bluuebunny/crossref_metadata_2025 huggingface dataset:
Inactivating p53 is essential for nerve growth factor receptor to promote melanoma-initiating cell-stemmed tumorigenesis
Authors: Jiang Leiwei , Huang Shibo , Wang Jieqiong , Zhang Yiwei , Xiong Yuqing , Zeng Shelya X. , Lu Hua
Published: July 2020

Nerve growth factor receptor (NGFR, CD271, or p75NTR) is highly expressed in melanoma-initiating cells (MICs) and is critical for their proliferation and tumorigenesis, and yet the underlying mechanism(s) remain incompletely understood. We previously showed that NGFR inhibits p53 activity in a negative feedback manner in various cancer cells. Here we report that this feedback inhibition of p53 by NGFR plays an essential role in maintaining the sphere formation (stem-like phenotype) and proliferation of MICs, and in promoting MIC-derived melanoma growth in vivo. Knockdown of NGFR markedly reduced the size and number of spheroid formation of melanoma cells, which can be rescued by ectopically expressed NGFR. This reduction was also reversed by depleting p53. Consistently, knockdown of NGFR led to the suppression of MIC-derived xenograft tumor growth by inducing the p53 pathway. These results demonstrate that the NGFR-p53 feedback loop is essential for maintaining MIC stem-like phenotype and MIC-derived tumorigenesis, and further validates NGFR as a potential target for developing a molecule-based therapy against melanoma.
Preserving nanoscale features in polymers during laser induced graphene formation using sequential infiltration synthesis
Authors: Bergsman David S. , Getachew Bezawit A. , Cooper Christopher B. , Grossman Jeffrey C.
Published: July 2020

Direct lasing of polymeric membranes to form laser induced graphene (LIG) offers a scalable and potentially cheaper alternative for the fabrication of electrically conductive membranes. However, the high temperatures induced during lasing can deform the substrate polymer, altering existing micro- and nanosized features that are crucial for a membrane’s performance. Here, we demonstrate how sequential infiltration synthesis (SIS) of alumina, a simple solvent-free process, stabilizes polyethersulfone (PES) membranes against deformation above the polymers’ glass transition temperature, enabling the formation of LIG without any changes to the membrane’s underlying pore structure. These membranes are shown to have comparable sheet resistance to carbon-nanotube-composite membranes. They are electrochemically stable and maintain their permeability after lasing, demonstrating their competitive performance as electrically conductive membranes. These results demonstrate the immense versatility of SIS for modifying materials when combined with laser induced graphitization for a variety of applications.
Imaging spatiotemporal evolution of molecules and active sites in zeolite catalyst during methanol-to-olefins reaction
Authors: Gao Mingbin , Li Hua , Liu Wenjuan , Xu Zhaochao , Peng Shichao , Yang Miao , Ye Mao , Liu Zhongmin
Published: July 2020

Direct visualization of spatiotemporal evolution of molecules and active sites during chemical transformation in individual catalyst crystal will accelerate the intuitive understanding of heterogeneous catalysis. So far, widespread imaging techniques can only provide limited information either with large probe molecules or in model catalyst of large size, which are beyond the interests of industrial catalysis. Herein, we demonstrate a feasible deep data approach via synergy of multiscale reaction-diffusion simulation and super-resolution structured illumination microscopy to  illustrate the dynamical evolution of spatiotemporal distributions of gas molecules, carbonaceous species and acid sites in SAPO-34 zeolite crystals of several micrometers that are typically used in industrial methanol-to-olefins process. The profound insights into the inadequate utilization of activated acid sites and rapid deactivation are unveiled. The notable elucidation of molecular reaction-diffusion process  at the scale of single catalyst crystal via this approach opens an interesting method for mechanism study in materials synthesis and catalysis.
Light-triggered switching of liposome surface charge directs delivery of membrane impermeable payloads in vivo
Authors: Arias-Alpizar Gabriela , Kong Li , Vlieg Redmar C. , Rabe Alexander , Papadopoulou Panagiota , Meijer Michael S. , Bonnet Sylvestre , Vogel Stefan , van Noort John , Kros Alexander , Campbell Frederick
Published: July 2020

Surface charge plays a fundamental role in determining the fate of a nanoparticle, and any encapsulated contents, in vivo. Herein, we describe, and visualise in real time, light-triggered switching of liposome surface charge, from neutral to cationic, in situ and in vivo (embryonic zebrafish). Prior to light activation, intravenously administered liposomes, composed of just two lipid reagents, freely circulate and successfully evade innate immune cells present in the fish. Upon in situ irradiation and surface charge switching, however, liposomes rapidly adsorb to, and are taken up by, endothelial cells and/or are phagocytosed by blood resident macrophages. Coupling complete external control of nanoparticle targeting together with the intracellular delivery of encapsulated (and membrane impermeable) cargos, these compositionally simple liposomes are proof that advanced nanoparticle function in vivo does not require increased design complexity but rather a thorough understanding of the fundamental nano-bio interactions involved.
Inhibition of transition metals dissolution in cobalt-free cathode with ultrathin robust interphase in concentrated electrolyte
Authors: Liu Wei , Li Jinxing , Li Wenting , Xu Hanying , Zhang Chao , Qiu Xinping
Published: July 2020

