bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracer‐Guided Characterization of Dominant Pore Networks and Implications for Permeability and Wettability in Shale
Authors: Peng Sheng , Reed Robert M. , Xiao Xianghui , Yang Yang , Liu Yijin
Published: February 2019

Pore network characterization is an important aspect in unconventional reservoir evaluation. While application of the technique of scanning electron microscope (SEM) brings substantial advances in pore characterization in shale, understanding the connected pore network that dominates flow in shale samples is limited by using SEM alone because of small fields of view and lack of views of connectivity in 3D. In this research, a technique integrating tracer imbibition, micro‐computed tomography (CT) imaging, and SEM imaging was developed to provide a solution for multiscale imaging in shale. Tracer imbibition indicates pore connectivity; micro‐CT imaging after tracer imbibition thus provides an overview of the connected pore network at the millimeter scale. With guidance from micro‐CT images after tracer imbibition, a more accurate and detailed characterization of pore systems and related mineralogy can be conducted using higher‐resolution SEM. The method was applied to five samples from Wolfcamp and Eagle Ford Formations. Results reveal the effectiveness of the integrated method by showing different patterns of distribution of the dominant pore network and different controlling mineralogy. Dominant porosity, estimated from grayscale analyses, displays a good correlation with permeability. This result indicates that dominant porosity is more relevant to permeability than is total porosity. Results from imbibition tests are also compared with that from contact angle measurement, and important implications on wettability can be obtained. The integrated method thus has the capacity to link the dominant pore network and wettability with microscale to submicroscale mineralogy, which can help better understand the pore systems and fluid flow in shale.
Frontogenesis and the Creation of Fine‐Scale Vertical Phytoplankton Structure
Authors: de Verneil A. , Franks P. J. S. , Ohman M. D.
Published: February 2019

Fine‐scale spatial structuring of phytoplankton patches has significant consequences for the marine food web, from altering phytoplankton exposure to surface light and limiting nutrients, to influencing the foraging of zooplankton, modifying carbon export, and impacting patterns of diversity. Hence, it is important to identify these fine‐scale features and determine what generates their variability. Here we present evidence of fine‐scale, tilted, interleaved layers in salinity and chlorophyll‐a fluorescence observed in free‐fall Moving Vessel Profiler surveys across a frontal system west of Point Conception, California. The observed covariability of hydrographic and biological properties allows for decomposition of the features into different water histories. Our analyses suggest that recently upwelled coastal water subsequently advected and intermingled with surrounding water masses from farther offshore. Orientations of the fine layers found in the filament are consistent with restratification and downwelling due to an ageostrophic secondary circulation brought on by frontogenesis. Finite size Lyapunov exponents, a Lagrangian diagnostic calculated from remote sensing data, provide positive evidence for frontogenetic convergence occurring upstream of the feature and allow for direct comparisons with in situ data to gauge their general utility in defining dynamical boundaries. These results highlight how frontal systems not only horizontally compress the biological niches represented by formerly disparate water masses but also create vertical structure and patchiness that can rapidly change over submesoscales.
Geographical Distribution of Thundersnow Events and Their Properties From GPM Ku‐Band Radar
Authors: Adhikari Abishek , Liu Chuntao
Published: February 2019

Six‐years (2010–2015) of snow lightning characteristics and climatology, including seasonal, diurnal, and surface temperature distribution, are generated. The World Wide Lightning Location Network (WWLLN) and the National Lightning Detection Network lightning observations are collocated with Modern‐Era Retrospective Analysis for Research and Application (MERRA‐2) temperatures. Cold season lightning events are identified as lightning with the MERRA‐2 two‐meter surface temperature colder than 0 °C and then further classified as snow lightning or thundersnow, when the entire vertical temperature profile is below 2 °C, and as freezing rain lightning when there is a temperature warmer than 2 °C somewhere in the column above the freezing surface. The statistics of snow lightning events from WWLLN and National Lightning Detection Network are well matched and are consistent with the climatology of thundersnow days reported at ground‐based stations over the United States. Using 4 years of observations from the Global Precipitation Measuring Mission Ku band radar, 443 Thunder Snow Features (TSFs) are defined, having a contiguous area of nonzero near surface snow precipitation derived from the Ku band radar and MERRA‐2 data, along with collocated WWLLN lightning flashes. The majority (about 394) are found over high mountainous regions such the Himalayas, Tibet, the Andes, and the Zagros mountain regions. Low‐elevation TSFs (45) are observed over the continental and coastal regions. Though only a small number of TSFs are identified with 4 years of Global Precipitation Mission data, most TSFs have maximum radar reflectivity above 30 dBZ at temperature colder than −10 °C, which indicates the importance of the noninductive charging process in these events.
Rapid Changes in Land‐Sea Thermal Contrast Across China's Coastal Zone in a Warming Climate
Authors: Yao Yulong , Zou Xinqing , Zhao Yifei , Wang Teng
Published: February 2019

