bluuebunny/crossref_metadata_2025 huggingface dataset:
Streptococcus pneumoniaeinfection promotes histone H3 dephosphorylation by modulating host PP1 phosphatase
Authors: Dong Wenyang , Rasid Orhan , Chevalier Christine , Connor Michael , Eldridge Matthew , Hamon Melanie Anne
Published: January 2020

Pathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show for the first time that a natural colonizer,Streptococcus pneumoniae, also induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10, during infection of respiratory epithelial cells. Two bacterial factors are important for the induction of this modification: the bacterial toxin PLY, a pore-forming toxin, and the pyruvate oxidase SpxB, an enzyme responsible for H2O2production. The combined effects of PLY and H2O2lead to host signaling which culminates in H3S10 dephosphorylation, mediated by the host cell phosphatase PP1. Strikingly,S. pneumoniaeinfection induces dephosphorylation and associated activation of PP1 catalytic activity. Colonization of cells, which lacked active PP1, resulted in the impairment of intracellularS. pneumoniaesurvival. Interestingly, PP1 activation mediating H3S10 dephosphorylation is not restricted toS. pneumoniaeand appears to be a general epigenomic mechanism favoring intracellular survival.
CHLOROPLAST UNUSUAL POSITIONING 1 is a new type of actin nucleation factor in plants
Authors: Kong Sam-Geun , Shimada Atsushi , Kijima Saku T. , Hirose Keiko , Katoh Kaoru , Ahn Jeongsu , Higa Takeshi , Takano Akira , Nakamura Yuki , Suetsugu Noriyuki , Kohda Daisuke , Uyeda Taro Q. P. , Wada Masamitsu
Published: January 2020

Plants have evolved unique responses to fluctuating light conditions in their environment. One such response, chloroplast photorelocation movement, optimizes photosynthesis under weak light and prevents photodamage under strong light. CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1) plays a pivotal role in the light-responsive chloroplast movements, which are driven by dynamic reorganization of chloroplast actin (cp-actin) filaments. In this study, we demonstrated that fluorescently tagged CHUP1 colocalized and was coordinately reorganized with cp-actin filaments during chloroplast movement inArabidopsis thaliana. The resulting asymmetric distribution of CHUP1 was reversibly regulated by the blue light receptor phototropin. X-ray crystallography indicated that the CHUP1 C-terminal domain shares structural similarity with the formin homology 2 (FH2) domain, although there is no sequence similarity between the two domains. The CHUP1 C-terminal domain stimulated actin polymerization in the presence of profilin. We conclude that CHUP1 is a novel, plant-specific actin nucleator that functions in cp-actin-based chloroplast movement.

Highlights

Blue light changes the distribution pattern of CHUP1

Formin FH2 and CHUP1 C-terminal domains are structurally similar but not homologous

CHUP1 nucleates and severs actin filaments in vitro

CHUP1 is a novel, plant-specific actin nucleator for chloroplast movement
Mg2+modulates the activity of hyperpolarization-activated calcium currents in plant cells
Authors: Lemtiri-Chlieh Fouad , Arold Stefan T. , Gehring Chris
Published: January 2020

Hyperpolarization-activated calcium channels (HACCs) are found in the plasma membrane and tonoplast of many plant cell types where they have an important role in Ca2+-dependent signaling. The unusual gating properties of HACCs in plants, i.e., activation by membrane hyperpolarization rather than depolarization, dictates that HACCs are normally open at physiological hyperpolarized resting membrane potentials (the so called pump or P-state), thus, if not regulated, they would be continuously leaking Ca2+into cells. In guard cells, HACCs are permeable to Ca2+, Ba2+and Mg2+, activated by H2O2and the plant hormone abscisic acid (ABA) and their activity is greatly reduced by low amounts of free cytosolic Ca2+([Ca2+]Cyt) and hence will close during [Ca2+]Cytsurges. Here we demonstrate that the presence of the commonly used Mg-ATP inside the cell greatly reduces HACC activity especially at voltages ≤ −200 mV and that Mg2+causes this block. We therefore conclude, firstly, that physiological cytosolic Mg2+levels affect HACCs gating and that channel opening requires either high negative voltages (≥ −200 mV) and/or displacement of Mg2+away from the immediate vicinity of the channel. Secondly, based on structural comparisons with Mg2+-sensitive animal inward-rectifying K+channel, we propose that the likely candidate HACCS described here are cyclic nucleotide gated channels (CNGCs), many of which also contain a conserved di-acidic Mg2+-binding motif within their pores. This conclusion is consistent with the electrophysiological data. Finally, we propose that Mg2+, much like in animal cells, is an important component in Ca2+signalling and homeostasis in plants.
A Bayesian nonparametric semi-supervised model for integration of multiple single-cell experiments
Authors: Verma Archit , Engelhardt Barbara
Published: January 2020

