bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular IL-37 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells via activation of the PI3K/AKT signaling pathway
Authors: Ye Chenyi , Zhang Wei , Hang Kai , Chen Mo , Hou Weiduo , Chen Jianzhong , Chen Xi , Chen Erman , Tang Lan , Lu Jinwei , Ding Qianhai , Jiang Guangyao , Hong Baojian , He Rongxin
Published: October 2019

Interleukin (IL)-37, a pivotal anti-inflammatory cytokine and a fundamental inhibitor of innate immunity, has recently been shown to be abnormally expressed in several autoimmune-related orthopedic diseases, including rheumatoid arthritis, ankylosing spondylitis, and osteoporosis. However, the role of IL-37 during osteogenic differentiation of mesenchymal stem cells (MSCs) remains largely unknown. In this study, extracellular IL-37 significantly increased osteoblast-specific gene expression, the number of mineral deposits, and alkaline phosphatase activity of MSCs. Moreover, a signaling pathway was activated in the presence of IL-37. The enhanced osteogenic differentiation of MSCs due to supplementation of IL-37 was partially rescued by the presence of a PI3K/AKT signaling inhibitor. Using a rat calvarial bone defect model, IL-37 significantly improved bone healing. Collectively, these findings indicate that extracellular IL-37 enhanced osteogenesis of MSCs, at least in part by activation of the PI3K/AKT signaling pathway.
Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice
Authors: Zhang Changli , Smith Madeline P. , Zhou George K. , Lai Alon , Hoy Robert C. , Mroz Victoria , Torre Olivia M. , Laudier Damien M. , Bradley Elizabeth W. , Westendorf Jennifer J. , Iatridis James C. , Illien-Jünger Svenja
Published: October 2019

Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.
LINC00978 promotes the progression of hepatocellular carcinoma by regulating EZH2-mediated silencing of p21 and E-cadherin expression
Authors: Xu Xueying , Gu Jianmei , Ding Xiaoge , Ge Guohong , Zang Xueyan , Ji Runbi , Shao Meng , Mao Zheying , Zhang Yu , Zhang Jiayin , Mao Fei , Qian Hui , Xu Wenrong , Cai Hui , Wang Feng , Zhang Xu
Published: October 2019

Long non-coding RNAs (lncRNAs) have been suggested as important regulators of cancer development and progression in hepatocellular carcinoma (HCC). Nevertheless, the clinical value and biological roles of LINC00978 in HCC remain unclear. In this study, we detected the expression of LINC00978 in tumor tissues and serum of HCC patients, examined the roles of LINC00978 in HCC progression and elucidated the underlying molecular mechanisms. We found that LINC00978 expression was upregulated in tumor tissues and serum of HCC patients. Higher serum levels of LINC00978 could distinguish HCC patients from hepatitis and liver cirrhosis patients and healthy controls. LINC00978 knockdown inhibited HCC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. Overexpression of LINC00978 led to the opposite effects. LINC00978 knockdown also inhibited HCC growth and metastasis in mouse tumor models. Mechanistically, LINC00978 bound to EZH2 and mediated its accumulation at the promoter region of p21 and E-cadherin genes, leading to the trimethylation of H27K3 and the inhibition of p21 and E-cadherin expression. Moreover, the simultaneous depletion of p21 and E-cadherin expression reversed the inhibitory effects of LINC00978 knockdown on HCC cell proliferation, migration, and invasion. Taken together, these findings suggest that LINC00978 promotes HCC progression by inhibiting p21 and E-cadherin expression via EZH2-mediated epigenetic silencing. LINC00978 may represent a novel biomarker for HCC diagnosis, prognosis, and therapy.
Highly structured homolog pairing reflects functional organization of the Drosophila genome
Authors: AlHaj Abed Jumana , Erceg Jelena , Goloborodko Anton , Nguyen Son C. , McCole Ruth B. , Saylor Wren , Fudenberg Geoffrey , Lajoie Bryan R. , Dekker Job , Mirny Leonid A. , Wu C.-ting
Published: October 2019

Trans-homolog interactions have been studied extensively in Drosophila, where homologs are paired in somatic cells and transvection is prevalent. Nevertheless, the detailed structure of pairing and its functional impact have not been thoroughly investigated. Accordingly, we generated a diploid cell line from divergent parents and applied haplotype-resolved Hi-C, showing that homologs pair with varying precision genome-wide, in addition to establishing trans-homolog domains and compartments. We also elucidate the structure of pairing with unprecedented detail, observing significant variation across the genome and revealing at least two forms of pairing: tight pairing, spanning contiguous small domains, and loose pairing, consisting of single larger domains. Strikingly, active genomic regions (A-type compartments, active chromatin, expressed genes) correlated with tight pairing, suggesting that pairing has a functional implication genome-wide. Finally, using RNAi and haplotype-resolved Hi-C, we show that disruption of pairing-promoting factors results in global changes in pairing, including the disruption of some interaction peaks.
Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance
Authors: Stamoulis Georgios , Garieri Marco , Makrythanasis Periklis , Letourneau Audrey , Guipponi Michel , Panousis Nikolaos , Sloan-Béna Frédérique , Falconnet Emilie , Ribaux Pascale , Borel Christelle , Santoni Federico , Antonarakis Stylianos E.
Published: October 2019

