holds when matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants, suggesting that this result is not due to these potential confounding factors. Lastly, we introduce a new statisticHR(j)which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that deleterious alleles tend to be located on different haplotypes more often than are neutral alleles. Our findings suggest that either interference or negative epistasis plays a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influencing genome-wide patterns of LD.
Bayesian non-parametric clustering of single-cell mutation profiles
Authors: Borgsmüller Nico , Bonet Jose , Marass Francesco , Gonzalez-Perez Abel , Lopez-Bigas Nuria , Beerenwinkel Niko
Published: January 2020

The high resolution of single-cell DNA sequencing (scDNA-seq) offers great potential to resolve intra-tumor heterogeneity by distinguishing clonal populations based on their mutation profiles. However, the increasing size of scDNA-seq data sets and technical limitations, such as high error rates and a large proportion of missing values, complicate this task and limit the applicability of existing methods. Here we introduce BnpC, a novel non-parametric method to cluster individual cells into clones and infer their genotypes based on their noisy mutation profiles. BnpC employs a Dirichlet process mixture model coupled with a Markov chain Monte Carlo sampling scheme, including a modified split-merge move and a novel posterior estimator to predict clones and genotypes. We benchmarked our method comprehensively against state-of-the-art methods on simulated data using various data sizes, and applied it to three cancer scDNA-seq data sets. On simulated data, BnpC compared favorably against current methods in terms of accuracy, runtime, and scalability. Its inferred genotypes were the most accurate, and it was the only method able to run and produce results on data sets with 10,000 cells. On tumor scDNA-seq data, BnpC was able to identify clonal populations missed by the original cluster analysis but supported by supplementary experimental data. With ever growing scDNA-seq data sets, scalable and accurate methods such as BnpC will become increasingly relevant, not only to resolve intra-tumor heterogeneity but also as a pre-processing step to reduce data size. BnpC is freely available under MIT license athttps://github.com/cbg-ethz/BnpC.
An ancient satellite repeat controls gene expression and embryonic development inAedes aegyptithrough a highly conserved piRNA
Authors: Halbach Rebecca , Miesen Pascal , Joosten Joep , Taşköprü Ezgi , Pennings Bas , Vogels Chantal B.F. , Merkling Sarah H. , Koenraadt Constantianus J. , Lambrechts Louis , van Rij Ronald P.
Published: January 2020

Tandem repeat elements such as the highly diverse class of satellite repeats occupy large parts of eukaryotic chromosomes. Most occur at (peri)centromeric and (sub)telomeric regions and have been implicated in chromosome organization, stabilization, and segregation1. Others are located more dispersed throughout the genome, but their functions remained largely enigmatic. Satellite repeats in euchromatic regions were hypothesized to regulate gene expressionin cisby modulation of the local heterochromatin, orin transvia repeat-derived transcripts2,3. Yet, due to a lack of experimental models, gene regulatory potential of satellite repeats remains largely unexplored. Here we show that, in the vector mosquitoAedes aegypti, a satellite repeat promotes sequence-specific gene silencing via the expression of two abundant PIWI-interacting RNAs (piRNAs). Strikingly, whereas satellite repeats and piRNA sequences generally evolve extremely fast4-6, this locus was conserved for approximately 200 million years, suggesting a central function in mosquito biology. Tandem repeat-derived piRNA production commenced shortly after egg-laying and inactivation of the most abundant of the two piRNAs in early embryos resulted in an arrest of embryonic development. Transcriptional profiling in these embryos revealed the failure to degrade maternally provided transcripts that are normally cleared during maternal-to-zygotic transition. Our results reveal a novel mechanism in which satellite repeats regulate global gene expressionin transvia piRNA-mediated gene silencing, which is fundamental to embryonic development. These findings highlight the regulatory potential of this enigmatic class of repeats.
Protrudin functions as a scaffold in the endoplasmic reticulum to support axon regeneration in the adult central nervous system
Authors: Petrova Veselina , Pearson Craig S. , Tribble James R. , Solano Andrea G. , Reid Evan , Williams Pete A. , Geller Herbert M. , Eva Richard , Fawcett James W.
Published: January 2020

Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration bothin vitroin primary cortical neurons andin vivoin the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.
Downregulation of both mismatch repair and non-homologous end-joining pathways in hypoxic brain tumour cell lines
Authors: Cowman Sophie , Pizer Barry , Sée Violaine
Published: January 2020