Joint analysis of multiple single cell RNA-sequencing (scRNA-seq) data is confounded by technical batch effects across experiments, biological or environmental variability across cells, and different capture processes across sequencing platforms. Manifold alignment is a principled, effective tool for integrating multiple data sets and controlling for confounding factors. We demonstrate that the semi-supervised t-distributed Gaussian process latent variable model (sstGPLVM), which projects the data onto a mixture of fixed and latent dimensions, can learn a unified low-dimensional embedding for multiple single cell experiments with minimal assumptions. We show the efficacy of the model as compared with state-of-the-art methods for single cell data integration on simulated data, pancreas cells from four sequencing technologies, induced pluripotent stem cells from male and female donors, and mouse brain cells from both spatial seqFISH+and traditional scRNA-seq.

Code and data is available athttps://github.com/architverma1/sc-manifold-alignment
Mechanical Regulation of Microvascular Angiogenesis
Authors: Ruehle Marissa A. , Eastburn Emily A. , LaBelle Steven A. , Krishnan Laxminarayanan , Weiss Jeffrey A. , Boerckel Joel D. , Wood Levi B. , Guldberg Robert E. , Willett Nick J.
Published: January 2020

Neovascularization is a critical early step toward successful tissue regeneration during wound healing. While vasculature has long been recognized as highly mechanosensitive (to fluid shear, pulsatile luminal pressure, etc.), the effects of extracellular matrix strains on angiogenesis are poorly understood. Previously, we found that dynamic matrix compressionin vivopotently regulated neovascular growth during tissue regeneration; however, whether matrix deformations directly regulate00 angiogenesis remained unknown. Here, we tested the effects of load initiation time, strain magnitude, and mode of compressive deformation (uniform compression vs. compressive indentation that also introduced shear stress) on neovascularization and key angiogenic and mechanotransduction signaling pathways by microvascular fragmentsin vitro. We hypothesized that neovascularization would be enhanced by delayed, moderate compression and inhibited by early, high magnitude compression and by compressive indentation. Consistent with our hypothesis, early, high magnitude loading inhibited vessel growth, while delayed loading enhanced vessel growth. Compressive indentation led to longer, more branched networks than uniform compression – particularly at high strain magnitude. Gene expression was differentially regulated by time of load initiation; genes associated with active angiogenic sprouts were downregulated by early loading but upregulated by delayed loading. Canonical gene targets of the YAP/TAZ mechanotransduction pathway were increased by loading and abrogated by pharmacological YAP inhibition. Together, these data demonstrate that neovascularization is directly responsive to dynamic matrix strain and is particularly sensitive to the timing of load initiation. This work further identifies putative mechanoregulatory angiogenic mechanisms and implicates a critical role for dynamic mechanical cues in vascularized tissue regeneration.

Statement of Significance

Mechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, remarkably little is known about the effects of bulk extracellular matrix deformation on the nascent vessel networks found in healing tissues. Here, we demonstrated that load initiation time, magnitude, and mode all regulate microvascular growth, as well as upstream angiogenic and mechanotransduction signaling pathways. Across all tested magnitudes and modes, microvascular network formation and upstream signaling were powerfully regulated by the timing of load initiation. This work provides a new foundational understanding of how extracellular matrix mechanics regulate angiogenesis and has critical implications for clinical translation of new regenerative medicine therapies and physical rehabilitation strategies designed to enhance revascularization during tissue regeneration.
Initial virome characterization of the common cnidarian lab modelNematostella vectensis
Authors: Lewandowska Magda , Hazan Yael , Moran Yehu
Published: January 2020

The role of viruses in forming a stable holobiont has been a subject of extensive research in the recent years. However, many emerging model organisms still lack any data on the composition of the associated viral communities. Here, we re-analyzed seven publicly available transcriptome datasets of the starlet sea anemoneNematostella vectensis, the most commonly used anthozoan lab model, and searched for viral sequences. We applied a straightforward, yet powerful approach ofde novoassembly followed by homology-based virus identification and a multi-step, thorough taxonomic validation. The comparison of different lab populations ofN. vectensisrevealed the existence of the core virome composed of 21 viral sequences, present in all adult datasets. Unexpectedly, we observed almost complete lack of viruses in the samples from the early developmental stages which together with the identification of the viruses shared with the major source of the food in the lab, the brine shrimpArtemia salina, shed new light on the course of viral species acquisition inN. vectensis. Our study provides an initial, yet comprehensive insight intoN. vectensisvirome and sets the first foundation for functional studies of viruses and antiviral systems in this lab model cnidarian.
A regulatory domain in the K2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes
Authors: Arazi Eden , Blecher Galit , Zilberberg Noam
Published: January 2020

