bluuebunny/crossref_metadata_2025 huggingface dataset:
From Value to Saliency: Neural Computations of Subjective Value under Uncertainty in PTSD
Authors: Jia Ruonan , Ruderman Lital , Gordon Charles , Ehrlich Daniel , Horvath Mark , Mirchandani Serena , DeFontes Clara , Southwick Steven , Krystal John H. , Harpaz-Rotem Ilan , Levy Ifat
Published: April 2020

Military personnel engaged in combat are vulnerable to Posttraumatic Stress Disorder (PTSD), following traumatic experiences in the battlefield. Prior research has mostly employed fear-related paradigms to unravel neural underpinnings of fear dysregulation in individuals with PTSD. The ability to acquire and update fear responses depends critically on the individual’s ability to cope with uncertainty, yet the role of individual uncertainty attitudes in the development of trauma-related psychopathology has hardly been examined. Here, we investigated the association between PTSD-related alterations and the subjective valuation of uncertain outcomes during decision-making. We used a monetary gambling paradigm inspired by behavioral economics in conjunction with fMRI and explored neural markers of both vulnerability and resilience to PTSD in a group of combat veterans. Behaviorally, PTSD symptom severity was associated with increased aversion to uncertainty. Neurally, activity in the ventromedial prefrontal cortex (vmPFC) during valuation of uncertain options was associated with PTSD symptoms, an effect which was specifically driven by numbing symptoms. Moreover, the neural encoding of the subjective value of those uncertain options was markedly different in the brains of veterans diagnosed with PTSD, compared to veterans who experienced trauma but did not develop PTSD. Most notably, veterans with PTSD exhibited enhanced representations of the saliency of rewards and punishments in the neural valuation system, especially in ventral striatum, compared with trauma-exposed controls. Our results point to a link between the function of the valuation system under uncertainty and the development and maintenance of PTSD symptoms, and stress the significance of studying reward processes in PTSD.
Interactive dynamics of matrix adhesion and reaction-diffusion predict diverse multiscale strategies of cancer cell invasion
Authors: Pramanik Durjay , Jolly Mohit Kumar , Bhat Ramray
Published: April 2020

The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane to their surrounding collagenous stroma. Invasion can be morphologically diverse, ranging from dispersed mesenchymal cells to multicellular collectives. When breast cancer cells are cultured within basement membrane-like matrix (BM), or Type 1 collagen, or a combination of both, they exhibit collective-, dispersed mesenchymal-, and hybrid collective-dispersed (multiscale) invasion, respectively. In this paper, we asked how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them. A rigorous computational exploration of invasion was performed within an experimentally motivated Cellular Potts-based modeling environment. The model comprises of adhesive interactions between cancer cells, BM- and collagen-like extracellular matrix (ECM), and reaction-diffusion-based remodeling of ECM. The model outputs were parameters cognate to dispersed- and collective- invasion. Input sweeps gave rise to a spatial output distribution that consisted of dispersed-, collective- and multiscale- invasion. K-means clustering of the output distribution followed by silhouette analysis revealed three optimal clusters: one signifying indolent invasion and two representing multiscale invasions, which we call collective-multiscale (CMI), and dispersed multiscale invasion (DMI), respectively. Constructing input-output mapped phenotypic spaces suggested that adhesion to BM- and collagen- matrix specify CMI and DMI respectively. Parameter perturbations confirmed these associations and revealed how the cellular phenotype may transition between the three states. Our systems-level analysis provides quantitative insights into how the diversity in matrix microenvironments may steer invasion into distinct phenotypic modes during metastasis.
A pharmacological interactome platform for discovery of pain mechanisms and targets
Authors: Wangzhou Andi , Paige Candler , Neerukonda Sanjay V , Dussor Gregory , Ray Pradipta R , Price Theodore J
Published: April 2020

Cells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naïve and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligand-receptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.
Genetic characterization ofStreptococcus pyogenes emm89 strains isolated in Japan from 2011 to 2019
Authors: Hirose Yujiro , Yamaguchi Masaya , Takemoto Norihiko , Miyoshi-Akiyama Tohru , Sumitomo Tomoko , Nakata Masanobu , Ikebe Tadayoshi , Hanada Tomoki , Yamaguchi Takahiro , Kawahara Ryuji , Okuno Rumi , Otsuka Hitoshi , Matsumoto Yuko , Terashima Yuji , Kazawa Yu , Nakanishi Noriko , Uchida Kaoru , Akiyama Yumi , Iwabuchi Kaori , Nakagawa Chikara , Yamamoto Kazunari , Kawabata Shigetada
Published: April 2020