Glioblastoma, a grade IV astrocytoma, has a poor survival rate in part due to ineffective treatment options available. These tumours are heterogeneous with areas of low oxygen levels, termed hypoxic regions. Many intra-cellular signalling pathways, including DNA repair, can be altered by hypoxia. Since DNA damage induction and subsequent activation of DNA repair mechanisms is the cornerstone of glioblastoma treatment, alterations to DNA repair mechanisms could have a direct influence on treatment success. Our aim was to elucidate the impact of chronic hypoxia on DNA repair gene expression in a range of glioblastoma cell lines. We adopted a NanoString transcriptomic approach to examine the expression of 180 DNA repair related genes in four classical glioblastoma cell lines (U87-MG, U251-MG, D566-MG, T98G) exposed to 5 days of normoxia (21% O2), moderate (1% O2) or severe (0.1% O2) hypoxia. We observed altered gene expression in several DNA repair pathways including homologous recombination repair, non-homologous end-joining and mismatch repair, with hypoxia primarily resulting in downregulation of gene expression. The extend of gene expression changes was function of the hypoxic severity. Some, but not all, of these downregulations were directly under the control of HIF activity. For example, the downregulation ofLIG4, a key component of non-homologous end-joining, was reversed upon inhibition of the hypoxia inducible factor (HIF). In contrast, the downregulation of the mismatch repair gene,PMS2, was not affected by HIF inhibition. This suggests that numerous molecular mechanisms lead to hypoxia-induced reprogramming of the transcriptional landscape of DNA repair. Whilst the global impact of hypoxia on DNA repair gene expression is likely to lead to genomic instability, tumorigenesis and reduced sensitivity to anti-cancer treatment, treatment re-sensitizing might require additional approaches to a simple HIF inhibition.
scTPA: A web tool for single-cell transcriptome analysis of pathway activation signatures
Authors: Zhang Yan , Zhang Yaru , Hu Jun , Zhang Ji , Guo Fangjie , Zhou Meng , Zhang Guijun , Yu Fulong , Su Jianzhong
Published: January 2020

The most fundamental challenge in current single-cell RNA-seq data analysis is functional interpretation and annotation of cell clusters. The biological pathways in distinct cell types have different activation patterns, which facilitates understanding cell functions in single-cell transcriptomics. However, no effective web tool has been implemented for single-cell transcriptomic data analysis based on prior biological pathway knowledge. Here, we introduce scTPA (http://sctpa.bio-data.cn/sctpa), which is a web-based platform providing pathway-based analysis of single-cell RNA-seq data in human and mouse. scTPA incorporates four widely-used gene set enrichment methods to estimate the pathway activation scores of single cells based on a collection of available biological pathways with different functional and taxonomic classifications. The clustering analysis and cell-type-specific activation pathway identification were provided for the functional interpretation of cell types from pathway-oriented perspective. An intuitive interface allows users to conveniently visualize and download single-cell pathway signatures. Together, scTPA is a comprehensive tool to identify pathway activation signatures for dissecting single cell heterogeneity.
Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2
Authors: Sharma Shalu , Mukherjee Ananda Kishore , Roy Shuvra Shekhar , Bagri Sulochana , Lier Silje , Verma Meenakshi , Sengupta Antara , Kumar Manish , Nesse Gaute , Pandey Deo Prakash , Chowdhury Shantanu
Published: January 2020

Tight regulatory mechanisms to maintain repression of human Telomerase (hTERT), the sole protein that synthesizes telomeres, is crucial for normal adult somatic cells. In contrast, enhanced telomerase activity and resulting pathological maintenance of telomeres, is widely understood as causal in >90% of human cancers. These implicate underlying mechanisms connectinghTERTregulation and telomeres, possibly through telomeric proteins, that remain unclear. In light of of recent work by us and others showing non-telomeric function of the telomere-binding protein TRF2, here we examined whether and how TRF2 affectedhTERTregulation. Direct binding of TRF2 – spanning ∼450 bp of thehTERTpromoter from the Transcriptional Start Site (TSS) – led to TRF2-dependent recruitment of the polycomb repressor complex PRC2 in both normal and cancer cells. This induced repressor histone modifications resulting in TRF2-dependenthTERTrepression. Mutations in thehTERTpromoter, found frequently in aggressive glioblastoma and reported to destabilize the G-quadruplex structure, resulted in loss of TRF2 binding and consequenthTERTover-expression. Conversely, using G-quadruplex-stabilizing ligands we regained TRF2 binding,hTERTre-suppression, in highly proliferating glioblastoma cells with telomerase hyperactivation due tohTERTpromoter mutations. Together, results herein demonstrate direct control ofhTERTthrough TRF2 in a G-quadruplex-dependent manner – implicating mechanisms of how telomerase regulation might be linked to telomeres in normal and cancer cells.
Genomic analyses provide insights into peach local adaptation and responses to climate change
Authors: Li Yong , Cao Ke , Li Nan , Zhu Gengrui , Fang Weichao , Chen Changwen , Wang Xinwei , Zeng Xiuli , Guo Jian , Zhang Shanshan , Wang Qi , Ding Tiyu , Wang Jiao , Guan Liping , Wang Junxiu , Liu Kuozhan , Guo Wenwu , Arús Pere , Huang Sanwen , Fei Zhangjun , Wang Lirong
Published: January 2020