Potassium K2P(‘leak’) channels conduct current across the entire physiological voltage range and carry leak or ‘background’ currents that are, in part, time- and voltage-independent. K2P2.1 channels (i.e., TREK-1, KCNK2) are highly expressed in excitable tissues, where they play a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report for the first time that human K2P2.1 channel activity is regulated by monoterpenes (MTs). We found that cyclic, aromatic monoterpenes containing a phenol moiety, such as carvacrol, thymol and 4-IPP had the most profound effect on current flowing through the channel (up to a 6-fold increase). By performing sequential truncation of the carboxyl-terminal domain of the channel and testing the activity of several channel regulators, we identified two distinct regulatory domains within this portion of the protein. One domain, as previously reported, was needed for regulation by arachidonic acid, anionic phospholipids and temperature changes. Within a second domain, a triple arginine residue motif (R344-346), an apparent PIP2-binding site, was found to be essential for regulation by holding potential changes and important for regulation by monoterpenes.
Architecture and self-assembly of theClostridium sporogenes/botulinumspore surface illustrate a general protective strategy across spore formers
Authors: Janganan Thamarai K. , Mullin Nic , Dafis-Sagarmendi Ainhoa , Brunt Jason , Tzokov Svetomir B. , Stringer Sandra , Moir Anne , Chaudhuri Roy , Fagan Robert P. , Hobbs Jamie K. , Bullough Per A.
Published: January 2020

Spores, the infectious agents of many Firmicutes, are remarkably resilient cell forms. Even distant relatives have similar spore architectures incorporating protective proteinaceous envelopes. We reveal in nanometer detail how the outer envelope (exosporium) inClostridium sporogenes(surrogate forC. botulinumgroup I), and in other Clostridial relatives, forms a hexagonally symmetric molecular filter. A cysteine-rich protein, CsxA, when expressed inE. coli, self-assembles into a highly thermally stable structure identical to native exosporium. Like exosporium, CsxA arrays require harsh reducing conditions for disassembly. We conclude thatin vivo, CsxA self-organises into a highly resilient, disulphide cross-linked array decorated with additional protein appendages enveloping the forespore. This pattern is remarkably similar inBacillusspores, despite lack of protein homology. In both cases,intracellulardisulphide formation is favoured by the high lattice symmetry. We propose that cysteine-rich proteins identified in distantly related spore formers may adopt a similar strategy for intracellular assembly of robust protective structures.
PAX2 Induces Tubular-Like Structures in Normal and Ovarian Cancer Cells
Authors: Alwosaibai Kholoud , Al-Hujaily Ensaf Munawer , Alamri Salmah , Garson Kenneth , Vanderhyden Barbara C.
Published: January 2020

In adult tissues, PAX2 protein is expressed in normal oviductal epithelial cells but not in normal ovarian surface epithelial cells. Studies have reported that PAX2 is expressed in a subset of serous ovarian carcinoma cases but the role of PAX2 in the initiation and progression of ovarian cancer remains unknown. The aim of this study was to understand the biological consequences ofPax2expression in normal and cancerous mouse epithelial (MOSE) cells. We found thatPax2overexpression in both normal and cancerous ovarian epithelial cells induced the formation of vascular channels bothin vitroandin vivo. The results indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells.
Cardiac Microlesions Form During Severe BacteremicEnterococcus faecalisInfection
Authors: Brown Armand O. , Singh Kavindra V. , Cruz Melissa R. , Kaval Karan Gautam , Francisco Liezl E. , Murray Barbara E. , Garsin Danielle A.
Published: January 2020

Enterococcus faecalisis a significant cause of hospital-acquired bacteremia. Herein, the discovery is reported that cardiac microlesions form during severe bacteremicE. faecalisinfection in mice. The cardiac microlesions were identical in appearance to those formed byStreptococcus pneumoniaeduring invasive pneumococcal disease (IPD). However,E. faecalisdoes not encode the virulence determinants implicated in pneumococcal microlesion formation. Rather, disulfide bond forming protein DsbA was found to be required forE. faecalisvirulence in aC. elegansmodel and was necessary for efficient cardiac microlesion formation. Furthermore,E. faecalispromoted cardiomyocyte apoptotic and necroptotic cell death at sites of microlesion formation. Additionally, loss of DsbA caused an increase in pro-inflammatory cytokines unlike the wild-type strain, which suppressed the immune response. In conclusion, we establish thatE. faecalisis capable of forming cardiac microlesions and identify features of both the bacterium and the host response that are mechanistically involved.

