bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical Analysis of Individual Solar Active Regions
Authors: Kromyda Garyfallia , Vlahos Loukas
Published: July 2018

In the last decades, numerous observational and computational studies have shown that the global flare distribution is a power-law with a slope less than 2. In these studies, active regions are treated as statistically indistinguishable. To test this, we identify and separately analyze the flares produced by ten individual active regions (2006-2016). In five regions, we find a single power-law distribution, with a slope of a < 2. In the other five, we find a broken double power-law distribution, with slopes a1 < 2 and a2 > 2.
Comparison of Predictive Efficiency of Topological Descriptors and SHARP in Solar Flares Forecasting
Authors: Knyazeva Irina , Urtiev Fedor , Makarenko Nikolay
Published: July 2018

In the current paper, we investigate topological invariants, calculated by HMI LOS magnetograms as complexity descriptors of solar magnetic fields. We compared them with the physical parameters provided by the Space-weather HMI Active Region Patches (SHARP). We have repeated forecasting experiment of Stanford Solar Observatories Group with the same positive and negative active region patches database, but replace SHARP parameters with topological invariants of corresponding LOS magnetograms. The classification results turned out practically identical to those obtained by the Stanford Solar Observatory group. This means that using LOS magnetograms retains enough complexity for magnetic field description.
The Forecast of Space Weather According to Ground-Based Observatories
Authors: Tlatov Andrey
Published: July 2018

The space weather forecast can be conditionally divided into three components: 1) The forecast of recurrent slowly varying events which are associated with the topology of a large-scale magnetic field; 2) Evaluation of fluxes of ultraviolet and extreme radiation; 3) Detecting and determining the parameters of eruptions and CME. All three components can be observed and evaluated by ground-based telescopes. In this article we describe the telescopes of the space weather service in Kislovodsk Mountain Astronomical Station. Telescope-magnetograph STOP for the forecast of recurrent events and patrol telescopes-spectrographs for detecting CME and estimating hard radiation fluxes.
Determining the Polar Cusp Longitudinal Location from Pc5 Geomagnetic Field Measurements at a Pair of High Latitude Stations
Authors: Lepidi Stefania , Francia Patrizia , Cafarella Lili , Di Mauro Domenico , Marzocchetti Martina
Published: July 2018

We use low frequency geomagnetic field measurements at two Antarctic stations to statistically investigate the longitudinal location of the polar cusp. The two stations are both located in the polar cap at a geomagnetic latitude close to the cusp latitude; they are separated by one hour in magnetic local time. At each station the Pc5 power maximizes when the station approaches the cusp, i.e. around magnetic local noon. The comparison between the Pc5 power at the two stations allows to determine the longitudinal location of the cusp. Our analysis is conducted considering separately different orientation of the interplanetary magnetic field. The results, which indicate longitudinal shifts of the polar cusp depending on the selected conditions, are discussed in relation to previous studies of the polar cusp location based on polar magnetospheric satellite data.
On the Evolution of Pre-Flare Patterns of a 3-Dimensional Model of AR 11429
Authors: Korsós M. B. , Poedts S. , Gyenge N. , Georgoulis M. K. , Yu S. , Bisoi S. K. , Yan Y. , Ruderman M. S. , Erdélyi R.
Published: July 2018

We apply a novel pre-flare tracking of sunspot groups towards improving the estimation of flare onset time by focusing on the evolution of the 3D magnetic field construction of AR 11429. The 3D magnetic structure is based on potential field extrapolation encompassing a vertical range from the photosphere through the chromosphere and transition region into the low corona. The basis of our proxy measure of activity prediction is the so-called weighted horizontal gradient of magnetic field (WGM) defined between spots of opposite polarities close to the polarity inversion line of an active region. The temporal variation of the distance of the barycenter of the opposite polarities is also found to possess potentially important diagnostic information about the flare onset time estimation as function of height similar to its counterpart introduced initially in an application at the photosphere only in Korsós et al. (2015). We apply the photospheric pre-flare behavioural patterns of sunspot groups to the evolution of their associated 3D-constructed AR 11429 as function of height. We found that at a certain height in the lower solar atmosphere the onset time may be estimated much earlier than at the photosphere or at any other heights. Therefore, we present a tool and recipe that may potentially identify the optimum height for flare prognostic in the solar atmosphere allowing to improve our flare prediction capability and capacity.
Spatial Inhomogeneity in Solar Faculae
Authors: Elek A. , Gyenge N. , Korsós M. B. , Erdélyi R.
Published: July 2018

In this paper, we investigate the inhomogeneous spatial distribution of solar faculae. The focus is on the latitudinal and longitudinal distributions of these highly localised features covering ubiquitously the solar surface. The statistical analysis is based on white light observations of the Solar and Heliospheric Observatory (SOHO) and Solar Dynamics Observatory (SDO) between 1996 and 2014. We found that the fine structure of the latitudinal distribution of faculae displays a quasi-biennial oscillatory pattern. Furthermore, the longitudinal distribution of photospheric solar faculae does not show homogeneous behaviour either. In particular, the non-axisymmetric behaviour of these events show similar properties as that of the active longitude (AL) found in the distribution of sunspots. Our results, preliminary though, may provide a valuable observational constrain for developing the next-generation solar dynamo model.
Variability of the Vertical Total Electron Content, from GPS data, during 2 to 8 November 2015, Using Oukaimeden and Rabat Stations in Morocco
Authors: El bouyahyaoui Khaoula , Bounhir Aziza , Benkhaldoun Zouhair , FLEURY Rolland , Amory-Mazaudier Christine , Kaab Mohamed
Published: July 2018