Aneuploidy is a major source of gene dosage imbalance due to copy number alterations (CNA), and viable human trisomies are model disorders of altered gene expression. We study gene and allele-specific expression (ASE) of 9668 single-cell fibroblasts from trisomy 21 (T21) discordant twins and from mosaic T21, T18, T13 and T8. We examine 928 single cells with deep scRNAseq. Expected and observed overexpression of trisomic genes in trisomic vs. diploid bulk RNAseq is not detectable in trisomic vs. diploid single cells. Instead, for trisomic genes with low-to-average expression, their altered gene dosage is mainly due to the higher fraction of trisomic cells simultaneously expressing these genes, in agreement with a stochastic 2-state burst-like model of transcription. These results, confirmed in a further analysis of 8740 single fibroblasts with shallow scRNAseq, suggest that the specific transcriptional profile of each gene contributes to the phenotypic variability of trisomies. We propose an improved model to understand the effects of CNA and, generally, of gene regulation on gene dosage imbalance.
Gain-through-filtering enables tuneable frequency comb generation in passive optical resonators
Authors: Bessin Florent , Perego Auro M. , Staliunas Kestutis , Turitsyn Sergei K. , Kudlinski Alexandre , Conforti Matteo , Mussot Arnaud
Published: October 2019

Optical frequency combs (OFCs), consisting of a set of phase-locked, equally spaced laser frequency lines, have enabled a great leap in precision spectroscopy and metrology since seminal works of Hänsch et al. Nowadays, OFCs are cornerstones of a wealth of further applications ranging from chemistry and biology to astrophysics and including molecular fingerprinting and light detection and ranging (LIDAR) systems, among others. Driven passive optical resonators constitute the ideal platform for OFC generation in terms of compactness and low energy footprint. We propose here a technique for the generation of OFCs with a tuneable repetition rate in externally driven optical resonators based on the gain-through-filtering process, a simple and elegant method, due to asymmetric spectral filtering on one side of the pump wave. We demonstrate a proof-of-concept experimental result in a fibre resonator, pioneering a new technique that does not require specific engineering of the resonator dispersion to generate frequency-agile OFCs.
Rh single atoms on TiO2 dynamically respond to reaction conditions by adapting their site
Authors: Tang Yan , Asokan Chithra , Xu Mingjie , Graham George W. , Pan Xiaoqing , Christopher Phillip , Li Jun , Sautet Philippe
Published: October 2019

Single-atom catalysts are widely investigated heterogeneous catalysts; however, the identification of the local environment of single atoms under experimental conditions, as well as operando characterization of their structural changes during catalytic reactions are still challenging. Here, the preferred local coordination of Rh single atoms is investigated on TiO2 during calcination in O2, reduction in H2, CO adsorption, and reverse water gas shift (RWGS) reaction conditions. Theoretical and experimental studies clearly demonstrate that Rh single atoms adapt their local coordination and reactivity in response to various redox conditions. Single-atom catalysts hence do not have static local coordinations, but can switch from inactive to active structure under reaction conditions, hence explaining some conflicting literature accounts. The combination of approaches also elucidates the structure of the catalytic active site during reverse water gas shift. This insight on the real nature of the active site is key for the design of high-performance catalysts.
A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1
Authors: Botello-Smith Wesley M. , Jiang Wenjuan , Zhang Han , Ozkan Alper D. , Lin Yi-Chun , Pham Christine N. , Lacroix Jérôme J. , Luo Yun
Published: October 2019

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel’s mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value.
Enhancing electron diffusion length in narrow-bandgap perovskites for efficient monolithic perovskite tandem solar cells
Authors: Yang Zhibin , Yu Zhenhua , Wei Haotong , Xiao Xun , Ni Zhenyi , Chen Bo , Deng Yehao , Habisreutinger Severin N. , Chen Xihan , Wang Kang , Zhao Jingjing , Rudd Peter N. , Berry Joseph J. , Beard Matthew C. , Huang Jinsong
Published: October 2019

Developing multijunction perovskite solar cells (PSCs) is an attractive route to boost PSC efficiencies to above the single-junction Shockley-Queisser limit. However, commonly used tin-based narrow-bandgap perovskites have shorter carrier diffusion lengths and lower absorption coefficient than lead-based perovskites, limiting the efficiency of perovskite-perovskite tandem solar cells. In this work, we discover that the charge collection efficiency in tin-based PSCs is limited by a short diffusion length of electrons. Adding 0.03 molar percent of cadmium ions into tin-perovskite precursors reduce the background free hole concentration and electron trap density, yielding a long electron diffusion length of 2.72 ± 0.15 µm. It increases the optimized thickness of narrow-bandgap perovskite films to 1000 nm, yielding exceptional stabilized efficiencies of 20.2 and 22.7% for single junction narrow-bandgap PSCs and monolithic perovskite-perovskite tandem cells, respectively. This work provides a promising method to enhance the optoelectronic properties of narrow-bandgap perovskites and unleash the potential of perovskite-perovskite tandem solar cells.
Intranasal acellular pertussis vaccine provides mucosal immunity and protects mice from Bordetella pertussis
Authors: Boehm Dylan T. , Wolf M. Allison , Hall Jesse M. , Wong Ting Y. , Sen-Kilic Emel , Basinger Hayden D. , Dziadowicz Sebastian A. , Gutierrez Maria de la Paz , Blackwood Catherine B. , Bradford Shelby D. , Begley Katherine A. , Witt William T. , Varney Melinda E. , Barbier Mariette , Damron F. Heath
Published: October 2019