This work presents the observation of cardiac microlesion formation during severe blood stream infection withEnterococcus faecalisin mice. Moreover, we identify the contribution of a novel enterococcal virulence determinant in modulating microlesion formation and the host immune response.
Bioluminescence dynamics in single germinating bacterial spores reveal metabolic heterogeneity
Authors: Frentz Zak , Dworkin Jonathan
Published: January 2020

Spore-forming bacteria modulate their metabolic rate by over 5 orders of magnitude as they transition between dormant spores and vegetative cells, and thus represent an extreme case of phenotypic variation. During environmental changes in nutrient availability, clonal populations of spore-forming bacteria exhibit individual differences in cell fate, timing of phenotypic transitions, and gene expression. One potential source of this variability is metabolic heterogeneity, but this has not yet been measured, as existing single-cell methods are not easily applicable to spores due to their small size and strong autofluorescence. Here, we use the bacterial bioluminescence system and a highly sensitive microscope to measure metabolic dynamics in thousands ofB. subtilisspores as they germinate. We observe and quantitate large variations in the bioluminescence dynamics across individual spores that can be decomposed into contributions from variability in germination timing, the amount of endogenously produced luminescence substrate, and the intracellular reducing power. This work shows that quantitative measurement of spore metabolism is possible and thus it opens venues for future study of the thermodynamic nature of dormant states.
Oxidative stress delays development and alters gene function in the agricultural pest moth,Helicoverpa armigera
Authors: Apirajkamol Nonthakorn (Beatrice) , James Bill , Walsh Tom K , McGaughran Angela
Published: January 2020

Stress is a widespread phenomenon that all organisms must endure. Common in nature is oxidative stress, which can interrupt cell homeostasis to cause cell damage and may be derived from respiration or from environmental exposure thought diet. As a result of the routine exposure from respiration, many organisms can mitigate the effects of oxidative stress, but less is known about responses to oxidative stress from other sources.Helicoverpa armigerais a major agricultural pest moth that causes significant damage to crops worldwide. Here, we examined the effects of oxidative stress onH. armigeraby chronically exposing individuals to paraquat - a free radical producer - and measuring changes in development (weight, developmental rate, lifespan), and gene expression.

We found that oxidative stress strongly affected development inH. armigera, with stressed samples spending more time as caterpillars than control samples (>24 vs. ∼15 days, respectively) and living longer overall. We found 1,618 up- and 761 down-regulated genes, respectively, in stressed vs. control samples. In the up-regulated gene set were genes associated with cell senescence and apoptosis and an over-representation of biological processes related to cuticle and chitin development, glycine metabolism, and oxidation-reduction.

Oxidative stress clearly impacts physiology and biochemistry inH. armigeraand the interesting finding of an extended lifespan in stressed individuals could demonstrate hormesis, the process whereby toxic compounds can actually be beneficial at low doses. Collectively, our findings provide new insights into genomic responses to oxidative stress in invertebrates.
Synthesis of geological and comparative phylogeographic data point to climate, not mountain uplift, as driver of divergence across the Eastern Andean Cordillera
Authors: Rodríguez-Muñoz Erika , Montes Camilo , Crawford Andrew J.
Published: January 2020

Aim

To evaluate the potential role of the orogeny of the Eastern Cordillera (EC) of the Colombian Andes and the Mérida Andes (MA) of Venezuela as drivers of vicariance between populations of 37 tetrapod lineages co-distributed on both flanks, through geological reconstruction and comparative phylogeographic analyses.

Location

Northwestern South America

Methods

We first reviewed and synthesized published geological data on the timing of uplift for the EC-MA. We then combined newly generated mitochondrial DNA sequence data with published datasets to create a comparative phylogeographic dataset for 37 independent tetrapod lineages. We reconstructed time-calibrated molecular phylogenies for each lineage under Bayesian inference to estimate divergence times between lineages located East and West of the Andes. We performed a comparative phylogeographic analysis of all lineages within each class of tetrapod using hierarchical approximate Bayesian computation (hABC) to test for synchronous vicariance across the EC-MA. To evaluate the potential role of life history in explaining variation in divergence times among lineages, we evaluated 13 general linear models (GLM) containing up to six variables each (maximum elevation, range size, body length, thermoregulation, type of dispersal, and taxonomic class).

Results

Our synthesis of geological evidence suggested that the EC-MA reached significant heights by 38–33 million years ago (Ma) along most of its length, and we reject the oft-cited date of 2–5 Ma. Based on mtDNA divergence from 37 lineages, however, the median estimated divergence time across the EC-MA was 3.26 Ma (SE = 2.84) in amphibians, 2.58 Ma (SE = 1.81) in birds, 2.99 Ma (SE = 4.68) in reptiles and 1.43 Ma (SE = 1.23) in mammals. Using Bayes Factors, the hypothesis for a single temporal divergence interval containing synchronous divergence events was supported for mammals and but not supported for amphibians, non-avian reptiles, or birds. Among the six life-history variables tested, only thermoregulation successfully explained variation in divergence times (minimum AICc,R20.10), with homeotherms showing more recent divergence relative to poikilotherms.