The low Coulombic efficiency during cycling hinders the application of Cobalt-free lithium-rich materials in lithium-ion batteries. Here we demonstrated that the dissolution of iron, rather than traditionally acknowledged manganese, is mainly responsible for the low Coulombic efficiency of the iron-substituted cobalt-free lithium-rich material. Besides, we presented an approach to inhibit the dissolution of transition metal ions by using concentrated electrolytes. We found that the cathode electrolyte interphase (CEI) layer formed in the concentrated electrolyte is a uniform and robust LiF-rich CEI, which is a sharp contrast with the uneven and fragile organic-rich CEI formed in the dilute electrolyte. The LiF-rich CEI not only effectively inhibits the dissolution of TMs but also stabilizes the cathode structure. The Coulombic efficiency, cycling stability, rate performance, and safety of the Fe-substituted cobalt-free lithium-rich cathode material in the concentrated electrolyte have been improved tremendously.
Basement membrane damage by ROS- and JNK-mediated Mmp2 activation drives macrophage recruitment to overgrown tissue
Authors: Diwanji Neha , Bergmann Andreas
Published: July 2020

Macrophages are a major immune cell type infiltrating tumors and promoting tumor growth and metastasis. To elucidate the mechanism of macrophage recruitment, we utilize an overgrowth tumor model (“undead” model) in larval Drosophila imaginal discs that are attached by numerous macrophages. Here we report that changes to the microenvironment of the overgrown tissue are important for recruiting macrophages. First, we describe a correlation between generation of reactive oxygen species (ROS) and damage of the basement membrane (BM) in all neoplastic, but not hyperplastic, models examined. ROS and the stress kinase JNK mediate the accumulation of matrix metalloproteinase 2 (Mmp2), damaging the BM, which recruits macrophages to the tissue. We propose a model where macrophage recruitment to and activation at overgrowing tissue is a multi-step process requiring ROS- and JNK-mediated Mmp2 upregulation and BM damage. These findings have implications for understanding the role of the tumor microenvironment for macrophage activation.
PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria
Authors: Elbaz-Alon Yael , Guo Yuting , Segev Nadav , Harel Michal , Quinnell Daniel E. , Geiger Tamar , Avinoam Ori , Li Dong , Nunnari Jodi
Published: July 2020

Endosomes are compositionally dynamic organelles that regulate signaling, nutrient status and organelle quality by specifying whether material entering the cells will be shuttled back to the cell surface or degraded by the lysosome. Recently, membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endosomes have emerged as important players in endosomal protein sorting, dynamics and motility. Here, we show that PDZD8, a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain-containing ER transmembrane protein, utilizes distinct domains to interact with Rab7-GTP and the ER transmembrane protein Protrudin and together these components localize to an ER-late endosome MCS. At these ER-late endosome MCSs, mitochondria are also recruited to form a three-way contact. Thus, our data indicate that PDZD8 is a shared component of two distinct MCSs and suggest a role for SMP-mediated lipid transport in the regulation of endosome function.
Non-cuttable material created through local resonance and strain rate effects
Authors: Szyniszewski Stefan , Vogel Rene , Bittner Florian , Jakubczyk Ewa , Anderson Miranda , Pelacci Manuel , Chinedu Ajoku , Endres Hans-Josef , Hipke Thomas
Published: July 2020

We have created a new architected material, which is both highly deformable and ultra‐resistant to dynamic point loads. The bio-inspired metallic cellular structure (with an internal grid of large ceramic segments) is non-cuttable by an angle grinder and a power drill, and it has only 15% steel density. Our architecture derives its extreme hardness from the local resonance between the embedded ceramics in a flexible cellular matrix and the attacking tool, which produces high-frequency vibrations at the interface. The incomplete consolidation of the ceramic grains during the manufacturing also promoted fragmentation of the ceramic spheres into micron-size particulate matter, which provided an abrasive interface with increasing resistance at higher loading rates. The contrast between the ceramic segments and cellular material was also effective against a waterjet cutter because the convex geometry of the ceramic spheres widened the waterjet and reduced its velocity by two orders of magnitude. Shifting the design paradigm from static resistance to dynamic interactions between the material phases and the applied load could inspire novel, metamorphic materials with pre-programmed mechanisms across different length scales.
Long-term effects of medical management on growth and weight in individuals with urea cycle disorders
Authors: Posset Roland , Garbade Sven F. , Gleich Florian , Gropman Andrea L. , de Lonlay Pascale , Hoffmann Georg F. , Garcia-Cazorla Angeles , Nagamani Sandesh C. S. , Baumgartner Matthias R. , Schulze Andreas , Dobbelaere Dries , Yudkoff Marc , Kölker Stefan , Zielonka Matthias ,   Urea Cycle Disorders Consortium (UCDC), Ah Mew Nicholas , Berry Susan A. , McCandless Shawn E. , Coughlin Curtis , Enns Gregory , Gallagher Renata C. , Burrage Lindsay C. , Seminara Jennifer , Harding Cary O. , Burgard Peter , Le Mons Cynthia , Merritt J. Lawrence , Stricker Tamar , Bedoyan Jirair K. , Berry Gerard T. , Diaz George A. , Wong Derek , Tuchman Mendel , Waisbren Susan , Weisfeld-Adams James D. ,   European registry and network for Intoxication type Metabolic Diseases (E-IMD), Burlina Alberto B. , Leão Teles Elisa , Pedrón-Giner Consuelo , Lund Allan M. , Dionisi-Vici Carlo , Williams Monique , Mütze Ulrike , Karall Daniela , Blasco-Alonso Javier , Couce Maria L. , Sykut-Cegielska Jolanta , Augoustides-Savvopoulou Persephone , Ruiz Gomez Angeles , Barić Ivo , Schiff Manuel , Chien Yin-Hsiu , Lindner Martin , Chabrol Brigitte , Skouma Anastasia , Zeman Jiri , Sokal Etienne , Santer René , Eyskens Francois , Freisinger Peter , Peña-Quintana Luis , Roland Dominique , Cortès-Saladelafont Elisenda , Djordjevic Maja
Published: July 2020