Current acellular pertussis vaccines fall short of optimal protection against the human respiratory pathogenBordetella pertussisresulting in increased incidence of a previously controlled vaccine- preventable disease. Natural infection is known to induce a protective mucosal immunity. Therefore, in this study, we aimed to use acellular pertussis vaccines to recapitulate these mucosal immune responses. We utilized a murine immunization and challenge model to characterize the efficacy of intranasal immunization (IN) with DTaP vaccine or DTaP vaccine supplemented with curdlan, a known Th1/Th17 promoting adjuvant. Protection from IN delivered DTaP was compared to protection mediated by intraperitoneal injection of DTaP and whole-cell pertussis vaccines. We tracked fluorescently labeled DTaP after immunization and detected that DTaP localized preferentially in the lungs while DTaP with curdlan was predominantly in the nasal turbinates. IN immunization with DTaP, with or without curdlan adjuvant, resulted in anti-B. pertussisand anti-pertussis toxin IgG titers at the same level as intraperitoneally administered DTaP. IN immunization was able to protect againstB. pertussischallenge and we observed decreased pulmonary pro-inflammatory cytokines, neutrophil infiltrates in the lung, and bacterial burden in the upper and lower respiratory tract at day 3 post challenge. Furthermore, IN immunization with DTaP triggered mucosal immune responses such as production ofB. pertussis-specific IgA, and increased IL-17A. Together, the induction of a mucosal immune response and humoral antibody-mediated protection associated with an IN administered DTaP and curdlan adjuvant warrant further exploration as a pertussis vaccine candidate formulation.
Contactless transient carrier spectroscopy and imaging technique using lock-in free carrier emission and absorption
Authors: Rougieux Fiacre E. , Kwapil Wolfram , Heinz Friedemann , Siriwardhana Manjula , Schubert Martin C.
Published: October 2019

In this paper we present a contactless transient carrier spectroscopy and imaging technique for traps in silicon. At each pixel, we fit the transient decay of the trap emission which allows us to obtain both the trap time constant and trap concentration. Here we show that this technique allows for high-resolution images. Furthermore, this technique also allows to discriminate between the presence of thermal donors or oxygen precipitates in as-grown wafers, without requiring a thermal donor killing step.
Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo
Authors: de la Fuente Revenga Mario , Shin Jong M. , Vohra Hiba Z. , Hideshima Kelsey S. , Schneck Matthew , Poklis Justin L. , González-Maeso Javier
Published: October 2019

Head-twitch behavior (HTR) is the behavioral signature of psychedelic drugs upon stimulation of the serotonin 5-HT2A receptor (5-HT2AR) in rodents. Following the previous report of a semi-automated detection of HTR based on the dynamics of mouse’s head movement, here we present a system for the identification of individual HTR events in a fully automated fashion. The validity of this fully automated HTR detection system was tested with the psychedelic drug DOI in 5-HT2AR-KO mice, and via evaluation of potential sources of false-positive and false-negative HTR events. The increased throughput in data processing achieved via automation afforded the possibility of conducting otherwise time consuming HTR time-course studies. To further assess the versatility of our system, we also explored the pharmacological interactions between 5-HT2AR and the metabotropic glutamate receptor 2 (mGluR2). Our data demonstrate the potentiation effect of the mGluR2/3 antagonist LY341495 on DOI-induced HTR, as well as the HTR-blocking effect of the mGluR2/3 agonist and antipsychotic drug in development LY404039. This fully automated system can contribute to speed up our understanding of 5-HT2AR’s pharmacology and its characteristic behavioral outputs in rodents.
Micro-scale modelling of the urban wind speed for air pollution applications
Authors: Ottosen Thor-Bjørn , Ketzel Matthias , Skov Henrik , Hertel Ole , Brandt Jørgen , Kakosimos Konstantinos E.
Published: October 2019

Modelling wind speeds in urban areas have many applications e.g. in relation to assessment of wind energy, modelling air pollution, and building design and engineering. Models for extrapolating the urban wind speed exist, but little attention has been paid to the influence of the upwind terrain and the foundations for the extrapolation schemes. To analyse the influence of the upwind terrain and the foundations for the extrapolation of the urban wind speed, measurements from six urban and non-urban stations were explored, and a model for the urban wind speed with and without upwind influence was developed and validated. The agreement between the wind directions at the stations is found to be good, and the influence of atmospheric stability, horizontal temperature gradients, land-sea breeze, temperature, global radiation and Monin-Obukhov Length is found to be small, although future work should explore if this is valid for other urban areas. Moreover, the model is found to perform reasonably well, but the upwind influence is overestimated. Areas of model improvement are thus identified. The upwind terrain thus influences the modelling of the urban wind speed to a large extent, and the fundamental assumptions for the extrapolation scheme are fulfilled for this specific case.
Cm(III) retention by calcium silicate hydrate (C-S-H) gel and secondary alteration phases in carbonate solutions with high ionic strength: A site-selective TRLFS study
Authors: Wolter Jan-Martin , Schmeide Katja , Huittinen Nina , Stumpf Thorsten
Published: October 2019

