bluuebunny/crossref_metadata_2025 huggingface dataset:
Paleoproductivity and Stratification Across the Subarctic Pacific Over Glacial‐Interglacial Cycles
Authors: Costa Kassandra M. , McManus Jerry F. , Anderson Robert F.
Published: August 2018

In the Subarctic Pacific, variability in productivity on glacial‐interglacial timescales is often attributed to changes in stratification and nutrient delivery to the surface, but the mechanisms driving this relationship are poorly constrained. Records extending beyond the last glacial maximum from both the open ocean and the marginal seas are required to investigate the timing and magnitude of different influential processes through the full glacial cycle. In this study we generated 231Pa/230Th over 210,000 years in order to capture two full glacial cycles of paleoproductivity on the Juan de Fuca Ridge in the East Subarctic Pacific. The sedimentary 231Pa/230Th ratios are always equal to or greater than the seawater production ratio (0.093), consistent with enhanced biological scavenging in this region. The temporal pattern of 231Pa/230Th burial is remarkably coherent with changes in climate, with high values (0.20) during peak interglacial periods descending to low values (0.10) during peak glacial conditions, consistent with other long productivity records from this region. We investigate the possible contributions of temperature, sea ice formation, Bering Strait closure, wind strength, upwelling, and subsurface nutrient concentrations as possible mechanisms by which physical and/or chemical stratification emerged during glacial periods. Due to the low sea surface salinity in the North Pacific, cooling actually weakens the density gradient in surface (0–200 m) waters. To create the steep density profiles that characterize physical stratification, additional processes to reduce the salinity of surface waters must occur during glacial periods. We suggest that regional sea ice formation and Bering Strait closure may have contributed to freshening surface waters and enhancing physical stratification during glacial periods. Additionally, simulated weak winds in this region due to the southward shift of the glacial westerlies may have further reduced surface mixing depths in the Subarctic Pacific. Finally, previous model simulations suggest strong glacial wind stress curl in the Subarctic Pacific, but enhanced Ekman divergence of nutrient‐poor subsurface waters would have little impact on stimulating productivity in surface waters of the Subarctic Pacific. We therefore suggest that the combined effects of surface freshening, weak winds, and lower subsurface nutrient concentrations may all have contributed to lower productivity during glacial periods in the Subarctic Pacific.
Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression
Authors: Lin Hao-Yu , Liang Yuan-Ke , Dou Xiao-Wei , Chen Chun-Fa , Wei Xiao-Long , Zeng De , Bai Jing-Wen , Guo Yu-Xian , Lin Fang-Fang , Huang Wen-He , Du Cai-Wen , Li Yao-Chen , Chen Min , Zhang Guo-Jun
Published: August 2018

Notch3 and GATA binding protein 3 (GATA-3) have been, individually, shown to maintain luminal phenotype and inhibit epithelial–mesenchymal transition (EMT) in breast cancers. In the present study, we report that Notch3 expression positively correlates with that of GATA-3, and both are associated with estrogen receptor-α (ERα) expression in breast cancer cells. We demonstrate in vitro and in vivo that Notch3 suppressed EMT and breast cancer metastasis by activating GATA-3 transcription. Furthermore, Notch3 knockdown downregulated GATA-3 and promoted EMT; while overexpression of Notch3 intracellular domain upregulated GATA-3 and inhibited EMT, leading to a suppression of metastasis in vivo. Moreover, inhibition or overexpression of GATA-3 partially reversed EMT or mesenchymal–epithelial transition induced by Notch3 alterations. In breast cancer patients, high GATA-3 expression is associated with higher Notch3 expression and lower lymph node metastasis, especially for hormone receptor (HR) positive cancers. Herein, we demonstrate a novel mechanism whereby Notch3 inhibit EMT by transcriptionally upregulating GATA-3 expression, at least in part, leading to the suppression of cancer metastasis in breast cancers. Our findings expand our current knowledge on Notch3 and GATA-3's roles in breast cancer metastasis.
Otx2 promotes granule cell precursor proliferation and Shh-dependent medulloblastoma maintenance in vivo
Authors: El Nagar Salsabiel , Chakroun Almahdi , Le Greneur Coralie , Figarella-Branger Dominique , Di Meglio Thomas , Lamonerie Thomas , Billon Nathalie
Published: August 2018