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.
Persistence of coastal upwelling after a plunge in upwelling-favourable wind
Authors: Jung Jihun , Cho Yang-Ki
Published: July 2020

Unprecedented coastal upwelling off the southern coast of the Korean Peninsula was reported during the summer of 2013. The upwelling continued for more than a month after a plunge in upwelling-favourable winds and had serious impacts on fisheries. This is a rare phenomenon, as most coastal upwelling events relax a few days after the wind weakens. In this study, observational data and numerical modelling results were analysed to investigate the cause of the upwelling and the reason behind it being sustained for such an extended period. Coastal upwelling was induced by an upwelling-favourable wind in July, resulting in the dynamic uplift of deep, cold water. The dynamic uplift decreased the steric sea level in the coastal region. The sea level difference between the coastal and offshore regions produced an intensified cross-shore pressure gradient that enhanced the surface geostrophic current along the coast. The strong surface current maintained the dynamic uplift due to geostrophic equilibrium. This positive feedback between the dynamic uplift and geostrophic adjustment sustained the coastal upwelling for a month following a plunge in the upwelling-favourable wind.
High expression of TCN1 is a negative prognostic biomarker and can predict neoadjuvant chemosensitivity of colon cancer
Authors: Liu Guang-jie , Wang Yao-jie , Yue Meng , Zhao Lian-mei , Guo Yong-Dong , Liu Yue-ping , Yang Hui-chai , Liu Fang , Zhang Xue , Zhi Liang-hui , Zhao Jing , Sun Yan-Hua , Wang Gui-ying
Published: July 2020

Transcobalamin (TCN1) is a vitamin B12 (cobalamin)-binding protein that regulates cobalamin homeostasis. Recent studies and bioinformatic analyses have found that TCN1 is highly expressed in cancer tissues and is associated with tumour aggressiveness and poor prognosis. The present study aimed to detect TCN1 as a novel biomarker for prognosis and chemosensitivity of colon cancer. Next-generation sequencing showed that TCN1 was one of several upregulated mRNAs in colon cancer, which was verified by further bioinformatics analyses. Western blotting (n = 9) and quantitative real time polymerase chain reaction (qRT-PCR, n = 30) revealed that TCN1 was highly expressed in colon cancer tissues at both the protein and mRNA level. A total of 194 cases of colon cancer were examined by immunohistochemistry and revealed that TCN1 expression level was related to advanced stages (P < 0.005). Kaplan–Meier analysis verified that patients with lower TCN1 expression usually had longer overall survival (P = 0.008). In addition, TCN1 was highly expressed in pulmonary metastatic tumour tissues (n = 37, P = 0.025) and exhibited higher levels in right-sided colon cancer than in left-sided colon cancer (P = 0.029). TCN1 expression in specimens that had received neoadjuvant chemotherapy decreased compared with that in colonoscopy biopsy tissues (n = 42, P = 0.009). Further bioinformatics analyses verified that apoptosis pathways might have a role in high TCN1 expression. All the studies revealed that TCN1 expression in colon cancer was significantly associated with malignant biological behaviour. Therefore, TCN1 could be used as a novel biomarker for colon cancer aggressiveness and prognosis and might also be a potential biomarker for predicting neoadjuvant chemosensitivity.
Neuronal activity remodels the F-actin based submembrane lattice in dendrites but not axons of hippocampal neurons
Authors: Lavoie-Cardinal Flavie , Bilodeau Anthony , Lemieux Mado , Gardner Marc-André , Wiesner Theresa , Laramée Gabrielle , Gagné Christian , De Koninck Paul
Published: July 2020

The nanoscale organization of the F-actin cytoskeleton in neurons comprises membrane-associated periodical rings, bundles, and longitudinal fibers. The F-actin rings have been observed predominantly in axons but only sporadically in dendrites, where fluorescence nanoscopy reveals various patterns of F-actin arranged in mixed patches. These complex dendritic F-actin patterns pose a challenge for investigating quantitatively their regulatory mechanisms. We developed here a weakly supervised deep learning segmentation approach of fluorescence nanoscopy images of F-actin in cultured hippocampal neurons. This approach enabled the quantitative assessment of F-actin remodeling, revealing the disappearance of the rings during neuronal activity in dendrites, but not in axons. The dendritic F-actin cytoskeleton of activated neurons remodeled into longitudinal fibers. We show that this activity-dependent remodeling involves $$\text {Ca}^{2+}$$Ca2+ and NMDA receptor-dependent mechanisms. This highly dynamic restructuring of dendritic F-actin based submembrane lattice into longitudinal fibers may serve to support activity-dependent membrane remodeling, protein trafficking and neuronal plasticity.
Microdomains form on the luminal face of neuronal extracellular vesicle membranes
Authors: Matthies Doreen , Lee Nathanael Y. J. , Gatera Ian , Pasolli H. Amalia , Zhao Xiaowei , Liu Hui , Walpita Deepika , Liu Zhe , Yu Zhiheng , Ioannou Maria S.
Published: July 2020