Streptococcal toxic shock syndrome (STSS) caused byStreptococcus pyogenes emm89 strains has been increasing in several countries and reported to be linked with a recently emerged clade ofemm89 strains, designated clade 3. In Japan, epidemiological and genetic information foremm89 strains remains elusive. In this study, we utilizedemm89 strains isolated from both STSS (89 isolates) and non-STSS (72 isolates) infections in Japan from 2011 to 2019, and conducted whole-genome sequencing and comparative analysis, which resulted in classification of a large majority into clade 3 regardless of disease severity. In addition, STSS-associated genes and SNPs were found in clade 3 strains, including mutations of streptokinase (Ska), control of virulence sensor (CovS), serum opacity factor (SOF), sortase (SrtB), and fibronectin-binding protein F1 (PrtF1), and absence of thehylP1gene encoding hyaluronidase. These findings provide insights into notable genetic features ofemm89 strains.
Toxoplasma gondiico-opts the unfolded protein response to enhance migration and dissemination of infected host cells
Authors: Augusto Leonardo , Martynowicz Jennifer , Amin Parth H. , Alakhras Nada S. , Kaplan Mark H. , Wek Ronald C. , Sullivan William J.
Published: April 2020

Toxoplasma gondiiis an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence ofToxoplasmaparasitism is increased migratory activity of host cells, which facilitates dissemination. Here we show thatToxoplasmatriggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further found that host IRE1, an ER stress sensor protein activated duringToxoplasmainfection, also plays a noncanonical role in actin remodeling by binding filamin A in infected cells. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells,Toxoplasmaenhances host cell migrationin vitroand dissemination of the parasite to host organsin vivo. Our study identifies novel mechanisms used byToxoplasmato induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis.

Importance

Cells that are infected with the parasiteToxoplasma gondiiexhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this study, we identify a new mechanism used byToxoplasmato hijack its host cell and increase its mobility. We further show that the ability ofToxoplasmato increase host cell migration does not involve the enzymatic activity of IRE1, but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination ofToxoplasmain vivo. Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.
Peptide:MHC dependent activation of natural killer cells through KIR2DS2 generates anti-tumor responses
Authors: Rettman Pauline , Blunt Matthew D. , Mbiribindi Berenice , Fulton Rebecca , Schittenhelm Ralf B. , Pulido Andres Vallejo , Bastidas-Legarda Leidy , Polak Marta E. , Ayala Rochelle , Purcell Anthony W. , Al-Shamkhani Aymen , Retiere Christelle , Khakoo Salim I.
Published: April 2020

Natural killer (NK) cells are key components of the immune response to viral infections and cancer. Their functions are controlled by activating and inhibitory killer-cell immunoglobulin-like receptors (KIR) which have MHC class I ligands. KIR2DS2 is an activating KIR, that binds conserved viral peptides in the context of HLA-C and has been associated with protective responses to both cancer and viral infections. We sought to investigate whether NK cells can be specifically activated in a peptide:MHC dependent manner to generate functional immune responses as a potential immunotherapeutic strategy.

We developed a peptide-based KIR targeting DNA vaccine. Immunizing KIR-Tg mice with the vaccine construct generatedin vivopeptide-specific activation of KIR2DS2-positive NK cells leading to canonical and cross-reactive peptide specific immune responsesin vitro, and alsoin vivoinhibition of tumor growth. Using immunopeptidomics we identified that the nuclear export protein XPO1, which has been associated with a poor prognosis in many different human cancers, furnishes an HLA-C restricted cancer-associated peptide ligand for KIR2DS2-positive NK cells. We thus define a novel strategy to activate KIR in a peptide-specific manner and identify a rationale for its use in cancer immunotherapy.

Significance statement

Natural killer (NK) cells are known to have important roles in determining the outcomes of viral infections and cancer. The killer cell immunoglobulin-like receptors (KIR), and in particular the activating receptor KIR2DS2, have been associated with the outcome of a number of different human cancers. Specific activation of NK cells through KIR2DS2 is challenging because it shares high (>98%) sequence homology with related inhibitory KIR. We have used a peptide:MHC targeting strategy to activate NK cells through KIR2DS2 and identified a novel cancer-associated ligand for this receptor. The work provides a proof-of-concept for targeting NK cells through activating KIR as a cancer immunotherapy strategy.
Autotransporters drive biofilm formation and auto-aggregation in the diderm FirmicuteVeillonella parvula
Authors: Béchon Nathalie , Jiménez-Fernández Alicia , Witwinowski Jerzy , Bierque Emilie , Taib Najwa , Cokelaer Thomas , Ma Laurence , Ghigo Jean-Marc , Gribaldo Simonetta , Beloin Christophe
Published: April 2020