In this work we present a method for detecting the activity of the ionosphere (TEC) and we illustrate the signature of the solar activity on the vertical total electron content VTEC, during 02 to 08 November 2015, using GPS measurements obtained from two stations in Morocco, the first one in Marrakech at Observatory of Oukaimeden OUCA (31°12′23.3″ N 7°51′58.8″ W), the second in Rabat, Rabt (33.9981°N;353.1457°E, geographic).
Challenges and Strategic Research Plans for Earth and Heliosphere: Research Infrastructures, Projects and Initiatives
Authors: Mann Ingrid , Kauristi Kirsti , Bamford Ruth , McCrea Ian , Moen Joeran , Oksavik Kjellmar , Yamauchi Masanori , Gullikstad Magnar Johnsen , Turunen Esa
Published: July 2018

We describe existing research infrastructures relevant for space weather and open issues of space weather research including the need for sustainable observation networks and for high-quality data products as basis for model development. The local relevance in Europe for studies of the ionosphere at high latitude is described. We propose as possible a way forward to sustain space weather research in Europe to establish a European research infrastructure project for space weather research and observations.
Dynamics of an Active Earthflow Inferred From Surface Wave Monitoring
Authors: Bertello Lara , Berti Matteo , Castellaro Silvia , Squarzoni Gabriela
Published: July 2018

Earthflows are clay‐rich, slow‐moving landslides subjected to periodic accelerations. During the stage of rapid movement, most earthflows exhibit a change in behavior from a solid to a fluid‐like state. Although this behavior has been extensively documented in the field, the mechanism leading to the rapid acceleration of earthflows is still poorly understood. Some studies suggest that earthflows essentially behave as Coulomb plastic solids, attributing the flow‐like appearance to distributed internal shearing; others believe that these landslides can be treated as viscous fluids, pointing out that the material undergoes a phase transition by increasing its moisture content. Minimal data are currently available to support these different findings. In this study, we present the results of periodic and continuous measurements of Rayleigh wave velocity carried out in an active earthflow located in the northern Apennines of Italy. Our data indicate that the material undergoes significant changes in shear stiffness and undrained strength during rapid movements. In particular, the material exhibits a substantial drop of Rayleigh wave velocity as the earthflow accelerates, followed by a slow return to predisturbance Rayleigh velocities as the landslide decelerates. Soon after a surge, the earthflow material is extremely soft and the estimated gravimetric water content is above the liquid limit. In the following months, the shear stiffness gradually increases and the water content decreases to the plastic limit following a nonlinear trend typical of a consolidation process. These data demonstrate that the earthflow transforms into a viscous fluid by softening of the material and by water entrainment.
Youth Urge Action on Climate Change and Environmental Justice
Authors: Showstack Randy
Published: July 2018

Marches on Saturday in Washington, D. C., and other cities spring from “a sliver of hope left” to act against climate change.
Solar Wind Induced Waves in the Skies of Mars: Ionospheric Compression, Energization, and Escape Resulting From the Impact of Ultralow Frequency Magnetosonic Waves Generated Upstream of the Martian Bow Shock
Authors: Collinson Glyn , Wilson Lynn B. , Omidi Nick , Sibeck David , Espley Jared , Fowler Christopher M. , Mitchell David , Grebowsky Joseph , Mazelle Christian , Ruhunusiri Suranga , Halekas Jasper , Frahm Rudy , Zhang Tielong , Futaana Yoshifumi , Jakosky Bruce
Published: July 2018

Using data from the National Aeronautics and Space Administration Mars Atmosphere and Voltatile EvolutioN and the European Space Agency Mars Express spacecraft, we show that transient phenomena in the foreshock and solar wind can directly inject energy into the ionosphere of Mars. We demonstrate that the impact of compressive ultralow frequency waves in the solar wind on the induced magnetospheres drive compressional, linearly polarized, magnetosonic ultralow frequency waves in the ionosphere, and a localized electromagnetic "ringing" at the local proton gyrofrequency. The pulsations heat and energize ionospheric plasmas. A preliminary survey of events shows that no special upstream conditions are required in the interplanetary magnetic field or solar wind. Elevated ion densities and temperatures in the solar wind near to Mars are consistent with the presence of an additional population of Martian ions, leading to ion‐ion instablities, associated wave‐particle interactions, and heating of the solar wind. The phenomenon was found to be seasonal, occurring when Mars is near perihelion. Finally, we present simultaneous multipoint observations of the phenomenon, with the Mars Express observing the waves upstream, and Mars Atmosphere and Voltatile EvolutioN observing the response in the ionosphere. When these new observations are combined with decades of previous studies, they collectively provide strong evidence for a previously undemonstrated atmospheric loss process at unmagnetized planets: ionospheric escape driven by the direct impact of transient phenomena from the foreshock and solar wind.
Late Permian Bimodal Volcanic Rocks in the Northern Qiangtang Terrane, Central Tibet: Evidence for Interaction Between the Emeishan Plume and the Paleo‐Tethyan Subduction System
Authors: Wang Jun , Wang Qiang , Zhang Chunfu , Dan Wei , Qi Yue , Zhang Xiu‐Zheng , Xia Xiao‐Ping
Published: July 2018