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication and have been implicated in several pathologies including those of the central nervous system. They are released by all cell types, including neurons, and are highly heterogenous in size and composition. Yet much remains unknown regarding the biophysical characteristics of different EVs. Here, using cryo-electron microscopy (cryoEM), we analyzed the size distribution and morphology of EVs released from primary cortical neurons. We discovered massive macromolecular clusters on the luminal face of EV membranes. These clusters are predominantly found on medium-sized vesicles, suggesting that they may be specific to microvesicles as opposed to exosomes. We propose that these clusters serve as microdomains for EV signaling and play an important role in EV physiology.
Injection of seminal fluid into the hemocoel of honey bee queens (Apis mellifera) can stimulate post-mating changes
Authors: Jasper W. Cameron , Brutscher Laura M. , Grozinger Christina M. , Niño Elina L.
Published: July 2020

Honey bee queens undergo dramatic behavioral (e.g., reduced sexual receptivity), physiological (e.g., ovary activation, ovulation, and modulation of pheromone production) and transcriptional changes after they complete mating. To elucidate how queen post-mating changes are influenced by seminal fluid, the non-spermatozoa-containing component of semen, we injected queens with semen or seminal fluid alone. We assessed queen sexual receptivity (as measured by likelihood to take mating flights), ovary activation, worker retinue response (which is influenced by queen pheromone production), and transcriptional changes in queen abdominal fat body and brain tissues. Injection with either seminal fluid or semen resulted in decreased sexual receptivity, increased attractiveness of queens to workers, and altered expression of several genes that are also regulated by natural mating in queens. The post-mating and transcriptional changes of queens receiving seminal fluid were not significantly different from queens injected with semen, suggesting that components in seminal fluid, such as seminal fluid proteins, are largely responsible for stimulating post-mating changes in queens.
Sequence analysis of nonulosonic acid biosynthetic gene clusters in Vibrionaceae and Moritella viscosa
Authors: Halsør Marie-Josée Haglund , Altermark Bjørn , Ræder Inger Lin Uttakleiv
Published: July 2020

Nonulosonic acid (NulO) biosynthesis in bacteria is directed by nab gene clusters that can lead to neuraminic, legionaminic or pseudaminic acids. Analysis of the gene content from a set mainly composed of Aliivibrio salmonicida and Moritella viscosa strains reveals the existence of several unique nab clusters, for which the NulO products were predicted.
This prediction method can be used to guide tandem mass spectrometry studies in order to verify the products of previously undescribed nab clusters and identify new members of the NulOs family.
Author Correction: Enhanced endothelial motility and multicellular sprouting is mediated by the scaffold protein TKS4
Authors: Mehes Elod , Barath Monika , Gulyas Marton , Bugyik Edina , Geiszt Miklos , Szoor Arpad , Lanyi Arpad , Czirok Andras
Published: July 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Recurrent probabilistic neural network-based short-term prediction for acute hypotension and ventricular fibrillation
Authors: Tsuji Toshio , Nobukawa Tomonori , Mito Akihisa , Hirano Harutoyo , Soh Zu , Inokuchi Ryota , Fujita Etsunori , Ogura Yumi , Kaneko Shigehiko , Nakamura Ryuji , Saeki Noboru , Kawamoto Masashi , Yoshizumi Masao
Published: July 2020

In this paper, we propose a novel method for predicting acute clinical deterioration triggered by hypotension, ventricular fibrillation, and an undiagnosed multiple disease condition using biological signals, such as heart rate, RR interval, and blood pressure. Efforts trying to predict such acute clinical deterioration events have received much attention from researchers lately, but most of them are targeted to a single symptom. The distinctive feature of the proposed method is that the occurrence of the event is manifested as a probability by applying a recurrent probabilistic neural network, which is embedded with a hidden Markov model and a Gaussian mixture model. Additionally, its machine learning scheme allows it to learn from the sample data and apply it to a wide range of symptoms. The performance of the proposed method was tested using a dataset provided by Physionet and the University of Tokyo Hospital. The results show that the proposed method has a prediction accuracy of 92.5% for patients with acute hypotension and can predict the occurrence of ventricular fibrillation 5 min before it occurs with an accuracy of 82.5%. In addition, a multiple disease condition can be predicted 7 min before they occur, with an accuracy of over 90%.
Everyday bodily movement is associated with creativity independently from active positive affect: a Bayesian mediation analysis approach
Authors: Rominger Christian , Fink Andreas , Weber Bernhard , Papousek Ilona , Schwerdtfeger Andreas R.
Published: July 2020