Coastal areas are important sites of environmental and socioeconomic activities and are significantly influenced by climate change. Here we analyzed the current and future responses of spatiotemporal characteristics of land‐sea thermal contrast (LSTC) along China's coastal zone to global warming. Using the European Centre for Medium‐Range Weather Forecasts Re‐Analysis (ERA)‐Interim and 18 Coupled Model Intercomparison Project 5 models, we find that the rate of global warming significantly influenced the LSTC in summer. The LSTC first decreased and then increased during the warming and hiatus periods, respectively. In winter, the LSTC decreased in the Bohai Sea coastal zone, Yellow Sea‐East China Sea coastal zone, and South China Sea coastal zone at rates of 0.46 (p < 0.01), 0.18 (p < 0.01), and 0.19 °C/decade, respectively. Spatially, the LSTC decreased in summer and winter with the decrease in latitude and increased in summer and winter with the decrease in longitude. These changes were caused by urbanization, land use changes, and topography. The spatial distribution was more strongly controlled by land than by sea. Meanwhile, the land/sea warming ratio was concentrated within the range of 0–1 and 1–2, and land/sea temperature variation trends commonly followed the same direction. Overall, land/sea surface temperature variations had similar amplitudes. Under three Representative Concentration Pathways (RCPs), the warming rate difference between land and sea in summer is small, but the land warms faster than the sea in winter, resulting in the LSTC decreasing fast in winter. Under RCP4.5 and RCP8.5, the linear trends in LSTC in Bohai Sea coastal zone, Yellow Sea‐East China Sea coastal zone, and South China Sea coastal zone ranged from 0.05 to 0.08 (p < 0.01) and 0.13 to 0.15 °C/decade (p < 0.01), respectively.
Observations Show Gravity Waves Above Antarctica Dance in Winter
Authors: Cook Terri
Published: February 2019

Year-round observations show gravity waves above Antarctica exhibit seasonal patterns that peak in winter, which could help researchers trace the source of this mysterious phenomenon.
LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p
Authors: Pan Yafang , Zhang Yu , Liu Wenwen , Huang Yan , Shen Xianjuan , Jing Rongrong , Pu Jiang , Wang Xudong , Ju Shaoqing , Cong Hui , Chen Hongmei
Published: February 2019

Radiotherapy, chemotherapy, autologous/allogeneic stem cell transplantation, and targeted drug therapy are currently available therapeutic options for multiple myeloma (MM), but the clinical outcome remains unsatisfactory owing to frequent occurrence of drug resistance. Anti apoptosis is one of the main mechanisms to mediate drug resistance. Studies have shown that MCL-1 plays a key role in the growth of cancer cells “escaping” drug attacks, but the underlying mechanism remains unclear. Our previous study demonstrated that lncRNA H19 was highly expressed in the serum of MM patients. Bioinformatics predicts that miR-29b-3p is the downstream target gene, and MCL-1 is the downstream target protein of miR-29b-3p. Therefore, we speculated that MCL-1 may be involved in the occurrence of drug resistance through epigenetics. On the basis of these previous findings, the present study was intended to explore the biological function of H19, interactions between the downstream target genes, and the effect of H19 on BTZ resistance of myeloma cells. In addition, in vivo experiments we have also confirmed that H19 promoted tumor growth and may develop resistance to bortezomib partly. It was found that H19 reduced cell sensitivity to the chemotherapeutic drug BTZ by working as a miRNA sponge to inhibit the expression of miR-29b-3p, enhance MCL-1 transcriptional translation and inhibit apoptosis. These findings may help gain insights into the molecular mechanism of acquired BTZ resistance and develop new drug targets for the clinical treatment of MM.
Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation
Authors: Li Zhanzhuo , Czechowicz Agnieszka , Scheck Amelia , Rossi Derrick J. , Murphy Philip M.
Published: February 2019

Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donor antigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with ≤ 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third party skin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non−genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.
Collateral sensitivity constrains resistance evolution of the CTX-M-15 β-lactamase
Authors: Rosenkilde Carola E. H. , Munck Christian , Porse Andreas , Linkevicius Marius , Andersson Dan I. , Sommer Morten O. A.
Published: February 2019

Antibiotic resistance is a major challenge to global public health. Discovery of new antibiotics is slow and to ensure proper treatment of bacterial infections new strategies are needed. One way to curb the development of antibiotic resistance is to design drug combinations where the development of resistance against one drug leads to collateral sensitivity to the other drug. Here we study collateral sensitivity patterns of the globally distributed extended-spectrum β-lactamase CTX-M-15, and find three non-synonymous mutations with increased resistance against mecillinam or piperacillin–tazobactam that simultaneously confer full susceptibility to several cephalosporin drugs. We show in vitro and in mice that a combination of mecillinam and cefotaxime eliminates both wild-type and resistant CTX-M-15. Our results indicate that mecillinam and cefotaxime in combination constrain resistance evolution of CTX-M-15, and illustrate how drug combinations can be rationally designed to limit the resistance evolution of horizontally transferred genes by exploiting collateral sensitivity patterns.
Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy
Authors: Haikala Heidi M. , Anttila Johanna M. , Marques Elsa , Raatikainen Tiina , Ilander Mette , Hakanen Henna , Ala-Hongisto Hanna , Savelius Mariel , Balboa Diego , Von Eyss Bjoern , Eskelinen Vilja , Munne Pauliina , Nieminen Anni I. , Otonkoski Timo , Schüler Julia , Laajala Teemu D. , Aittokallio Tero , Sihto Harri , Mattson Johanna , Heikkilä Päivi , Leidenius Marjut , Joensuu Heikki , Mustjoki Satu , Kovanen Panu , Eilers Martin , Leverson Joel D. , Klefström Juha
Published: February 2019