The developmental gene OTX2 is expressed by cerebellar granule cell precursors (GCPs), a cell population which undergoes massive expansion during the early postnatal period in response to sonic hedgehog (Shh). GCPs are thought to be at the origin of most medulloblastomas, a devastating paediatric cancer that arises in the developing cerebellum. OTX2 is overexpressed in all types of medulloblastomas, except in Shh-dependent type 2 medulloblastomas, although it has GCPs as cell-of-origin. This has led to the current view that OTX2 is not involved in tumorigenesis of this subgroup. How OTX2 might contribute to normal or tumoral GCP development in vivo remains unresolved. Here, we have investigated, for the first time, the physiological function of this factor in regulating proliferation and tumorigenesis in the developing mouse cerebellum. We first characterized Otx2-expressing cells in the early postnatal cerebellum and showed that they represent a unique subpopulation of highly proliferative GCPs. We next performed in vivo loss-of-function analysis to dissect out the role of Otx2 in these cells and identified a novel, Shh-independent, function for this factor in controlling postnatal GCP proliferation and cerebellum morphogenesis. Finally, we addressed the function of Otx2 in the context of type 2 medulloblastomas by directing Shh-dependent tumour formation in Otx2+ cells of the developing cerebellum and assessing the effects of Otx2 ablation in this context. We unravel an unexpected, mandatory function for Otx2 in sustaining cell proliferation and long-term maintenance of these tumours in vivo, therefore bringing unpredicted insight into the mechanisms of type 2 medulloblastoma subsistence. Together, these data pinpoint, for the first time, a crucial Shh-independent role for Otx2 in the control of proliferation of normal and tumoral granule cell precursors in vivo and make it an attractive candidate for targeted therapy in Shh-dependent medulloblastomas.
Annotation and functional clustering of circRNA expression in rhesus macaque brain during aging
Authors: Xu Kaiyu , Chen Dong , Wang Zhengbo , Ma Jian , Zhou Jian , Chen Nanhui , Lv Longbao , Zheng Yongtang , Hu Xintian , Zhang Yi , Li Jiali
Published: August 2018

The abundance and function of circular RNAs (circRNAs) in mammalian brain have been reported, but their alterations in the biology of brain aging remain elusive. Here, using deep RNA profiling with linear RNA digestion by RNase R we explored a comprehensive map of changes in circRNA expression in rhesus macaque (macaca mulatta) brain in two age groups from adult (10 y) to aged (20 y) periods. Total 17,050 well expressed, stable circRNAs were identified. Cluster analysis reveals that dynamic changes in circRNA expression show the spatial-, sex- and age-biased specificities. On the basis of separate profiling of the RNAs, age-related circRNAs show differential correlation to host mRNA expression. Furthermore, two voltage-dependent L- and R-type calcium channel gene-derived circCACNA2D1 and circCACNA1E negatively regulate their host mRNA expression. Our results demonstrate the power of changes in circRNA expression to reveal insights into a potentially circRNA-mediated regulatory mechanism underlying the biology of brain aging.
Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma
Authors: Manzano Mark , Patil Ajinkya , Waldrop Alexander , Dave Sandeep S. , Behdad Amir , Gottwein Eva
Published: August 2018

Primary effusion lymphoma (PEL) is caused by Kaposi’s sarcoma-associated herpesvirus. Our understanding of PEL is poor and therefore treatment strategies are lacking. To address this need, we conducted genome-wide CRISPR/Cas9 knockout screens in eight PEL cell lines. Integration with data from unrelated cancers identifies 210 genes as PEL-specific oncogenic dependencies. Genetic requirements of PEL cell lines are largely independent of Epstein-Barr virus co-infection. Genes of the NF-κB pathway are individually non-essential. Instead, we demonstrate requirements for IRF4 and MDM2. PEL cell lines depend on cellular cyclin D2 and c-FLIP despite expression of viral homologs. Moreover, PEL cell lines are addicted to high levels of MCL1 expression, which are also evident in PEL tumors. Strong dependencies on cyclin D2 and MCL1 render PEL cell lines highly sensitive to palbociclib and S63845. In summary, this work comprehensively identifies genetic dependencies in PEL cell lines and identifies novel strategies for therapeutic intervention.
Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease
Authors: Yao Chen , Chen George , Song Ci , Keefe Joshua , Mendelson Michael , Huan Tianxiao , Sun Benjamin B. , Laser Annika , Maranville Joseph C. , Wu Hongsheng , Ho Jennifer E. , Courchesne Paul , Lyass Asya , Larson Martin G. , Gieger Christian , Graumann Johannes , Johnson Andrew D. , Danesh John , Runz Heiko , Hwang Shih-Jen , Liu Chunyu , Butterworth Adam S. , Suhre Karsten , Levy Daniel
Published: August 2018

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
Distributed natural gas venting offshore along the Cascadia margin
Authors: Riedel M. , Scherwath M. , Römer M. , Veloso M. , Heesemann M. , Spence G. D.
Published: August 2018

Widespread gas venting along the Cascadia margin is investigated from acoustic water column data and reveals a nonuniform regional distribution of over 1100 mapped acoustic flares. The highest number of flares occurs on the shelf, and the highest flare density is seen around the nutrition-rich outflow of the Juan de Fuca Strait. We determine ∼430 flow-rates at ∼340 individual flare locations along the margin with instantaneous in situ values ranging from ∼6 mL min−1 to ∼18 L min−1. Applying a tidal-modulation model, a depth-dependent methane density, and extrapolating these results across the margin using two normalization techniques yields a combined average in situ flow-rate of ∼88 × 106 kg y−1. The average methane flux-rate for the Cascadia margin is thus estimated to ∼0.9 g y−1m−2. Combined uncertainties result in a range of these values between 4.5 and 1800% of the estimated mean values.
21st-century modeled permafrost carbon emissions accelerated by abrupt thaw beneath lakes
Authors: Walter Anthony Katey , Schneider von Deimling Thomas , Nitze Ingmar , Frolking Steve , Emond Abraham , Daanen Ronald , Anthony Peter , Lindgren Prajna , Jones Benjamin , Grosse Guido
Published: August 2018

