bluuebunny/crossref_metadata_2025 huggingface dataset:
THE SEMANTICS OF VALUE-RANGE NAMES AND FREGE’S PROOF OF REFERENTIALITY
Authors: SCHIRN MATTHIAS
Published: April 2018

In this article, I try to shed some new light onGrundgesetze§10, §29–§31 with special emphasis on Frege’s criteria and proof of referentiality and his treatment of the semantics of canonical value-range names. I begin by arguing against the claim, recently defended by several Frege scholars, that the first-order domain inGrundgesetzeis restricted to value-ranges (including the truth-values), but conclude that there is an irresolvable tension in Frege’s view. The tension has a direct impact on the semantics of the concept-script, not least on the semantics of value-range names. I further argue that despite first appearances truth-value names (sentences) play a distinguished role as semantic “target names” for “test names” in the criteria of referentiality (§29) and do not figure themselves as “test names” regarding referentiality. Accordingly, I show in detail that Frege’s attempt to demonstrate that by virtue of his stipulations “regular” value-range names have indeed been endowed with a unique reference, can plausibly be regarded as a direct application of the context principle. In a subsequent section, I turn to some special issues involved in §10. §10 is closely intertwined with §31 and in my and Richard Heck’s view would have been better positioned between §30 and §31. In a first step, I discuss the piecemeal strategy which Frege applies when he attempts to bestow a unique reference on value-range names in §3, §10–§12. In a second step, I critically analyze his tentative, but predictably unsuccessful proposal (in a long footnote to §10) to identify all objects whatsoever, including those already clad in the garb of value-ranges, with their unit classes. In conclusion, I present two arguments for my claim that Frege’s identification of the True and the False with their unit classes in §10 is illicit even if both the permutation argument and the identifiability thesis that he states in §10 are regarded as formally sound. The first argument is set out from the point of view of the syntax of his formal language. It suggests though that a reorganization of the exposition of the concept-script would have solved at least one of the problems to which the twin stipulations in §10 give rise. The second argument rests on semantic considerations. If it is sound, it may call into question, if not undermine the legitimacy of the twin stipulations.
Direct EUV/X‐Ray Modulation of the Ionosphere During the August 2017 Total Solar Eclipse
Authors: Mrak Sebastijan , Semeter Joshua , Drob Douglas , Huba J. D.
Published: April 2018

The great American total solar eclipse of 21 August 2017 offered a fortuitous opportunity to study the response of the atmosphere and ionosphere using a myriad of ground instruments. We have used the network of U.S. Global Positioning System receivers to examine perturbations in maps of ionospheric total electron content (TEC). Coherent large‐scale variations in TEC have been interpreted by others as gravity wave‐induced traveling ionospheric disturbances. However, the solar disk had two active regions at that time, one near the center of the disk and one at the edge, which resulted in an irregular illumination pattern in the extreme ultraviolet (EUV)/X‐ray bands. Using detailed EUV occultation maps calculated from the National Aeronautics and Space Administration Solar Dynamics Observatory Atmospheric Imaging Assembly images, we show excellent agreement between TEC perturbations and computed gradients in EUV illumination. The results strongly suggest that prominent large‐scale TEC disturbances were consequences of direct EUV modulation, rather than gravity wave‐induced traveling ionospheric disturbances.
Subsidence of Ionospheric Flows Triggered by Magnetotail Magnetic Reconnection During Transpolar Arc Brightening
Authors: Nowada Motoharu , Fear Robert C. , Grocott Adrian , Shi Quan‐Qi , Yang Jun , Zong Qiu‐Gang , Wei Yong , Fu Sui‐Yan , Pu Zu‐Yin , Mailyan Bagrat , Zhang Hui
Published: April 2018