Many studies provide compelling evidence for a fossil mantle plume beneath the Late Permian Emeishan large igneous province located near the southeastern margin of the central Tibetan Plateau, a region associated with the Paleo‐Tethyan subduction system. However, little is known about whether direct plume‐subduction interaction occurred during the Late Permian. Here we report geochronological, mineralogical, geochemical, and Sr‐Nd‐Hf‐O isotopic data for the Late Permian (~259–256 Ma) bimodal volcanic rocks (BVRs) in the northern Qiangtang Terrane (NQT), central Tibet. These BVRs consist mainly of basalts, rhyolites, and rhyolitic tuffs. The rhyolites with A‐type affinity were generated by partial melting of newly underplated basalts. Geochemical and isotopic data suggest that two components (ocean island basalt‐type mantle and subducted sediment‐derived fluid) were involved in the generation of the basalts in an extensional back‐arc region. Considering the Permian tectonic evolution of the NQT, we propose that this enriched ocean island basalt‐type mantle was distinct from the Paleo‐Tethyan depleted upper mantle. It most likely originated from Emeishan‐plume material that flowed westward from the South China Block to the nearby NQT, driven by slab rollback‐induced counterflow. The presence of high‐temperature A‐type rhyolites in bimodal back‐arc magmatism also indicates a special subduction setting influenced by a nearby plume. Thus, we propose that the Late Permian BVRs were the result of interaction between the Emeishan plume and the Paleo‐Tethyan subduction system.
MiR-361-3p regulates ERK1/2-induced EMT via DUSP2 mRNA degradation in pancreatic ductal adenocarcinoma
Authors: Hu Jisheng , Li Le , Chen Hongze , Zhang Guangquan , Liu Huan , Kong Rui , Chen Hua , Wang Yongwei , Li Yilong , Tian Fengyu , Lv Xinjian , Li Guanqun , Sun Bei
Published: July 2018

Metastasis remains one of the most intractable challenges in pancreatic ductal adenocarcinoma (PDAC) biology, and epithelial-to-mesenchymal transition (EMT) is essential to the epithelium-originated solid tumor metastasis cascade. Emerging evidence demonstrates that aberrant miRNA expression is involved in pancreatic cancer progression. We found that miR-361-3p was associated with an advanced stage of PDAC and poor prognosis. Hence, the effect of miR-361-3p on metastasis of PDAC cells was evaluated using Transwell assay and wound healing assay in vitro as well as orthotopic and liver metastasis pancreatic cancer models in vivo. Overexpression of miR-361-3p promoted pancreatic cancer cell migration and invasion in vitro, and miR-361-3p-elevated PDAC cells were prone to generating metastatic nodules in vivo. However, miR-361-3p showed no significant effect on the proliferation of PDAC cells in vivo or in vitro. Further study demonstrated that miR-361-3p could enhance EMT and ERK pathway activation, and ERK inhibitor could attenuate miR-361-3p-induced EMT. Luciferase assays, qPCR, and western blot and Ago2 co-immunoprecipitation were performed to identify the direct target of miR-361-3p. Mechanistic investigations identified DUSP2 as a direct target of miR-361-3p, and DUSP2 was revealed to be involved in miR-361-3p-induced EMT by directly leading to the inactivation of the ERK pathway. Moreover, we found that miR-361-3p-induced EMT was dependent on Ago2, the core component of RNA-induced silencing complex, while enforced expression of Ago2 enhanced the miR-361-3p-induced effect by promoting interference efficacy and specificity rather than regulating miR-361-3p stability and biogenesis. Thus, this study revealed that miR-361-3p functions as an oncomiR for promoting metastasis and identified the miR-361-3p/DUSP2/ERK axis as a novel EMT axis dependent on Ago2 in PDAC.
A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
Authors: Einarsdottir Berglind O. , Karlsson Joakim , Söderberg Elin M. V. , Lindberg Mattias F. , Funck-Brentano Elisa , Jespersen Henrik , Brynjolfsson Siggeir F. , Olofsson Bagge Roger , Carstam Louise , Scobie Martin , Koolmeister Tobias , Wallner Olof , Stierner Ulrika , Berglund Ulrika Warpman , Ny Lars , Nilsson Lisa M. , Larsson Erik , Helleday Thomas , Nilsson Jonas A.
Published: July 2018

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis
Authors: Jeong Seong-In , Kim Jung-Wook , Ko Kyung-Phil , Ryu Byung-Kyu , Lee Min-Goo , Kim Hyo-Jong , Chi Sung-Gil
Published: July 2018