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-XL inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.
Foiling covert channels and malicious classical post-processing units in quantum key distribution
Authors: Curty Marcos , Lo Hoi-Kwong
Published: February 2019

The existing paradigm for the security of quantum key distribution (QKD) suffers from two fundamental weaknesses. First, covert channels have emerged as an important threat and have attracted a lot of attention in security research in conventional information and communication systems. Covert channels (e.g. memory attacks) can fatally break the security of even device-independent quantum key distribution (DI-QKD), whenever QKD devices are re-used. Second, it is often implicitly assumed that the classical post-processing units of a QKD system are trusted. This is a rather strong assumption and is very hard to justify in practice. Here, we propose a new paradigm for the security of QKD that addresses these two fundamental problems. Specifically, we show that by using verifiable secret sharing and multiple optical devices and classical post-processing units, one could re-establish the security of QKD. Our techniques are rather general and they apply to both DI-QKD and non-DI-QKD.
Transcriptomic profiles of tumor-associated neutrophils reveal prominent roles in enhancing angiogenesis in liver tumorigenesis in zebrafish
Authors: Huo Xiaojing , Li Hankun , Li Zhen , Yan Chuan , Agrawal Ira , Mathavan Sinnakaruppan , Liu Jianjun , Gong Zhiyuan
Published: February 2019

We have previously demonstrated the pro-tumoral role of neutrophils using a kras-induced zebrafish hepatocarcinogenesis model. To further illustrate the molecular basis of the pro-tumoral role, Tumor-associated neutrophils (TANs) were isolated by fluorescence-activated cell sorting (FACS) and transcriptomic analyses were carried out by RNA-Seq. Differentially expressed gene profiles of TANs from larvae, male and female livers indicate great variations during liver tumorigenesis, but the common responsive canonical pathways included an immune pathway (Acute Phase Response Signaling), a liver metabolism-related pathway (LXR/RXR Activation) and Thrombin Signaling. Consistent with the pro-tumoral role of TANs, gene module analysis identified a consistent down-regulation of Cytotoxicity module, which may allow continued proliferation of malignant cells. Gene Set Enrichment Analysis indicated up-regulation of several genes promoting angiogenesis. Consistent with this, we found decreased density of blood vessels accompanied with decreased oncogenic liver sizes in neutrophil-depleted larvae. Collectively, our study has indicated some molecular mechanisms of the pro-tumoral roles of TANs in hepatocarcinogenesis, including weakened immune clearance against tumor cells and enhanced function in angiogenesis.
Dentate gyrus μ-opioid receptor-mediated neurogenic processes are associated with alterations in morphine self-administration
Authors: Zhang Haolin , Jia Meng , Wang Xue-Wei , Ye Can , Li Yijing , Wang Na , Elefant Felice , Ma Hui , Cui Cailian
Published: February 2019

Adult hippocampal dentate gyrus (DG) neural stem cells (NSCs) continuously undergo proliferation and differentiation, producing new functional neurons that remodel existing synaptic circuits. Although proliferation of these adult DG NSCs has been implicated in opiate dependence, whether NSC neuronal differentiation and subsequent dendritogenesis are also involved in such addictive behavior remains unknown. Here, we ask whether opiate exposure alters differentiation and dendritogenesis of DG NSCs and investigate the possibility that these alterations contribute to opiate addiction. We show that rat morphine self-administration (MSA), a paradigm that effectively mimics human opiate addiction, increases NSC neuronal differentiation and promotes neuronal dendrite growth in the adult DG. Further, we demonstrate that the μ-opioid receptor (MOR) is expressed on DG NSCs and that MSA leads to a two-fold elevation of endogenous MOR levels in doublecortin expressing (DCX+) NSC progenies in the rat DG. MOR expression is also detected in the cultured rat NSCs and morphine treatment in vitro increases NSC neuronal differentiation and dendritogenesis, suggesting that MOR mediates the effect of morphine on NSC neuronal differentiation and maturation. Finally, we show that conditional overexpression of MOR in DG NSCs under a doxycycline inducible system leads to facilitation of the acquisition of MSA in rats, without affecting the extinction process. We advocate that targeting MOR selectively in the DG NSC population might offer a novel therapeutic intervention for morphine addiction.
A simple protocol for isolating mouse lung endothelial cells
Authors: Wang Jinping , Niu Niu , Xu Suowen , Jin Zheng Gen
Published: February 2019