We studied the Cm(III) retention by calcium silicate hydrate (C-S-H), portlandite (Ca(OH)2) and their alteration products calcite, vaterite, and aragonite in high ionic strength carbonate-containing solutions representing specific formation waters. For this, we synthesized C-S-H gels with calcium to silicon (C/S) ratios of 1.0 and 2.0 in the absence and presence of Cm(III), resulting in Cm(III)-free and Cm(III) doped C-S-H gel, respectively. For phase identification purposes we applied X-ray diffraction (XRD) while for the identification of the Cm(III)/C-S-H binding mode we applied site-selective time-resolved laser-induced luminescence spectroscopy (TRLFS). The stability of Cm(III) doped phases under repository-relevant conditions was evaluated by studying the time-dependent release of Cm(III) from the Cm(III) doped C-S-H gel into leaching solutions containing 0.02 M NaHCO3 or 2.5 M NaCl/0.02 M NaHCO3 over 60 d. Speciation changes of Cm(III) due to leaching were followed with TRLFS while C-S-H structure alterations and secondary phase formation were monitored with XRD. From the results it could be concluded that Cm(III) is not mobilized by aqueous carbonate but either remains incorporated in the C-S-H structure and portlandite or becomes partially re-immobilized into secondary CaCO3 phases. The presence of NaCl led to an accelerated conversion of metastable secondary CaCO3 phases into calcite.
Radon concentration in self-bottled mineral spring waters as a possible public health issue
Authors: Di Carlo C. , Lepore L. , Venoso G. , Ampollini M. , Carpentieri C. , Tannino A. , Ragno E. , Magliano A. , D’Amario C. , Remetti R. , Bochicchio F.
Published: October 2019

Since 2013, the Council Directive 2013/51/Euratom has been regulating the content of radioactive substances in water intended for human consumption. However, mineral waters are exempted from this regulation, including self-bottled springs waters, where higher radon concentration are expected. Therefore, a systematic survey has been conducted on all the 33 mineral spring waters of Lazio (a region of Central Italy) in order to assess if such waters, when self-bottled, may be of concern for public health. Waters have been sampled in two different ways to evaluate the impact of bottling on radon concentration. Water sampling was possible for 20 different spring waters, with 6 samples for each one. The results show that 2 (10%) of measured mineral spring waters returned radon concentrations higher than 100 Bq L−1, i.e., the parametric value established by the Council Directive. These results, if confirmed by other surveys involving a higher number of mineral spring waters, would suggest regulating also these waters, especially in countries like Italy for which: (i) mineral water consumption is significant; (ii) mineral concession owners generally allow the consumers to fill bottles and containers, intended for transport and subsequent consumption, directly from public fountains or from fountains within the plant; (iii) the consumers’ habit of drinking self-bottled mineral water is widespread.
Bayesian spatial analysis of cholangiocarcinoma in Northeast Thailand
Authors: Suwannatrai Apiporn T. , Thinkhamrop Kavin , Clements Archie C. A. , Kelly Matthew , Suwannatrai Kulwadee , Thinkhamrop Bandit , Khuntikeo Narong , Gray Darren J. , Wangdi Kinley
Published: October 2019

Cholangiocarcinoma (CCA) is a malignant neoplasm of the biliary tract. Thailand reports the highest incidence of CCA in the world. The aim of this study was to map the distribution of CCA and identify spatial disease clusters in Northeast Thailand. Individual-level data of patients with histopathologically confirmed CCA, aggregated at the sub-district level, were obtained from the Cholangiocarcinoma Screening and Care Program (CASCAP) between February 2013 and December 2017. For analysis a multivariate Zero-inflated, Poisson (ZIP) regression model was developed. This model incorporated a conditional autoregressive (CAR) prior structure, with posterior parameters estimated using Bayesian Markov chain Monte Carlo (MCMC) simulation with Gibbs sampling. Covariates included in the models were age, sex, normalized vegetation index (NDVI), and distance to water body. There was a total of 1,299 cases out of 358,981 participants. CCA incidence increased 2.94 fold (95% credible interval [CrI] 2.62–3.31) in patients >60 years as compared to ≤60 years. Males were 2.53 fold (95% CrI: 2.24–2.85) more likely to have CCA when compared to females. CCA decreased with a 1 unit increase of NDVI (Relative Risk =0.06; 95% CrI: 0.01–0.63). When posterior means were mapped spatial clustering was evident after accounting for the model covariates. Age, sex and environmental variables were associated with an increase in the incidence of CCA. When these covariates were included in models the maps of the posterior means of the spatially structured random effects demonstrated evidence of spatial clustering.
Development of superluminal pulse propagation in a serial array of high-Q ring resonators
Authors: Morita Yuma , Tomita Makoto
Published: October 2019