A transpolar arc (TPA), which extended from postmidnight to prenoon, was seen on 16 September 2001 in the Northern Hemisphere under northward interplanetary magnetic field (IMF)‐Bz and weakly dawnward IMF‐By conditions. Super Dual Auroral Radar Network detected significant westward plasma flows just equatorward of the poleward edge of the midnight sector auroral oval. These plasma flows were confined to closed field lines and are identified as the ionospheric plasma flow signature of tail reconnection during IMF northward nonsubstorm intervals (TRINNIs). These TRINNI flows persisted for 53 min from prior to the TPA appearance to the cessation of TPA growth. They are usually observed before (and during) intervals when TPAs are present, but in this case, subsided after the TPA was completely connected to the dayside. Additional slower flows across the open/closed polar cap boundary were seen at the TPA onset time in the same magnetic local time sector as the nightside end of the TPA. These ionospheric flows suggest that magnetotail reconnection significantly contributed to the TPA formation, as proposed by Milan et al. (, https://doi.org/10.1029/2004JA010835). We propose a possible scenario for an absence of the TRINNI flows during the TPA brightening by considering the relation between the extent of the magnetotail reconnection line mapped onto nightside auroral oval and the TPA width; TRINNI flows would subside when the extent of X‐line is comparable to the TPA width. Therefore, our results suggest that the fate (absence or presence) of TRINNI flows on closed field lines during the TPA formation would be closely related with magnetotail reconnection extent.
Buoyancy Waves in Earth's Magnetosphere: Calculations for a 2‐D Wedge Magnetosphere
Authors: Wolf R. A. , Toffoletto F. R. , Schutza A. M. , Yang J.
Published: April 2018

To improve theoretical understanding of the braking oscillations observed in Earth's inner plasma sheet, we have derived a theoretical model that describes k∥ = 0 magnetohydrodynamic waves in an idealized magnetospheric configuration that consists of a 2‐D wedge with circular‐arc field lines. The low‐frequency, short‐perpendicular‐wavelength mode obeys a differential equation that is often used to describe buoyancy oscillations in a neutral atmosphere, so we call those waves “buoyancy waves,” though the magnetospheric buoyancy force results from magnetic tension rather than gravity. Propagation of the wave is governed mainly by a position‐dependent frequency ωb, the “buoyancy frequency,” which is a fundamental property of the magnetosphere. The waves propagate if ωb > ω but otherwise evanesce. In the wedge magnetosphere, ωb turns out to be exactly the fundamental oscillation frequency for poloidal oscillations of a thin magnetic filament, and we assume that the same is true for the real magnetosphere. Observable properties of buoyancy oscillations are discussed, but propagation characteristics vary considerably with the state of the magnetosphere. For a given event, the buoyancy frequency and propagation characteristics can be determined from pressure and density profiles and a magnetic field model, and these characteristics have been worked out for one typical configuration. A localized disturbance that initially resembles a dipolarizing flux bundle spreads east‐west and also penetrates into the plasmasphere to some extent. The calculated amplitude near the center of the original wave packet decays in a few oscillation periods, even though our calculation includes no dissipation.
Laboratory Investigation Into the Formation and Dissociation Process of Gas Hydrate by Low‐Field NMR Technique
Authors: Ge Xinmin , Liu Jianyu , Fan Yiren , Xing Donghui , Deng Shaogui , Cai Jianchao
Published: April 2018

We monitored the gas hydrate through low‐field nuclear magnetic resonance measurement. An observed decrease of the relaxation time (T2) intensity corresponds to the formation process, whereas an increase of the intensity corresponds to the dissociation process. The right domain of the spectrum with T2 larger than 10 ms disappears gradually with the formation time, whereas the left domain with T2 smaller than 1 ms remains invariant, indicating the gas hydrate forms preferentially in larger pores. In addition, the right domain increases rapidly with the dissociation time, revealing that the gas hydrate preferentially decomposes in large pores. The spectrum distributions move toward the fast relaxation domain with the growth of gas hydrate, because the generated gas hydrate occupies the large pore and accelerate the relaxation rate. There is no obvious relationship between the gas hydrate saturation and the porosity, whereas the volume and preliminary dissociation ratio are strongly correlated with the porosity.
Numerical Modeling of Historical Storm Tides and Waves and Their Interactions Along the U.S. East and Gulf Coasts
Authors: Marsooli Reza , Lin Ning
Published: April 2018