Main conclusions

Our results reject the hypothesis of the rise Andean Cordillera as driver of vicariance of lowland population because divergence dates are too recent and too asynchronous. We discuss alternative explanations, including dispersal through mountain passes, and suggest that changes in the climatic conditions during the Pliocene and Pleistocene interacted with tetrapod physiology, promoting older divergences in amphibians and reptiles relative to mammals and birds on an already established orogen.
What drives male association tendencies in wild zebrafish? Role of female and vegetation densities
Authors: Ghoshal Aditya , Bhat Anuradha
Published: January 2020

Mating strategies in species is context-dependent and driven by several ecological and demographic factors. In natural habitats, a multitude of ecological factors interact and these eventually determine mating preferences and mate choice decisions among species. While zebrafish (Danio rerio) is a widely studied biological model organism, our understanding of their mating preferences, strategies and their underlying ecological drivers are still limited. Here, we explore the role of ecological factors such as spatial variation (or patchiness) in mate density and associated vegetation cover in determining mate association tactics among males in a wild zebrafish population. We employed a multi-choice experimental design for a better representation of ecologically relevant scenarios. Our results revealed that when presented with patches with increasing female densities, males displayed only a marginal increase in preference for higher female density patches. However, when female density varied concomitantly with variation in vegetation cover, the males associated more with higher foliage density patches irrespective of the female density in that patch. Our findings throw light on the complex interaction between these two most basic ecological factors in determining mate search strategies and mate associations among these group-living fish species.
Iron and Lipocalin-2 Modulate Cellular Responses in the Tumor Micro-environment of Pancreatic Ductal Adenocarcinoma
Authors: Pita-Grisanti Valentina , Dangel Andrew W. , Gumpper Kristyn , Ludwig Andrea , Ueltschi Olivia , Mo Xiaokui , Pietrzak Maciej , Webb Amy , Hwang Rosa F. , Traczek Madelyn , Badi Niharika , Cruz-Monserrate Zobeida
Published: January 2020

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with poor outcomes. Iron is known to signal cellular responses, and its levels are regulated by lipocalin-2 (LCN2) expression, a PDAC pro-tumorigenic molecule. However, how iron and LCN2 function in PDAC is unclear. Here we demonstrate that iron levels regulate PDAC cell proliferation, invasion, expression of epithelial to mesenchymal tumor markers, and pro-inflammatory cytokines. Iron chelation increased the expression of the LCN2 receptorSLC22A17in pancreatic stellate cells and the anti-metastatic geneNDRG1in PDAC cells. Deletion ofLcn2in mouse tumor cells modulated the expression of genes involved in extracellular matrix deposition and cell migration. Moreover, cellular iron responses were dependent on theKrasmutation status of cells, andLCN2expression levels. Deletion ofLcn2expression in PDAC suggests a protective role against metastasis. Thus, iron modulation and LCN2 blockade could serve as potential therapeutic approaches against PDAC.
Quantifying the impact of Human Leukocyte Antigen on the human gut microbiome
Authors: Andeweg Stijn P. , Keşmir Can , Dutilh Bas E.
Published: January 2020

Objective

The gut microbiome is affected by a number of factors, including the innate and adaptive immune system. The major histocompatibility complex (MHC), or the human leukocyte antigen (HLA) in humans, performs an essential role in vertebrate immunity, and is very polymorphic in different populations. HLA determines the specificity of T lymphocyte and natural killer (NK) cell responses, including against the commensal bacteria present in the human gut. Thus, it is likely that our HLA molecules and thereby the adaptive immune response, can shape the composition of our microbiome. Here, we investigated the effect of HLA haplotype on the microbiome composition.

Results

We performed HLA typing and microbiota composition analyses on 3,002 public human gut microbiome datasets. We found that (i) individuals with functionally similar HLA molecules (i.e. presenting similar peptides) are also similar in their microbiota, and (ii) HLA homozygosity correlated with microbiome diversity, suggesting that diverse immune responses limit microbiome diversity.

Conclusion

Our results show a statistical association between host HLA haplotype and gut microbiome composition. Because the HLA haplotype is a readily measurable parameter of the human immune system, these results open the door to incorporating the immune system into predictive microbiome models.