We experimentally examined the development of superluminal pulse propagation through a serial array of high-Q ring resonators that provides a dynamic recurrent loop. As the propagation distance, i.e., the number of ring resonators that the pulses passed through increased, the pulse advancement increased linearly, largely maintaining its Gaussian shape. The sharp edge encoded at the front of the pulse was, however, neither advanced nor delayed, in good accordance with the idea that information propagates at the speed of light. We also carried out a numerical simulation on the superluminal to subluminal transition of the pulse velocity, which appeared after the pulse had propagated a long distance. The time delays, which we calculated using the saddle point method and based on the net delay, were in good agreement with our results, even when predictions based on the traditional group delay failed completely. This demonstrates the superluminal to subluminal transition of the propagation velocity.
Polyamine supplementation reduces DNA damage in adipose stem cells cultured in 3-D
Authors: Minguzzi Manuela , Guidotti Serena , Platano Daniela , D’Adamo Stefania , Cetrullo Silvia , Assirelli Elisa , Santi Spartaco , Mariani Erminia , Trisolino Giovanni , Filardo Giuseppe , Flamigni Flavio , Borzì Rosa Maria
Published: October 2019

According to previous research, natural polyamines exert a role in regulating cell committment and differentiation from stemness during skeletal development. In order to assess whether distinct polyamine patterns are associated with different skeletal cell types, primary cultures of stem cells, chondrocytes or osteoblasts were dedicated for HPLC analysis of intracellular polyamines. Spermine (SPM) and Spermidine (SPD) levels were higher in adipose derived stem cells (ASC) compared to mature skeletal cells, i.e. chondrocytes and osteoblasts, confirming the connection of polyamine content with stemness. To establish whether polyamines can protect ASC against oxidative DNA damage in a 3-D differentiation model, the level of γH2AX was measured by western blot, and found to correlate with age and BMI of patients. Addition of either polyamine to ASC was able to hinder DNA damage in the low micromolecular range, with marked reduction of γH2AX level at 10 µM SPM and 5 µM SPD. Molecular analysis of the mechanisms that might underlie the protective effect of polyamine supplementation evidences a possible involvement of autophagy. Altogether, these results support the idea that polyamines are able to manage both stem cell differentiation and cell oxidative damage, and therefore represent appealing tools for regenerative and cell based applications.
ADP-dependent glucokinase regulates energy metabolism via ER-localized glucose sensing
Authors: Imle Roland , Wang Bei-Tzu , Stützenberger Nicolas , Birkenhagen Jana , Tandon Amol , Carl Matthias , Himmelreich Nastassja , Thiel Christian , Gröne Hermann-Josef , Poschet Gernot , Völkers Mirko , Gülow Karsten , Schröder Anne , Carillo Sara , Mittermayr Stefan , Bones Jonathan , Kamiński Marcin Mikołaj , Kölker Stefan , Sauer Sven Wolfgang
Published: October 2019

Modulation of energy metabolism to a highly glycolytic phenotype, i.e. Warburg effect, is a common phenotype of cancer and activated immune cells allowing increased biomass-production for proliferation and cell division. Endoplasmic reticulum (ER)-localized ADP-dependent glucokinase (ADPGK) has been shown to play a critical role in T cell receptor activation-induced remodeling of energy metabolism, however the underlying mechanisms remain unclear. Therefore, we established and characterized in vitro and in vivo models for ADPGK-deficiency using Jurkat T cells and zebrafish. Upon activation, ADPGK knockout Jurkat T cells displayed increased cell death and ER stress. The increase in cell death resulted from a metabolic catastrophe and knockout cells displayed severely disturbed energy metabolism hindering induction of Warburg phenotype. ADPGK knockdown in zebrafish embryos led to short, dorsalized body axis induced by elevated apoptosis. ADPGK hypomorphic zebrafish further displayed dysfunctional glucose metabolism. In both model systems loss of ADPGK function led to defective N- and O-glycosylation. Overall, our data illustrate that ADPGK is part of a glucose sensing system in the ER modulating metabolism via regulation of N- and O-glycosylation.
Changes of Gene Expression in Euglena gracilis Obtained During the 29th DLR Parabolic Flight Campaign
Authors: Krüger Julia , Richter Peter , Stoltze Julia , Strauch Sebastian M. , Krüger Marcus , Daiker Viktor , Prasad Binod , Sonnewald Sophia , Reid Stephen , Lebert Michael
Published: October 2019

Parabolic flight maneuvers of Novespace’s Airbus A310 ZERO-G produce subsequent phases of hypergravity (about 20 s), microgravity (about 22 s) and another 20 s hypergravity on experiments located in the experiment area of the aircraft. The 29thDLR parabolic flight campaign consisted of four consecutive flight days with thirty-one parabolas each day.Euglena graciliscells were fixed with TRIzol during different acceleration conditions at the first and the last parabola of each flight. Samples were collected and analyzed with microarrays for one-color gene expression analysis. The data indicate significant changes in gene expression inE.graciliswithin short time. Hierarchical clustering shows that changes induced by the different accelerations yield reproducible effects at independent flight days. Transcription differed between the first and last parabolas indicating adaptation effects in the course of the flight. Different gene groups were found to be affected in different phases of the parabolic flight, among others, genes involved in signal transduction, calcium signaling, transport mechanisms, metabolic pathways, and stress-response as well as membrane and cytoskeletal proteins. In addition, transcripts of other areas, e.g., DNA and protein modification, were altered. The study contributes to the understanding of short-term effects of microgravity and different accelerations on cells at a molecular level.
Transcriptome Sequencing of Peripheral Blood Mononuclear Cells from Elite Controller-Long Term Non Progressors
Authors: Díez-Fuertes Francisco , De La Torre-Tarazona Humberto Erick , Calonge Esther , Pernas Maria , Alonso-Socas María del Mar , Capa Laura , García-Pérez Javier , Sakuntabhai Anavaj , Alcamí José
Published: October 2019