Previous (predominantly) laboratory studies reported positive relations of physical activity (or everyday bodily movement) with executive functioning, some even showed effects on creative thinking. Furthermore, positive-activated affect was found to be positively associated with everyday bodily movements and creativity. The mechanisms, however, underlying these relationships are poorly understood. The aim of this study was twofold: Firstly, we investigated whether everyday bodily movement was associated with creative performance. Secondly, we examined if positive-activated affect may mediate the association between bodily movement and creative performance. In a sample of 79 participants everyday bodily movement was recorded during five consecutive days using accelerometers. Creativity in the figural and verbal domain was assessed with performance tests, along with self-reported positive-activated affect as a trait. Findings revealed that creativity, positive-activated affect, and everyday bodily movement were associated with each other. However, positive-activated affect did not mediate the association between everyday bodily movement and creative performance. The pattern of findings argues for shared variance between bodily movement and creativity (fluency and originality) that is largely independent from variations in positive-activated affect.
Salt templated and graphene nanoplatelets draped copper (GNP-draped-Cu) composites for dramatic improvements in pool boiling heat transfer
Authors: Rishi Aniket M. , Kandlikar Satish G. , Gupta Anju
Published: July 2020

We demonstrate a novel technique to achieve highly surface active, functional, and tunable hierarchical porous coated surfaces with high wickability using a combination of ball milling, salt-templating, and sintering techniques. Specifically, using ball-milling to obtain graphene nanoplatelets (GNP) draped copper particles followed by salt templated sintering to induce the strength and cohesiveness to the particles. The salt-templating method was specifically used to promote porosity on the coatings. A systematic study was conducted by varying size of the copper particles, ratio of GNP to copper particles, and process parameters to generate a variety of microporous coatings possessing interconnected pores and tunnels that were observed using electron microscopy. Pool boiling tests exhibited a very high critical heat flux of 289 W/cm2 at a wall superheat of just 2.2 °C for the salt templated 3 wt% GNP draped 20 µm diameter copper particles with exceedingly high wicking rates compared to non-salt-templated sintered coatings. The dramatic improvement in the pool boiling performance occurring at a very low surface temperature due to tunable surface properties is highly desirable in heat transfer and many other engineering applications.
FKS1 mutation associated with decreased echinocandin susceptibility of Aspergillus fumigatus following anidulafungin exposure
Authors: e Silva Ana Pinto , Miranda Isabel Marcos , Branco Joana , Oliveira Patricia , Faria-Ramos Isabel , Silva Raquel M. , Rodrigues Acácio Gonçalves , Costa-de-Oliveira Sofia
Published: July 2020

Invasive aspergillosis (IA) is a potentially lethal infection that affects mostly immunocompromised patients caused by Aspergillus fumigatus. Echinocandins are a second-line therapy against IA, used as a salvage therapy as well as for empirical or prophylactic therapy. Although they cause lysis of growing hyphal tips, they are considered fungistatic against molds. In vivo echinocandins resistance is uncommon; however, its wide clinical use could shortly lead to the emergence of A. fumigatus resistance. The aims of the present work was to assess the development of reduced echinocandins susceptibility phenotype by a A. fumigatus strain and to unveil the molecular mechanism underlying such phenotype. We induced in vitro cross-resistance to echinocandins following exposure of A. fumigatus to anidulafungin. Stability of the resistant phenotype was confirmed after removal of anidulafungin pressure. The FKS1 gene was partially sequenced and a E671Q mutation was found. A computational approach suggests that it can play an important role in echinocandin resistance. Given the emerging importance of this mechanism for clinical resistance in pathogenic fungi, it would be prudent to be alert to the potential evolution of this resistant mechanism in Aspergillus spp infecting patients under echinocandins therapeutics.
Role of internal tide mixing in keeping the deep Andaman Sea warmer than the Bay of Bengal
Authors: Jithin A. K. , Francis P. A.
Published: July 2020

Vertical profiles of temperature obtained from various hydrographic datasets show that deep waters (below 1,200 m) in the Andaman Sea are warmer (about 2 °C) than that of the Bay of Bengal. As a result, the biochemical properties in the deep waters also exhibit significant differences between these two basins. Higher temperature in the deep waters of Andaman Sea compared to the BoB had been widely attributed to the enclosed nature of the Andaman Sea. In this study, we show that strong tidal energy dissipation in the Andaman Sea also plays an important role in maintaining the higher temperatures in the deep waters. Dissipation rates inferred from the hydrographic data and internal tide energy budget suggests that the rate of vertical mixing in the Andaman Sea is about two-orders of magnitude larger than that in the Bay of Bengal. This elevated internal tide induced vertical mixing results in the efficient transfer of heat into the deeper layers, which keeps the deep Andaman Sea warm. Numerical experiments conducted using a high-resolution setup of Regional Ocean Modelling System (ROMS) further confirm the effect of tidal mixing in the Andaman Sea.
The complete mitochondrial genome of Indian gaur, Bos gaurus and its phylogenetic implications
Authors: Kamalakkannan Ranganathan , Bhavana Karippadakam , Prabhu Vandana R. , Sureshgopi Dhandapani , Singha Hijam Surachandra , Nagarajan Muniyandi
Published: July 2020