X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a proapoptotic tumor suppressor that is frequently inactivated in multiple human cancers. However, the molecular basis for the XAF1-mediated growth inhibition remains largely undefined. Here, we report that XAF1 forms a positive feedback loop with interferon regulatory factor-1 (IRF-1) and functions as a transcriptional coactivator of IRF-1 to suppress tumorigenesis. Under various stressful conditions, XAF1 transcription is activated by IRF-1, and elevated XAF1 stabilizes and activates IRF-1. Mechanistically, XAF1 binds to the multifunctional domain 2 of IRF-1 via the zinc finger domain 6, thereby hindering C-terminus of Hsc70-interacting protein (CHIP) interaction with and ubiquitination of IRF-1. Activation of the IRF-1−XAF1 loop greatly increases stress-induced apoptosis and decreases the invasive capability of tumor cells. Oncogenic Ras and growth factors interfere with the IRF-1−XAF1 interplay via Erk-mediated repression of XAF1 transcription. Furthermore, XAF1 enhances IRF-1-mediated transcription of proapoptotic genes via the XAF1-IRF-1 complex formation on these target promoters. Meanwhile, XAF1 inhibits NF-κB-mediated tumor cell malignancy by reinforcing IRF-1 binding to a subset of coregulated promoters. Expression levels of IRF-1 and XAF1 correlate tightly in both cancer cell lines and primary tumors, and XAF1-induced tumor regression is markedly attenuated in IRF-1-depleted tumors. Collectively, this study identifies a novel mechanism of XAF1-mediated tumor suppression, uncovering XAF1 as a feedback coactivator of IRF-1 under stressful conditions.
Shutdown of ER-associated degradation pathway rescues functions of mutant iduronate 2-sulfatase linked to mucopolysaccharidosis type II
Authors: Osaki Yosuke , Saito Atsushi , Kanemoto Soshi , Kaneko Masayuki , Matsuhisa Koji , Asada Rie , Masaki Takao , Orii Kenji , Fukao Toshiyuki , Tomatsu Shunji , Imaizumi Kazunori
Published: July 2018

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a devastating progressive disease caused by mutations in the iduronate 2-sulfatase (IDS) gene. IDS is one of the sulfatase enzymes required for lysosomal degradation of glycosaminoglycans. Mutant proteins linked to diseases are often prone to misfolding. These misfolded proteins accumulate in the endoplasmic reticulum (ER) and are degraded by the ubiquitin–proteasome pathway (ER-associated degradation (ERAD)). The decreased enzyme activities of IDS mutants may be due to accelerated degradation by ERAD. However, intracellular dynamics including degradation of IDS mutants is unexplored. In this report, we examined biochemical and biological characteristics of wild-type (WT) IDS and IDS mutants expressed in HeLa cells. IDS was shown to be glycosylated in the ER and Golgi apparatus and proteolytically cleaved to generate the mature forms in the Golgi apparatus. The mature WT IDS was translocated to the lysosome. In contrast, all IDS mutants we examined were found to accumulate in the ER and could not efficiently translocate to the lysosome. Accumulated IDS mutants in the ER were ubiquitinated by ERAD-related ubiquitin E3 ligase HRD1 followed by degradation via ERAD. Suppressed degradation of ‘attenuated’ mutant A85T IDS (the late-onset form of MPS II) by inhibiting ERAD components improved translocation to the lysosome and its activities. Our novel findings provide alternative targets to current principal therapies for MPS II. These perspectives provide a potenti al framework to develop fundamental therapeutic strategies and agents.
The actin cytoskeletal architecture of estrogen receptor positive breast cancer cells suppresses invasion
Authors: Padilla-Rodriguez Marco , Parker Sara S. , Adams Deanna G. , Westerling Thomas , Puleo Julieann I. , Watson Adam W. , Hill Samantha M. , Noon Muhammad , Gaudin Raphael , Aaron Jesse , Tong Daoqin , Roe Denise J. , Knudsen Beatrice , Mouneimne Ghassan
Published: July 2018

Estrogen promotes growth of estrogen receptor-positive (ER+) breast tumors. However, epidemiological studies examining the prognostic characteristics of breast cancer in postmenopausal women receiving hormone replacement therapy reveal a significant decrease in tumor dissemination, suggesting that estrogen has potential protective effects against cancer cell invasion. Here, we show that estrogen suppresses invasion of ER+ breast cancer cells by increasing transcription of the Ena/VASP protein, EVL, which promotes the generation of suppressive cortical actin bundles that inhibit motility dynamics, and is crucial for the ER-mediated suppression of invasion in vitro and in vivo. Interestingly, despite its benefits in suppressing tumor growth, anti-estrogenic endocrine therapy decreases EVL expression and increases local invasion in patients. Our results highlight the dichotomous effects of estrogen on tumor progression and suggest that, in contrast to its established role in promoting growth of ER+ tumors, estrogen has a significant role in suppressing invasion through actin cytoskeletal remodeling.
The must-have and nice-to-have experimental and computational requirements for functional frequency doubling deep-UV crystals
Authors: Halasyamani P. Shiv , Rondinelli James M.
Published: July 2018

Inorganic materials exhibiting second-harmonic generation (SHG) are used to generate coherent radiation at wavelengths where solid-state laser sources are not available; that is, the deep UV (DUV) below 200 nm. Here, we describe the structure and optical property requirements that should be assessed to conclusively demonstrate the discovery of a functional DUV material for nonlinear optical (NLO) applications.
Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes
Authors: Ransom Ryan C. , Foster Deshka S. , Salhotra Ankit , Jones Ruth Ellen , Marshall Clement D. , Leavitt Tripp , Murphy Matthew P. , Moore Alessandra L. , Blackshear Charles P. , Brett Elizabeth A. , Wan Derrick C. , Longaker Michael T.
Published: July 2018

Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through the packaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.
Discovery and control of culturable and viable but non-culturable cells of a distinctive Lactobacillus harbinensis strain from spoiled beer
Authors: Liu Junyan , Deng Yang , Li Lin , Li Bing , Li Yanyan , Zhou Shishui , Shirtliff Mark E. , Xu Zhenbo , Peters Brian M.
Published: July 2018

Occasional beer spoilage incidents caused by false-negative isolation of lactic acid bacteria (LAB) in the viable but non-culturable (VBNC) state, result in significant profit loss and pose a major concern in the brewing industry. In this study, both culturable and VBNC cells of an individual Lactobacillus harbinensis strain BM-LH14723 were identified in one spoiled beer sample by genome sequencing, with the induction and resuscitation of VBNC state for this strain further investigated. Formation of the VBNC state was triggered by low-temperature storage in beer (175 ± 1.4 days) and beer subculturing (25 ± 0.8 subcultures), respectively, and identified by both traditional staining method and PMA-PCR. Resuscitated cells from the VBNC state were obtained by addition of catalase rather than temperature upshift, changing medium concentration, and adding other chemicals, and both VBNC and resuscitated cells retained similar beer-spoilage capability as exponentially growing cells. In addition to the first identification of both culturable and VBNC cells of an individual L. harbinensis strain from spoiled beer, this study also for the first time reported the VBNC induction and resuscitation, as well as verification of beer-spoilage capability of VBNC and resuscitated cells for the L. harbinensis strain. Genes in association with VBNC state were also identified by the first genome sequencing of beer spoilage L. harbinensis. The results derived from this study suggested the contamination and spoilage of beer products by VBNC and resuscitated L. harbinensis strain BM-LH14723.
A novel triple combination of pharmacological chaperones improves F508del-CFTR correction
Authors: Carlile Graeme W. , Yang Qi , Matthes Elizabeth , Liao Jie , Radinovic Stevo , Miyamoto Carol , Robert Renaud , Hanrahan John W. , Thomas David Y.
Published: July 2018

Pharmacological chaperones (e.g. VX-809, lumacaftor) that bind directly to F508del-CFTR and correct its mislocalization are promising therapeutics for Cystic Fibrosis (CF). However to date, individual correctors provide only ~4% improvement in lung function measured as FEV1, suggesting that multiple drugs will be needed to achieve substantial clinical benefit. Here we examine if multiple sites for pharmacological chaperones exist and can be targeted to enhance the rescue of F508del-CFTR with the premise that additive or synergistic rescue by multiple pharmacological chaperones compared to single correctors indicates that they have different sites of action. First, we found that a combination of the pharmacological chaperones VX-809 and RDR1 provide additive correction of F508del-CFTR. Then using cellular thermal stability assays (CETSA) we demonstrated the possibility of a third pharmacologically important site using the novel pharmacological chaperone tool compound 4-methyl-N-[3-(morpholin-4-yl) quinoxalin-2-yl] benzenesulfonamide (MCG1516A). All three pharmacological chaperones appear to interact with the first nucleotide-binding domain (NBD1). The triple combination of MCG1516A, RDR1, and VX-809 restored CFTR function to >20% that of non-CF cells in well differentiated HBE cells and to much higher levels in other cell types. Thus the results suggest the presence of at least three distinct sites for pharmacological chaperones on F508del-CFTR NBD1, encouraging the development of triple corrector combinations.
Rhythmicity of Mood Symptoms in Individuals at Risk for Psychiatric Disorders
Authors: Pilz Luísa K. , Carissimi Alicia , Oliveira Melissa A. B. , Francisco Ana Paula , Fabris Raul C. , Medeiros Madeleine S. , Scop Marina , Frey Benicio N. , Adan Ana , Hidalgo Maria Paz
Published: July 2018

Despite emerging evidence that disruption in circadian rhythms may contribute to the pathophysiology of psychiatric disorders, there is a significant knowledge gap on the rhythmicity of psychological symptoms. Here, we aimed at investigating the rhythmicity of mood symptoms in individuals at risk for psychiatric disorders. 391 Brazilian and 317 Spanish participants completed the Self-Reporting Questionnaire-20 for non-psychotic mental disorders; the Mood Rhythm Instrument was used to assess rhythmicity of mood symptoms and the Munich ChronoType Questionnaire to assess sleep patterns. We found that the rhythmicity of specific mood-related symptoms and behaviors, particularly pessimism and motivation to exercise, were associated with being at risk for psychiatric disorders, even after controlling for sleep timing, sleep deficit, and season of data collection. We also found that the peak of some mood symptoms and behaviors were different between individuals at high vs. low risk for psychiatric disorders, with specific differences between countries. These results are consistent with previous research showing that circadian misalignment is associated with higher risk for mental health conditions. These findings also suggest that lifestyle changes preventing circadian misalignment might be useful to reduce the risk of psychiatric disorders, where cultural differences must be taken into account.
Fate and transport of radioactive gypsum stack water entering the Floridan aquifer due to a sinkhole collapse
Authors: Sandhu Daljit , Singh Arvind , Duranceau Steven J. , Nam Boo Hyun , Mayo Talea , Wang Dingbao
Published: July 2018

