bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal resource conditions favor a summertime increase in North Pacific diatom–diazotroph associations
Authors: Follett Christopher L , Dutkiewicz Stephanie , Karl David M , Inomura Keisuke , Follows Michael J
Published: February 2018

In the North Pacific Subtropical Gyre (NPSG), an annual pulse of sinking organic carbon is observed at 4000 m between July and August, driven by large diatoms found in association with nitrogen fixing, heterocystous, cyanobacteria: Diatom–Diazotroph Associations (DDAs). Here we ask what drives the bloom of DDAs and present a simplified trait-based model of subtropical phototroph populations driven by observed, monthly averaged, environmental characteristics. The ratio of resource supply rates favors nitrogen fixation year round. The relative fitness of DDA traits is most competitive in early summer when the mixed layer is shallow, solar irradiance is high, and phosphorus and iron are relatively abundant. Later in the season, as light intensity drops and phosphorus is depleted, the traits of small unicellular diazotrophs become more competitive. The competitive transition happens in August, at the time when the DDA export event occurs. This seasonal dynamic is maintained when embedded in a more complex, global-scale, ecological model, and provides predictions for the extent of the North Pacific DDA bloom. The model provides a parsimonious and testable hypothesis for the stimulation of DDA blooms.
Microbial cycling of isoprene, the most abundantly produced biological volatile organic compound on Earth
Authors: McGenity Terry J , Crombie Andrew T , Murrell J Colin
Published: February 2018

Isoprene (2-methyl-1,3-butadiene), the most abundantly produced biogenic volatile organic compound (BVOC) on Earth, is highly reactive and can have diverse and often detrimental atmospheric effects, which impact on climate and health. Most isoprene is produced by terrestrial plants, but (micro)algal production is important in aquatic environments, and the relative bacterial contribution remains unknown. Soils are a sink for isoprene, and bacteria that can use isoprene as a carbon and energy source have been cultivated and also identified using cultivation-independent methods from soils, leaves and coastal/marine environments. Bacteria belonging to the Actinobacteria are most frequently isolated and identified, and Proteobacteria have also been shown to degrade isoprene. In the freshwater-sediment isolate, Rhodococcus strain AD45, initial oxidation of isoprene to 1,2-epoxy-isoprene is catalyzed by a multicomponent isoprene monooxygenase encoded by the genes isoABCDEF. The resultant epoxide is converted to a glutathione conjugate by a glutathione S-transferase encoded by isoI, and further degraded by enzymes encoded by isoGHJ. Genome sequence analysis of actinobacterial isolates belonging to the genera Rhodococcus, Mycobacterium and Gordonia has revealed that isoABCDEF and isoGHIJ are linked in an operon, either on a plasmid or the chromosome. In Rhodococcus strain AD45 both isoprene and epoxy-isoprene induce a high level of transcription of 22 contiguous genes, including isoABCDEF and isoGHIJ. Sequence analysis of the isoA gene, encoding the large subunit of the oxygenase component of isoprene monooxygenase, from isolates has facilitated the development of PCR primers that are proving valuable in investigating the ecology of uncultivated isoprene-degrading bacteria.
Coral bleaching from a single cell perspective
Authors: Nielsen Daniel Aagren , Petrou Katherina , Gates Ruth D
Published: February 2018

Ocean warming is resulting in increased occurrence of mass coral bleaching; a response in which the intracellular algal endosymbionts (Symbiodinium sp.) are expelled from the coral host due to physiological stress. This detrimental process is often attributed to overproduction of reactive oxygen species (ROS) that leak out of the endosymbionts and causes damage to the host cell, though direct evidence validating this link is limited. Here, for the first time, we used confocal microscopy and fluorescent dyes to investigate if endosymbiont ROS production significantly and predictably affects physiological parameters in its host cell. Heat treatment resulted in a 60% reduction in coral symbiont density, a ~70% increase in median endosymbiont ROS and a small reduction in photosystem efficiency (FV/FM, 11%), indicating absence of severe light stress. Notably, no other physiological parameters were affected in either endosymbionts or host cells, including reduced glutathione and ROS-induced lipid peroxidation. Taken together, the increase in endosymbiont ROS could not be linked to physiological damage in either partner, suggesting that oxidative stress is unlikely to have been the driver for symbiont expulsion in this study.
SPRY2 is a novel MET interactor that regulates metastatic potential and differentiation in rhabdomyosarcoma
Authors: Saini Masum , Verma Aakanksha , Mathew Sam J.
Published: February 2018

Rhabdomyosarcoma (RMS) is a predominantly pediatric soft-tissue cancer where the tumor cells exhibit characteristics of the developing skeletal muscle, and the two most common sub-types are embryonal and alveolar RMS. Elevated activation of the receptor tyrosine kinase (RTK) MET is frequent in RMS and is thought to cause increased tumor metastasis and lack of differentiation. However, the reasons underlying dysregulated MET expression and activation in RMS are not well understood. Therefore, we explored the role of Sprouty 2 (SPRY2), a modulator of RTK signaling, in regulating MET. We identify SPRY2 as a novel MET interactor that colocalizes with and binds MET in both embryonal and alveolar RMS. We find that depletion of SPRY2 leads to MET degradation, resulting in reduced migratory and clonogenic potential, and induction of differentiation in both embryonal and alveolar RMS, outcomes that are identical to depletion of MET. Activation of the ERK/MAPK pathway, known to be crucial for regulating cell migration and whose inhibition is required for myogenic differentiation, was downregulated upon depletion of MET or SPRY2. This provides a direct connection to the decreased migration and induction of differentiation upon depletion of MET or SPRY2. Thus, these data indicate that SPRY2 interacts with MET and stabilizes it in order to maintain signaling downstream of MET, which keeps the ERK/MAPK pathway active, resulting in metastatic potential and inhibition of differentiation in RMS. Our results identify a novel mechanism by which MET signaling is stabilized in RMS, and is a potential target for therapeutic intervention in RMS.
The cytotoxicity of coxsackievirus B3 is associated with a blockage of autophagic flux mediated by reduced syntaxin 17 expression
Authors: Tian Lang , Yang Yeyi , Li Chunyun , Chen Jia , Li Zhuoying , Li Xin , Li Shentang , Wu Fang , Hu Zhangxue , Yang Zuocheng
Published: February 2018