The Negativicutes are a clade of Firmicutes that have retained the ancestral diderm character and possess an outer membrane. One of the best studied Negativicute,Veillonella parvula, is an anaerobic commensal and opportunistic pathogen inhabiting complex human microbial communities, including the gut and the dental plaque microbiota. Whereas adhesion and biofilm capacity ofV. parvulais expected to be crucial for its maintenance and development in these environments, studies ofV. parvulaadhesion have been hindered by the lack of efficient genetic tools to perform functional analyses in this bacterium. Here, we took advantage of a recently described naturally transformableV. parvulaisolate, SKV38, and adapted tools developed for the closely relatedClostridia spp. to perform random transposon and targeted mutagenesis to identifyV. parvulagenes involved in biofilm formation. We show that type V secreted autotransporters -typically found in diderm bacteria-are the main determinants ofV. parvulaauto-aggregation and biofilm formation, which compete with each other for binding either to cells or to surfaces, with strong consequences onV. parvulabiofilm formation capacity. We also show that inactivation of the gene coding for a poorly characterized metal-dependent phosphohydrolase HD domain protein conserved in the Firmicutes and their closely related diderm phyla inhibits autotransporter-mediated biofilm formation. This study paves the way for further molecular characterization ofV. parvulainteractions with other bacteria and the host within complex microbiota environments.
Immunity-and-Matrix-Regulatory Cells Derived from Human Embryonic Stem Cells Safely and Effectively Treat Mouse Lung Injury and Fibrosis
Authors: Wu Jun , Song Dingyun , Li Zhongwen , Guo Baojie , Xiao Yani , Liu Wenjing , Liang Lingmin , Feng Chunjing , Gao Tingting , Chen Yanxia , Li Ying , Wang Zai , Wen Jianyan , Yang Shengnan , Liu Peipei , Wang Lei , Wang Yukai , Peng Liang , Stacey Glyn Nigel , Hu Zheng , Feng Guihai , Li Wei , Huo Yan , Jin Ronghua , Shyh-Chang Ng , Zhou Qi , Wang Liu , Hu Baoyang , Dai Huaping , Hao Jie
Published: April 2020

Lung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice (GMP) requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from umbilical cord mesenchymal stem cells (UCMSCs), such as higher levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and FDA-approved pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), our findings suggest that IMRCs are ready for clinical trials on lung disorders.
Lateral gene transfer of anion-conducting channelrhodopsins between green algae and giant viruses
Authors: Rozenberg Andrey , Oppermann Johannes , Wietek Jonas , Fernandez Lahore Rodrigo Gaston , Sandaa Ruth-Anne , Bratbak Gunnar , Hegemann Peter , Béjà Oded
Published: April 2020

Channelrhodopsins (ChRs) are algal light-gated ion channels widely used as optogenetic tools for manipulating neuronal activity1,2. Four ChR families are currently known. Green algal3–5and cryptophyte6cation-conducting ChRs (CCRs), cryptophyte anion-conducting ChRs (ACRs)7, and the MerMAID ChRs8. Here we report the discovery of a new family of phylogenetically distinct ChRs encoded by marine giant viruses and acquired from their unicellular green algal prasinophyte hosts. These previously unknown viral and green algal ChRs act as ACRs when expressed in cultured neuroblastoma-derived cells and are likely involved in behavioral responses to light.
The deubiquitylase USP9X controls ribosomal stalling
Authors: Clancy Anne , Heride Claire , Pinto-Fernández Adán , Kallinos Andreas , Kayser-Bricker Katherine J. , Wang Weiping , Smith Victoria , Elcocks Hannah , Davis Simon , Fessler Shawn , McKinnon Crystal , Katz Marie , Hammonds Tim , Jones Neil P. , O’Connell Jonathan , Follows Bruce , Mischke Steven , Caravella Justin A. , Ioannidis Stephanos , Dinsmore Christopher , Kim Sunkyu , Behrens Axel , Komander David , Kessler Benedikt M. , Urbé Sylvie , Clague Michael J.
Published: April 2020

When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin and ZNF598 ubiquitin E3 ligases respectively, through ubiquitylation of the eS10 and uS10 sub-units of the ribosome. It is common for the stability of RING E3 ligases to be regulated by an interacting deubiquitylase (DUB), which often opposes auto-ubiquitylation of the E3. Here, we show that the DUB USP9X directly interacts with ZNF598 and regulates its abundance through the control of protein stability in human cells. We have developed a highly specific small molecule inhibitor of USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome associated protein stability and reveals loss of ZNF598 and Makorin 2. In the absence of USP9X or following chemical inhibition of its catalytic activity, steady state levels of Makorins and ZNF598 are diminished and the ribosomal quality control pathway is impaired.
Structure of the lysosomal SCARF (L-SCARF) complex, an Arf GAP haploinsufficient in ALS and FTD
Authors: Su Ming-Yuan , Zoncu Roberto , Hurley James H.
Published: April 2020