Permafrost carbon feedback (PCF) modeling has focused on gradual thaw of near-surface permafrost leading to enhanced carbon dioxide and methane emissions that accelerate global climate warming. These state-of-the-art land models have yet to incorporate deeper, abrupt thaw in the PCF. Here we use model data, supported by field observations, radiocarbon dating, and remote sensing, to show that methane and carbon dioxide emissions from abrupt thaw beneath thermokarst lakes will more than double radiative forcing from circumpolar permafrost-soil carbon fluxes this century. Abrupt thaw lake emissions are similar under moderate and high representative concentration pathways (RCP4.5 and RCP8.5), but their relative contribution to the PCF is much larger under the moderate warming scenario. Abrupt thaw accelerates mobilization of deeply frozen, ancient carbon, increasing 14C-depleted permafrost soil carbon emissions by ~125–190% compared to gradual thaw alone. These findings demonstrate the need to incorporate abrupt thaw processes in earth system models for more comprehensive projection of the PCF this century.
Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy
Authors: Logue Susan E. , McGrath Eoghan P. , Cleary Patricia , Greene Stephanie , Mnich Katarzyna , Almanza Aitor , Chevet Eric , Dwyer Róisín M. , Oommen Anup , Legembre Patrick , Godey Florence , Madden Emma C. , Leuzzi Brian , Obacz Joanna , Zeng Qingping , Patterson John B. , Jäger Richard , Gorman Adrienne M. , Samali Afshin
Published: August 2018

Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
The role of metal vacancies during high-temperature oxidation of alloys
Authors: Oleksak Richard P. , Kapoor Monica , Perea Daniel. E. , Holcomb Gordon R. , Doğan Ömer N.
Published: August 2018

An improved understanding of high-temperature alloy oxidation is key to the design of structural materials for next-generation energy conversion technologies. An often overlooked, yet fundamental aspect of this oxidation process concerns the fate of the metal vacancies created when metal atoms are ionized and enter the growing oxide layer. In this work, we provide direct experimental evidence showing that these metal vacancies can be inseparably linked to the oxidation process beginning at the very early stages. The coalescence of metal vacancies at the oxide/alloy interface results initially in the formation of low-density metal and eventually in nm-sized voids. The simultaneous and subsequent oxidation of these regions fills the vacated space and promotes adhesion between the growing oxide and the alloy substrate. These structural transformations represent an important deviation from conventional metal oxidation theory, and this improved understanding will aid in the development of new structural alloys with enhanced oxidation resistance.
Differentiating cognitive or motor dimensions associated with the perception of fall-related self-efficacy in Parkinson’s disease
Authors: Chomiak Taylor , Watts Alexander , Burt Jacqueline , Camicioli Richard , Tan Sun Nee , McKeown Martin J. , Hu Bin
Published: August 2018

In Parkinson’s disease (PD), concurrent declines in cognitive and motor domain function can severely limit an individual’s ability to conduct daily tasks. Current diagnostic methods, however, lack precision in differentiating domain-specific contributions of cognitive or motor impairments based on a patients’ clinical manifestation. Fear of falling (FOF) is a common clinical manifestation among the elderly, in which both cognitive and motor impairments can lead to significant barriers to a patients’ physical and social activities. The present study evaluated whether a set of analytical and machine-learning approaches could be used to help delineate boundary conditions and separate cognitive and motor contributions to a patient’s own perception of self-efficacy and FOF. Cognitive and motor clinical scores, in conjunction with FOF, were collected from 57 Parkinson’s patients during a multi-center rehabilitation intervention trial. Statistical methodology was used to extract a subset of uncorrelated cognitive and motor components associated with cognitive and motor predictors, which were then used to independently identify and visualize cognitive and motor dimensions associated with FOF. We found that a central cognitive process, extracted from tests of executive, attentional, and visuoperceptive function, was a unique and significant independent cognitive predictor of FOF in PD. In addition, we provide evidence that the approaches described here may be used to computationally discern specific types of FOF based on separable cognitive or motor models. Our results are consistent with a contemporary model that the deterioration of a central cognitive mechanism that modulates self-efficacy also plays a critical role in FOF in PD.
Remote quantum clock synchronization without synchronized clocks
Authors: Ilo-Okeke Ebubechukwu O. , Tessler Louis , Dowling Jonathan P. , Byrnes Tim
Published: August 2018