Coxsackievirus B3 (CVB3) is an important human pathogen linked to cardiac arrhythmias and acute heart failure. CVB3 infection has been reported to induce the formation of autophagosomes that support the viral replication in host cells. Interestingly, our study shows that the accumulation of autophagosomes during CVB3 infection is caused by a blockage of autophagosome–lysosome fusion rather than the induction of autophagosome biogenesis. Moreover, CVB3 decreases the transcription and translation of syntaxin 17 (STX17), a SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein involved in autophagosome–lysosome fusion. Overexpression of STX17 restored the autophagic flux, alleviated the virus-induced lysosomal dysfunction, and decreased the apoptosis induced by CVB3 infection in HeLa cells. Taken together, our results suggest that CVB3 infection impairs the autophagic flux by blocking autophagosome–lysosome fusion. These findings thus point to potential new therapeutic strategies targeting STX17 or autophagosome–lysosome fusion for treating CVB3-associated diseases.
BRM270 inhibits cancer stem cell maintenance via microRNA regulation in chemoresistant A549 lung adenocarcinoma cells
Authors: Kwon Taeho , Chandimali Nisansala , Huynh Do Luong , Zhang Jiao Jiao , Kim Nameun , Bak Yesol , Yoon Do-Young , Yu Dae-Yeul , Lee Jae Cheol , Gera Meeta , Ghosh Mrinmoy , Park Yang Ho , Jeong Dong Kee
Published: February 2018

Chemotherapy is a standard treatment for non-small-cell lung cancer (NSCLC). However, the dose-limiting toxicity of drugs and the development of chemoresistance are major clinical challenges to successful management of NSCLC. Asian traditional medicine is gaining global attention as a non-toxic alternative to chemotherapy. BRM270 is an extract formulated from seven Asian medicinal plants that has been shown to inhibit tumor cell proliferation in diverse cancer types. We previously demonstrated that BRM270 suppresses tumorigenesis by negatively regulating nuclear factor-κB signaling in multidrug-resistant cancer stem cells (CSCs). In this study we report that the growth, migration, and invasion of normal human lung adenocarcinoma cells and their chemoresistant derivatives was inhibited by BRM270 treatment. Notably, BRM270 was found to modulate CSC self-renewal and tumor-initiating capacity via positive regulation of the miRNA-128. Thus, combination therapy with miRNA-128 and BRM270 may be an effective treatment strategy for chemoresistant NSCLC.
Pyruvate kinase M2 regulates photoreceptor structure, function, and viability
Authors: Rajala Ammaji , Wang Yuhong , Brush Richard S. , Tsantilas Kristine , Jankowski Connor S. R. , Lindsay Ken J. , Linton Jonathan D. , Hurley James B. , Anderson Robert E. , Rajala Raju V. S.
Published: February 2018

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that is expressed in cancer cells. Its role in tumor metabolism is not definitively established, but investigators have suggested that regulation of PKM2 activity can cause accumulation of glycolytic intermediates and increase flux through the pentose phosphate pathway. Recent evidence suggests that PKM2 also may have non-metabolic functions, including as a transcriptional co-activator in gene regulation. We reported previously that PKM2 is abundant in photoreceptor cells in mouse retinas. In the present study, we conditionally deleted PKM2 (rod-cre PKM2-KO) in rod photoreceptors and found that the absence of PKM2 causes increased expression of PKM1 in rods. Analysis of metabolic flux from U-13C glucose shows that rod-cre PKM2-KO retinas accumulate glycolytic intermediates, consistent with an overall reduction in the amount of pyruvate kinase activity. Rod-cre PKM2-KO mice also have an increased NADPH availability could favor lipid synthesis, but we found no difference in phospholipid synthesis between rod-cre PKM2 KO and PKM2-positive controls. As rod-cre PKM2-KO mice aged, we observed a significant loss of rod function, reduced thickness of the photoreceptor outer segment layer, and reduced expression of photoreceptor proteins, including PDE6β. The rod-cre PKM2-KO retinas showed greater TUNEL staining than wild-type retinas, indicating a slow retinal degeneration. In vitro analysis showed that PKM2 can regulate transcriptional activity from the PDE6β promoter in vitro. Our findings indicate that both the metabolic and transcriptional regulatory functions of PKM2 may contribute to photoreceptor structure, function, and viability.
Glycogen synthase kinase-3β inhibition promotes lysosome-dependent degradation of c-FLIPL in hepatocellular carcinoma
Authors: Zhang Na , Liu Xiaojia , Liu Lu , Deng Zhesong , Zeng Qingxuan , Pang Weiqiang , Liu Yang , Song Danqing , Deng Hongbin
Published: February 2018