Endothelial dysfunction is the common molecular basis of multiple human diseases, such as atherosclerosis, diabetes, hypertension, and acute lung injury. Therefore, primary isolation of high-purity endothelial cells (ECs) is crucial to study the mechanisms of endothelial function and disease pathogenesis. Mouse lung ECs (MLECs) are widely used in vascular biology and lung cell biology studies such as pulmonary inflammation, angiogenesis, vessel permeability, leukocyte/EC interaction, nitric oxide production, and mechanotransduction. Thus, in this paper, we describe a simple, and reproducible protocol for the isolation and culture of MLECs from adult mice using collagenase I-based enzymatic digestion, followed by sequential sorting with PECAM1 (also known as CD31)- and ICAM2 (also known as CD102)-coated microbeads. The morphology of isolated MLECs were observed with phase contrast microscope. MLECs were authenticated by CD31 immunoblotting, and immunofluorescent staining of established EC markers VE-cadherin and von Willebrand factor (vWF). Cultured MLECs also showed functional characteristics of ECs, evidenced by DiI-oxLDL uptake assay and THP-1 monocyte adhesion assay. Finally, we used MLECs from endothelium-specific enhancer of zeste homolog 2 (EZH2) knockout mice to show the general applicability of our protocol. To conclude, we describe here a simple and reproducible protocol to isolate highly pure and functional ECs from adult mouse lungs. Isolation of ECs from genetically engineered mice is important for downstream phenotypic, genetic, or proteomic studies.
Repeated human deciduous tooth-derived dental pulp cell reprogramming factor transfection yields multipotent intermediate cells with enhanced iPS cell formation capability
Authors: Soda Miki , Saitoh Issei , Murakami Tomoya , Inada Emi , Iwase Yoko , Noguchi Hirofumi , Shibasaki Shinji , Kurosawa Mie , Sawami Tadashi , Terunuma Miho , Kubota Naoko , Terao Yutaka , Ohshima Hayato , Hayasaki Haruaki , Sato Masahiro
Published: February 2019

Human tissue-specific stem cells (hTSCs), found throughout the body, can differentiate into several lineages under appropriate conditions in vitro and in vivo. By transfecting terminally differentiated cells with reprogramming factors, we previously produced induced TSCs from the pancreas and hepatocytes that exhibit additional properties than iPSCs, as exemplified by very low tumour formation after xenogenic transplantation. We hypothesised that hTSCs, being partially reprogrammed in a state just prior to iPSC transition, could be isolated from any terminally differentiated cell type through transient reprogramming factor overexpression. Cytochemical staining of human deciduous tooth-derived dental pulp cells (HDDPCs) and human skin-derived fibroblasts following transfection with Yamanaka’s factors demonstrated increased ALP activity, a stem cell marker, three weeks after transfection albeit in a small percentage of clones. Repeated transfections (≤3) led to more efficient iPSC generation, with HDDPCs exhibiting greater multipotentiality at two weeks post-transfection than the parental intact HDDPCs. These results indicated the utility of iPSC technology to isolate TSCs from HDDPCs and fibroblasts. Generally, a step-wise loss of pluripotential phenotypes in ESCs/iPSCs occurs during their differentiation process. Our present findings suggest that the reverse phenomenon can also occur upon repeated introduction of reprogramming factors into differentiated cells such as HDDPCs and fibroblasts.
Diagnostic Efficacy of Synthesized 2D Digital Breast Tomosynthesis in Multi-ethnic Malaysian Population
Authors: Mumin N. Ab , Rahmat K. , Fadzli F. , Ramli M. T , Westerhout C. J. , Ramli N. , Rozalli F. I. , Ng K. H.
Published: February 2019

Synthesized 2D images can be reconstructed from tomosynthesis images in breast imaging. This study aims to investigate the diagnostic efficacy of synthesized 2D images (C-View) in comparison to full field digital mammography (FFDM) when used with digital breast tomosynthesis (DBT) in multi-ethnic Malaysian population. FFDM and C-View images (n = 380) were independently evaluated by three readers through Breast Imaging Reporting and Data System (BI-RADS) categorisation, breast density and lesion characterisation. Statistical analysis was done comparing sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of C-View + DBT with FFDM + DBT as standard of reference. Very good interreader agreement in BI-RADS category and density assessment between C-View + DBT and FFDM + DBT, with high sensitivity, specificity, PPV and NPV of C-View + DBT when compared with FFDM + DBT. There was comparable PPV between C-View + DBT and FFDM + DBT, with histopathology as gold standard. High level of interreader agreement in BI-RADS category and density assessment for FFDM + DBT and C-View + DBT. There was good agreement between FFDM + DBT and C-View + DBT in mass characterization, and almost perfect agreement in calcification and asymmetric density. 52.2% lower radiation dose incurred when using C-View + DBT. Hence, synthesized 2D images are comparable to FFDM with reduction in radiation dose within the limits of Malaysian multi-ethnic population.
Electrical Heating Performance of Electro-Conductive Para-aramid Knit Manufactured by Dip-Coating in a Graphene/Waterborne Polyurethane Composite
Authors: Kim Hyelim , Lee Sunhee , Kim Hanseong
Published: February 2019