A major outstanding problem for many quantum clock synchronization protocols is the hidden assumption of a common phase reference between the parties to be synchronized. In general, the definition of the quantum states between two parties do not have consistent phase definitions, which can lead to an unknown systematic error. We show that despite prior arguments to the contrary, it is possible to remove this unknown phase via entanglement purification. This closes the loophole for entanglement based quantum clock synchronization protocols, which is a non-local approach to synchronize two clocks independent of the properties of the intervening medium. Starting with noisy Bell pairs, we show that the scheme produces a singlet state for any combination of (i) differing basis conventions for Alice and Bob; (ii) an overall time offset in the execution of the purification algorithm; and (iii) the presence of a noisy channel. Error estimates reveal that better performance than existing classical Einstein synchronization protocols should be achievable using current technology.
Freezing out of a low-energy bulk spin exciton in SmB6
Authors: Akintola Kolawole , Pal Anand , Dunsiger Sarah R. , Fang Alex C. Y. , Potma Matt , Saha Shanta R. , Wang Xiangfeng , Paglione Johnpierre , Sonier Jeff E.
Published: August 2018

The Kondo insulator SmB6 is purported to develop into a robust topological insulator at low temperatures. Yet there are several puzzling and unexplained physical properties of the insulating bulk. It has been proposed that bulk spin excitons may be the source of these anomalies and may also adversely affect the topologically protected metallic surface states. Here, we report muon spin rotation measurements of SmB6 that show thermally activated behavior for the temperature dependence of the transverse-field relaxation rate below 20 K and a decreasing contact hyperfine field contribution to the positive muon Knight shift below 5–6 K. Our data are consistent with the freezing out of a bulk low-energy (~1 meV) spin exciton concurrent with the appearance of metallic surface conductivity. Furthermore, our results support the idea that spin excitons play some role in the anomalous low-temperature bulk properties of SmB6.
Simulating quantum dynamical phenomena using classical oscillators: Landau-Zener-Stückelberg-Majorana interferometry, latching modulation, and motional averaging
Authors: Ivakhnenko O. V. , Shevchenko S. N. , Nori Franco
Published: August 2018

A quantum system can be driven by either sinusoidal, rectangular, or noisy signals. In the literature, these regimes are referred to as Landau-Zener-Stückelberg-Majorana (LZSM) interferometry, latching modulation, and motional averaging, respectively. We demonstrate that these pronounced and interesting effects are also inherent in the dynamics of classical two-state systems. We discuss how such classical systems are realized using either mechanical, electrical, or optical resonators. In addition to the fundamental interest of such dynamical phenomena linking classical and quantum physics, we believe that these are attractive for the classical analogue simulation of quantum systems.
Characterization of avian influenza virus attachment patterns to human and pig tissues
Authors: Eriksson Per , Lindskog Cecilia , Engholm Ebbe , Blixt Ola , Waldenström Jonas , Munster Vincent , Lundkvist Åke , Olsen Björn , Jourdain Elsa , Ellström Patrik
Published: August 2018

Wild birds of Anseriformes and Charadriiformes are natural reservoirs of influenza A viruses (IAVs). Occasionally, IAVs transmit and adapt to mammalian hosts, and are maintained as epidemic strains in their new hosts. Viral adaptions to mammalian hosts include altered receptor preference of host epithelial sialylated oligosaccharides from terminal α2,3-linked sialic acid (SA) towards α2,6-linked SA. However, α2,3-linked SA has been found in human respiratory tract epithelium, and human infections by avian IAVs (AIVs) have been reported. To further explore the attachment properties of AIVs, four AIVs of different subtypes were investigated on human and pig tissues using virus histochemistry. Additionally, glycan array analysis was performed for further characterization of IAVs’ receptor structure tropism. Generally, AIV attachment was more abundant to human tissues than to pig tissues. The attachment pattern was very strong to human conjunctiva and upper respiratory tract, but variable to the lower respiratory tract. AIVs mainly attached to α2,3-linked SA, but also to combinations of α2,3- and α2,6-linked SA. The low attachment of these AIV isolates to pig tissues, but high attachment to human tissues, addresses the question whether AIVs in general require passage through pigs to obtain adaptions towards mammalian receptor structures.
Practical Three-Minute Synthesis of Acid-Coated Fluorescent Carbon Dots with Tuneable Core Structure
Authors: Hill Stephen A. , Benito-Alifonso David , Davis Sean A. , Morgan David J. , Berry Monica , Galan M. Carmen
Published: August 2018

We report a one-pot, three-minute synthesis of carboxylic acid-decorated fluorescent carbon dots (COOH-FCDs) with tuneable core morphology dependent on the surface passivating agent. Mechanism investigations highlighted the presence of key pyrazine and polyhydroxyl aromatic motifs, which are formed from the degradation of glucosamine in the presence of a bifunctional linker bearing acid and amine groups. The novel COOH-FCDs are selective Fe3+ and hemin sensors. Furthermore, the FCDs are shown to be non-toxic, fluorescent bioimaging agents for cancer cells.
Subcellular Peptide Localization in Single Identified Neurons by Capillary Microsampling Mass Spectrometry
Authors: Zhang Linwen , Khattar Nikkita , Kemenes Ildiko , Kemenes Gyorgy , Zrinyi Zita , Pirger Zsolt , Vertes Akos
Published: August 2018