Glycogen synthase kinase-3β (GSK-3β) is a ubiquitously expressed serine/threonine kinase involved in a variety of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK-3β inhibition triggered ASK1-JNK-dependent apoptosis in human hepatocellular carcinoma (HCC) cells. However, the comprehensive picture of downstream GSK-3β-regulated pathways/functions remains elusive. In this study, we showed that GSK-3β was aberrantly activated in HCC. Pharmacological inhibition and genetic depletion of GSK-3β suppressed the growth and induced caspase-dependent apoptosis in HCC cells. In addition, GSK-3β inhibition-induced apoptosis through downregulation of c-FLIPL in HCC, which was caused by biogenesis of functional lysosomes and subsequently c-FLIPL translocated to lysosome for degradation. This induction of the lysosome-dependent c-FLIPL degradation was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Moreover, GSK-3β inhibition-induced TFEB translocation acts through activation of AMPK and subsequently suppression of mTOR activity. Thus our findings reveal a novel mechanism by which inhibition of GSK-3β promotes lysosome-dependent degradation of c-FLIPL. Our study shows that GSK-3β may become a promising therapeutic target for HCC.
Baicalin administration attenuates hyperglycemia-induced malformation of cardiovascular system
Authors: Wang Guang , Liang Jianxin , Gao Lin-rui , Si Zhen-peng , Zhang Xiao-tan , Liang Guo , Yan Yu , Li Ke , Cheng Xin , Bao Yongping , Chuai Manli , Chen Li-guo , Lu Da-xiang , Yang Xuesong
Published: February 2018

In this study, the effects of Baicalin on the hyperglycemia-induced cardiovascular malformation during embryo development were investigated. Using early chick embryos, an optimal concentration of Baicalin (6 μM) was identified which could prevent hyperglycemia-induced cardiovascular malformation of embryos. Hyperglycemia-enhanced cell apoptosis was reduced in embryos and HUVECs in the presence of Baicalin. Hyperglycemia-induced excessive ROS production was inhibited when Baicalin was administered. Analyses of SOD, GSH-Px, MQAE and GABAA suggested Baicalin plays an antioxidant role in chick embryos possibly through suppression of outwardly rectifying Cl(−) in the high-glucose microenvironment. In addition, hyperglycemia-enhanced autophagy fell in the presence of Baicalin, through affecting the ubiquitin of p62 and accelerating autophagy flux. Both Baicalin and Vitamin C could decrease apoptosis, but CQ did not, suggesting autophagy to be a protective function on the cell survival. In mice, Baicalin reduced the elevated blood glucose level caused by streptozotocin (STZ). Taken together, these data suggest that hyperglycemia-induced embryonic cardiovascular malformation can be attenuated by Baicalin administration through suppressing the excessive production of ROS and autophagy. Baicalin could be a potential candidate drug for women suffering from gestational diabetes mellitus.
The oncogene Etv5 promotes MET in somatic reprogramming and orchestrates epiblast/primitive endoderm specification during mESCs differentiation
Authors: Zhang Jinglong , Cao Hongxia , Xie Jing , Fan Chen , Xie Youlong , He Xin , Liao Mingzhi , Zhang Shiqiang , Wang Huayan
Published: February 2018

Unipotent spermatogonial stem cells (SSCs) can be efficiently reprogrammed into pluripotent stem cells only by manipulating the culture condition, without introducing exogenous reprogramming factors. This phenotype raises the hypothesis that the endogenous transcription factors (TFs) in SSCs may facilitate reprogramming to acquire pluripotency. In this study, we screened a pool of SSCs TFs (Bcl6b, Lhx1, Foxo1, Plzf, Id4, Taf4b, and Etv5), and found that oncogene Etv5 could dramatically increase the efficiency of induced pluripotent stem cells (iPSCs) generation when combined with Yamanaka factors. We also demonstrated that Etv5 could promote mesenchymal-epithelial transition (MET) at the early stage of reprogramming by regulating Tet2-miR200s-Zeb1 axis. In addition, Etv5 knockdown in mouse embryonic stem cells (mESCs) could decrease the genomic 5hmC level by downregulating Tet2. Furthermore, the embryoid body assay revealed that Etv5 could positively regulate primitive endoderm specification through regulating Gata6 and negatively regulate epiblast specification by inhibiting Fgf5 expression. In summary, our findings provide insights into understanding the regulation mechanisms of Etv5 under the context of somatic reprogramming, mESCs maintenance, and differentiation.
Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy
Authors: Celestini Valentina , Tezil Tugsan , Russo Luciana , Fasano Candida , Sanese Paola , Forte Giovanna , Peserico Alessia , Lepore Signorile Martina , Longo Giovanna , De Rasmo Domenico , Signorile Anna , Gadaleta Raffaella Maria , Scialpi Natasha , Terao Mineko , Garattini Enrico , Cocco Tiziana , Villani Gaetano , Moschetta Antonio , Grossi Valentina , Simone Cristiano
Published: February 2018

While aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism. Using FoxO3A−/− cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being impaired in their nuclear or mitochondrial subcellular localization, we show that mitochondrial FoxO3A promotes survival in response to metabolic stress. In cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for apoptosis induction by metformin. Elucidation of FoxO3A mitochondrial vs. nuclear functions in cancer cell homeostasis might help devise novel therapeutic strategies to selectively disable FoxO3A prosurvival activity.
Preserving self-renewal of porcine pluripotent stem cells in serum-free 3i culture condition and independent of LIF and b-FGF cytokines
Authors: Ma Yangyang , Yu Tong , Cai Yuanxing , Wang Huayan
Published: February 2018