The environment has constantly shaped plant genomes, but the genetic bases underlying how plants adapt to environmental influences remain largely unknown. We constructed a high-density genomic variation map by re-sequencing genomes of 263 geographically representative peach landraces and wild relatives. A combination of whole-genome selection scans and genome-wide environmental association studies (GWEAS) was performed to reveal the genomic bases of peach local adaptation to diverse climates comprehensively. A total of 2,092 selective sweeps that underlie local adaptation to both mild and extreme climates were identified, including 339 sweeps conferring genomic pattern of adaptation to high altitudes. Using GWEAS, a total of 3,496 genomic loci strongly associated with 51 specific environmental variables were detected. The molecular mechanism underlying adaptive evolution of high drought, strong UV-B, cold hardiness, sugar content, flesh color, and bloom date were revealed. Finally, based on 30 years of observation, a candidate gene associated with bloom date advance, representing peach responses to global warming, was identified. Collectively, our study provides insights into molecular bases of how environments have shaped peach genomes by natural selection and adds valuable genome resources and candidate genes for future studies on evolutionary genetics, adaptation to climate changes, and future breeding.
Fast and efficient generation of knock-in human organoids using homology-independent CRISPR/Cas9 precision genome editing
Authors: Artegiani Benedetta , Hendriks Delilah , Beumer Joep , Kok Rutger , Zheng Xuan , Joore Indi , de Sousa Lopes Susana Chuva , van Zon Jeroen , Tans Sander , Clevers Hans
Published: January 2020

CRISPR/Cas9 technology has revolutionized genome editing and is applicable to the organoid field. However, precise integration of exogenous DNA sequences in human organoids awaits robust knock-in approaches. Here, we describeCRISPR/Cas9-mediatedHomology-independentOrganoidTransgenesis (CRISPR-HOT), which allows efficient generation of knock-in human organoids representing different tissues. CRISPR-HOT avoids extensive cloning and outperforms homology directed repair (HDR) in achieving precise integration of exogenous DNA sequences at desired loci, without the necessity to inactivate TP53 in untransformed cells, previously used to increase HDR-mediated knock-in. CRISPR-HOT was employed to fluorescently tag and visualize subcellular structural molecules and to generate reporter lines for rare intestinal cell types. A double reporter labelling the mitotic spindle by tagged tubulin and the cell membrane by tagged E-cadherin uncovered modes of human hepatocyte division. Combining tubulin tagging with TP53 knock-out revealed TP53 involvement in controlling hepatocyte ploidy and mitotic spindle fidelity. CRISPR-HOT simplifies genome editing in human organoids.
The Flemmingsome reveals an ESCRT-to-membrane coupling required for completion of cytokinesis
Authors: Addi Cyril , Presle Adrien , Frémont Stéphane , Cuvelier Frédérique , Rocancourt Murielle , Milin Florine , Schmutz Sandrine , Chamot-Rooke Julia , Douché Thibaut , Duchateau Magalie , Gianetto Quentin Giai , Ménager Hervé , Matondo Mariette , Zimmermann Pascale , Gupta-Rossi Neetu , Echard Arnaud
Published: January 2020