Single cell mass spectrometry (MS) is uniquely positioned for the sequencing and identification of peptides in rare cells. Small peptides can take on different roles in subcellular compartments. Whereas some peptides serve as neurotransmitters in the cytoplasm, they can also function as transcription factors in the nucleus. Thus, there is a need to analyze the subcellular peptide compositions in identified single cells. Here, we apply capillary microsampling MS with ion mobility separation for the sequencing of peptides in single neurons of the mollusk Lymnaea stagnalis, and the analysis of peptide distributions between the cytoplasm and nucleus of identified single neurons that are known to express cardioactive Phe-Met-Arg-Phe amide-like (FMRFamide-like) neuropeptides. Nuclei and cytoplasm of Type 1 and Type 2 F group (Fgp) neurons were analyzed for neuropeptides cleaved from the protein precursors encoded by alternative splicing products of the FMRFamide gene. Relative abundances of nine neuropeptides were determined in the cytoplasm. The nuclei contained six of these peptides at different abundances. Enabled by its relative enrichment in Fgp neurons, a new 28-residue neuropeptide was sequenced by tandem MS.
Method for the Destruction of Endotoxin in Synthetic Spider Silk Proteins
Authors: Decker Richard E. , Harris Thomas I. , Memmott Dylan R. , Peterson Christopher J. , Lewis Randolph V. , Jones Justin A.
Published: August 2018

Although synthetic spider silk has impressive potential as a biomaterial, endotoxin contamination of the spider silk proteins is a concern, regardless of the production method. The purpose of this research was to establish a standardized method to either remove or destroy the endotoxins present in synthetic spider silk proteins, such that the endotoxin level was consistently equal to or less than 0.25 EU/mL, the FDA limit for similar implant materials. Although dry heat is generally the preferred method for endotoxin destruction, heating the silk proteins to the necessary temperatures led to compromised mechanical properties in the resultant materials. In light of this, other endotoxin destruction methods were investigated, including caustic rinses and autoclaving. It was found that autoclaving synthetic spider silk protein dopes three times in a row consistently decreased the endotoxin level 10–20 fold, achieving levels at or below the desired level of 0.25 EU/mL. Products made from triple autoclaved silk dopes maintained mechanical properties comparable to products from untreated dopes while still maintaining low endotoxin levels. Triple autoclaving is an effective and scalable method for preparing synthetic spider silk proteins with endotoxin levels sufficiently low for use as biomaterials without compromising the mechanical properties of the materials.
PP4397/FlgZ provides the link between PP2258 c-di-GMP signalling and altered motility in Pseudomonas putida
Authors: Wirebrand Lisa , Österberg Sofia , López-Sánchez Aroa , Govantes Fernando , Shingler Victoria
Published: August 2018

Bacteria swim and swarm using rotating flagella that are driven by a membrane-spanning motor complex. Performance of the flagella motility apparatus is modulated by the chemosensory signal transduction system to allow navigation through physico-chemical gradients – a process that can be fine-tuned by the bacterial second messenger c-di-GMP. We have previously analysed thePseudomonas putidasignalling protein PP2258 that has the capacity to both synthesize and degrade c-di-GMP. A PP2258 null mutant displays reduced motility, implicating the c-di-GMP signal originating from this protein in control ofP. putidamotility. InEscherichia coliandSalmonella, the PilZ-domain protein YcgR mediates c-di-GMP responsive control of motility through interaction with the flagellar motors. Here we provide genetic evidence that theP. putidaprotein PP4397 (also known as FlgZ), despite low sequence homology and a different genomic context to YcgR, functions as a c-di-GMP responsive link between the signal arising from PP2258 and alterations in swimming and swarming motility inP. putida.
COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix
Authors: Willis-Owen Saffron A. G. , Thompson Anna , Kemp Paul R. , Polkey Michael I. , Cookson William O. C. M. , Moffatt Miriam F. , Natanek Samantha A.
Published: August 2018

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.
Trends of Visual Impairment and Blindness in the Singapore Chinese Population over a Decade
Authors: Tham Yih-Chung , Lim Sing-Hui , Shi Yuan , Chee Miao-Li , Zheng Ying Feng , Chua Jacqueline , Saw Seang-Mei , Foster Paul , Aung Tin , Wong Tien Yin , Cheng Ching-Yu
Published: August 2018