We apply a coupled circulation‐wave model to simulate extreme sea levels induced by tropical cyclones at the basin scale. We quantify storm tides, surges, waves, and their interactions for historical tropical cyclones (1988–2015) in the western North Atlantic Ocean. Comparisons between model results and field observations along the U.S. East and Gulf Coasts indicate that the overall performance of the model is satisfactory, with a root‐mean‐square error, bias, and Willmott skill of, respectively, 0.31, −0.04 m, and 0.9 for storm tides and 1.94 m, −0.22 m, and 0.87 for significant wave heights. Model results show that the highest surge levels were generated in Western Long Island Sound and NY/NJ Harbor, along the coasts of the Carolinas and Southwest Florida, near the Mississippi River delta, and along the coasts of Louisiana and East Texas. We find that the nonlinear tide‐surge interaction is often significant, but its contribution to peak storm tides induced by the most extreme events (i.e., storms that caused storm tides larger than 2 m) was moderate (−12% to 5%). We find that the maximum wave setup was relatively large (tens of cm) in most coastal regions, but it did not necessarily coincide with the peak storm tide. The contribution of wave setup to peak storm tides induced by the most extreme events was less than 17%. Finally, we show that while some offshore storms did not affect the coastal areas with high storm surges or strong winds, they generated the largest historical wave setup at the coast.
Investigating Satellite Precipitation Uncertainty Over Complex Terrain
Authors: Bartsotas N. S. , Anagnostou E. N. , Nikolopoulos E. I. , Kallos G.
Published: April 2018

The estimation of heavy precipitation events is a particularly difficult task, especially over high mountainous terrain typically associated with scant availability of in situ observations. Therefore, quantification of precipitation variability in such data‐limited regions relies on remote sensing estimates, due to their global coverage and near real‐time availability. However, strong underestimation of precipitation associated with low‐level orographic enhancement often limits the quantitative use of these data in applications. This study utilizes state‐of‐the‐art numerical weather prediction simulations, toward the reduction of quantitative errors in satellite precipitation estimates and an insight on the nature of detection limitations. Satellite precipitation products based on different retrieval algorithms (Climate Prediction Center morphing method, Precipitation Estimation from Remotely Sensed Information Using Artificial Neural Networks‐Cloud Classification System, and Global Satellite Mapping of Precipitation) are evaluated for their performance in a number of storm events over mountainous areas with distinct storm characteristics: Upper Blue Nile in Ethiopia and Alto Adige in NE Italy. High‐resolution (1 and 2 km) simulations from the Regional Atmospheric Modeling System/Integrated Community Limited Area Modeling System are used to derive adjustments to the magnitude of satellite estimates. Finally, a microphysical investigation is presented for occurrences of erroneous precipitation detection from the satellite instruments. Statistical indexes showcase improvement in numerical weather prediction‐adjusted satellite products and microphysical commodities among cases of no detection are discussed.
Analysis of Rock Abundance on Lunar Surface From Orbital and Descent Images Using Automatic Rock Detection
Authors: Li Yuan , Wu Bo
Published: April 2018

Information on the distribution and abundance of rocks on the lunar surface is essential for understanding the characteristics of lunar regolith and for selecting suitable landing sites for lunar exploration missions. This paper first presents a novel automatic rock detection approach based on the gradient differences in illumination direction. Multiple‐source images covering different regions of the lunar surface are then used for rock detection and rock abundance analysis, including the Chang'E‐3 descent images (0.02–0.17 m/pixel) around the landing area, the Lunar Reconnaissance Orbiter (LRO) Narrow Angle Camera images (0.3–1.1 m/pixel) at the landing sites of the Chang'E‐3, Luna 17, and Luna 23, and the LRO Narrow Angle Camera image mosaic (1.5 m/pixel) in the Oceanus Procellarum area. A rock abundance model using an exponential form is derived from the results of the abovementioned analysis to describe the overall cumulative fractional area of rocks versus their diameters. The rock detection results and the derived rock abundance estimated by the proposed model are compared with the ground measurements obtained using the rover images of the Chang'E‐3 landing site and the LRO Diviner Radiometer‐derived rock abundance. A comparison analysis indicates that the derived rock abundance model can feasibly represent the rock abundance in various situations on local and large scales. In general, a remarkable consistency is observed between our results and the results obtained using the ground measurements at the Chang'E‐3 landing site and the orbit measurements from the Diviner radiometer, while our rock detection results and rock abundance model exhibit better performance in presenting detailed information in local areas. Further analyses on rock abundance and the crater morphology and other crater characteristics in the Oceanus Procellarum area indicate that it is feasible to use rock abundance information to estimate the surface maturity.
Scientists Examine Novel Options to Save Coral Reefs
Authors: Showstack Randy
Published: April 2018