Cytokinesis requires the constriction of ESCRT-III filaments on the side of the midbody, where abscission occurs. After ESCRT recruitment at the midbody, it is not known how the ESCRT-III machinery localizes to the abscission site. To reveal novel actors involved in abscission, we obtained the proteome of intact, post-abscission midbodies (Flemmingsome) and identified 489 proteins enriched in this organelle. Among those proteins, we further characterized a plasma membrane-to-ESCRT module composed of the transmembrane proteoglycan syndecan-4, ALIX and syntenin, a protein that bridges ESCRT-III/ALIX to syndecans. The three proteins were highly recruited first at the midbody then at the abscission site, and their depletion delayed abscission. Mechanistically, direct interactions between ALIX, syntenin and syndecan-4 were essential for proper enrichment of the ESCRT-III machinery at the abscission site, but not at the midbody. We propose that the ESCRT-III machinery must be physically coupled to a membrane protein at the cytokinetic abscission site for efficient scission, revealing novel common requirements in cytokinesis, exosome formation and HIV budding.
The WD and linker domains of ATG16L1 required for non-canonical autophagy limit lethal respiratory infection by influenza A virus at epithelial surfaces
Authors: Wang Yingxue , Zhang Weijiao , Jefferson Matthew , Sharma Parul , Bone Ben , Kipar Anja , Coombes Janine L. , Pearson Timothy , Man Angela , Zhekova Alex , Bao Yongping , Tripp Ralph A , Yamauchi Yohei , Carding Simon R. , Mayer Ulrike , Powell Penny P. , Stewart James P. , Wileman Thomas
Published: January 2020

Respiratory viruses such as influenza A virus (IAV) and SARS-CoV-2 (Covid-19) cause pandemic infections where cytokine storm syndrome, lung inflammation and pneumonia lead to high mortality. Given the high social and economic cost of these viruses, there is an urgent need for a comprehensive understanding of how the airways defend against virus infection. Viruses entering cells by endocytosis are killed when delivered to lysosomes for degradation. Lysosome delivery is facilitated by non-canonical autophagy pathways that conjugate LC3 to endo-lysosome compartments to enhance lysosome fusion. Here we use mice lacking the WD and linker domains of ATG16L1 to demonstrate that non-canonical autophagy protects mice from lethal IAV infection of the airways. Mice with systemic loss of non-canonical autophagy are exquisitely sensitive to low-pathogenicity murine-adapted IAV where extensive viral replication throughout the lungs, coupled with cytokine amplification mediated by plasmacytoid dendritic cells, leads to fulminant pneumonia, lung inflammation and high mortality. IAV infection was controlled within epithelial barriers where non-canonical autophagy slowed fusion of IAV with endosomes and reduced activation of interferon signalling. This was consistent with conditional mouse models andex vivoanalysis showing that protection against IAV infection of lung was independent of phagocytes and other leukocytes. This establishes non-canonical autophagy pathways in airway epithelial cells as a novel innate defence mechanism that can restrict IAV infection and lethal inflammation at respiratory surfaces.
Statistical analysis of no observed effect concentrations or levels in eco-toxicological assays with overdispersed count endpoints
Authors: Hothorn Ludwig A. , Kluxen Felix M.
Published: January 2020

In (eco-)toxicological hazard characterization, the No Observed Adverse Effect Concentration or Level (NOAEC or NOAEL) approach is used and often required despite of its known limitations. For count data, statistical testing can be challenging, due to several confounding factors, such as zero inflation, low observation numbers, variance heterogeneity, over- or under-dispersion when applying the Poisson model or hierarchical experimental designs. As several tests are available for count data, we selected sixteen tests suitable for overdispersed counts and compared them in a simulation study. We assessed their performance considering data sets containing mixing distribution and over-dispersion with different observation numbers. It shows that there is no uniformly best approach because the assumed data conditions and assumptions are very different. However, the Dunnett-type procedure based on most likely transformation can be recommended, because of its size and power behavior, which is relatively better over most data conditions as compared to the available alternative test methods, and because it allows flexible modeling and effect sizes can be estimated by confidence intervals. Related R-code is provided for real data examples.
The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death
Authors: Carriere Candace H. , Sing Anson D. , Wang Wendy Xueyi , Jones Brian E. , Yee Yohan , Ellegood Jacob , Marocha Julie , Maganti Harinad , Awofala Lola , Aziz Amar , Lerch Jason P. , Lefebvre Julie L.
Published: January 2020

Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the cortex, the formation of inhibitory networks occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The molecular mechanisms that select GABAergic interneurons to survive or die are unknown. Here we report that the clustered Protocadherins regulate GABAergic cell survival in the developing brain. Deletion of thePcdh-gammagenes (Pcdhgs) from GABAergic neurons in mice causes a severe loss of inhibitory neurons in multiple brain regions and results in motor deficits and seizure activities. By focusing on the neocortex and cerebellar cortex, we demonstrate that GABAergic interneuron loss results from elevated apoptosis during the postnatal wave ofBax-dependent programmed cell death. Pro-survival AKT signals are reduced inPcdhg-deficient interneurons, diminishing the intrinsic capacity of interneurons to compete and incorporate into developing networks. We propose that the Pcdhgs mediate selective GABAergic interneuron survival to contribute to the formation of balanced inhibitory networks.
Neuraminidase activity mediates IL-6 production through TLR4 and p38/ERK MAPK signaling in MRL/lpr mesangial cells
Authors: Sundararaj Kamala P. , Rodgers Jessalyn , Angel Peggi , Wolf Bethany , Nowling Tamara K.
Published: January 2020

Mesangial cells (MCs), considered the immune cell of the kidney, secrete a number of cytokines including IL-6, which serves as an autocrine factor for MCs stimulating proliferation. IL-6 is associated with disease in patients and mouse strains with lupus nephritis, promoting tissue damage. Previously, we demonstrated the activity or levels of the enzyme neuraminidase (NEU) is increased in the kidneys of lupus mice and urine of human patients with nephritis and that NEU activity plays a role in mediating IL-6 secretion from lupus prone MRL/lpr primary mouse MCs. In this study, we further elucidate the mechanisms by which NEU activity mediates cytokine production by primary lupus prone MCs. MRL/lpr primary MCs were cultured with lupus serum to stimulate cytokine production in the absence or presence of NEU activity inhibitor. Our results show lupus serum increases NEU activity, and secretion of GM-CSF and MIP1α, in addition to IL-6, is significantly reduced when NEU activity is inhibited. mRNA expression ofIl-6andGm-csfwas also increased in response to lupus serum, and reduced when NEU activity was inhibited. Using neutralizing antibodies to specific receptors, inhibitors of MAP kinase signaling pathways, and LPS stimulation we show TLR4 and p38/ERK MAPK play a role in NEU-mediated secretion of IL-6. Together, our results suggest NEU activity plays an important role in the response of lupus prone MCs to factor(s) in lupus serum that stimulates IL-6 expression and secretion through TLR4-p38/ERK MAPK signaling, likely through desialyation of one or more glycoproteins in this pathway.
Origin of perseveration in the trade-off between reward and complexity
Authors: Gershman Samuel J.
Published: January 2020

When humans and other animals make repeated choices, they tend to repeat previously chosen actions independently of their reward history. This paper locates the origin of perseveration in a trade-off between two computational goals: maximizing rewards and minimizing the complexity of the action policy. We develop an information-theoretic formalization of policy complexity and show how optimizing the trade-off leads to perseveration. Analysis of two data sets reveals that people attain close to optimal trade-offs. Parameter estimation and model comparison supports the claim that perseveration quantitatively agrees with the theoretically predicted functional form.
CREB transcription in the medial prefrontal cortex regulates the formation of long-term associative recognition memory
Authors: Barker Gareth Robert , Wong Liang Fong , Uney James B. , Warburton Elizabeth C.
Published: January 2020

The medial prefrontal cortex (mPFC) is known to be critical for specific forms of long-term recognition memory, however the cellular mechanisms in the mPFC that underpin memory maintenance have not been well characterized. This study examined the importance of phosphorylation of cAMP responsive element binding protein (CREB) in the mPFC for different forms of long-term recognition memory in the rat. Adenoviral transduction of the mPFC with a dominant-negative inhibitor of CREB impaired object-in-place memory following a 6 or 24 h retention delay, but no impairment was observed following delays of 5 min or 3 h. Long-term object temporal order memory and spatial temporal order memory was also impaired. In contrast, there were no impairments in novel object recognition or object location memory. These results establish, for the first time, the importance of CREB phosphorylation within the mPFC for memory of associative and temporal information crucial to recognition.
fragHAR: towardsab initioquantum-crystallographic X-ray structure refinement for polypeptides and proteins
Authors: Bergmann Justin , Davidson Max , Oksanen Esko , Ryde Ulf , Jayatilaka Dylan
Published: January 2020