Mutation ofC9ORF72is the most prevalent defect in amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD). Together with hexanucleotide repeat expansion, haploinsufficiency ofC9ORF72contributes to neuronal dysfunction. We determined the structure of the SMCR8-C9orf72-WDR41 complex by cryo-EM. C9orf72 and SMCR8 are both longin-DENN domain proteins, while WDR41 is a beta-propeller protein that binds to SMCR8 such that the whole structure resembles an eye slip hook. Contacts between WDR41 and SMCR8DENNdrive lysosomal localization in amino acid starvation. The structure suggested that SMCR8-C9orf72 was a small GTPase activating protein (GAP). We found that SMCR8-C9orf72-WDR41 is a GAP for Arf family small GTPases, and refer to it as the Lysosomal SMCR8-C9orf72 Arf GAP (“L-SCARF”) complex. These data rationalize the function of C9orf72 both in normal physiology and in ALS/FTD.
The Use of Dipeptide Supplementation as a Means of Mitigating the Negative Effects of Dietary Soybean Meal on Zebrafish Danio rerio
Authors: Molinari Giovanni S. , Wojno Michal , McCracken Vance J. , Kwasek Karolina
Published: April 2020

Soybean meal (SBM) is the most common source of protein used to replace fishmeal (FM) in aquaculture diets. SBM inclusion in diets has been found to negatively affect growth and induce intestinal inflammation in fish. The objective of this study was to determine the effect of health-promoting dipeptide (carnosine, anserine, alanyl-glutamine) supplementation into SBM-based feeds on growth performance, intestinal health, and muscle free amino acid composition, an indicator of dietary amino acid availability, in a zebrafish model. There were 5 treatment groups in this study. The first group ( (+) Control ) received a FM-based diet. The second group ( (-) Control ) received SBM-based diet. The last three groups ( Ala-Glu, Car, and Ans) were fed SBM-based diets, supplemented with alanyl-glutamine, carnosine, and anserine respectively. All groups received their respective diets during 33-59 dph. The Ala-Glu and Car groups experienced a significantly higher weight gain than the (-) Control group, weighing 35.38% and 33.96% more, respectively at the conclusion of the study. There were no significant differences among gene expression between the groups, but Ala-Glu had the highest expression of both nutrient absorption genes measured, PepT1 and fabp2 . Ala-Glu had significantly longer intestinal villi, and a significantly higher villus length-to-width ratio than the (-) Control group. Among the free amino acid composition, the Car group had a significantly higher post-prandial concentration of lysine, compared to the (-) Control group. The increase in villi surface area and expression of nutrient absorption genes represent an improvement in intestinal absorptive capacity in the Ala-Glu group. The increase in lysine concentration may signify an increase in the retention of protein in the fish in the Car group. The results from this study provide support for the use of alanyl-glutamine and carnosine supplementation as a means of improving growth performance of zebrafish fed with a 100% SBM-based diet.
Full three-dimensional imaging deep through multicellular thick samples with subcellular resolution by structured illumination microscopy and adaptive optics
Authors: Lin Ruizhe , Kipreos Edward T. , Zhu Jie , Khang Chang Hyun , Kner Peter
Published: April 2020

Structured Illumination Microscopy enables live imaging with resolutions of ~120 nm. Unfortunately, optical aberrations can lead to loss of resolution and artifacts in Structured Illumination Microscopy rendering the technique unusable in samples thicker than a single cell. Here we report on the combination of Adaptive Optics and Structured Illumination Microscopy enabling imaging with 140 nm lateral and 585 nm axial resolution in tissue culture cells, C. elegans, and rice blast fungus. We demonstrate that AO improves resolution and reduces artifacts, making full 3D SIM possible in thicker samples.
RubyACRs, non-algal anion channelrhodopsins with highly red-shifted absorption
Authors: Govorunova Elena G. , Sineshchekov Oleg A. , Li Hai , Wang Yumei , Brown Leonid S. , Spudich John L.
Published: April 2020

Channelrhodopsins are light-gated ion channels widely used to control neuronal firing with light (optogenetics). We report two previously unknown families of anion channelrhodopsins (ACRs), one from the heterotrophic protists labyrinthulomycetes and the other from haptophyte algae. Four closely related labyrinthulomycete ACRs, named RubyACRs here, exhibit a unique retinal binding pocket that creates spectral sensitivities with maxima at 590-610 nm, the most red-shifted channelrhodopsins known, long-sought for optogenetics, and more broadly the most red-shifted microbial rhodopsins so far reported. We identified three spectral tuning residues critical for the red-shifted absorption. Photocurrents recorded from the RubyACR fromAurantiochytrium limacinum(designatedAlACR1) under single-turnover excitation exhibited biphasic decay, the rate of which was only weakly voltage-dependent, in contrast to that in previously characterized cryptophyte ACRs, indicating differences in channel gating mechanisms between the two ACR families. Moreover, inA. limacinumwe identified three ACRs with absorption maxima at 485, 545, and 590 nm, indicating color-sensitive photosensing with blue, green and red spectral variation of ACRs within individual species of the labyrinthulomycete family. We also report energy transfer from a cytoplasmic fluorescent protein domain to the retinal chromophore bound within RubyACRs, not seen in similar constructs in other channelrhodopsins.