Groundwater aquifers are an essential source of drinking water, and must be protected against contamination. Phosphogypsum stacks originating from the processing of phosphate rock contain small amounts of radionuclides, such as 226Ra. In September 2016, a sinkhole located beneath a phosphogypsum stack collapsed under central Florida’s carbonate karst terrain, where the aquifer is mostly confined, raising concern over water quality in the regions nearby. Monitoring and modeling the transport of the contaminated plume is vital to ensure drinking water criteria are met and to improve decision making regarding treatment. To achieve this, a geochemical modeling using PHREEQC software was employed to investigate the trajectory of the plume based on hydraulic and hydrologic conditions. Adsorption was simulated as a removal mechanism that could further reduce the intensity of the plume. The aquifer’s response to the release of contaminated water from the collapsed stack was quantified by simulating a number of scenarios, including variable radionuclide leakage quantities. Results suggest that it may take between 11–17 years and between 5.2 to 8.3 km from the sinkhole leak to reduce radionuclide concentrations to previous levels. Coupling the adsorption effect by minerals in Floridan aquifer (e.g. ferrihydrite, carbonate) can reduce radionuclide migration time to 9–16 years and distances between 4.3 to 7.8 km from the sinkhole leak. It can also reduce the distance needed to lower radionuclide concentrations, though not significantly. Additionally, due to the complexities of soil chemistry, the importance of groundwater remediation is emphasized.
Regulation of cytochrome c oxidase activity by modulation of the catalytic site
Authors: Schäfer Jacob , Dawitz Hannah , Ott Martin , Ädelroth Pia , Brzezinski Peter
Published: July 2018

The respiratory supercomplex factor 1 (Rcf 1) in Saccharomyces cerevisiae binds to intact cytochrome c oxidase (CytcO) and has also been suggested to be an assembly factor of the enzyme. Here, we isolated CytcO from rcf1Δ mitochondria using affinity chromatography and investigated reduction, inter-heme electron transfer and ligand binding to heme a3. The data show that removal of Rcf1 yields two CytcO sub-populations. One of these sub-populations exhibits the same functional behavior as CytcO isolated from the wild-type strain, which indicates that intact CytcO is assembled also without Rcf1. In the other sub-population, which was shown previously to display decreased activity and accelerated ligand-binding kinetics, the midpoint potential of the catalytic site was lowered. The lower midpoint potential allowed us to selectively reduce one of the two sub-populations of the rcf1Δ CytcO, which made it possible to investigate the functional behavior of the two CytcO forms separately. We speculate that these functional alterations reflect a mechanism that regulates O2 binding and trapping in CytcO, thereby altering energy conservation by the enzyme.
Deep-ultraviolet Raman scattering spectroscopy of monolayer WS2
Authors: Liu Hsiang-Lin , Yang Teng , Tatsumi Yuki , Zhang Ye , Dong Baojuan , Guo Huaihong , Zhang Zhidong , Kumamoto Yasuaki , Li Ming-Yang , Li Lain-Jong , Saito Riichiro , Kawata Satoshi
Published: July 2018

Raman scattering measurements of monolayer WS2 are reported as a function of the laser excitation energies from the near-infrared (1.58 eV) to the deep-ultraviolet (4.82 eV). In particular, we observed several strong Raman peaks in the range of 700∼850 cm−1 with the deep-ultraviolet laser lights (4.66 eV and 4.82 eV). Using the first-principles calculations, these peaks and other weak peaks were appropriately assigned by the double resonance Raman scattering spectra of phonons around the M and K points in the hexagonal Brillouin zone. The relative intensity of the first-order $${{\boldsymbol{E}}}_{{\bf{2}}{\boldsymbol{g}}}^{{\bf{1}}}$$

E

2
g

1

to A1g peak changes dramatically with the 1.58 eV and 2.33 eV laser excitations, while the comparable relative intensity was observed for other laser energies. The disappearance of the $${{\boldsymbol{E}}}_{{\bf{2}}{\boldsymbol{g}}}^{{\bf{1}}}$$

E

2
g

1

peak with the 1.58 eV laser light comes from the fact that valley polarization of the laser light surpasses the $${{\boldsymbol{E}}}_{{\bf{2}}{\boldsymbol{g}}}^{{\bf{1}}}$$

E

2
g

1

mode since the $${{\boldsymbol{E}}}_{{\bf{2}}{\boldsymbol{g}}}^{{\bf{1}}}$$

E

2
g

1

mode is the helicity-exchange Raman mode. On the other hand, the disappearance of the A1g peak with the 2.33 eV laser light might be due to the strain effect on the electron-phonon matrix element.
Preparation, physicochemical characterization and antimicrobial activities of novel two phenolic chitosan Schiff base derivatives
Authors: Hassan Mohamed A. , Omer Ahmed M. , Abbas Eman , Baset Walid M. A. , Tamer Tamer M.
Published: July 2018