The firstab initioaspherical structure refinement against experimental X-ray structure factors for polypeptides and proteins using a fragmentation approach to break up the protein into residues and solvent, thereby speeding up quantum-crystallographic Hirshfeld atom refinement (HAR) calculations, is described. It it found that the geometric and atomic displacement parameters from the new fragHAR method are essentially unchanged from a HAR on the complete unfragmented system when tested on dipeptides, tripeptides and hexapeptides. The largest changes are for the parameters describing H atoms involved in hydrogen-bond interactions, but it is shown that these discrepancies can be removed by including the interacting fragments as a single larger fragment in the fragmentation scheme. Significant speed-ups are observed for the larger systems. Using this approach, it is possible to perform a highly parallelized HAR in reasonable times for large systems. The method has been implemented in theTONTOsoftware.
Cascading transitions toward unconventional charge density wave states in the quasi-two-dimensional monophosphate tungsten bronze P4W16O56
Authors: Duverger-Nédellec Elen , Pautrat Alain , Kolincio Kamil K. , Hervé Laurence , Pérez Olivier
Published: January 2020

Single crystals of the m = 8 member of the low-dimensional monophosphate tungsten bronzes (PO2)4(WO3)2m
family were grown by chemical vapour transport technique and the high crystalline quality obtained allowed a reinvestigation of the physical and structural properties. Resistivity measurements revealed three anomalies at T
C1 = 258 K, T
C2 = 245 K and T
C3 = 140 K, never observed until now. Parallel X-ray diffraction investigations showed a specific signature associated with three structural transitions, i.e. the appearance of different sets of satellite reflections below T
C1, T
C2 and T
C3. Several harmonics of intense satellite reflections were observed, reflecting the non-sinusoidal nature of the structural modulations and a strong electron–phonon coupling in the material. These transitions could be associated with the formation of three successive unconventional charge density wave states.
Structure and photophysical and electrochemical properties of a copper porphyrin complex with a three-dimensional framework
Authors: Chen Wen-Tong
Published: January 2020

Porphyrins and metalloporphyrins can generally show attractive structural motifs and interesting properties. A new copper porphyrin, namely poly[[μ-chlorido-[μ5-5,10,15,20-tetrakis(pyridin-4-yl)-21H,23H-porphine]tricopper(I)] [aquadichloridocopper(II)]], {[Cu3(C40H24N8)Cl][CuCl2(H2O)]}
n
(1), was synthesized by the self-assembly of copper chloride with 5,10,15,20-tetrakis(pyridin-4-yl)-21H,23H-porphine under solvothermal conditions. The structure of this copper porphyrin was characterized by single-crystal X-ray crystallography and elemental analysis. The porphyrin macrocycle shows a distorted saddle geometry, with the four pyrrole rings slightly distorted in an alternating mode either upwards or downwards. The copper ions show three-coordinated triangular and four-coordinated square-planar geometries. Every copper–porphyrin unit connects to 12 others via four μ4-bridging Cu2Cl moieties to complete the three-dimensional framework of compound 1, with isolated CuCl2(H2O) units located in the voids. This copper porphyrin displays a red photoluminescence. Electrochemical measurements showed that compound 1 has two redox waves (E
1/2 = −160 and 91 mV).
Two new NiII and ZnII metal–organic frameworks of glutarate and 1,4-bis[(2-methyl-1H-imidazol-1-yl)methyl]benzene ligands: syntheses, structures and luminescence sensing properties
Authors: Zhao Fang-Hua , Li Zhong-Lin , Zhang Shu-Fang , Han Jian-Hui , Zhang Mei , Han Jun , Lin Yu-Wen , You Jin-Mao
Published: January 2020

Two new metal–organic frameworks (MOFs), namely, three-dimensional poly[diaquabis{μ2-1,4-bis[(2-methyl-1H-imidazol-1-yl)methyl]benzene}bis(μ2-glutarato)dinickel(II)] monohydrate], {[Ni2(C5H6O4)2(C16H18N4)2(H2O)2]·H2O}
n
or {[Ni2(Glu)2(1,4-mbix)2(H2O)2]·H2O}
n
, (I), and two-dimensional poly[[{μ2-1,4-bis[(2-methyl-1H-imidazol-1-yl)methyl]benzene}(μ2-glutarato)zinc(II)] tetrahydrate], {[Zn(C5H6O4)(C16H18N4)]·4H2O}
n
or {[Zn(Glu)(1,4-mbix)]·4H2O}
n
(II), have been synthesized hydrothermally using glutarate (Glu2−) mixed with 1,4-bis[(2-methyl-1H-imidazol-1-yl)methyl]benzene (1,4-mbix), and characterized by single-crystal X-ray diffraction, IR and UV–Vis spectroscopy, powder X-ray diffraction, and thermogravimetric and photoluminescence analyses. NiII MOF (I) shows a 4-connected 3D framework with point symbol 66, but is not a typical dia network. ZnII MOF (II) displays a two-dimensional 44-sql network with one-dimensional water chains penetrating the grids along the c direction. The solid-state photoluminescence analysis of (II) was performed at room temperature and the MOF exhibits highly selective sensing toward Fe3+ and Cr2O7
2− ions in aqueous solution.
Metal-directed supramolecular architectures based on the bifunctional ligand 2,5-bis(1H-1,2,4-triazol-1-yl)terephthalic acid
Authors: Cai Hua , Li Na , Zhang Nan , Yang Zhenyun , Cao Jing , Lin Yating , Min Nan , Wang Jia
Published: January 2020