Significance Statement

Our identification and characterization of two ACR families, one from non-photosynthetic microorganisms, shows that light-gated anion conductance is more widely spread among eukaryotic lineages than previously thought. The uniquely far red-shifted absorption spectra of the subset we designate RubyACRs provide the long-sought inhibitory optogenetic tools producing large passive currents activated by long-wavelength light, enabling deep tissue penetration. Previously only low-efficiency ion-pumping rhodopsins were available for neural inhibition by the orange-red region of the spectrum. The unusual amino acid composition of the retinal-binding pocket in RubyACRs expands our understanding of color tuning in retinylidene proteins. Finally, energy transfer from the fluorescent protein used as a tag on RubyACRs opens a potential new dimension in molecular engineering of optogenetic tools.
Endothelial basement membrane laminins as an environmental cue in monocyte differentiation to macrophages
Authors: Li Lixia , Song Jian , Chuquisana Omar , Hannocks Melanie-Jane , Loismann Sophie , Vogl Thomas , Roth Johannes , Hallmann Rupert , Sorokin Lydia
Published: April 2020

Monocyte differentiation to macrophages is triggered by migration across the endothelial barrier, which is constituted by both endothelial cells and their underlying basement membrane. We address here the role of the endothelial basement membrane laminins (laminins 411 and 511) in this monocyte to macrophage switch. Chimeric mice carrying CX3CR1-GFP bone marrow were employed to track CCL2-induced monocyte extravasation in a cremaster muscle model using intravital microscopy, revealing faster extravasation in mice lacking endothelial laminin 511 (Tek-cre::Lama5-/-) and slower extravasation in mice lacking laminin 411 (Lama4-/-). CX3CR1-GFPlowextravasating monocytes were found to have a higher motility at laminin 511 low sites and to preferentially exist vessels at these sites. However,in vitroexperiments reveal that this is not due to effects of laminin 511 on monocyte migration mode nor on the tightness of the endothelial barrier. Rather, using an intestinal macrophage replenishment model andin vitrodifferentiation studies we demonstrate that laminin 511 together with the attached endothelium collectively promote monocyte differentiation to macrophages. Macrophage differentiation is associated with a change in integrin profile, permitting differentiating macrophages to distinguish between laminin 511 high and low areas and to migrate preferentially across laminin 511 low sites. These studies highlight the endothelial basement membrane as a critical site for monocyte differentiation to macrophages, which may be relevant to the differentiation of other cells at vascular niches.
Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice
Authors: Muniappan Latha , Okuyama Michihiro , Javidan Aida , Thiagarajan Devi , Jiang Weihua , Moorleghen Jessica J. , Yang Lihua , Balakrishnan Anju , Howatt Deborah A. , Uchida Haruhito A. , Saido Takaomi C. , Subramanian Venkateswaran
Published: April 2020

BACKGROUND

Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix (ECM) with contractile filaments. During AAA development, (i) aortic medial degeneration is associated with loss of smooth muscle cell (SMC) integrity, and (ii) fibrogenic mesenchymal cells (FMSCs) mediates ECM remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Angiotensin II (AngII)-induced AAAs in low density receptor deficient (LDLR-/-) mice.

OBJECTIVES

To evaluate the functional contribution of FMSCs-derived calpain-2 on (i) cytoskeletal structural protein and ECM alterations, and (ii) AAA progression.

METHODS

Calpain-2 protein, and cytoskeletal protein (e.g. filamin or talin) fragmentation in human and mice AAA tissues were assessed by immunohistochemical and western blot analyses. LDLR-/- mice that were either inducible-whole body or FMSC-specific calpain-2 deficient were fed a fat-enriched diet and infused with AngII for 4 weeks. The association of cytoskeletal protein to ECM was evaluated using aortic SMCs, in vitro. In addition, the effect of calpain-2 deficiency on the stability of established AAA was examined.

RESULTS

Calpain-2 protein, and filamin/talin fragmentation are significantly elevated in AAAs. Ubiquitous or FMSC-specific depletion of calpain-2 suppressed AngII-induced AAAs, filamin/talin fragmentation and promoted ECM protein, collagen. Calpain-2 silencing in SMCs reduced AngII-induced filamin/talin fragmentation. In addition, silencing of filamin or talin in SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed established AAA rupture.