An electro-conductive para-aramid knit was manufactured by a dip-coating in a graphene/waterborne polyurethane(WPU) composite for confirming to use as a fabric heating element applicable to a protective clothing requiring durability. The para-aramid knit was dipped in 8 wt% graphene/WPU composite solution up to five-coat cycles. As a result of electro-conductive textile by number of dip-coating cycles, the electrical, and specifically electrical heating performances were increased number of cycles from one to five. The sample with the best electrical and electrical heating performance was the five-coat sample, and to improve those properties it was hot-pressed at 100 °C, 120 °C, 140 °C and 160 °C. After hot pressing, the entire surface of the sample was filled with graphene/WPU composite and indicated smoothly surface, thus the electrical and electrical heating performance was improved than the five-coat sample. The best performance of was indicated hot-pressed at 140 °C, with a surface resistivity and capacitance of 7.5 × 104 Ω/sq and 89.4 pF, respectively. When a voltage of 50 V was applied, the surface temperature reached 54.8 °C. The five-coat sample with hot-pressed at 140 °C could be applied to a heat-resistant para-aramid knit glove with the touch screen of a mobile phone and electric heating performance.
Tropical storms influence the movement behavior of a demersal oceanic fish species
Authors: Bacheler Nathan M. , Shertzer Kyle W. , Cheshire Robin T. , MacMahan Jamie H.
Published: February 2019

Extreme weather events strongly influence marine, freshwater, and estuarine ecosystems in myriad ways. We quantified movements of a demersal oceanic fish species (gray triggerfish Balistes capriscus; N = 30) before, during, and after two hurricanes in 2017 using fine-scale acoustic telemetry at a 37-m deep study site in North Carolina, USA. During storms, gray triggerfish movement and emigration rates were 100% and 2550% higher, respectively, than on days with no storms. We found that increased movement rates were much more strongly correlated with wave orbital velocity (i.e., wave-generated oscillatory flow at the seabed) than either barometric pressure or bottom water temperature, two covariates that have been demonstrated to be important for organisms in shallower water. Higher movement rates during storms were due to increased mobility at night, and emigrations typically occurred at night in the direction of deeper water. Overall, we found significant storm effects on the movement behavior of a demersal fish species in the open ocean, despite our study occurring in deeper water than previous studies that have examined storm effects on animal movement. We conclude that tropical storms are a driving force behind the structure of marine ecosystems, in part by influencing movements of mobile animals.
Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model
Authors: Cafora Marco , Deflorian Gianluca , Forti Francesca , Ferrari Laura , Binelli Giorgio , Briani Federica , Ghisotti Daniela , Pistocchi Anna
Published: February 2019

Cystic fibrosis (CF) is a hereditary disease due to mutations in the CFTR gene and causes mortality in humans mainly due to respiratory infections caused by Pseudomonas aeruginosa. In a previous work we used phage therapy, which is a treatment with a mix of phages, to actively counteract acute P. aeruginosa infections in mice and Galleria mellonella larvae. In this work we apply phage therapy to the treatment of P. aeruginosa PAO1 infections in a CF zebrafish model. The structure of the CFTR channel is evolutionary conserved between fish and mammals and cftr-loss-of-function zebrafish embryos show a phenotype that recapitulates the human disease, in particular with destruction of the pancreas. We show that phage therapy is able to decrease lethality, bacterial burden, and the pro-inflammatory response caused by PAO1 infection. In addition, phage administration relieves the constitutive inflammatory state of CF embryos. To our knowledge, this is the first time that phage therapy is used to cure P. aeruginosa infections in a CF animal model. We also find that the curative effect against PAO1 infections is improved by combining phages and antibiotic treatments, opening a useful therapeutic approach that could reduce antibiotic doses and time of administration.
Structure of two purple pigments, catechinopyranocyanidins A and B from the seed-coat of the small red bean, Vigna angularis
Authors: Yoshida Kumi , Nagai Nobukazu , Ichikawa Yoshiki , Goto Miki , Kazuma Kohei , Oyama Kin-ichi , Koga Kazushi , Hashimoto Masaru , Iuchi Satoru , Takaya Yoshiaki , Kondo Tadao
Published: February 2019

The small red bean, Vigna angularis, is primarily used to produce the “an-paste” component of Japanese sweets. Through the manufacturing process, the red seed-coat pigment is transferred to the colorless “an-particles”, imparting a purple color. However, the major pigment in the seed coat has not yet been identified, although it is historically presumed to be an anthocyanin. Here, we report the isolation and structural determination of two hydrophobic purple pigments in the seed coat via instrumental analysis and derivatization. The new pigments, catechinopyranocyanidins A and B, contain a novel pyranoanthocyanidin skeleton condensed with a catechin and cyanidin ring system, and no sugar moieties. Catechinopyranocyanidins A and B are diastereomers with a different configuration at the catechin moiety, and both are purple in color in strongly acidic-to-neutral media. Catechinopyranocyanidins A and B are very stable under dark conditions, but, labile to light and decompose to colorless compounds. Thus, these pigments exhibit quite different chemical properties compared to simple anthocyanidins.
Elevated carbon flux in deep waters of the South China Sea
Authors: Shih Yung-Yen , Lin Hsi-Hsiang , Li Dewang , Hsieh Hsueh-Han , Hung Chin-Chang , Chen Chen-Tung Arthur
Published: February 2019