IMPORTANCE

The microorganisms that live in the digestive tracts of humans, known as the gut microbiome, are essential for hosts survival as they support crucial functions. For example, they support the host in facilitating the uptake of nutrients and give colonization resistance against pathogens. The composition of the gut microbiome varies among humans. Studies have proposed multiple factors driving the observed variation, including; diet, lifestyle, and health condition. Another major influence on the microbiome is the host’s genetic background. We hypothesized the immune system to be one of the most important genetic factors driving the differences observed between gut microbiomes. Therefore, we are interested in linking the polymorphic molecules that play a role in human immune responses to the composition of the microbiome. HLA molecules are the most polymorphic molecules in our genome and therefore makes an excellent candidate to test such an association/link. To our knowledge for the first time, our results indicate a significant impact of the HLA on the human gut microbiome composition.
Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice
Authors: Okugawa Eisuke , Ogino Himari , Shigenobu Tomofumi , Yamakage Yuko , Tsuiji Hitomi , Oishi Hisashi , Kohno Takao , Hattori Mitsuharu
Published: January 2020

Reelin is a secreted protein that plays versatile roles in neuronal development and function, and hypoactivity of Reelin is implicated in many neuropsychiatric disorders. The strength of Reelin signaling is regulated by proteolytic processing, but its importancein vivois not yet fully understood. Here, we generated Reelin knock-in (PA-DV KI) mice in which the key cleavage site of Reelin was abolished by mutation. As expected, the cleavage of Reelin was severely abrogated in the cerebral cortex and hippocampus of PA-DV KI mice. The amount of Dab1, whose degradation is induced by Reelin signaling, decreased in these tissues, indicating that the signaling strength of Reelin was augmented. The brains of PA-DV KI mice were largely structurally normal, but unexpectedly, the hippocampal layer was disturbed. This phenotype was ameliorated in hemizygote PA-DV KI mice, indicating that excess Reelin signaling is detrimental to hippocampal layer formation. The neuronal dendrites of PA-DV KI mice had more branches and were elongated compared to wild-type mice. These results present the first direct evidence of the physiological importance of Reelin cleavage and suggest that inhibition of Reelin cleavage would counteract neuropsychiatric disorders without causing severe systemic side effects.
Quantitative Analysis of Tissue Secretome Reveals the Diagnostic and Prognostic Value of Carbonic Anhydrase II in Hepatocellular Carcinoma
Authors: Xing Xiaohua , Yuan Hui , Liu Hongzhi , Tan Xionghong , Zhao Bixing , Wang Yingchao , Ouyang Jiahe , Lin Minjie , Huang Aimin , Liu Xiaolong
Published: January 2020

Early detection and intervention are key strategies to reduce mortality, increase long-term survival and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ) quantitative proteomic strategy was used to study the secretome in conditioned media from HCC cancerous tissues, surrounding noncancerous and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 secretory proteins were identified to be dysregulated in the cancerous and surrounding noncancerous tissues compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients than that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence (TTR) and overall survival (OS). Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition (EMT) pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis and provides a valuable resource of the HCC secretome for investigating serological biomarkers.
Temperature controlled high-throughput magnetic tweezers show striking difference in activation energies of replicating viral RNA-dependent RNA polymerases
Authors: Seifert M. , van Nies P. , Papini F.S. , Arnold J.J. , Poranen M.M. , Cameron C.E. , Depken M. , Dulin D.
Published: January 2020

RNA virus survival depends on efficient viral genome replication, which is performed by the viral RNA dependent RNA polymerase (RdRp). The recent development of high throughput magnetic tweezers has enabled the simultaneous observation of dozens of viral RdRp elongation traces on kilobases long templates, and this has shown that RdRp nucleotide addition kinetics is stochastically interrupted by rare pauses of 1-1000 s duration, of which the short-lived ones (1-10 s) are the temporal signature of a low fidelity catalytic pathway. We present a simple and precise temperature controlled system for magnetic tweezers to characterize the replication kinetics temperature dependence between 25°C and 45°C of RdRps from three RNA viruses, i.e. the double-stranded RNA bacteriophage Φ6, and the positive-sense single-stranded RNA poliovirus (PV) and human rhinovirus C (HRV-C). We found that Φ6 RdRp is largely temperature insensitive, while PV and HRV-C RdRps replication kinetics are activated by temperature. Furthermore, the activation energies we measured for PV RdRp catalytic state corroborate previous estimations from ensemble pre-steady state kinetic studies, further confirming the catalytic origin of the short pauses and their link to temperature independent RdRp fidelity. This work will enable future temperature controlled study of biomolecular complex at the single molecule level.
Plant-derived Cellulose Scaffolds for Bone Tissue Engineering
Authors: Latour Maxime Leblanc , Tarar Maryam , Hickey Ryan J. , Cuerrier Charles M. , Catelas Isabelle , Pelling Andrew E.
Published: January 2020