The elite controller (EC)-long term non-progressor (LTNP) phenotype represent a spontaneous and advantageous model of HIV-1 control in the absence of therapy. The transcriptome of peripheral blood mononuclear cells (PBMCs) collected from EC-LTNPs was sequenced by RNA-Seq and compared with the transcriptomes from other phenotypes of disease progression. The transcript abundance estimation combined with the use of supervised classification algorithms allowed the selection of 20 genes and pseudogenes, mainly involved in interferon-regulated antiviral mechanisms and cell machineries of transcription and translation, as the best predictive genes of disease progression. Differential expression analyses between phenotypes showed an altered calcium homeostasis in EC-LTNPs evidenced by the upregulation of several membrane receptors implicated in calcium-signaling cascades and intracellular calcium-mobilization and by the overrepresentation of NFAT1/Elk-1-binding sites in the promoters of the genes differentially expressed in these individuals. A coordinated upregulation of host genes associated with HIV-1 reverse transcription and viral transcription was also observed in EC-LTNPs –i.e. p21/CDKN1A, TNF, IER3 and GADD45B. We also found an upregulation of ANKRD54 in EC-LTNPs and viremic LTNPs in comparison with typical progressors and a clear alteration of type-I interferon signaling as a consequence of viremia in typical progressors before and after receiving antiretroviral therapy.
Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish
Authors: Manchanda Aayushi , Chatterjee Paroma , Bonventre Josephine A. , Haggard Derik E. , Kindt Katie S. , Tanguay Robert L. , Johnson Colin P.
Published: October 2019

The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytosis, it is unclear whether these functions are conserved across species. To address this question, we characterized the impact of otoferlin depletion in zebrafish larvae and found defects in synaptic vesicle recycling, abnormal synaptic ribbons, and higher resting calcium concentrations in hair cells. We also observed abnormal expression of the calcium binding hair cell genes s100s and parvalbumin, as well as the nogo related proteins rtn4rl2a and rtn4rl2b. Exogenous otoferlin partially restored expression of genes affected by endogenous otoferlin depletion. Our results suggest that in addition to vesicle recycling, depletion of otoferlin disrupts resting calcium levels, alters synaptic ribbon architecture, and perturbs transcription of hair cells specific genes during zebrafish development.
Antihyperlipidemic and hepatoprotective properties of alkali- and enzyme-extractable polysaccharides by Dictyophora indusiata
Authors: Wang Wenshuai , Liu Honghong , Zhang Yiwen , Feng Yanbo , Yuan Fangfang , Song Xinling , Gao Zheng , Zhang Jianjun , Song Zhen , Jia Le
Published: October 2019

Hyperlipidemia, a very common disease throughout the world, usually gives rise to severe liver damages. The current experiment was to investigate the antihyperlipidemic and hepatoprotective properties of alkali- and enzyme-extractable Dictyophora indusiata polysaccharides (Al-DPS and En-DPS) on the hyperlipidemic mice. The results of animal experiment in vivo showed that treatment with Al-DPS or En-DPS could improve the excessive level of lipid profiles in serum and liver, as well as strengthen antioxidant status. In addition, the histopathological observations of liver testified that polysaccharides were capable of attenuating hepatic cell injury. The primary structural features of Al-DPS and En-DPS were demonstrated by HPGPC, HPLC, FT-IR and NMR. Glucose tolerance test manifested that polysaccharides were able to restrain the rise of blood sugar. The results indicated that Al-DPS and En-DPS may be considered as novel compounds to treat hyperlipidemia and also act as hepatoprotective agents.
Topography and behavioral relevance of the global signal in the human brain
Authors: Li Jingwei , Bolt Taylor , Bzdok Danilo , Nomi Jason S. , Yeo B. T. Thomas , Spreng R. Nathan , Uddin Lucina Q.
Published: October 2019

The global signal in resting-state functional MRI data is considered to be dominated by physiological noise and artifacts, yet a growing literature suggests that it also carries information about widespread neural activity. The biological relevance of the global signal remains poorly understood. Applying principal component analysis to a large neuroimaging dataset, we found that individual variation in global signal topography recapitulates well-established patterns of large-scale functional brain networks. Using canonical correlation analysis, we delineated relationships between individual differences in global signal topography and a battery of phenotypes. The first canonical variate of the global signal, resembling the frontoparietal control network, was significantly related to an axis of positive and negative life outcomes and psychological function. These results suggest that the global signal contains a rich source of information related to trait-level cognition and behavior. This work has significant implications for the contentious debate over artifact removal practices in neuroimaging.
Toll-like receptor 3 as a new marker to detect high risk early stage Non-Small-Cell Lung Cancer patients
Authors: Bianchi Francesca , Milione Massimo , Casalini Patrizia , Centonze Giovanni , Le Noci Valentino M. , Storti Chiara , Alexiadis Spyridon , Truini Mauro , Sozzi Gabriella , Pastorino Ugo , Balsari Andrea , Tagliabue Elda , Sfondrini Lucia
Published: October 2019