CONCLUSION

Calpain-2 activation promotes cytoskeletal structural protein fragmentation and ECM degradation of experimental AAA aortas. Treatment with calpain-2 specific inhibitor may facilitate the clinical management of AAA.
Gap Junctions Amplify Spatial Variations in Cell Volume in Proliferating Solid Tumors
Authors: McEvoy Eoin , Han Yulong , Guo Ming , Shenoy Vivek B.
Published: April 2020

Cancer progression is driven by cell proliferation, apoptosis, and matrix invasion, which in turn depend on a myriad of factors including microenvironment stiffness, nutrient supply, and intercellular communication. Cell proliferation is regulated by volume, but in 3D clusters it remains unclear how multiple cells interact to control their size. In this study, we propose a mechano-osmotic model to investigate the evolution of volume dynamics within multicellular systems. Volume control depends on an interplay between multiple cellular constituents, including gap junctions, mechanosensitive ion channels, energy consuming ion transporters, and the actomyosin cortex, that coordinate to manipulate cellular osmolarity. In connected cells, mechanical loading is shown to significantly affect how these components cooperate to transport ions, and precise volume control is impacted by the emergence of osmotic pressure gradients between cells. Consequent increases in cellular ion concentrations drive swelling, while a loss of ions impedes the compression resistance of cells. Combining the modeling framework with novel experiments, we identify how gap junctions can amplify spatial variations in cell volume within multicellular spheroids and, further, describe how the process depends on proliferation-induced solid stress. Our model provides new insight into the role of gap junctions in cancer progression and can help guide the development of therapeutics that target inter- and extra-cellular ion transport.
Combinatorial patterns of graded RhoA activation and uniform F-actin depletion promote tissue curvature
Authors: Denk-Lobnig Marlis , Heer Natalie C , Martin Adam C
Published: April 2020

During development, gene expression regulates cell mechanics and shape to sculpt tissues. Epithelial folding proceeds through distinct cell shape changes that occur in different regions of a tissue. Here, using quantitative imaging inDrosophila melanogaster, we investigate how patterned cell shape changes promote tissue bending during early embryogenesis. We find that the transcription factors Twist and Snail combinatorially regulate a unique multicellular pattern of junctional F-actin density, which corresponds to whether cells apically constrict, stretch, or maintain their shape. Part of this pattern is a gradient in junctional F-actin and apical myosin-2, and the width of this gradient regulates tissue curvature. The actomyosin gradient results from a gradient in RhoA activation that is refined by a balance between RhoGEF2 and the RhoGAP C-GAP. Thus, cell behavior in the ventral furrow is choreographed by the interplay of distinct gene expression patterns and this coordination regulates tissue shape.
Testing of a `hard' X-ray interferometer for experimental investigations
Authors: Eyramjyan Tigran H. , Mesropyan Mesrop H. , Mnatsakanyan Tamara S. , Balyan Minas K.
Published: April 2020

A `hard' X-ray LLL interferometer is tested for experimental investigations. The interferometer has both a base and a `ceiling', which are rigidly connected through columns. As a result, the interferometer does not have uncontrollable preliminary moiré. The intensity distribution is uniform in the interfering beams. It is shown that the interferometer is very sensitive to minor mechanical stresses. As a result, the interferometer must be freely placed on the goniometer head. Constant-thickness fringes are obtained using a wedge with a vertically placed apex. The volumes available for specimen placement are limited due to the existence of the ceiling. These difficulties can be overcome. The hard interferometer can be used for object and deformation investigations.
Modeling of high-side active clamp forward converter with resistive parasitics
Authors: Maturi Krishnaja , Samanta Susovon
Published: April 2020

Purpose

The purpose of this paper is to derive the small-signal/canonical model derivation of the high-side active clamp forward converter (ACFC) with diode rectification for ideal and with resistive parasitics. It also covers the analysis of ACFC small-signal model with resistive parasitics using computer-aided modeling software Personal Computer Simulation Program with Integrated Circuit Emphasis (PSPICE) 16.6. The effects of variation of system parameters on the ACFC’s state transfer functions and operations have been highlighted in this paper.

Design/methodology/approach

The large-signal model and small-signal model of the ACFC with diode rectification has been derived using AC small-signal modeling approach.

Findings

The operating point of the converter changes with the consideration of resistive parasitics compared with the ideal case. The response obtained from the hardware matches with the time domain response of the averaged model and switch model developed in PSPICE.

Research limitations/implications

This paper limits the study of ACFC small-signal behavior by using computer-aided design software PSPICE. The dead time of the converter is not considered because it is negligible when compared with the on and off time. The leakage inductance which plays a role in zero voltage switching of the ACFC switches is neglected in the analysis as it is very small compared to the magnetizing inductance. The switching losses are not considered in the modeling.