This study intends to develop novel two antimicrobial phenolic chitosan Schiff bases (I) and (II) via coupling of chitosan with Indole-3-carboxaldehyde and 4-dimethylaminobenzaldehyde, respectively, for boosting the antimicrobial activity of native chitosan. The alterations in the chemical structure and morphology of the Schiff bases were verified using FT-IR, electronic spectrum analysis, and SEM, whereas the thermal properties were investigated by TGA and DSC instruments. The results obtained from the potentiometric analysis referred that the degrees of substitution were 1.15 and 12.05% for Schiff bases (I) and (II), respectively. The antimicrobial activities of Schiff base (I) were significantly augmented more than Schiff base (II) and chitosan. Minimum inhibitory concentration (MIC) of Schiff base (I) was perceived at 50 µg/ml against tested microorganisms except forB.cereusandC.albicans. The highest concentration of Schiff base (I) could inhibit the growth of Gram-positive up to 99%. However, Schiff base (II) recorded the maximum inhibition rate versus Gram-positive approximately 82%. The cytotoxicity of the developed materials was estimated by MTT assay that substantiated their safety to fibroblast cells. The findings emphasized that the developed Schiff bases might be implemented as antimicrobial contenders to pure chitosan for treatments of wound infections.
A Gustatory Receptor Used for Rapid Detection of Tyrophagus putrescentiae in Fungi Hosts
Authors: Qu Shao-Xuan , Wang Xiao-Fei , Li Hui-Ping , Luo Xin , Ma Lin
Published: July 2018

The storage mite,Tyrophagus putrescentiae, found worldwide in many habitats, is an important pest of edible fungi in China. Storage mites are tiny and difficult to observe, especially when they occur in fungi composts. In this study, one gustatory receptor protein (TputGR1) was identified from the transcriptome ofT. putrescentiae. Phylogenetic analysis of GRs families from 10 arthropod species revealed that TputGR1 had high homology with the SccaGR1 of Sarcoptes scabiei and TurtGR1-2 ofTetranychus urticae, but low homology with other insect species,Drosophila melanogaster,Anopheles gambiae,Bombyx mori,Aedes aegypti,Culex quinquefasciatus, andPediculus humanus. We developed a detection system for the mite on fungi hosts using the GR protein and the loop-mediated isothermal amplification (LAMP). This procedure was rapid (60 min from sampling to result) and had high sensitivity (0.5 ng/mL). LAMP provided rapid and reliable detection ofT. putrescentiae. It has good specificity for single samples and for large-scale surveys.
In vivo neutralization of the protagonist role of macrophages during the chronic inflammatory stage of Huntington’s disease
Authors: Pido-Lopez Jeffrey , Andre Ralph , Benjamin Agnesska C. , Ali Nadira , Farag Sahar , Tabrizi Sarah J. , Bates Gillian P.
Published: July 2018

Neurodegenerative diseases, characterised by the progressive and selective neuronal death in the central nervous system, are frequently accompanied by an activated immune system. In Huntington’s disease (HD), clinical and animal studies show evidence of immune activity, along with hyper-reactive monocyte/macrophage responses, while application of immunosuppressive regimens have imparted beneficial effects to HD mice. These findings suggest a contributory role of the immune system in HD pathology, with immune-based interventions offering a potential therapeutic strategy. Herein, we show that peripheral and CNS immune system activity increased with disease progression in HD mouse models and defined the phenotype of the immune response. Additionally, the depletion of monocytes and macrophagesin vivo, via clodronate liposome treatment, revealed a major contributory role of these innate immune cells to the chronic inflammatory milieu observed during the course of the disease. This suggests that peripheral immunomodulatory strategies targeting monocytes and macrophages could be relevant for HD.
In vivo targeted single-nucleotide editing in zebrafish
Authors: Tanaka Shingo , Yoshioka Shin , Nishida Keiji , Hosokawa Hiroshi , Kakizuka Akira , Maegawa Shingo
Published: July 2018

To date, several genome editing technologies have been developed and are widely utilized in many fields of biology. Most of these technologies, if not all, use nucleases to create DNA double-strand breaks (DSBs), raising the potential risk of cell death and/or oncogenic transformation. The risks hinder their therapeutic applications in humans. Here, we show that in vivo targeted single-nucleotide editing in zebrafish, a vertebrate model organism, can be successfully accomplished with the Target-AID system, which involves deamination of a targeted cytidine to create a nucleotide substitution from cytosine to thymine after replication. Application of the system to two zebrafish genes, chordin (chd) and one-eyed pinhead (oep), successfully introduced premature stop codons (TAG or TAA) in the targeted genomic loci. The modifications were heritable and faithfully produced phenocopies of well-known homozygous mutants of each gene. These results demonstrate for the first time that the Target-AID system can create heritable nucleotide substitutions in vivo in a programmable manner, in vertebrates, namely zebrafish.
Protective role of vitamin B6 (PLP) against DNA damage in Drosophila models of type 2 diabetes
Authors: Merigliano Chiara , Mascolo Elisa , La Torre Mattia , Saggio Isabella , Vernì Fiammetta
Published: July 2018

Growing evidence shows that improper intake of vitamin B6 increases cancer risk and several studies indicate that diabetic patients have a higher risk of developing tumors. We previously demonstrated that in Drosophila the deficiency of Pyridoxal 5′ phosphate (PLP), the active form of vitamin B6, causes chromosome aberrations (CABs), one of cancer prerequisites, and increases hemolymph glucose content. Starting from these data we asked if it was possible to provide a link between the aforementioned studies. Thus, we tested the effect of low PLP levels on DNA integrity in diabetic cells. To this aim we generated two Drosophila models of type 2 diabetes, the first by impairing insulin signaling and the second by rearing flies in high sugar diet. We showed that glucose treatment induced CABs in diabetic individuals but not in controls. More interestingly, PLP deficiency caused high frequencies of CABs in both diabetic models demonstrating that hyperglycemia, combined to reduced PLP level, impairs DNA integrity. PLP-depleted diabetic cells accumulated Advanced Glycation End products (AGEs) that largely contribute to CABs as α-lipoic acid, an AGE inhibitor, rescued not only AGEs but also CABs. These data, extrapolated to humans, indicate that low PLP levels, impacting on DNA integrity, may be considered one of the possible links between diabetes and cancer.
Fouling Development in A/O-MBR under Low Organic Loading Condition and Identification of Key Bacteria for Biofilm Formations
Authors: Takimoto Yuya , Hatamoto Masashi , Ishida Takaya , Watari Takahiro , Yamaguchi Takashi
Published: July 2018