We measured particulate organic carbon (POC) fluxes from the euphotic zone into the twilight zone and deep waters (>1000 m) that occurred between the shelf and the basin in the South China Sea (SCS) and at the SouthEast Asia Time Series Station (SEATS) using floating sediment trap arrays. Additionally, selected sinking particles were imaged by scanning electron microscope (SEM) to reveal particle morphology and composition. Results showed large variations in POC fluxes with elevated values (32–104 mg-C m−2 d−1) below the euphotic zone and a trend towards lower values in the deep SCS. Vertical POC fluxes measured in deep waters between the shelf and the SCS basin were much higher than those estimated by Martin’s attenuation equation. These elevated POC fluxes in deep waters were attributed to lateral particle transport as opposed to enhanced settling out of the euphotic zone. SEM images of sinking particles at 150 m show abundant marine biogenic detritus, while those in deep waters contained a higher proportion of lithogenic material. A great deal of the spatial variability in POC fluxes across the twilight zone and deep waters of the SCS cannot be represented by current biogeochemical models.
Blood-based analysis of type-2 diabetes mellitus susceptibility genes identifies specific transcript variants with deregulated expression and association with disease risk
Authors: Christodoulou Maria-Ioanna , Avgeris Margaritis , Kokkinopoulou Ioanna , Maratou Eirini , Mitrou Panayota , Kontos Christos K. , Pappas Efthimios , Boutati Eleni , Scorilas Andreas , Fragoulis Emmanuel G.
Published: February 2019

Despite significant progress by genome-wide association studies, the ability of genetic variants to conduce to the prediction or prognosis of type-2 diabetes (T2D) is weak. Expression analysis of the corresponding genes may suggest possible links between single-nucleotide polymorphisms and T2D phenotype and/or risk. Herein, we investigated the expression patterns of 24 T2D-susceptibility genes, and their individual transcript variants (tv), in peripheral blood of T2D patients and controls (CTs), applying RNA-seq and real-time qPCR methodologies, and explore possible associations with disease features. Our data revealed the deregulation of certain transcripts in T2D patients. Among them, the down-regulation of CAPN10 tv3 was confirmed as an independent predictor for T2D. In patients, increased expression of CDK5 tv2, CDKN2A tv3 or THADA tv5 correlated positively with serum insulin levels, of CDK5 tv1 positively with % HbA1c levels, while in controls, elevated levels of TSPAN8 were associated positively with the presence of T2D family history. Herein, a T2D-specific expression profile of specific transcripts of disease-susceptibility genes is for the first time described in human peripheral blood. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.
3D-Spatial encoding with permanent magnets for ultra-low field magnetic resonance imaging
Authors: Vogel Michael W. , Guridi Ruben Pellicer , Su Jiasheng , Vegh Viktor , Reutens David C.
Published: February 2019

We describe with a theoretical and numerical analysis the use of small permanent magnets moving along prescribed helical paths for 3D spatial encoding and imaging without sample adjustment in ultra-low field magnetic resonance imaging (ULF-MRI). With our developed method the optimal magnet path and orientation for a given encoding magnet number and instrument architecture can be determined. As a proof-of-concept, we studied simple helical magnet paths and lengths for one and two encoding magnets to evaluate the imaging efficiency for a mechanically operated ULF-MRI instrument with permanent magnets. We demonstrate that a single encoding magnet moving around the sample in a single revolution suffices for the generation of a 3D image by back projection.
Robust and efficient knock-in in embryonic stem cells and early-stage embryos of the common marmoset using the CRISPR-Cas9 system
Authors: Yoshimatsu Sho , Okahara Junko , Sone Takefumi , Takeda Yuta , Nakamura Mari , Sasaki Erika , Kishi Noriyuki , Shiozawa Seiji , Okano Hideyuki
Published: February 2019

Genome editing technology greatly facilitates the genetic modification of various cells and animals. The common marmoset (Callithrix jacchus), a small non-human primate which exhibits high reproductive efficiency, is a widely used animal model in biomedical research. Developing genome editing techniques in the common marmoset will further enhance its utility. Here, we report the successful establishment of a knock-in (KI) method for marmoset embryonic stem cells (ESCs), which is based on the CRISPR-Cas9 system. The use of CRISPR-Cas9, mediated by homologous recombination (HR), enhanced the KI efficiency in marmoset ESCs. Furthermore, we succeeded in performing KI in early-stage marmoset embryos. In the course of the experiments, we found that HR in the marmoset ESCs is innately highly efficient. This suggested that the marmoset possesses a repair mechanism for DNA double-strand breaks. The current study will facilitate the generation of genetically modified marmosets and gene function analysis in the marmoset.
Paternal leakage and mtDNA heteroplasmy in Rhipicephalus spp. ticks
Authors: Mastrantonio Valentina , Latrofa Maria Stefania , Porretta Daniele , Lia Riccardo Paolo , Parisi Antonio , Iatta Roberta , Dantas-Torres Filipe , Otranto Domenico , Urbanelli Sandra
Published: February 2019