Plant-derived cellulose biomaterials have recently been utilized in several tissue engineering applications. Naturally-derived cellulose scaffolds have been shown to be highly biocompatiblein vivo, possess structural features of relevance to several tissues, as well as support mammalian cell invasion and proliferation. Recent work utilizing decellularized apple hypanthium tissue has shown that it possesses a pore size and properties similar to trabecular bone. In the present study, we examined the potential of apple-derived cellulose scaffolds for bone tissue engineering (BTE). Confocal microscopy revealed that the scaffolds had a suitable pore size for BTE applications. To analyze theirin vitromineralization potential, MC3T3-E1 pre-osteoblasts were seeded in either bare cellulose scaffolds or in composite scaffolds composed of cellulose and collagen I. Following chemically-induced differentiation, scaffolds were mechanically tested and evaluated for mineralization. The Young’s modulus of both types of scaffolds significantly increased after cell differentiation. Alkaline phosphatase and Alizarin Red staining further highlighted the osteogenic potential of the scaffolds. Histological sectioning of the constructs revealed complete invasion by the cells and mineralization throughout the entire constructs. Finally, scanning electron microscopy demonstrated the presence of mineral aggregates deposited on the scaffolds after differentiation, and energy-dispersive spectroscopy confirmed the presence of phosphate and calcium. In summary, our results indicate that plant-derived cellulose is a promising scaffold candidate for bone tissue engineering applications.
Sources of Off-Target Effects of Vagus Nerve Stimulation Using the Helical Clinical Lead in Domestic Pigs
Authors: Nicolai Evan N. , Settell Megan L. , Knudsen Bruce E. , McConico Andrea L. , Gosink Brian A. , Trevathan James K. , Baumgart Ian W. , Ross Erika K. , Pelot Nicole A. , Grill Warren M. , Gustafson Kenneth J. , Shoffstall Andrew J. , Williams Justin C. , Ludwig Kip A.
Published: January 2020

Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically. Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Contraction of the cricoarytenoid muscle occurred at low amplitudes (∼0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (∼1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 µA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.
Evaluation of the performance and implications of multinationals: a framework of issues
Authors: Pearce Robert D. , Tang Yuxuan
Published: January 2020

Purpose

The purpose of this paper is to evaluate multinational enterprises’ (MNEs) performance and impact in contexts beyond their own internal objectives.

Design/methodology/approach

Based on an “eclectic” paradigm and the range of motivations, the framework is designed around three layers of evaluation: “efficiency” as static optimisation, “growth and development” as the dynamics of change on a purely economic view; political/economic sphere in terms of the outcomes of “distribution”, and “sovereignty” on the more purely political concern of how MNEs may undermine countries’ policy independence.

Findings

MNE and national economies have to use current sources of competitiveness efficiently while addressing the necessity to reinforce and refocus them through time. Within these broad agendas, significant interactions and outcomes reflect a range of contingencies conditioned by both MNE objectives and hosts’ competitive status.

Originality/value

The paper concerns economics and MNE role in globalisation. The paper defines a framework of four generic evaluative issues of MNE performance, which subsume a wider range of important but more niche concerns.
Modelling of temperature distribution along PCB thickness in different substrates during reflow
Authors: Straubinger Daniel , Bozsóki István , Bušek David , Illés Balázs , Géczy Attila
Published: January 2020

Purpose

In this paper, analytical modelling of heat distribution along the thickness of different printed circuit board (PCB) substrates is presented according to the 1 D heat transient conduction problem. This paper aims to reveal differences between the substrates and the geometry configurations and elaborate on further application of explicit modelling.

Design/methodology/approach

Different substrates were considered: classic FR4 and polyimide, ceramics (BeO, Al2O3) and novel biodegradables (polylactic-acid [PLA] and cellulose acetate [CA]). The board thicknesses were given in 0.25 mm steps. Results are calculated for heat transfer coefficients of convection and vapour phase (condensation) soldering. Even heat transfer is assumed on both PCB sides.

Findings

It was found that temperature distributions along PCB thicknesses are mostly negligible from solder joint formation aspects, and most of the materials can be used in explicit reflow profile modelling. However PLA shows significant temperature differences, pointing to possible modelling imprecisions. It was also shown, that while the difference between midplane and surface temperatures mainly depend on thermal diffusivity, the time to reach solder alloy melting point on the surface depends on volumetric heat capacity.

Originality/value

Results validate the applicability of explicit heat transfer modelling of PCBs during reflow for different heat transfer methods. The results can be incorporated into more complex simulations and profile predicting algorithms for industrial ovens controlled in the wake of Industry 4.0 directives for better temperature control and ultimately higher soldering quality.
Quantitatively evaluating the effects of flash fire exposure on the mechanical performance of thermal protective clothing
Authors: Deng Meng , Tian Miao , Wang Yunyi , Wang Min
Published: January 2020

Purpose

The purpose of this paper is to determine the effect of flash fire exposure on the mechanical properties of single-layer thermal protective clothing.