Immune and epithelial cells express TLR3, a receptor deputed to respond to microbial signals activating the immune response. The prognostic value of TLR3 in cancer is debated and no data are currently available in NSCLC, for which therapeutic approaches that target the immune system are providing encouraging results. Dissecting the lung immune microenvironment could provide new prognostic markers, especially for early stage NSCLC for which surgery is the only treatment option. In this study we investigated the expression and the prognostic value of TLR3 on both tumor and immune compartments of stage I NSCLCs. In a cohort of 194 NSCLC stage I, TLR3 immunohistochemistry expression on tumor cells predicted a favorable outcome of early stage NSCLC, whereas on the immune cells infiltrating the tumor stroma, TLR3 expression associated with a poor overall survival. Patients with TLR3-positive immune infiltrating cells, but not tumor cells showed a worse prognosis compared with all other patients. The majority of TLR3-expressing immune cells resulted to be macrophages and TLR3 expression associates with PD-1 expression. TLR3 has an opposite prognostic significance when expressed on tumor or immune cells in early stage NCSCL. Analysis of TLR3 in tumor and immune cells can help in identifying high risk stage I patients for which adjuvant treatment would be beneficial.
Investigation of the Guinea fowl and domestic fowl hybrids as potential surrogate hosts for avian cryopreservation programmes
Authors: Molnár Mariann , Lázár Bence , Sztán Nikoletta , Végi Barbara , Drobnyák Árpád , Tóth Roland , Liptói Krisztina , Marosán Miklós , Gócza Elen , Nandi Sunil , McGrew Michael J. , Várkonyi Eszter Patakiné
Published: October 2019

In the last decade, avian gene preservation research has focused on the use of the early precursors of the reproductive cells, the primordial germ cells (PGCs). This is because avian PGCs have a unique migration route through the vascular system which offers easy accessibility. Furthermore, culturing of the cells in vitro, freezing/thawing, reintegration into a recipient embryo and the development of the germ cells can be carried out in well-defined laboratory circumstances. The efficient recovery of the donor genotype and the frequency of germline transmission from the surrogate host animals are still areas which need further development. Thus, the aim of the present study was to investigate an infertile interspecific hybrid (recipient) as an appropriate host for primordial germ cells from native poultry breeds. Guinea fowl × chicken hybrids were produced, the crossing was repeated inversely. The phenotype, the hatching time, the hatching rate, the sex ratio, the presence of own germ cells, the fertility and the phenotype of viable hybrids and the incidence of chromosomal abnormalities of dead hybrid embryos were described. 6.65% viable offspring was obtained with crossing of Guinea fowl females with domestic fowl males. Crossing of domestic fowl hens with Guinea fowl male resulted in lower fertility, 0.14% viable offspring. Based on the investigations, the observed offspring from the successful crossing were sterile male hybrids, thus an extreme form of Haldane’s rule was manifested. The sterile hybrid male embryos were tested by injecting fluorescently labeled chicken PGCs. The integration rate of labeled PGCs was measured in 7.5-day, 14.5-day and 18.5-day old embryonic gonads. 50%, 5.3% and 2.4% of the injected hybrid embryos survived and 40%, 5.3% and 2.4% of the examined gonads contained fluorescent labeled donor PGCs. Therefore, these sterile hybrid males may be suitable recipients for male PGCs and possibly for female PGCs although with lower efficiency. This research work shows that the sterility of hybrids can be used in gene conservation to be a universal host for PGCs of different avian species.
Green Synthesis of Substituted Anilines and Quinazolines from Isatoic Anhydride-8-amide
Authors: Gondi Sudershan R. , Bera Asim K. , Westover Kenneth D.
Published: October 2019

Synthetic methods used to generate substituted anilines and quinazolines, both privileged pharmacological structures, are cumbersome, hazardous or, in some cases, unavailable. We developed a straightforward method for making isatoic anhydride-8-amide from isatin-7-carboxylic acid as a tool to easily produce a range of quinazoline and substituted aniline derivatives using adaptable pH-sensitive cyclization chemistry. The approaches are inexpensive, simple, fast, efficient at room temperature and scalable, enabling the synthesis of both established and new quinazolines and also highly substituted anilines including cyano derivatives.
Microscopic Characterization of Biological and Inert Particles Associated with Spacecraft Assembly Cleanroom
Authors: Malli Mohan Ganesh Babu , Stricker Moogega Cooper , Venkateswaran Kasthuri
Published: October 2019