Derivation of bona fide porcine pluripotent stem cells is still a critical issue because porcine embryonic stem cells (ESCs) are not available yet, and most of the culture conditions to maintain porcine induced pluripotent stem cells (piPSCs) are based on conditions for mouse and human iPS cells. In this study, we generated a doxycycline-inducible porcine iPS cell line (DOX-iPSCs) and used it to screen the optimal culture condition to sustain the self-renewal of piPSCs. We found that LIF and b-FGF were required for porcine cell reprogramming, but were not essential cytokines for maintaining the self-renewal and pluripotency of piPSCs. A serum-free 3i medium, which includes three inhibitors CHIR99021, SB431542, and PD0325901, three cytokines BMP4, SCF, and IL-6, and human platelet lysates (PL), was made through serious selections. In 3i condition, the doxycycline-inducible iPSCs could be passaged for a long term without the addition of doxycycline, and the flattened morphology of intermediate state piPSCs could convert to the naïve-like morphology with the increase in endogenous pluripotent gene expressions. Additionally, pPSC cell line isolated from 5.5 days blastocysts could be sustained in 3i medium and the expression of endogenous pluripotent genes OCT4, ESRRB, and STELLA was significantly increased. Our finding directed a new reprogramming strategy by using 3i condition to maintain and convert primed piPSCs into naïve-like pluripotent state. A combination of traditional LIF/b-FGF conditions and 3i condition may help us to find out an appropriate reprogramming approach to generate the naïve state of porcine iPSCs.
LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during late mitosis
Authors: Hong Ye , Sonneville Remi , Wang Bin , Scheidt Viktor , Meier Bettina , Woglar Alexander , Demetriou Sarah , Labib Karim , Jantsch Verena , Gartner Anton
Published: February 2018

Faithful chromosome segregation and genome maintenance requires the removal of all DNA bridges that physically link chromosomes before cells divide. Using C. elegans embryos we show that the LEM-3/Ankle1 nuclease defines a previously undescribed genome integrity mechanism by processing DNA bridges right before cells divide. LEM-3 acts at the midbody, the structure where abscission occurs at the end of cytokinesis. LEM-3 localization depends on factors needed for midbody assembly, and LEM-3 accumulation is increased and prolonged when chromatin bridges are trapped at the cleavage plane. LEM-3 locally processes chromatin bridges that arise from incomplete DNA replication, unresolved recombination intermediates, or the perturbance of chromosome structure. Proper LEM-3 midbody localization and function is regulated by AIR-2/Aurora B kinase. Strikingly, LEM-3 acts cooperatively with the BRC-1/BRCA1 homologous recombination factor to promote genome integrity. These findings provide a molecular basis for the suspected role of the LEM-3 orthologue Ankle1 in human breast cancer.
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
Authors: Herling Carmen D. , Abedpour Nima , Weiss Jonathan , Schmitt Anna , Jachimowicz Ron Daniel , Merkel Olaf , Cartolano Maria , Oberbeck Sebastian , Mayer Petra , Berg Valeska , Thomalla Daniel , Kutsch Nadine , Stiefelhagen Marius , Cramer Paula , Wendtner Clemens-Martin , Persigehl Thorsten , Saleh Andreas , Altmüller Janine , Nürnberg Peter , Pallasch Christian , Achter Viktor , Lang Ulrich , Eichhorst Barbara , Castiglione Roberta , Schäfer Stephan C. , Büttner Reinhard , Kreuzer Karl-Anton , Reinhardt Hans Christian , Hallek Michael , Frenzel Lukas P. , Peifer Martin
Published: February 2018

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.
Author Correction: North Atlantic variability and its links to European climate over the last 3000 years
Authors: Moffa-Sánchez Paola , Hall Ian R.
Published: February 2018

In the original version of this Article, the third sentence of the first paragraph of the “Changes in the input of polar waters into the Labrador Sea” section of the Results originally incorrectly read ‘During the spring-summer months, after the winter convection has ceased in the Labrador Sea, its northwest boundary currents (the EGC and IC) support restratification of the surface ocean through lateral transport.’ The correct version states ‘northeast’ instead of ‘northwest’. The fifth sentence of the second paragraph of the same section originally incorrectly read “In contrast, in the western section of the Nordic Seas, under the presence of warm Atlantic waters of the Norwegian Current, Nps was found to calcify deeper in the water column (100–200 m), whereas in the east under the influence of the EGC polar waters it calcified closer to the surface at a similar depth as Tq23.” The correct version states ‘eastern’ instead of ‘western’ and ‘west’ instead of ‘east’.The seventh sentence of the same paragraph originally incorrectly read “Small/large differences in Δδ18ONps-Tq indicating increased/decreased presence of warm and salty Atlantic IC waters vs. polar EGC waters in the upper water column, respectively.” The correct version starts ‘Large/small’ rather than ‘Small/large’.These errors have been corrected in both the PDF and HTML versions of the Article.
Secondary Phase Interaction at Interfaces of High-Strength Brazed Joints made using Liquid Phase Sintered Alumina Ceramics and Ag-Cu-Ti Braze Alloys
Authors: Kassam T. A. , Hari Babu N. , Ludford N. , Yan S. , Howkins A.
Published: February 2018