Practical implications

The mathematical computation of deriving the system transfer functions from canonical model is complex and time consuming.

Originality/value

The modeling with resistive parasitics improves the effectiveness of the equivalent model. Also, the analysis with computer-aided modeling software PSPICE gives reliable results in less time.
Design of efficient graphene plasmonic coupling circuits for THz applications
Authors: Amanatiadis Stamatis A. , Zygiridis Theodoros , Kantartzis Nikolaos V.
Published: April 2020

Purpose

The coupling characteristics between adjacent circuits are crucial for their efficient design in terms of electromagnetic compatibility features. Specifically, either the wireless power transfer can be enhanced or the interference can be limited. This paper aims to the extraction of the coupling characteristics of surface plasmon polariton waves propagating onto graphene layers to facilitate the telecommunication system design for advanced THz applications.

Design/methodology/approach

The surface conductivity of graphene is described at the far-infrared spectrum and modelled accurately by means of a properly modified finite-difference time-domain) scheme. Then, a series of numerical simulations for different coupling setups is conducted to extract an accurate generalised parametric coupling model that is dependent explicitly on the fundamental propagation features of graphene.

Findings

The coupling coefficients of two basic waveguiding setups are examined thoroughly. The initial one includes two parallel graphene layers of infinite dimensions, and it is observed that the coupling is influenced via the ratio between their distances to the confinement of the surface wave. The second scenario is composed of graphene microstrips that are parallel to their small edge, namely, microstrip width. The extracted numerical results indicate that the coupling coefficient depends on the ratio between widths to wavelength.

Originality/value

The accurate extraction of the generalised coupling coefficients for graphene surface wave circuits is conducted in this work via an adjustable numerical technique for a novel family of plasmonic couplers. It is derived that only the fundamental propagation features of graphene, such as the wavelength and the confinement of the surface waves, have an effect on the coupling calculation, thus enabling a consistent electromagnetic compatibility study.
A novel forecast model based on CF-PSO-SVM approach for predicting the roll gap in acceleration and deceleration process
Authors: Hu Yunjian , Sun Jie , Peng Wen , Zhang Dianhua
Published: April 2020

Purpose

In the cold rolling process, friction coefficient, oil film thickness and other factors vary dramatically with the change in the rolling speed, which seriously affects the strip thickness deviation. This paper aims to improve the strip control precision with the forecast roll gap model based on CF-PSO-SVM approach in the rolling process.

Design/methodology/approach

In this paper, a novel forecasting model of the roll gap based on support vector machine (SVM) optimized by particle swarm optimization with compression factor (CF-PSO) is proposed. Based on lots of online data, the roll gap models regressed by PSO-SVM, genetic algorithm (GA)-SVM and CF-PSO-SVM are obtained and verified through evaluating the performances with the decision coefficient (R2), mean absolute error and root mean square error. In addition, with the good forecasting performances of CF-PSO-SVM, a roll gap compensation model is studied.

Findings

The results indicate that the proposed CF-PSO-SVM has excellent learning regression ability compared with other optimization algorithms. Meanwhile, a roll gap compensation model based on the rolling speed and plastic coefficient is obtained, which has been proved validated in product.

Originality/value

In this paper, the SVM algorithm is combined with traditional rolling technology to solve the problems in actual production, which has great supporting significance for the improvement of production efficiency.
Parametric optimization of USM parameters by Taguchi and NSGA-II for the development of µ-channels on pure titanium
Authors: Gupta Rahul Dev , Gupta Pardeep , Khanna Rajesh
Published: April 2020

Purpose

This paper consolidates and presents the results of a work conducted to fabricate micro-channels on titanium grade-2 material by ultrasonic machining process (USM). In this research, the effects of important USM parameters, namely, kind of abrasives and its size, concentration of slurry, USM power rating and feed rate, have been probed on micro-channels quality for average surface roughness and process throughput in the form of material removal rate.

Design/methodology/approach

Multiple micro-channels on commercially pure titanium (i.e. Ti grade-2) have been fabricated in a single pass by employing micro-tool based USM process. Taguchi-based L18 (mixed level) OA has been selected for experimental design. Analysis of variance (ANOVA) study and regression modeling have also been done. Non-Dominated Sorting Genetic Algorithm (NSGA-II) has been used for process optimization to get optimum values of material removal rate (MRR) and surface roughness (SR).

Findings

The influence of important USM variables on SR and MRR have been investigated, and NSGA-II-based multi-response optimization has been done. The best surface roughness values obtained via NSGA-II solution for SiC and B4C are 0.354 µm and 1.303 µm, respectively. Scanned electron microscopic investigation proves the fabrication of micro-channels with smooth surfaces, and minimum burrs and other defects. The material removed from the surface was due to ductile fractures.