Paternal leakage of mitochondrial DNA (mtDNA) and heteroplasmy have been recently described in several animal species. In arthropods, by searching in the Scopus database, we found only 23 documented cases of paternal leakage. Therefore, although arthropods represent a large fraction of animal biodiversity, this phenomenon has been investigated only in a paucity of species in this phylum, thus preventing a reliable estimate of its frequency. Here, we investigated the occurrence of paternal leakage and mtDNA heteroplasmy in ticks belonging to one of the most significant tick species complexes, the so-called Rhipicephalus sanguineussensu lato. By developing a multiplex allele-specific PCR assay targeting a fragment of the 12S rRNA ribosomal region of the mtDNA, we showed the occurrence of paternal leakage and mtDNA heteroplasmy in R. sanguineuss.l. ticks originated from experimental crosses, as well as in individuals collected from the field. Our results add a new evidence of paternal leakage in arthropods and document for the first time this phenomenon in ticks. Furthermore, they suggest the importance of using allele-specific assays when searching for paternal leakage and/or heteroplasmy, as standard sequencing methods may fail to detect the rare mtDNA molecules.
FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression
Authors: Varghese Vidhya , Magnani Luca , Harada-Shoji Narumi , Mauri Francesco , Szydlo Richard M. , Yao Shang , Lam Eric W.-F. , Kenny Laura M.
Published: February 2019

Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Plasmodium falciparum specific helicase 2 is a dual, bipolar helicase and is crucial for parasite growth
Authors: Chauhan Manish , Tuteja Renu
Published: February 2019

Human malaria infection is a major challenge across the globe and is responsible for millions of deaths annually. Rapidly emerging drug resistant strains against the new class of anti-malarial drugs are major threat to control the disease burden worldwide. Helicases are present in every organism and have important role in various nucleic acid metabolic processes. Previously we have reported the presence of three parasite specific helicases (PSH) in Plasmodium falciparum 3D7 strain. Here we present the detailed biochemical characterization of PfPSH2. PfPSH2 is DNA and RNA stimulated ATPase and is able to unwind partially duplex DNA and RNA substrates. It can translocate in both 3′ to 5′ and 5′ to 3′ directions. PfPSH2 is expressed in all the stages of intraerythrocytic development and it is localized in cytoplasm in P. falciparum 3D7 strain. The dsRNA mediated inhibition study suggests that PfPSH2 is important for the growth and survival of the parasite. This study presents the detailed characterization of PfPSH2 and lays the foundation for future development of PfPSH2 as drug target.
2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain
Authors: Jeon Albert Byungyun , Ackart David F. , Li Wei , Jackson Mary , Melander Roberta J. , Melander Christian , Abramovitch Robert B. , Chicco Adam J. , Basaraba Randall J. , Obregón-Henao Andrés
Published: February 2019

There is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of in vivo biofilm-like communities of M. tuberculosis could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an in vitro M. tuberculosis biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated β-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against M. tuberculosis correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against M. tuberculosis, providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.
Expression of microRNAs 16, 20a, 150 and 155 in anal squamous intraepithelial lesions from high-risk groups
Authors: Albuquerque Andreia , Fernandes Mara , Stirrup Oliver , Teixeira Ana Luísa , Santos Joana , Rodrigues Marta , Rios Elisabete , Macedo Guilherme , Medeiros Rui
Published: February 2019

Anal squamous intraepithelial lesions (ASIL) or anal intraepithelial neoplasia (AIN) are precancerous lesions. microRNAs (miRNAs) have been implicated in cervical carcinogenesis, but have never been assessed in anal precancerous lesions. Our aim was to evaluate the expression of miR-16, miR-20a, miR-150 and miR-155 in several grades of ASIL obtained from high-risk patients, submitted to anal cancer screening from July 2016 to January 2017. Lesions were classified according to the Lower Anogenital Squamous Terminology (LAST) in low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), and the AIN classification in AIN1, AIN2 and AIN3. A hundred and five biopsies were obtained from 60 patients. Ten samples were negative (9.5%), 63 were LSIL (60%) and 32 were HSIL (30.5%) according to the LAST. Twenty seven (26%) were negative for dysplasia, 46 were classified as AIN1 (44%), 14 as AIN2 (13%) and 18 as AIN3 (17%) according to the AIN classification. There was no statistically significant difference in the fold expression of miR-16, miR-20a, miR-150 and miR-155, according to either classification. Although non- significant, there was an increasing trend in the miR-155 fold expression from negative samples to HSIL, with the highest fold expression increase in both LSIL and HSIL compared to the other miRNAs.
A novel fluorescent sensing platform based on metal-polydopamine frameworks for the dual detection of kanamycin and oxytetracycline
Authors: A Ravikumar , P Panneerselvam
Published: February 2019