Membrane fouling in membrane bioreactors (MBR) remains a major issue and knowledge of microbes associated with biofilm formation might facilitate the control of this phenomenon, Thus, an anoxic/oxic membrane bioreactor (A/O-MBR) was operated under an extremely low organic loading rate (0.002 kg-COD·m−3·day−1) to induce membrane fouling and the major biofilm-forming bacteria were identified. After operation under extremely low organic loading condition, the reactor showed accumulation of total nitrogen and phosphorus along with biofilm development on the membrane surface. Thus, membrane fouling induced by microbial cell lysis was considered to have occurred. Although no major changes were observed in the microbial community structure of the activated sludge in the MBR before and after membrane fouling, uncultured bacteria were specifically increased in the biofilm. Therefore, bacteria belonging to candidate phyla including TM6, OD1 and Gammaproteobacteria could be important biofilm-forming bacteria.
Scalable Generation of Multi-mode NOON States for Quantum Multiple-phase Estimation
Authors: Zhang Lu , Chan Kam Wai Clifford
Published: July 2018

Multi-mode NOON states have been attracting increasing attentions recently for their abilities of obtaining supersensitive and superresolved measurements for simultaneous multiple-phase estimation. In this paper, four different methods of generating multi-mode NOON states with a high photon number were proposed. The first method is a linear optical approach that makes use of the Fock state filtration to reduce lower-order Fock state terms from the coherent state inputs, which are jointly combined to produce a multi-mode NOON state with the triggering of multi-fold single-photon coincidence detections (SPCD) and appropriate postselection. The other three methods (two linear and one nonlinear) use N-photon Fock states as the inputs and require SPCD triggering only. All of the four methods can theoretically create a multi-mode NOON state with an arbitrary photon number. Comparisons among these four methods were made with respect to their feasibility and efficiency. The first method is experimentally most feasible since it takes considerably fewer photonic operations and, more importantly, requires neither the use of high-N Fock states nor high-degree of nonlinearity.
The coffee bean transcriptome explains the accumulation of the major bean components through ripening
Authors: Cheng Bing , Furtado Agnelo , Henry Robert J.
Published: July 2018

The composition of the maturing coffee bean determines the processing performance and ultimate quality of the coffee produced from the bean. Analysis of differences in gene expression during bean maturation may explain the basis of genetic and environmental variation in coffee quality. The transcriptome of the coffee bean was analyzed at three stages of development, immature (green), intermediate (yellow) and mature (red). A total of more than 120 million 150 bp paired-end reads were collected by sequencing of transcripts of triplicate samples at each developmental stage. A greater number of transcripts were expressed at the yellow stage. As the beans matured the types of highly expressed transcripts changed from transcripts predominantly associated with galactomannan, triacylglycerol (TAG), TAG lipase, 11 S and 7S-like storage protein and Fasciclin-like arabinogalactan protein 17 (FLA17) in green beans to transcripts related to FLA1 at the yellow stage and TAG storage lipase SDP1, and SDP1-like in red beans. This study provides a genomic resource that can be used to investigate the impact of environment and genotype on the bean transcriptome and develop coffee varieties and production systems that are better adapted to deliver quality coffee despite climate variations.
Prognostic role of carotid intima-media thickness in off-pump coronary artery bypass surgery
Authors: Ham Sung-Yeon , Song Jong-Wook , Shim Jae-Kwang , Soh Sarah , Kim Hee-Jung , Kwak Young-Lan
Published: July 2018

Carotid intima-media thickness (IMT) is a well-known predictor of adverse outcomes in the ischemic heart disease patients; however, evidence is lacking in patients undergoing off-pump coronary artery bypass surgery (OPCAB). Data from 407 patients who underwent OPCAB between April 2013 and August 2016 were retrospectively reviewed. A composite of cardiovascular morbidity endpoints was defined as the presence of stroke, acute myocardial infarction, new cardiac arrhythmia (newly developed atrial fibrillation, atrial flutter, or atrioventricular block), cardiovascular death, or cerebrovascular death within 30 days after surgery. Increased carotid IMT was defined as ≥0.9 mm on one or both sides. The incidence of a composite of cardiovascular morbidity endpoints was 24.0% in the normal IMT group (n = 221) and 34.4% in the increased IMT group (n = 186) (p = 0.021). Multivariable analysis revealed increased IMT (odds ratio 1.719, 95% confidence interval 1.108 to 2.666, p = 0.016) and preoperative renal replacement therapy (odds ratio 4.264, 95% confidence interval 1.679 to 10.829, p = 0.002) as independent predictors of a composite of cardiovascular morbidity endpoints. In patients undergoing OPCAB, preoperative assessment of carotid IMT may help predicting the development of a postoperative composite of cardiovascular morbidity endpoints.