Originality/value

Miniaturization is a modern trend these days to solve many precision, scientific and industrial problems. To manufacture precise micro-products, shapes and features, advanced and micro-machining processes can play a very prominent role. Micro-channels are typical micro-features required in micro-fluidic applications like micro heat exchangers and micro-pumps. Exhaustive review of existing research work indicated that precision micromachining of various materials can be effectively performed using USM, though not much work has been undertaken to explore the feasibility of multiple micro-channels in a single run using USM. The current work fulfills the gap, where multiple micro-channels on commercially pure titanium (i.e. Ti grade-2) have been fabricated in a single pass by employing micro-tool-based USM process.
Industry drivers of multinational companies’ externalization choice: a conceptual framework and application to Korea–China film co-productions
Authors: Moon Hwy-Chang , Yin Wenyan
Published: April 2020

Purpose

This conceptual paper aims to explore under what conditions multinational companies (MNCs) are more likely to internationalize through externalization modes.

Design/methodology/approach

This paper complements previous studies by proposing three industry-specific factors that affect MNCs’ decision for externalization. It then applies this framework to the case of Korean MNCs’ strategic choice when entering the Chinese film market which is highly regulated by the government, to illustrate how such a framework works in practice.

Findings

This paper suggests that MNCs are more likely to choose externalization entry modes under the three industry conditions: when the business grows fast, when there are best practices of industry standard and when the business requires multi-competence. It also shows that the three conditions explain well the growing Korea–China co-productions in the Chinese film market.

Practical implications

This paper provides useful implications for the government’s regulatory effectiveness. The protectionist policies of the host government are valid only in an industry where the three conditions are met, as they increase the possibility of domestic firms’ participation by encouraging foreign MNCs to shift their entry mode from sole venture toward alliances with domestic firms.

Originality/value

This paper enriches the entry-mode research by indicating that MNCs’ externalization decisions need to consider these industry-specific factors. In addition, it also contributes to the understanding on why some countries maintain their high attractiveness for foreign MNCs, whereas other countries do not, given the similar level of restrictive government regulations.
When and why organizational cynicism leads to CWBs
Authors: Naseer Saima , Raja Usman , Syed Fauzia , Baig Muhammad Usman Anwar
Published: April 2020

Purpose

Using conservation of resources theory (COR), the authors test the combined effects of cynicism and psychological capital on counterproductive work behaviors (CWBs) mediated through emotional exhaustion.

Design/methodology/approach

The authors use a time-lagged independent source sample (N = 181) consisting of employee–peer dyads from service industry in Pakistan.

Findings

Moderated mediated regression analyses indicated that emotional exhaustion mediates the relationship between organizational cynicism and counterproductive work behaviors. Psychological capital moderates the relationship between organizational cynicism and emotional exhaustion such that organizational cynicism is positively related to exhaustion when psychological capital is low. Furthermore, conditional indirect effects show that emotional exhaustion mediates the relationship between organizational cynicism and counterproductive work behaviors only when employees' psychological capital is low.

Originality/value

The study suggests new mechanisms and boundary conditions through which cynicism triggers CWBs. The authors discuss the implications of the study’s findings and suggest possible directions for future research.
Landscape epidemiology of ash dieback
Authors: Grosdidier Marie , Scordia Thomas , Ioos Renaud , Marçais Benoit
Published: April 2020

Ash dieback is induced by Hymenoscyphus fraxineus, an invasive pathogenic fungus. It is causing severe damage to European ash populations. However, the local environment, such as climate or site conditions, is known to affect ash dieback.

We studied the landscape epidemiology of the disease on a 22 km2 area in north‐eastern France at two stages of the invasion process using Bayesian spatio‐temporal models fitted with integrated nested Laplace approximation (INLA). Several features characterizing disease severity, crown dieback, frequency of collar canker and density of infected leaf debris in the litter were determined on a regular grid over a 3.5 × 6.5 km area. We first analysed the effect of landscape features on the disease establishment stage in 2012, 2 years after the first report of the disease in the area, and then on further disease development, in 2016–2018.

Landscape features had little impact on the disease at the establishment stage, but strongly determined its further development. Local fragmentation of tree cover was the most important factor, with trees that are isolated or in hedges far less affected than trees in a forest environment. We showed that they were subjected to different microclimates, with higher crown temperatures unfavourable to pathogen development. Low host density strongly reduced disease development. The presence of large ash populations in the vicinity affected local disease severity up to several hundred metres.

Synthesis. We showed that the landscape characteristics strongly affect the development and spread of ash dieback. The disease is far less severe in forest conditions when ash density is low or in open canopies such as hedges and isolated trees. Ash trees are often in these types of landscapes, which should strongly limit the overall impact of ash dieback.