By the solvothermal reactions of 2,5-bis(1H-1,2,4-triazol-1-yl)terephthalic acid (H2
L) with transition-metal ions, two novel polymeric complexes, namely, poly[diaqua[μ4-2,5-bis(1H-1,2,4-triazol-1-yl)terephthalato]cobalt(II)], [Co(C12H6N6O4)(H2O)2]
n
, (1), and poly[[diaqua[μ4-2,5-bis(1H-1,2,4-triazol-1-yl)terephthalato]nickel(II)] dihydrate], {[Ni(C12H6N6O4)(H2O)2]·2H2O}
n
, (2), were isolated. Both polymers have been characterized by FT–IR spectroscopy, elemental analysis and single-crystal X-ray diffraction analysis. The complexes have similar two-dimensional layered structures and coordination modes. Furthermore, the two-dimensional layered structures bear distinct intermolecular hydrogen-bonding interactions and π–π stacking interactions to form two different three-dimensional supramolecular networks based on 44-subnets. The structural variation depends on the nature of the metal cations. The results of variable-temperature magnetization measurements (χ
MT−T and χ
M
−1−T) show that complexes (1) and (2) display antiferromagnetic behaviour.
Bond length of perchlorate at different temperatures: X-ray and neutron comparison
Authors: Olmstead Marilyn M.
Published: January 2020

The averages (average deviations from the mean are given in square brackets) of uncorrected Cl—O bond distances in a perchlorate anion from an X-ray diffraction analysis of (N-{2-[bis(pyridin-2-ylmethyl)amino]ethyl}pyridine-2-carboxamidato)(nitric oxide)manganese perchlorate acetonitrile disolvate, [Mn(C20H20N5O)(NO)]ClO4·2CH3CN or [Mn(PaPy3)(NO)]ClO4·2CH3CN, decrease from 1.447 [4] Å at 10 K to 1.428 [4] Å at 170 K. The 10 K value is close to the neutron value (1.441 [1] Å) at 18 K. Comparisons are made with a second X-ray study at 30 K [1.444 (8) Å] and to libration-corrected, density functional theory (DFT), and Cambridge Structural Database (CSD) values.
A meta-analysis of export spillovers from FDI: advanced vs emerging markets
Authors: Villar Cristina , Mesa Ramón Javier , Plà Barber Jose
Published: January 2020

Purpose

This paper analyzes the available literature on export spillovers from foreign direct investment (FDI) and their effects on domestic firms’ export activities. The purpose of this paper is to advance our knowledge of whether export spillovers from FDI exist, and if so if they differ according to the institutional context of the targeted markets (developed vs emerging markets).

Design/methodology/approach

Drawing from the pioneering work of Aitkenet al.(1997), the authors develop a meta-analysis using a selection of 73 studies for the period 1997–2018, including a wide range of developed and emerging markets.

Findings

The meta-analysis confirms a high probability of finding positive effects when studying the different types of spillovers. The authors also show that the type of export spillover depends on the institutional context. Spillovers drive a complementary effect which generates more direct commercial links between domestic firms and foreign multinationals for advanced economies, whereas for emerging markets the nature of the spillover generates a competition/imitation effect that pressures domestic firms to be better inserted into foreign markets. In emerging markets, local governments play a fundamental role in accompanying the local industry, not only with investments in infrastructure and training of human capital but also in the configuration of an institutional environment that favors this type of indirect linkages. In developed countries, two business strategies are particularly important as catalytic axes of competitive upgrading at the international level: cooperation agreements between domestic and foreign firms and integration. These processes of concentration are necessary to compete globally, and therefore, governments should promote this type of strategies.