We evaluated the prevalence of visual impairment (VI) and blindness among Chinese adults in the Singapore Chinese Eye Study (SCES, 2009–2011), and compared the trends with the Tanjong Pagar Survey, Singapore (TPS), conducted a decade earlier. The SCES comprised of 3,353 Chinese adults aged ≥40 years (response rate, 72.8%). Participants underwent standardized examinations, including measurements of presenting, and best-corrected visual acuity (VA). Bilateral VI (VA < 20/40 to ≥20/200) and blindness (VA < 20/200) were defined based on the United States definition (better-seeing eye). Age-standardized prevalence was calculated using the 2010 Singapore Chinese Population Census. Primary causes and factors associated with VI and blindness were evaluated. In SCES, the age-standardized prevalence of presenting bilateral VI and blindness were 17.7% and 0.6%, respectively; the age-standardised prevalence of best-corrected bilateral VI and blindness were 3.4% and 0.2%, respectively. The previous TPS reported similar rates of best-corrected bilateral VI (3.8%) and blindness (0.3%). In SCES, cataract remains the main cause for both best-corrected bilateral VI (76.0%) and blindness (50.0%). Older age, female, lower income, lower educational level, and smaller housing type were associated with presenting bilateral VI or blindness (all P ≤ 0.025). These findings will be useful for the planning of eye care services and resource allocation.
Assessing the augmentation of Amblydromalus limonicus with the supplementation of pollen, thread, and substrates to combat greenhouse whitefly populations
Authors: Lee Ming Hui , Zhang Zhi-Qiang
Published: August 2018

Due to issues with establishment and persistence of natural enemies in biological control, the provision of alternative food sources and oviposition sites are important factors to enhance pest control. In this study, three different supplementation treatments were examined for their ability to increase the populations of the predatory mite Amblydromalus limonicus, and its implications for greenhouse whitefly control on peppers and eggplants. These were: (1) pollen (Typha orientalis), (2) pollen and thread, (3) pollen, thread, and a substrate mixture of buckwheat, gorse, and rice husks, which were compared to a control treatment that had no supplementation. Significant treatment effects were found on pepper for A. limonicus (mite eggs p = 0.008, mobile mites p = <0.0001). The predatory mite successfully established and persisted at high population levels in the pollen-thread, and pollen-thread-substrate treatments. All supplementation treatments were able to control whitefly populations on peppers, while the control treatment failed to. The results obtained were formulated into possible application techniques for greenhouse growers to utilise.
Human tissue-engineered skeletal muscle: a novel 3D in vitro model for drug disposition and toxicity after intramuscular injection
Authors: Gholobova D. , Gerard M. , Decroix L. , Desender L. , Callewaert N. , Annaert P. , Thorrez L.
Published: August 2018

The development of laboratory-grown tissues, referred to as organoids, bio-artificial tissue or tissue-engineered constructs, is clearly expanding. We describe for the first time how engineered human muscles can be applied as a pre- or non-clinical model for intramuscular drug injection to further decrease and complement the use of in vivo animal studies. The human bio-artificial muscle (BAM) is formed in a seven day tissue engineering procedure during which human myoblasts fuse and differentiate to aligned myofibers in an extracellular matrix. The dimensions of the BAM constructs allow for injection and follow-up during several days after injection. A stereotactic setup allows controllable injection at multiple sites in the BAM. We injected several compounds; a dye, a hydrolysable compound, a reducible substrate and a wasp venom toxin. Afterwards, direct reflux, release and metabolism were assessed in the BAM constructs in comparison to 2D cell culture and isolated human muscle strips. Spectrophotometry and luminescence allowed to measure the release of the injected compounds and their metabolites over time. A release profile over 40 hours was observed in the BAM model in contrast to 2D cell culture, showing the capacity of the BAM model to function as a drug depot. We also determined compound toxicity on the BAMs by measuring creatine kinase release in the medium, which increased with increasing toxic insult. Taken together, we show that the BAM is an injectable human 3D cell culture model that can be used to measure release and metabolism of injected compounds in vitro.
Author Correction: Dual-organ invasion is associated with a lower survival rate than single-organ invasion in distal bile duct cancer: A multicenter study
Authors: Min Kyueng-Whan , Kim Dong-Hoon , Son Byoung Kwan , Moon Kyoung Min , Kim Eun-Kyung , Oh Young-Ha , Kwon Mi Jung , Choi Ho Soon
Published: August 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Heavy metals in Yinma River sediment in a major Phaeozems zone, Northeast China: Distribution, chemical fraction, contamination assessment and source apportionment
Authors: Guan Jiunian , Wang Jia , Pan He , Yang Chen , Qu Jiao , Lu Nan , Yuan Xing
Published: August 2018

Yinma River is a typical river in the major Phaeozems zone of Northeast China. It has been suffering an increasing environmental pressure from heavy metal contamination due to the rapid development of population, social-economy and urbanization as well as long term over cultivation. This study investigated the spatial distribution, chemical fraction of heavy metals (Cu, Pb, Zn, Cr, Cd, Ni, As, and Hg) in sediments of Yinma River based on BCR procedure, assessed the contamination level, and identified their sources via multivariate statistical analysis. The chemical fraction results indicated that Cd, Pb, Ni, and Zn exhibited higher mobility susceptibility and bioavailability with a significant and late anthropogenic origin. Hg and Cd might exert a potential hazardous influence on aquatic biota according to the geo-accumulation index (Igeo). The pollution load index (PLI) assessment suggested that all of the sediment samples have been contaminated. Multivariate statistical analysis revealed that Zn, Cu, Hg, Cd, and Pb reflected the anthropogenic sources with a close correlation with TOC and socio-economic development; Ni, As and Cr tended to represent the geochemical background. Furthermore, Changchun City and Shitoukoumen Reservoir as the major drinking water source may be hotspots of the heavy metal contamination in the watershed.
Novel monoclonal antibody L2A5 specifically targeting sialyl-Tn and short glycans terminated by alpha-2–6 sialic acids
Authors: Loureiro Liliana R. , Sousa Diana P. , Ferreira Dylan , Chai Wengang , Lima Luís , Pereira Carina , Lopes Carla B. , Correia Viviana G. , Silva Lisete M. , Li Chunxia , Santos Lúcio Lara , Ferreira José Alexandre , Barbas Ana , Palma Angelina S. , Novo Carlos , Videira Paula A.
Published: August 2018