The gaur is the largest extant cattle species and distributed across South and Southeast Asia. Around 85% of its current global population resides in India, however there has been a gradual decrease in the gaur population over the last two decades due to various anthropogenic activities. Mitochondrial genome is considered as an important tool for species identification and monitoring the populations of conservation concern and therefore it becomes an obligation to sequence the mitochondrial genome of Indian gaur. We report here for the first time 16,345 bp mitochondrial genome of four Indian gaur sequenced using two different approaches. Mitochondrial genome consisted of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region. Among the 37 genes, 28 were positioned on the H-strand and 9 were positioned on the L-strand. The overall base composition appeared to be 33.5% A, 27.2% T, 25.9% C and 13.4% G, which yielded a higher AT content. The phylogenetic analysis using complete mitochondrial genome sequences unambiguously suggested that gaur is the maternal ancestor of domestic mithun. Moreover, it also clearly distinguished the three sub species ofB. gaurusi.e.B. gaurus gaurus, B. gaurus readeiandB. gaurus hubbacki. Among the three sub species,B. gaurus gauruswas genetically closer toB. gaurus readeias compared toB. gaurus hubbacki. The findings of our study provide an insight into the genetic structure and evolutionary history of Indian gaur.
Simple liquid chromatography-electrospray ionization ion trap mass spectrometry method for the quantification of galacto-oxylipin arabidopsides in plant samples
Authors: Genva Manon , Andersson Mats X. , Fauconnier Marie-Laure
Published: July 2020

A simple and sensitive method to quantify five different arabidopsides by HPLC—ion trap mass spectrometry in complex plant samples was developed and validated. Arabidopsides are oxidized galactolipids first described in Arabidopsis thaliana but also produced by other plant species under stress conditions. External calibration was performed using arabidopsides purified from freeze-thawed Arabidopsis leaves. Lipids were extracted and pre-purified on an SPE silica column before HPLC–MS analysis. Arabidopsides were separated on a C18 column using a gradient of mQ water and acetonitrile:mQ water (85:15) supplemented with formic acid (0.2%) and ammonium formate (12 mM). The method was validated according to European commission decision 2002/657/CE. LOD, LOQ, linearity, intra-day and inter-day precision and accuracy, selectivity, matrix effects and recoveries were determined for the five metabolites. The established method is highly selective in a complex plant matrix. LOD and LOQ were, respectively, in the range 0.098–0.78 and 0.64–1.56 µM, allowing the arabidopside quantification from 25.6–62.4 nmol/g fresh weight. Calibration curve correlation coefficients were higher than 0.997. Matrix effects ranged from -2.09% to 6.10% and recoveries between 70.7% and 109%. The method was successfully applied to complex plant matrixes: Arabidopsis thaliana and Nasturtium officinale.
High-resolution and differential analysis of rat microglial markers in traumatic brain injury: conventional flow cytometric and bioinformatics analysis
Authors: Toledano Furman Naama , Gottlieb Assaf , Prabhakara Karthik S. , Bedi Supinder , Caplan Henry W. , Ruppert Katherine A. , Srivastava Amit K. , Olson Scott D. , Cox Charles S.
Published: July 2020

Traumatic brain injury (TBI) results in a cascade of cellular responses, which produce neuroinflammation, partly due to microglial activation. Transforming from surveying to primed phenotypes, microglia undergo considerable molecular changes. However, specific microglial profiles in rat remain elusive due to tedious methodology and limited availability of reagents. Here, we present a flow cytometry-based analysis of rat microglia 24 h after TBI using the controlled cortical impact model, validated with a bioinformatics approach. Isolated microglia are analyzed for morphological changes and their expression of activation markers using flow cytometry, traditional gating-based analysis methods and support the data by employing bioinformatics statistical tools. We use CD45, CD11b/c, and p2y12 receptor to identify microglia and evaluate their activation state using CD32, CD86, RT1B, CD200R, and CD163. The results from logic-gated flow cytometry analysis was validated with bioinformatics-based analysis and machine learning algorithms to detect quantitative changes in morphology and marker expression in microglia due to activation following TBI.
Early detection of type 2 diabetes mellitus using machine learning-based prediction models
Authors: Kopitar Leon , Kocbek Primoz , Cilar Leona , Sheikh Aziz , Stiglic Gregor
Published: July 2020

Most screening tests for T2DM in use today were developed using multivariate regression methods that are often further simplified to allow transformation into a scoring formula. The increasing volume of electronically collected data opened the opportunity to develop more complex, accurate prediction models that can be continuously updated using machine learning approaches. This study compares machine learning-based prediction models (i.e. Glmnet, RF, XGBoost, LightGBM) to commonly used regression models for prediction of undiagnosed T2DM. The performance in prediction of fasting plasma glucose level was measured using 100 bootstrap iterations in different subsets of data simulating new incoming data in 6-month batches. With 6 months of data available, simple regression model performed with the lowest average RMSE of 0.838, followed by RF (0.842), LightGBM (0.846), Glmnet (0.859) and XGBoost (0.881). When more data were added, Glmnet improved with the highest rate (+ 3.4%). The highest level of variable selection stability over time was observed with LightGBM models. Our results show no clinically relevant improvement when more sophisticated prediction models were used. Since higher stability of selected variables over time contributes to simpler interpretation of the models, interpretability and model calibration should also be considered in development of clinical prediction models.
A meta-analysis of multiple stressors on seagrasses in the context of marine spatial cumulative impacts assessment
Authors: Stockbridge Jackson , Jones Alice R. , Gillanders Bronwyn M.
Published: July 2020