NASA cleanrooms are certified by particle counts and are humidity-controlled, temperature-regulated, and oligotrophic in nature for assembling spacecraft subsystems. Microorganisms, which are not part of the cleanroom certification metrics, should not be overlooked when assessing the cleanliness of the facility since they can enter through soil or air, shed from humans, adapt to the oligotrophic conditions, and subsequently could contaminate spacecraft. These biogenic particles need to be identified to extend our knowledge of biological contamination for future NASA mission use. This study collected particles from the cleanroom and estimated the distribution of fallout microbial cell and inert dust particles using microscopy and molecular techniques. Aluminum coupon-based polycarbonate filter assemblies were deployed in the spacecraft assembly cleanroom facility to collect fallout particles. Epifluorescence and electron microscopy showed that particles varied in size and structure, and displayed live/dead biological and inert particle signatures from sources that include spores and fungal hyphae. Additionally, correlative epifluorescence and field emission scanning electron microscopy, combined with energy-dispersive X-ray analysis (for elemental compositions) methods, differentiated whether microbes adhering to particles were live/dead cells or inert particles. This visualization approach allowed for the classification of microorganisms as being standalone (free-living) or associated with a particle, as well as its characteristic size. Furthermore, time-course microscopy was used to determine the microbial cell growth and confirm the biological/molecular identification. Routine investigation of cleanroom biological and inert fallout particles will help to determine the biological load of spacecraft components and will also have direct relevance to the pharmaceutical and medical industries. One of the main objectives for NASA’s current and future missions is to prevent forward and back contamination of exploring planets. The goal of this study is to determine the association of microorganisms with the inert, natural cleanroom fallout particles and to ascertain whether microorganisms prefer to adhere to a particle size. A novel microscopy technique was developed, and by utilizing various molecular techniques, particles and associated microbial phylogeny were characterized. An accurate assessment of the microbes associated with cleanroom particles is necessary to protect the health of the people who occupy the room for long duration for aeronautical, medical, and pharmaceutical industries.
Interaction of tumor cells and astrocytes promotes breast cancer brain metastases through TGF-β2/ANGPTL4 axes
Authors: Gong Xianghui , Hou Zhimin , Endsley Michael P. , Gronseth Emily I. , Rarick Kevin R. , Jorns Julie M. , Yang Qiuhui , Du Zhenggui , Yan Ke , Bordas Michelle L. , Gershan Jill , Deepak Parashar , Geethadevi Anjali , Chaluvally-Raghavan Pradeep , Fan Yubo , Harder David R. , Ramchandran Ramani , Wang Ling
Published: October 2019

Metastatic outcomes depend on the interactions of metastatic cells with a specific organ microenvironment. Our previous studies have shown that triple-negative breast cancer (TNBC) MDA-MB-231 cells passaged in astrocyte-conditioned medium (ACM) show proclivity to form brain metastases, but the underlying mechanism is unknown. The combination of microarray analysis, qPCR, and ELISA assay were carried out to demonstrate the ACM-induced expression of angiopoietin-like 4 (ANGPTL4) in TNBC cells. A stable ANGPTL4-knockdown MDA-MB-231 cell line was generated by ANGPTL4 short-hairpin RNA (shRNA) and inoculated into mice via left ventricular injection to evaluate the role of ANGPTL4 in brain metastasis formation. The approaches of siRNA, neutralizing antibodies, inhibitors, and immunoprecipitation were used to demonstrate the involved signaling molecules. We first found that ACM-conditioned TNBC cells upregulated the expression of ANGPTL4, a secreted glycoprotein whose effect on tumor progression is known to be tumor microenvironment- and tumor-type dependent. Knockdown of ANGPTL4 in TNBC MDA-MB-231 cells with shRNA decreased ACM-induced tumor cell metastatic growth in the brain and attributed to survival in a mouse model. Furthermore, we identified that astrocytes produced transforming growth factor-beta 2 (TGF-β2), which in part is responsible for upregulation of ANGPTL4 expression in TNBC through induction of SMAD signaling. Moreover, we identified that tumor cells communicate with astrocytes, where tumor cell-derived interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) increased the expression of TGF-β2 in astrocytes. Collectively, these findings indicate that the invading TNBC cells interact with astrocytes in the brain microenvironment that facilitates brain metastases of TNBC cells through a TGF-β2/ANGPTL4 axis. This provides groundwork to target ANGPTL4 as a treatment for breast cancer brain metastases.
Metabolomics for improved treatment monitoring of phenylketonuria: urinary biomarkers for non-invasive assessment of dietary adherence and nutritional deficiencies
Authors: Wild Jennifer , Shanmuganathan Meera , Hayashi Mika , Potter Murray , Britz-McKibbin Philip
Published: October 2019

Improved treatment monitoring of PKU patients: urinary biomarkers of dietary adherence and nutritional status.
Screening a specific Zn(ii)-binding peptide for improving the cognitive decline of Alzheimer's disease in APP/PS1 transgenic mice by inhibiting Zn2+-mediated amyloid protein aggregation and neurotoxicity
Authors: Zhang Xiaoyu , Zhong Manli , Zhao Pu , Zhang Xiancheng , Li You , Wang Xuliang , Sun Jia , Lan Wang , Sun Hehong , Wang Zhanyou , Gao Huiling
Published: October 2019

PZn screen from phage display technique and PZn loaded nanoparticles inhibiting Aβ aggregation and neurotoxicity in vitro and in vivo.
Targeted photothermal therapy of mice and rabbits realized by macrophage-loaded tungsten carbide
Authors: Gao Yan , Huang Weicheng , Yang Chunyu , Liu Zhao , Meng Hongxue , Yang Bin , Xu Yanling , Guo Chongshen
Published: October 2019

This work realized successful photothermal ablation of solid tumor on both mice and rabbits modal in a targetable way.