Incomplete O-glycosylation is a feature associated with malignancy resulting in the expression of truncated glycans such as the sialyl-Tn (STn) antigen. Despite all the progress in the development of potential anti-cancer antibodies, their application is frequently hindered by low specificities and cross-reactivity. In this study, a novel anti-STn monoclonal antibody named L2A5 was developed by hybridoma technology. Flow cytometry analysis showed that L2A5 specifically binds to sialylated structures on the cell surface of STn-expressing breast and bladder cancer cell lines. Moreover, immunoblotting assays demonstrated reactivity to tumour-associated O-glycosylated proteins, such as MUC1. Tumour recognition was further observed using immunohistochemistry assays, which demonstrated a high sensitivity and specificity of L2A5 mAb towards cancer tissue, using bladder and colorectal cancer tissues. L2A5 staining was exclusively tumoural, with a remarkable reactivity in invasive and metastasis sites, not detectable by other anti-STn mAbs. Additionally, it stained 20% of cases of triple-negative breast cancers, suggesting application in diseases with unmet clinical needs. Finally, the fine specificity was assessed using glycan microarrays, demonstrating a highly specific binding of L2A5 to core STn antigens and additional ability to bind 2–6-linked sialyl core-1 probes. In conclusion, this study describes a novel anti-STn antibody with a unique binding specificity that can be applied for cancer diagnostic and future development of new antibody-based therapeutic applications.
Complex bile duct network formation within liver decellularized extracellular matrix hydrogels
Authors: Lewis Phillip L. , Su Jimmy , Yan Ming , Meng Fanyin , Glaser Shannon S. , Alpini Gianfranco D. , Green Richard M. , Sosa-Pineda Beatriz , Shah Ramille N.
Published: August 2018

The biliary tree is an essential component of transplantable human liver tissue. Despite recent advances in liver tissue engineering, attempts at re-creating the intrahepatic biliary tree have not progressed significantly. The finer branches of the biliary tree are structurally and functionally complex and heterogeneous and require harnessing innate developmental processes for their regrowth. Here we demonstrate the ability of decellularized liver extracellular matrix (dECM) hydrogels to induce thein vitroformation of complex biliary networks using encapsulated immortalized mouse small biliary epithelial cells (cholangiocytes). This phenomenon is not observed using immortalized mouse large cholangiocytes, or with purified collagen 1 gels or Matrigel. We also show phenotypic stability via immunostaining for specific cholangiocyte markers. Moreover, tight junction formation and maturation was observed to occur between cholangiocytes, exhibiting polarization and transporter activity. To better define the mechanism of duct formation, we utilized three fluorescently labeled, but otherwise identical populations of cholangiocytes. The cells, in a proximity dependent manner, either branch out clonally, radiating from a single nucleation point, or assemble into multi-colored structures arising from separate populations. These findings present liver dECM as a promising biomaterial for intrahepatic bile duct tissue engineering and as a tool to study duct remodelingin vitro.
Experimental investigations on drag-reduction characteristics of bionic surface with water-trapping microstructures of fish scales
Authors: Wu Liyan , Jiao Zhibin , Song Yuqiu , Liu Cuihong , Wang Huan , Yan Yuying
Published: August 2018