Humans are placing more strain on the world’s oceans than ever before. Furthermore, marine ecosystems are seldom subjected to single stressors, rather they are frequently exposed to multiple, concurrent stressors. When the combined effect of these stressors is calculated and mapped through cumulative impact assessments, it is often assumed that the effects are additive. However, there is increasing evidence that different combinations of stressors can have non-additive impacts, potentially leading to synergistic and unpredictable impacts on ecosystems. Accurately predicting how stressors interact is important in conservation, as removal of certain stressors could provide a greater benefit, or be more detrimental than would be predicted by an additive model. Here, we conduct a meta-analysis to assess the prevalence of additive, synergistic, and antagonistic stressor interaction effects using seagrasses as case study ecosystems. We found that additive interactions were the most commonly reported in seagrass studies. Synergistic and antagonistic interactions were also common, but there was no clear way of predicting where these non-additive interactions occurred. More studies which synthesise the results of stressor interactions are needed to be able to generalise interactions across ecosystem types, which can then be used to improve models for assessing cumulative impacts.
Inhibition of mitotic kinase Mps1 promotes cell death in neuroblastoma
Authors: Simon Serrano Sonia , Sime Wondossen , Abassi Yasmin , Daams Renée , Massoumi Ramin , Jemaà Mohamed
Published: July 2020

Neuroblastoma is the most common paediatric cancer type. Patients diagnosed with high-risk neuroblastoma have poor prognosis and occasionally tumours relapse. As a result, novel treatment strategies are needed for relapse and refractory neuroblastoma patients. Here, we found that high expression of Mps1 kinase (mitotic kinase Monopolar Spindle 1) was associated with relapse-free neuroblastoma patient outcomes and poor overall survival. Silencing and inhibition of Mps1 in neuroblastoma or PDX-derived cells promoted cell apoptosis via the caspase-dependent mitochondrial apoptotic pathway. The mechanism of cell death upon Mps1 inhibition was dependent on the polyploidization/aneuploidization of the cells before undergoing mitotic catastrophe. Furthermore, tumour growth retardation was confirmed in a xenograft mouse model after Mps1-inhibitor treatment. Altogether, these results suggest that Mps1 expression and inhibition can be considered as a novel prognostic marker as well as a therapeutic strategy for the treatment of high-risk neuroblastoma patients.
Structure and co-occurrence patterns of bacterial communities associated with white faeces disease outbreaks in Pacific white-leg shrimp Penaeus vannamei aquaculture
Authors: Alfiansah Yustian Rovi , Peters Sonja , Harder Jens , Hassenrück Christiane , Gärdes Astrid
Published: July 2020

Bacterial diseases cause production failures in shrimp aquacultures. To understand environmental conditions and bacterial community dynamics contributing to white faeces disease (WFD) events, we analysed water quality and compared bacterial communities in water as well as in intestines and faeces of healthy and diseased shrimps, respectively, via 16S rRNA gene sequencing and qPCR of transmembrane regulatory protein (toxR), thermolabile haemolysin (tlh), and thermostable direct haemolysin genes of pathogenic Vibrio parahaemolyticus as a proxy for virulence. WFD occurred when pH decreased to 7.71–7.84, and Alteromonas, Pseudoalteromonas and Vibrio dominated the aquatic bacterial communities. The disease severity further correlated with increased proportions of Alteromonas, Photobacterium, Pseudoalteromonas and Vibrio in shrimp faeces. These opportunistic pathogenic bacteria constituted up to 60% and 80% of the sequences in samples from the early and advances stages of the disease outbreak, respectively, and exhibited a high degree of co-occurrence. Furthermore, toxR and tlh were detected in water at the disease event only. Notably, bacterial community resilience in water occurred when pH was adjusted to 8. Then WFD ceased without a mortality event. In conclusion, pH was a reliable indicator of the WFD outbreak risk. Dissolved oxygen and compositions of water and intestinal bacteria may also serve as indicators for better prevention of WFD events.
Activation of cerebellum and basal ganglia during the observation and execution of manipulative actions
Authors: Errante Antonino , Fogassi Leonardo
Published: July 2020

Studies on action observation mostly described the activation of a network of cortical areas, while less investigation focused specifically on the activation and role of subcortical nodes. In the present fMRI study, we investigated the recruitment of cerebellum and basal ganglia during the execution and observation of object manipulation performed with the right hand. The observation conditions consisted in: (a) observation of manipulative actions; (b) observation of sequences of random finger movements. In the execution conditions, participants had to perform the same actions or movements as in (a) and (b), respectively. The results of conjunction analysis showed significant shared activations during both observation and execution of manipulation in several subcortical structures, including: (1) cerebellar lobules V, VI, crus I, VIIIa and VIIIb (bilaterally); (2) globus pallidus, bilaterally, and left subthalamic nucleus; (3) red nucleus (bilaterally) and left thalamus. These findings support the hypothesis that the action observation/execution network also involves subcortical structures, such as cerebellum and basal ganglia, forming an integrated network. This suggests possible mechanisms, involving these subcortical structures, underlying learning of new motor skills, through action observation and imitation.
Ultra-compact high efficiency and low crosstalk optical interconnection structures based on inverse designed nanophotonic elements
Authors: Li Zikang , Li Guofeng , Huang Jie , Zhang Zhenrong , Yang Junbo , Yang Changming , Qian Yang , Xu Wenjie , Huang Huimin
Published: July 2020