Alumina-to-alumina brazed joints were formed using 96.0 and 99.7 wt.% Al2O3 ceramics using 150 µm thick Ticusil® (68.8Ag-26.7Cu-4.7 wt.% Ti) braze preforms. Brazing was conducted in a vacuum of 1 × 10−5 mbar at 850 °C for 10 minutes. Joint strengths were evaluated using four-point bend testing and were compared to the monolithic flexural strengths of standard alumina test bars according to ASTM C1161-13. Brazed joints made using 96.0 wt.% Al2O3 consistently outperformed brazed joints made using 99.7 wt.% Al2O3, despite similarities in both the flexural strengths of the standard alumina test bars and the microstructures of brazed joints. Secondary phase interaction led to the formation of Ti5Si3 reaction products at locations where the triple pocket grain boundaries of the 96.0 wt.% Al2O3 surface intersected the Ti-rich reaction layers. It is proposed that due to this interaction, brazed joints made using 96.0 wt.% Al2O3, which were relatively cost-effective to produce, achieved higher strengths than brazed joints made using 99.7 wt.% Al2O3.
Remodeling of the Candida glabrata cell wall in the gastrointestinal tract affects the gut microbiota and the immune response
Authors: Charlet Rogatien , Pruvost Youri , Tumba Gael , Istel Fabian , Poulain Daniel , Kuchler Karl , Sendid Boualem , Jawhara Samir
Published: February 2018

The gastrointestinal (GI) microbiota acts a natural barrier to the proliferation of opportunistic pathogens. Candida glabrata is an opportunistic yeast pathogen that has adapted to colonize all segments of the human GI tract. We observed an increase in Escherichia coli, Enterococcus faecalis, and Bacteroides vulgatus populations, and a decrease in Lactobacillus johnsonii, Bacteroides thetaiotaomicron, and Bifidobacterium animalis in mice with DSS-induced colitis. This reduction was more pronounced for L. johnsonii during C. glabrata overgrowth. In addition, C. glabrata overgrowth increased mouse mortality and inflammatory parameters, and modulated the expression of intestinal receptors and signaling pathways. The C. glabrata cell wall underwent various changes during the course of C. glabrata colonization, and showed a significant increase in chitin. C. glabrata deficient in chitin synthase-3 induced fewer inflammatory parameters than the parental strain during intestinal inflammation. Oral administration of chitin attenuated the impact of colitis, and reduced the number of aerobic bacteria and C. glabrata overgrowth, while chitinase-3-like protein-1 increased. This study provides evidence that inflammation of the gut alters the microbial balance and leads to C. glabrata cell wall remodeling through an increase in chitin, which is involved in promoting persistence of C. glabrata in the gut.
VPS4 is a dynamic component of the centrosome that regulates centrosome localization of γ-tubulin, centriolar satellite stability and ciliogenesis
Authors: Ott Carolyn , Nachmias Dikla , Adar Shai , Jarnik Michal , Sherman Shachar , Birnbaum Ramon Y. , Lippincott-Schwartz Jennifer , Elia Natalie
Published: February 2018

The hexameric AAA ATPase VPS4 facilitates ESCRT III filament disassembly on diverse intracellular membranes. ESCRT III components and VPS4 have been localized to the ciliary transition zone and spindle poles and reported to affect centrosome duplication and spindle pole stability. How the canonical ESCRT pathway could mediate these events is unclear. We studied the association of VPS4 with centrosomes and found that GFP-VPS4 was a dynamic component of both mother and daughter centrioles. A mutant, VPS4EQ, which can’t hydrolyze ATP, was less dynamic and accumulated at centrosomes. Centrosome localization of the VPS4EQ mutant, caused reduced γ-tubulin levels at centrosomes and consequently decreased microtubule growth and altered centrosome positioning. In addition, preventing VPS4 ATP hydrolysis nearly eliminated centriolar satellites and paused ciliogensis after formation of the ciliary vesicle. Zebrafish embryos injected with GFP-VPS4EQ mRNA were less viable, exhibited developmental defects and had fewer cilia in Kupffer’s vesicle. Surprisingly, ESCRT III proteins seldom localized to centrosomes and their depletion did not lead to these phenotypes. Our data support an ESCRT III-independent function for VPS4 at the centrosome and reveal that this evolutionary conserved AAA ATPase influences diverse centrosome functions and, as a result, global cellular architecture and development.
Autoantibodies against the Immunoglobulin-Binding Region of Ro52 Link its Autoantigenicity with Pathogen Neutralization
Authors: Burbelo Peter D. , Teos Leyla Y. , Herche Jesse L. , Iadarola Michael J. , Alevizos Ilias
Published: February 2018

Ro52/TRIM21 plays a key role in antibody-dependent pathogen neutralization and is a major autoantigen in systemic lupus erythematosus, Sjögren’s syndrome (SS), and other autoimmune diseases. Here we evaluated immunoreactivity against Ro52-related molecules in SS and healthy volunteers. Although most proteins examined were not antigenic, several TRIM paralogs, including TRIM22, and TRIM38, showed sporadic immunoreactivity in SS. In contrast, the murine Ro52 ortholog with limited linear homology demonstrated high levels of autoantibodies implicating the importance of shared conformational epitopes. To further explore the autoantigencity of Ro52, deletion and point mutant analyses were employed revealing previously hidden, robust autoantibodies directed against its C-terminal immunoglobulin-binding domain. Another autoantibody, rheumatoid factor, targeting the Fc region of IgG, strongly overlapped with Ro52 seropositivity (odds ratio 14; P < 0.0001). These convergent mechanistic findings support a model whereby intracellular Ro52-bound antibody-coated pathogen complexes, released or misprocessed from infected cells, drive autoantigenicity against Ro52 and the Fc region of IgG.
Caudal autotomy as anti-predatory behaviour in Palaeozoic reptiles
Authors: LeBlanc A. R. H. , MacDougall M. J. , Haridy Y. , Scott D. , Reisz R. R.
Published: February 2018