Biological surfaces with unique wettability in nature have provided an enormous innovation for scientists and engineers. More specifically, materials possessing various wetting properties have drawn considerable attention owing to their promising application prospects. Recently, great efforts have been concentrated on the researches on wetting-induced drag-reduction materials inspired by biology because of their ability to save energy. In this work, the drag-reduction characteristics of the bionic surface with delicate water-trapping microstructures of fish Ctenopharyngodon idellus scales were explored by experimental method. Firstly, the resistance of smooth surface and bionic surface experimental sample at different speeds was carefully tested through the testing system for operation resistance. Then, the contact angle (CA) of fish scale surface was measured by means of the contact angle measuring instrument. It was discovered that the bionic surface created a rewarding drag-reduction effect at a low speed, and the drag-reduction rate significantly displayed a downward trend with the increase in flow speed. Thus, when the rate was 0.66 m/s, the drag-reduction effect was at the optimum level, and the maximum drag reduction rate was 2.805%, which was in concordance with the simulated one. Furthermore, a contact angle (CA) of 11.5° appeared on the fish scale surface, exhibiting fine hydrophilic property. It further manifested the spreading-wetting phenomenon and the higher surface energy for the area of apical of fish scales, which played an important role in drag-reduction performance. This work will have a great potential in the engineering and transportation field.
Nomogram for prediction of non-proliferative diabetic retinopathy in juvenile-onset type 1 diabetes: a cohort study in an Asian population
Authors: Kang Eugene Yu-Chuan , Lo Fu-Sung , Wang Jung-Pan , Yeh Lung-Kun , Wu An-Lun , Tseng Yun-Ju , Yeh Chun-Ting , Liu Laura , Chen Kuan-Jen , Wu Wei-Chi , Lai Chi-Chun , Wang Nan-Kai ,   Chang Gung Juvenile Diabetes Eye Study Group, Chen Tun-Lu , Chao An-Ning , Hwang Yih-Shiou , Chen Yen-Po , Chen Yih-Hsin
Published: August 2018

The need for screening for retinopathy in patients with type 1 diabetes mellitus (T1DM) has been emphasised, but diagnostic delays were reported when screening was done at fixed intervals. To establish an individualised risk-prediction model to assist screening non-proliferative diabetic retinopathy (NPDR) in T1DM, we performed a retrospective cohort study enrolling participants in the Chang Gung Juvenile Diabetes Eye Study. There were 413 patients with 12 381 records analysed from 2005 to 2015. A time-dependent Cox proportional hazard analysis was used to evaluate the risks of NPDR development and a nomogram with risk-stratification indicators was established based on the results. During 97 months of follow-up, 43 of 413 patients (10.4%) developed NPDR. Male sex (HR: 0.4, 95% CI: 0.19–0.85), age 5–14 years at onset of T1DM (6.38, 2.41–16.87), duration of diabetes (1.57, 1.41–1.75), and hemoglobin A1c level (1.56, 1.35–1.80) were independently associated with NPDR. Using the nomogram offers a quick method in the clinical setting to interpret the risk of NPDR development. Based on its weighting, each of the independent factors is allocated a score, and the total points indicate the probabilities of NPDR occurring within 6 months, 1 year, and 3 years.
Three-stage processing of category and variation information by entangled interactive mechanisms of peri-occipital and peri-frontal cortices
Authors: Karimi-Rouzbahani Hamid
Published: August 2018

Object recognition has been a central question in human vision research. The general consensus is that the ventral and dorsal visual streams are the major processing pathways undertaking objects’ category and variation processing. This overlooks mounting evidence supporting the role of peri-frontal areas in category processing. Yet, many aspects of visual processing in peri-frontal areas have remained unattended including whether these areas play role only during active recognition and whether they interact with lower visual areas or process information independently. To address these questions, subjects were presented with a set of variation-controlled object images while their EEG were recorded. Considerable amounts of category and variation information were decodable from occipital, parietal, temporal and prefrontal electrodes. Using information-selectivity indices, phase and Granger causality analyses, three processing stages were identified showing distinct directions of information transaction between peri-frontal and peri-occipital areas suggesting their parallel yet interactive role in visual processing. A brain-plausible model supported the possibility of interactive mechanisms in peri-occipital and peri-frontal areas. These findings, while promoting the role of prefrontal areas in object recognition, extend their contributions from active recognition, in which peri-frontal to peri-occipital pathways are activated by higher cognitive processes, to the general sensory-driven object and variation processing.
Aristolochic acid I determine the phenotype and activation of macrophages in acute and chronic kidney disease
Authors: Honarpisheh Mohsen , Foresto-Neto Orestes , Steiger Stefanie , Kraft Franziska , Koehler Paulina , von Rauchhaupt Ekaterina , Potempa Jan , Adamowicz Karina , Koziel Joanna , Lech Maciej
Published: August 2018

Acute and chronic kidney injuries are multifactorial traits that involve various risk factors. Experimental animal models are crucial to unravel important aspects of injury and its pathophysiological mechanisms. Translating knowledge obtained from experimental approaches into clinically useful information is difficult; therefore, significant attention needs to be paid to experimental procedures that mimic human disease. Herein, we compared aristolochic acid I (AAI) acute and chronic kidney injury model with unilateral ischemic-reperfusion injury (uIRI), cisplatin (CP)- or folic acid (FA)-induced renal damage. The administration of AAI showed significant changes in serum creatinine and BUN upon CKD. The number of neutrophils and macrophages were highly increased as well as AAI-induced CKD characterized by loss of tubular epithelial cells and fibrosis. The in vitro and in vivo data indicated that macrophages play an important role in the pathogenesis of AA-induced nephropathy (AAN) associated with an excessive macrophage accumulation and an alternative activated macrophage phenotype. Taken together, we conclude that AA-induced injury represents a suitable and relatively easy model to induce acute and chronic kidney injury. Moreover, our data indicate that this model is appropriate and superior to study detailed questions associated with renal macrophage phenotypes.