In this paper, we combine inverse design concept and direct binary search algorithm to demonstrate three ultra-compact high efficiency and low crosstalk on-chip integrated optical interconnection basic devices in the entire wavelength range of 1,400–1600 nm based on silicon-on-insulator platform. A 90-degree waveguide bend with a footprint of only 2.4 × 2.4 μm2 is designed, whose transmission efficiency up to 0.18 dB. A waveguide crossing with a footprint of only 2.4 × 2.4 μm2 is designed, which can provide insertion loss of less than 0.5 dB and crosstalk (CL) of lower than − 19 dB. A same direction waveguide crossing with footprint of only 2.4 × 3.6 μm2 is designed, which can provide the insertion loss of less than 0.56 dB and the crosstalk of lower than − 21 dB. Then, we use them to form several ultra-compact optical interconnect basic structures and performed the simulation calculation. They overall achieve high performance. This will significantly improve the integration density.
KRAS(G12C)–AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations
Authors: Pantsar Tatu
Published: July 2020

The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug–protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)–AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS’ N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS’ switches. Overall, KRAS(G12C)–AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2–β3-loop. These results provide novel conformational insights on the molecular level to KRAS(G12C)–AMG 510 interactions and dynamics, providing new perspectives to RAS related drug discovery.
The prognostic role of preoperative serum albumin/globulin ratio in patients with non-metastatic renal cell carcinoma undergoing partial or radical nephrectomy
Authors: Chung Jae-Wook , Park Dong Jin , Chun So Young , Choi Seock Hwan , Lee Jun Nyung , Kim Bum Soo , Kim Hyun Tae , Kim Tae-Hwan , Yoo Eun Sang , Byun Seok-Soo , Hwang Eu Chang , Kang Seok Ho , Hong Sung-Hoo , Chung Jinsoo , Kwak Cheol , Kim Yong- June , Ha Yun-Sok , Kwon Tae Gyun
Published: July 2020

This multi-institutional study sought to clarify the association between the preoperative serum albumin/globulin ratio (AGR) and the prognosis of renal cell carcinoma (RCC) in a large cohort. This study encompassed eight institutions and 2,970 non-metastatic RCC patients who underwent a radical or partial nephrectomy from the Korean RCC (KORCC) database. A low AGR (1,143 patients; 38.5%) was defined as a preoperative AGR of less than 1.47 and a high AGR (1,827 patients; 61.5%) was defined as that 1.47 or greater. In the low AGR group, older age, female gender, the incidence of symptom presentation when diagnosed, diabetes, and hypertension was higher than in the high AGR group. Patients with low AGRs showed more progressive tumor stages with higher Fuhrman nuclear grades (all P-values < 0.05). Patients in the low AGR group had a significantly lower overall survival rate (OS) and recurrence-free survival rate (RFS) in the Kaplan–Meier curves (all P-values < 0.05). AGR was an independent prognostic factor for predicting the OS and RFS in the multivariate analysis (all P-values < 0.05). The preoperative AGR is approachable and economical to use clinically for estimating the prognosis of RCC patients treated with surgery.
Intracellular interplay between cholecystokinin and leptin signalling for satiety control in rats
Authors: Koizumi Hayato , Mohammad Shahid , Ozaki Tomoya , Muto Kiyokazu , Matsuba Nanami , Kim Juhyon , Pan Weihong , Morioka Eri , Mochizuki Takatoshi , Ikeda Masayuki
Published: July 2020

Cholecystokinin (CCK) and leptin are satiety-controlling peptides, yet their interactive roles remain unclear. Here, we addressed this issue using in vitro and in vivo models. In rat C6 glioma cells, leptin pre-treatment enhanced Ca2+ mobilization by a CCK agonist (CCK-8s). This leptin action was reduced by Janus kinase inhibitor (AG490) or PI3-kinase inhibitor (LY294002). Meanwhile, leptin stimulation alone failed to mobilize Ca2+ even in cells overexpressing leptin receptors (C6-ObRb). Leptin increased nuclear immunoreactivity against phosphorylated STAT3 (pSTAT3) whereas CCK-8s reduced leptin-induced nuclear pSTAT3 accumulation in these cells. In the rat ventromedial hypothalamus (VMH), leptin-induced action potential firing was enhanced, whereas nuclear pSTAT3 was reduced by co-stimulation with CCK-8s. To further analyse in vivo signalling interplay, a CCK-1 antagonist (lorglumide) was intraperitoneally injected in rats following 1-h restricted feeding. Food access was increased 3-h after lorglumide injection. At this timepoint, nuclear pSTAT3 was increased whereas c-Fos was decreased in the VMH. Taken together, these results suggest that leptin and CCK receptors may both contribute to short-term satiety, and leptin could positively modulate CCK signalling. Notably, nuclear pSTAT3 levels in this experimental paradigm were negatively correlated with satiety levels, contrary to the generally described transcriptional regulation for long-term satiety via leptin receptors.