Many lizards can drop a portion of their tail in response to an attack by a predator, a behaviour known as caudal autotomy. The capacity for intravertebral autotomy among modern reptiles suggests that it evolved in the lepidosaur branch of reptilian evolution, because no such vertebral features are known in turtles or crocodilians. Here we present the first detailed evidence of the oldest known case of caudal autotomy, found only among members of the Early Permian captorhinids, a group of ancient reptiles that diversified extensively and gained a near global distribution before the end-Permian  mass extinction event of the Palaeozoic. Histological and SEM evidence show that these early reptiles were the first amniotes that could autotomize their tails, likely as an anti-predatory behaviour. As in modern iguanid lizards, smaller captorhinids were able to drop their tails as juveniles, presumably as a mechanism to evade a predator, whereas larger individuals may have gradually lost this ability. Caudal autotomy in captorhinid reptiles highlights the antiquity of this anti-predator behaviour in a small member of a terrestrial community composed predominantly of larger amphibian and synapsid predators.
Chaotic Dynamics of Inner Ear Hair Cells
Authors: Faber Justin , Bozovic Dolores
Published: February 2018

Experimental records of active bundle motility are used to demonstrate the presence of a low-dimensional chaotic attractor in hair cell dynamics. Dimensionality tests from dynamic systems theory are applied to estimate the number of independent variables sufficient for modelling the hair cell response. Poincaré maps are constructed to observe a quasiperiodic transition from chaos to order with increasing amplitudes of mechanical forcing. The onset of this transition is accompanied by a reduction of Kolmogorov entropy in the system and an increase in transfer entropy between the stimulus and the hair bundle, indicative of signal detection. A simple theoretical model is used to describe the observed chaotic dynamics. The model exhibits an enhancement of sensitivity to weak stimuli when the system is poised in the chaotic regime. We propose that chaos may play a role in the hair cell’s ability to detect low-amplitude sounds.
Zearalenone altered the cytoskeletal structure via ER stress- autophagy- oxidative stress pathway in mouse TM4 Sertoli cells
Authors: Zheng Wanglong , Wang Bingjie , Si Mengxue , Zou Hui , Song Ruilong , Gu Jianhong , Yuan Yan , Liu Xuezhong , Zhu Guoqiang , Bai Jianfa , Bian Jianchun , Liu ZongPing
Published: February 2018

The aim of this study was to investigate the molecular mechanisms of the destruction of cytoskeletal structure by Zearalenone (ZEA) in mouse-derived TM4 cells. In order to investigate the role of autophagy, oxidative stress and endoplasmic reticulum(ER) stress in the process of destruction of cytoskeletal structure, the effects of ZEA on the cell viability, cytoskeletal structure, autophagy, oxidative stress, ER stress, MAPK and PI3K- AKT- mTOR signaling pathways were studied. The data demonstrated that ZEA damaged the cytoskeletal structure through the induction of autophagy that leads to the alteration of cytoskeletal structure via elevated oxidative stress. Our results further showed that the autophagy was stimulated by ZEA through PI3K-AKT-mTOR and MAPK signaling pathways in TM4 cells. In addition, ZEA also induced the ER stress which was involved in the induction of the autophagy through inhibiting the ERK signal pathway to suppress the phosphorylation of mTOR. ER stress was involved in the damage of cytoskeletal structure through induction of autophagy by producing ROS. Taken together, this study revealed that ZEA altered the cytoskeletal structure via oxidative stress - autophagy- ER stress pathway in mouse TM4 Sertoli cells.
Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways
Authors: Fang Qing-Qing , Wang Xiao-Feng , Zhao Wan-Yi , Ding Shi-Li , Shi Bang-Hui , Xia Ying , Yang Hu , Wu Li-Hong , Li Cai-Yun , Tan Wei-Qiang
Published: February 2018

Angiotensin-converting enzyme inhibitors (ACEIs) can improve the fibrotic processes in many internal organs. Recent studies have shown a relationship between ACEI with cutaneous scar formation, although it has not been confirmed, and the underlying mechanism is unclear. In this study, we cultured mouse NIH 3T3 fibroblasts with different concentrations of ACEI. We measured cell proliferation with a Cell Counting Kit-8 and collagen expression with a Sirius Red Collagen Detection Kit. Flow cytometry and western blotting were used to detect transforming growth factor β1 (TGF-β1) signaling. We also confirmed the potential antifibrotic activity of ACEI in a rat scar model. ACEI reduced fibroblast proliferation, suppressed collagen and TGF-β1 expression, and downregulated the phosphorylation of SMAD2/3 and TAK1, both in vitro and in vivo. A microscopic examination showed that rat scars treated with ramipril or losartan were not only narrower than in the controls, but also displayed enhanced re-epithelialization and neovascularization, and the formation of organized granulation tissue. These data indicate that ACEI inhibits scar formation by suppressing both TGF-β1/SMAD2/3 and TGF-β1/TAK1 pathways, and may have clinical utility in the future.
Small-Vessel Vasculopathy Due to Aberrant Autophagy in LAMP-2 Deficiency
Authors: Nguyen Huan T. , Noguchi Satoru , Sugie Kazuma , Matsuo Yoshiyuki , Nguyen Chuyen T. H. , Koito Hitoshi , Shiojima Ichiro , Nishino Ichizo , Tsukaguchi Hiroyasu
Published: February 2018