Originality/value

The study offers an original classification of the different types of spillovers based on the different channels through which MNE help local firms to improve their export performance and shows which specific spillover is associated with the different level of country development. These results have important implications in terms of theory development and managerial and policy implications.
Office cake culture
Authors: Walker Louise , Flannery Orla
Published: January 2020

Purpose

The purpose of this paper is to explore the characteristics of office cake (OC) consumption and the associated attitudes and behaviours among UK office workers to gain insight into the implications for workplace health.

Design/methodology/approach

A cross-sectional online questionnaire was completed by 940 respondents. Data were analysed using descriptive statistics and cross-tabulation withχ2tests for between-group difference.

Findings

Respondents reported both positive social and negative health-related consequences of OC. OC influenced eating behaviour through increased salience and availability, and the effects of social influencing. Almost all (94.8 per cent) reported ideal OC frequency to be once/week or less. Gender and age significantly affected attitudes and behaviour.

Research limitations/implications

The questionnaire was not validated so data accuracy could have been diminished or biased. Portion size was not examined and consumption data were self-reported which could have resulted in under-reporting. Only office workers were investigated therefore results may not be applicable to other workplaces.

Practical implications

OC appears to influence both the workplace eating environment and employee eating behaviour. It could therefore affect employee health and workplace health promotion programme efficacy. However the findings suggest that nudge-based initiatives could reduce OC consumption to make workplaces healthier while retaining social benefits.

Originality/value

The present study provides the first data on OC culture and insights on how to address it sensitively. It also highlights that sweet treats used for celebration and employee recognition should be considered a relevant part of workplace food provision alongside canteens and vending.
Assessment of performance of teamwork in construction projects delivery in South-Southern Nigeria
Authors: Adu Emmanuel Tayo , Opawole Akintayo
Published: January 2020

Purpose

Effort towards improving project performance has necessitated the need for effective teamwork among the stakeholders in the construction industry. The purpose of this paper is to identify the major attributes of effective teamwork and the challenges encountered by the team during construction with a view to improving performance of projects.

Design/methodology/approach

Data for the study were obtained through 420 structured questionnaires, which were administered to a sample of project participants including clients’, contractors’ and consultants’ organizations’ representatives in South-Southern region of Nigeria. Data collected were analyzed using percentage, mean item score and Kruskal–Wallis rank test.

Findings

The findings revealed leadership skills, top management support and interpersonal dynamics of the team among the critical attributes for effective teamwork. The prevailing challenges of effective teamwork were identified as essentially; poor leadership, poor rapport among team members and lack of effective communication.

Practical implications

The study ultimately provides implication for effective team building among clients’, consultants’ and contractors’ organizations towards efficient delivery of construction projects. Moreover, the stakeholders in the industry would find the results of this research useful in managing human and non-human components of construction projects through the understanding of the attributes and challenges of teamwork with ultimate aim of achieving effective project performance.

Originality/value

The findings reveal that all the key stakeholders’ organizations; clients, consultants and contractors’ organizations exhibit similar perceptions of the attributes and challenges confronting teamwork in construction project delivery. The empirical evidence provided on the attributes and challenges would therefore offer robust information in building effective project team by stakeholders during the planning and implementation stages, which is a right step towards enhancing construction project performance.
“Trolls” or “warriors of faith”?
Authors: Eberwein Tobias
Published: January 2020

Purpose

The idea that user comments on journalistic articles would help to increase the quality of the media has long been greeted with enthusiasm. By now, however, these high hopes have mostly evaporated. Practical experience has shown that user participation does not automatically lead to better journalism but may also result in hate speech and systematic trolling – thus having a dysfunctional impact on journalistic actors. Although empirical journalism research has made it possible to describe various kinds of disruptive follow-up communication on journalistic platforms, it has not yet succeeded in explaining what exactly drives certain users to indulge in flaming and trolling. This paper intends to fill this gap.

Design/methodology/approach

It does so on the basis of problem-centered interviews with media users who regularly publish negative comments on news websites.

Findings

The evaluation allows for a nuanced view on current phenomena of dysfunctional follow-up communication on journalistic news sites. It shows that the typical “troll” does not exist. Instead, it seems to be more appropriate to differentiate disruptive commenters according to their varying backgrounds and motives. Quite often, the interviewed users display a distinct political (or other) devotion to a certain cause that rather makes them appear as “warriors of faith.” However, they are united in their dissatisfaction with the quality of the (mass) media, which they attack critically and often with a harsh tone.

Originality/value

The study reflects these differences by developing a typology of dysfunctional online commenters. By helping to understand their aims and intentions, it contributes to the development of sustainable strategies for stimulating constructive user participation in a post-truth age.