Design/methodology/approach

The full-scale flame manikin tests were performed to simulate flash fire exposure. Two typical fire-resistant fabrics were investigated. The manikin was divided into seven body parts and the specimens meeting the requirements of tensile and tear strength standards were sampled. Fabric thickness, mass per unit area, tensile strength and tear strength were measured and analyzed.

Findings

The results revealed the significant influence of heat flux on both of tensile and tear strength. However, the regression analysis indicated the low R2 of the liner models. When the tensile and tear strength retention were reorganized based on the body parts, both of the multiple linear regression models for tensile and tear strength showed higher R2 than the one-variable linear regressions. Furthermore, the R2 of the multiple linear regression model for tear strength retention was remarkably higher than that of the tensile strength.

Practical implications

The findings suggested that greater attention should be paid to the local part of human body and more factors such as the air gap should be considered in the future thermal aging of firefighters’ clothing studies.

Originality/value

The outcomes provided useful information to evaluate the mechanical properties of thermal protective clothing and predict its service life.
Collectively innovating; modelling responsible exposure in heterarchical organisations
Authors: Schoellhammer Sarah , Gibb Stephen
Published: January 2020

Purpose

This paper aims to develop a model of collective innovation, with respect to innovation strategy, structure and culture in heterarchies. The enabling of collective innovation in heterarchies is conceptualised as “responsible exposure”.

Design/methodology/approach

A study adopting cross-case analysis was undertaken with five organisations perceived to have heterarchical characteristics. These included one small company, two medium-sized companies and two larger companies, all were European. Data from semi-structured interviews, a survey of staff and other sources provide evidence of collective innovation practices.

Findings

The cross-case analysis suggests that the management of collective innovation is different from “classic” innovation management. It is more about enabling “responsible exposure” than the management of “shelter” for collective innovation.

Research limitations/implications

The strength of cross-case analysis and conceptual framework validation is limited by the cases being all from the European region.

Practical implications

What strategy, structure and culture for “responsible exposure” may mean can be described. Heterarchies will always be relatively rare, though lessons from how they enable collective innovation can be more widely learned. Lessons for the wider population of organisation that combine hierarchical and heterarchical characteristics and seek greater innovation are identified.

Social implications

Collective innovation, which requires “responsible exposure” has implications for the capabilities of managers and professionals concerned with innovation.

Originality/value

The cross-case analysis of innovation in heterarchies is original, leading to the description of a model of “responsible exposure” for collective innovation.
Employee well-being of Finnish criminal investigators – mixed methods approach
Authors: Saari Tiina , Ellonen Noora , Vuorensyrjä Matti
Published: January 2020

Purpose

The purpose of this paper is to compare the employee well-being of police officers in different investigative groups. This paper analyses crime investigators’ employee well-being from four perspectives: organisational commitment, job satisfaction, exhaustion and turnover intentions.

Design/methodology/approach

The analysis is based on Finnish Police Personal Survey data (n=6,698), and qualitative and quantitative analysis methods are utilised.

Findings

Significant differences between investigative groups were found, and the police officers working in short-term investigations had the lowest level of well-being. The qualitative results revealed the employee- and organisational-level reasons behind these attitudes. One major issue is the lack of meaningfulness in work as the respondents describe their jobs as boring and monotonous and report that they do not have the appropriate resources to do their work as well as they wish.

Practical implications

To enhance the well-being of the investigators, police forces should improve the ways of leadership and invest more resources especially on short-term investigation to diminish the insecurity and ensure the quality and continuity of the work.

Originality/value

Research on the well-being of police officers has mostly focused on officers conducting surveillance or emergency operations, and there is very little knowledge of the well-being of crime investigators. This research adds to the limited knowledge on employee well-being of crime investigators.
Improving assessment capability for accounts receivable pool financiers
Authors: Song Xiao , Ying Hao , Zhao Xiande , Chen Lujie
Published: January 2020

Purpose

The accounts receivable pool (ARP) is an e-invoice management system that provides suppliers with easy access to financial service. The purpose of this paper is to focus on the strength and weakness of ARP mechanism and suggest efficient methods to identify creditworthy borrowers.

Design/methodology/approach

By decomposing the sales records of 348 ARP borrowers and predicting the occurrence of overdue incidences, this study first portrays the creditworthy borrowers by sales features. Then, content analysis was applied to measure the loadings of soft and hard information, and examined the effectiveness of different information structures in creditworthiness assessment.

Findings

For ARP borrowers, upward trend and low volatility reveal their creditworthiness. In order to identify creditworthy borrowers beforehand, ARP financiers who have elaborated more soft information and less hard information can perform better.

Originality/value

This study first discussed ARP finance from a critical perspective and underlines borrower assessment to eliminate the defect of loose recourse. The empirical evidence presents the sales features of creditworthy borrowers. Moreover, the results suggest an efficient approach for ARP financiers to conduct better assessment.