Lysosomal associated membrane protein 2 (LAMP2) is physiologically implicated in autophagy. A genetic LAMP2 defect causes Danon disease, which consists of two major phenotypes of myopathy and cardiomyopathy. In addition, arteriopathy may manifest on rare occasions but the pathological basis remains unknown. We encountered two Danon families that developed small-vessel vasculopathy in the coronary or cerebral arteries. To investigate the underlying mechanisms, we characterized the biological features of LAMP-2–deficient mice and cultured cells. LAMP-2–deficient mice at 9–24 months of age showed medial thickening with luminal stenosis due to proliferation of vascular smooth muscle cells (VSMC) in muscular arteries. Ultrastructural analysis of VSMC revealed various autophagic vacuoles scattered throughout the cytoplasm, suggesting impaired autophagy of long-lived metabolites and degraded organelles (i.e., mitochondria). The VSMC in Lamp2 null mice expressed more vimentin but less α-smooth muscle actin (α-SMA), indicating a switch from contractile to synthetic phenotype. Silencing of LAMP2 in cultured human brain VSMC showed the same phenotypic transition with mitochondrial fragmentation, enhanced mitochondrial respiration, and overproduction of reactive oxygen species (ROS). These findings indicate that LAMP-2 deficiency leads to arterial medial hypertrophy with the phenotypic conversion of VSMC, resulting from age-dependent accumulation of cellular waste generated by aberrant autophagy.
Iodine insertion and dispersion of refractive index in organic single crystal semiconductor
Authors: Kwon Seonho , Bae Junwan , Lee I. J.
Published: February 2018

Insertion of halogens such as bromine or iodine affects the electronic polarizability of ions and the local field inside the medium, and thus modifies the refractive index. Acquiring precise knowledge of the dispersion of refractive index and ultimately tailoring conventional semiconductors for wide-range refractive index control have been a vital issue to resolve before realizing advanced organic optoelectronic devices. In this report, dispersions of the refractive index of a single crystal tetramethyltetraselenafulvalene [C10H12Se4] (TMTSF) are thoroughly studied from broadband interference modulations of photoluminescence (PL) spectra at various temperatures and doping levels. A large enhancement of the refractive index, more than 20% of the intrinsic value, is achieved with inclusion of a small composition of iodide ions, while the structural and optical properties remain mostly intact. Nearly temperature independent dispersion of the refractive index suggests that, unlike most polymers in which the thermal expansion coefficient dominates over the change of polarizability with temperature, the latter enhances significantly and may become more or less comparable to the thermal expansion coefficient given by 1.71 × 10−4/K, when single crystal TMTSF is doped by iodine.
Cranial shape comparison for automated objective 3D craniosynostosis surgery planning
Authors: Tolhuisen Manon L. , de Jong Guido A. , van Damme Ruud J. M. , van der Heijden Ferdinand , Delye Hans H. K.
Published: February 2018

Virtual planning of open cranial vault reconstruction is used to simulate and define an pre-operative plan for craniosynostosis surgery. However, virtual planning techniques are subjective and dependent on the experience and preferences of the surgical team. To develop an objective automated 3D pre-operative planning technique for open cranial vault reconstructions, we used curvature maps for the shape comparison of the patient’s skull with an age-specific reference skull. We created an average skull for the age-group of 11–14 months. Also, we created an artificial test object and selected a cranial CT-scan of an 11 months old trigonocephaly patient as test case. Mesh data of skulls were created using marching cubes and raycasting. Curvature maps were computed using quadric surface fitting. The shape comparison was tested for the test object and the average skull. Finally, shape comparison was performed for the trigonocephalic skull with the average skull. Similar shapes and the area on the patient’s skull that maximally corresponded in shape with the reference shape were correctly identified. This study showed that curvature maps allow the comparison of craniosynostosis skulls with age-appropriate average skulls and a first step towards an objective user-independent pre-operative planning technique for open cranial vault reconstructions is made.
Correlation of 360-degree Surface Mapping In Vivo Bioluminescence with Multi-Spectral Optoacoustic Tomography in Human Xenograft Tumor Models
Authors: Brannen Andrew , Eggert Matthew , Nahrendorf Matthias , Arnold Robert , Panizzi Peter
Published: February 2018

Pre-clinical monitoring of tumor growth and identification of distal metastasis requires a balance between accuracy and expediency. Bioluminescence imaging (BLI) is often used to track tumor growth but is primarily limited to planar 2-dimensional (2D) imaging. Consistent subject placement within a standard top-mounted, single-detector small animal imager is vital to reducing variability in repeated same-animal measures over time. Here, we describe a method for tracking tumor development using a multi-angle BLI and photo-acoustic workflow. We correlate serial caliper measurements and 2D BLI to 360° BLI and photo-acoustic datasets for the same animals. Full 360° BLI showed improved correlations with both volumes obtained from caliper measurements and photo-acoustic segmentation, as compared to planar BLI. We also determined segmented tumor volumes from photo-acoustic datasets more accurately reflects true excised tumors’ volumes compared to caliper measurements. Our results demonstrate the distinct advantages of both 360° surface mapping by BLI and photo-acoustic methodologies for non-invasive tracking of tumor growth in pre-clinical academic settings. Furthermore, our design is fully implementable in all top-mounted, single-detector imagers, thereby providing the opportunity to shift the paradigm away from planar BLI into rapid BLI tomography applications.
Alteration of rocks by endolithic organisms is one of the pathways for the beginning of soils on Earth
Authors: Mergelov Nikita , Mueller Carsten W. , Prater Isabel , Shorkunov Ilya , Dolgikh Andrey , Zazovskaya Elya , Shishkov Vasily , Krupskaya Victoria , Abrosimov Konstantin , Cherkinsky Alexander , Goryachkin Sergey
Published: February 2018