In this study, we report the dual detection of kanamycin (KMY) and oxytetracycline (OTC) using metal polydopamine frameworks (MPDA) for the first time.
Cationic polymer-derived carbon dots for enhanced gene delivery and cell imaging
Authors: He Xi , Chen Ping , Zhang Ji , Luo Tian-Ying , Wang Hai-Jiao , Liu Yan-Hong , Yu Xiao-Qi
Published: February 2019

The transformation of cationic polymers derived from ring-opening polymerization to carbon dots was proved as a promising strategy for developing gene vectors with high efficiency and cell-imaging ability.
Magnetic performance and defect characterization studies of core–shell architectured MgFe2O4@BaTiO3multiferroic nanostructures
Authors: Abraham Ann Rose , Raneesh B. , Joseph Saju , Mohammed Arif P. , Nambissan P. M. G. , Das Dipankar , Rouxel Didier , Oluwafemi Oluwatobi Samuel , Thomas Sabu , Kalarikkal Nandakumar
Published: February 2019

Multiferroics that permit manipulation of magnetization vector exclusively by electric fields have spawned extensive interest for memory and logic device applications.
Development and application of a comprehensive machine learning program for predicting molecular biochemical and pharmacological properties
Authors: Choi Hwanho , Kang Hongsuk , Chung Kee-Choo , Park Hwangseo
Published: February 2019

We have developed and validated a comprehensive 3D-QSAR model for predicting various biochemical and pharmacological properties of organic molecules.
Cytochrome c oxidase structures suggest a four-state stochastic pump mechanism
Authors: Palese Luigi Leonardo
Published: February 2019

A simple stochastic model for a cytochrome c oxidase proton pump.
First-principles calculations of interfacial thermal transport properties between SiC/Si substrates and compounds of boron with selected group V elements
Authors: Sun Zhehao , Yuan Kunpeng , Zhang Xiaoliang , Tang Dawei
Published: February 2019

This study explores the phonon-level mechanisms for interfacial thermal transport, especially systematically analyzing the effect of crystal information at interfaces.
Cu(ii)-nanoparticle-derived structures under CO2 reduction conditions: a matter of shape
Authors: Basiratnia Amir , Rempel Jacob , Li Feng , Pogodaev Alexey , Zienchuk Thomas A. , Klinkova Anna
Published: February 2019

We investigate the structural evolution of Cu(OH)2 nanoparticle-derived electrodes under CO2 electroreduction conditions and its effect on their electrocatalytic performance.
Elucidating the mobility of H+and Li+ions in (Li6.25−xHxAl0.25)La3Zr2O12viacorrelative neutron and electron spectroscopy
Authors: Liu Xiaoming , Chen Yan , Hood Zachary D. , Ma Cheng , Yu Seungho , Sharafi Asma , Wang Hui , An Ke , Sakamoto Jeff , Siegel Donald J. , Cheng Yongqiang , Jalarvo Niina H. , Chi Miaofang
Published: February 2019

Neutron and electron spectroscopy reveal diffusion behavior of individual ions in lithium garnets, paving the way towards high-performance aqueous lithium batteries.
Reliable interfaces for EGaIn multi-layer stretchable circuits and microelectronics
Authors: Green Marques Daniel , Alhais Lopes Pedro , T. de Almeida Anibal , Majidi Carmel , Tavakoli Mahmoud
Published: February 2019

Multi-layer on-skin EMG with integrated chips and EgaIn stretchable circuitry for stretchable electronics, bio-monitoring and human–machine interaction.
Enantioselective synthesis of chiral heterocyclic biaryls via asymmetric Suzuki–Miyaura cross-coupling of 3-bromopyridine derivatives
Authors: Xia Wang , Zhang Zhen-Wei , Li Yongsu , Jiang Xiaoding , Liang Hao , Zhang Yaqi , Cao Rihui , Qiu Liqin
Published: February 2019

A series of chiral heterocyclic biaryls with a pyridyl moiety were prepared in moderate to good yields with up to 92% ee via asymmetric Suzuki–Miyaura coupling.
Thermoset elastomers covalently crosslinked by hard nanodomains of triblock copolymers derived from carvomenthide and lactide: tunable strength and hydrolytic degradability
Authors: Jang Jeongmin , Park Hyejin , Jeong Haemin , Mo Eunbi , Kim Yongbin , Yuk Jeong Suk , Choi Siyoung Q. , Kim Young-Wun , Shin Jihoon
Published: February 2019

Sustainable, mechanically reinforced, and hydrolytically degradable thermoset elastomers were synthesized by one-pot, three-step synthesis & crosslinking.
Vat photopolymerization of charged monomers: 3D printing with supramolecular interactions
Authors: Wilts Emily M. , Pekkanen Allison M. , White B. Tyler , Meenakshisundaram Viswanath , Aduba Donald C. , Williams Christopher B. , Long Timothy E.
Published: February 2019

Vat photopolymerization of a trimethylammonium ethyl acrylate chloride solution (TMAEA) resulted in a well-defined, fully soluble, 3D printed rook.