Subaerial endolithic systems of the current extreme environments on Earth provide exclusive insight into emergence and development of soils in the Precambrian when due to various stresses on the surfaces of hard rocks the cryptic niches inside them were much more plausible habitats for organisms than epilithic ones. Using an actualistic approach we demonstrate that transformation of silicate rocks by endolithic organisms is one of the possible pathways for the beginning of soils on Earth. This process led to the formation of soil-like bodies on rocksin situand contributed to the raise of complexity in subaerial geosystems. Endolithic systems of East Antarctica lack the noise from vascular plants and are among the best available natural models to explore organo-mineral interactions of a very old “phylogenetic age” (cyanobacteria-to-mineral, fungi-to-mineral, lichen-to-mineral). On the basis of our case study from East Antarctica we demonstrate that relatively simple endolithic systems of microbial and/or cryptogamic origin that exist and replicate on Earth over geological time scales employ the principles of organic matter stabilization strikingly similar to those known for modern full-scale soils of various climates.
Molecular basis of differential nitrogen use efficiencies and nitrogen source preferences in contrasting Arabidopsis accessions
Authors: Menz Jochen , Range Tim , Trini Johannes , Ludewig Uwe , Neuhäuser Benjamin
Published: February 2018

Natural accessions of Arabidopsis thaliana differ in their growth and development, but also vary dramatically in their nitrogen use efficiencies (NUE). The molecular basis for these differences has not been addressed yet. Experiments with five contrasting accessions grown in hydroponics at different levels of inorganic nitrogen confirmed low NUE of Col-0 and higher NUE in Tsu-0. At constant external nitrogen supply, higher NUE was based on nitrogen capture, rather than utilization of nitrogen for shoot biomass. This changed when a limited nitrogen amount was supplied. Nevertheless, the total NUE sequence remained similar. Interestingly, the two most contrasting accessions, Col-0 and Tsu-0, differed in the capture of single inorganic nitrogen sources, reflected by the differential consumption of 15N label from ammonium or nitrate, when supplied together. Tsu-0 acquired more nitrate than Col-0, both in roots and shoots. This preference was directly correlated with the expression of certain nitrogen uptake and assimilation systems in the root. However, early transcriptional responses of the root to nitrate deprivation were similar in both accessions, suggesting that the sensing of the external lack of nitrate was not different in the more nitrogen use efficient accession. Thus, a robust rapid nitrate-deprivation signaling exists in both genotypes.
True gene-targeting events by CRISPR/Cas-induced DSB repair of the PPO locus with an ectopically integrated repair template
Authors: de Pater Sylvia , Klemann Bart J. P. M. , Hooykaas Paul J. J.
Published: February 2018

In recent years, several tools have become available for improved gene-targeting (GT) in plants. DNA breaks at specific sites activate local DNA repair and recombination, including recombination with ectopic sequences leading to GT. Large-scale transformation with the repair template can be avoided by pre-insertion of the repair template in the genome and liberation by sequence-specific nucleases (in planta GT procedure). Here, we tested whether release of the repair template was required for GT. Plants were transformed with constructs encoding a CRISPR/Cas nuclease with a recognition site in the endogenous PPO gene and a repair template harboring a 5′ truncated PPO gene with two amino acid substitutions rendering the enzyme insensitive to the herbicide butafenacil. Selection resulted in so-called true GT events, repaired via homologous recombination at both ends of the gene and transmitted to the next generation. As the template was surrounded by geminiviral LIR sequences, we also tested whether replication of the template could be induced by crossing-in an integrated geminivirus REP gene. However, we could not find evidence for repair template replication by REP and we obtained similar numbers of GT events in these plants. Thus, GT is possible without any further processing of the pre-inserted repair template.
A novel P300 BCI speller based on the Triple RSVP paradigm
Authors: Lin Zhimin , Zhang Chi , Zeng Ying , Tong Li , Yan Bin
Published: February 2018

A brain–computer interface (BCI) is an advanced human–machine interaction technology. The BCI speller is a typical application that detects the stimulated source-induced EEG signal to identify the expected characters of the subjects. The current mainstream matrix-based BCI speller involves two problems that remain unsolved, namely, gaze-dependent and space-dependent problems. Some scholars have designed gaze-independent and space-independent spelling systems. However, this system still cannot achieve a satisfactory information transfer rate (ITR). In this paper, we propose a novel triple RSVP speller with gaze-independent and space-independent characteristics and higher ITR. The triple RSVP speller uses rapid serial visual presentation (RSVP) paradigm, each time presents three different characters, and each character is presented three times to increase the ITR. The results of the experiments show the triple RSVP speller online average accuracy of 0.790 and average online ITR of 20.259 bit/min, where the system spelled at a speed of 10 s per character, and the stimulus presentation interface is a 90 × 195 pixel rectangle. Thus, the triple RSVP speller can be integrated into mobile smart devices (such as smartphones, smart watches, and others).