Warming events prompt scientists to look at ecological, genetic, and engineering interventions.
Atmospheric Signature of the Agulhas Current
Authors: Nkwinkwa Njouodo Arielle Stela , Koseki Shunya , Keenlyside Noel , Rouault Mathieu
Published: April 2018

Western boundary currents play an important role in the climate system by transporting heat poleward and releasing it to the atmosphere. While their influence on extratropical storms and oceanic rainfall is becoming appreciated, their coastal influence is less known. Using satellite and climate reanalysis data sets and a regional atmospheric model, we show that the Agulhas Current is a driver of the observed band of rainfall along the southeastern African coast and above the Agulhas Current. The Agulhas current's warm core is associated with sharp gradients in sea surface temperature and sea level pressure, a convergence of low‐level winds, and a co‐located band of precipitation. Correlations among wind convergence, sea level pressure, and sea surface temperature indicate that these features show high degree of similarity to those in the Gulf Stream region. Model experiments further indicate that the Agulhas Current mostly impacts convective rainfall.
The Twisted Configuration of the Martian Magnetotail: MAVEN Observations
Authors: DiBraccio Gina A. , Luhmann Janet G. , Curry Shannon M. , Espley Jared R. , Xu Shaosui , Mitchell David L. , Ma Yingjuan , Dong Chuanfei , Gruesbeck Jacob R. , Connerney John E. P. , Harada Yuki , Ruhunusiri Suranga , Halekas Jasper S. , Soobiah Yasir , Hara Takuya , Brain David A. , Jakosky Bruce M.
Published: April 2018

Measurements provided by the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft are analyzed to investigate the Martian magnetotail configuration as a function of interplanetary magnetic field (IMF) BY. We find that the magnetotail lobes exhibit a ~45° twist, either clockwise or counterclockwise from the ecliptic plane, up to a few Mars radii downstream. Moreover, the associated cross‐tail current sheet is rotated away from the expected location for a Venus‐like induced magnetotail based on nominal IMF draping. Data‐model comparisons using magnetohydrodynamic simulations are in good agreement with the observed tail twist. Model field line tracings indicate that a majority of the twisted tail lobes are composed of open field lines, surrounded by draped IMF. We infer that dayside magnetic reconnection between the crustal fields and draped IMF creates these open fields and may be responsible for the twisted tail configuration, similar to what is observed at Earth.
Mineral Dust Instantaneous Radiative Forcing in the Arctic
Authors: Kylling A. , Groot Zwaaftink C. D. , Stohl A.
Published: April 2018

Mineral dust sources at high and low latitudes contribute to atmospheric dust loads and dust deposition in the Arctic. With dust load estimates from Groot Zwaaftink et al. (, https://doi.org/10.1002/2016JD025482), we quantify the mineral dust instantaneous radiative forcing (IRF) in the Arctic for the year 2012. The annual‐mean top of the atmosphere IRF is 0.225 W/m2, with the largest contributions from dust transported from Asia south of 60°N and Africa. High‐latitude (>60°N) dust sources contribute about 39% to top of the atmosphere IRF and have a larger impact (1 to 2 orders of magnitude) on IRF per emitted kilogram of dust than low‐latitude sources. Mineral dust deposited on snow accounts for nearly all of the bottom of the atmosphere IRF of 0.135 W/m2. More than half of the bottom of the atmosphere IRF is caused by dust from high‐latitude sources, indicating substantial regional climate impacts rarely accounted for in current climate models.
Plant Growth‐Promoting Rhizobacteria (PGPR) Reduce Evaporation and Increase Soil Water Retention
Authors: Zheng Wenjuan , Zeng Saiqi , Bais Harsh , LaManna Jacob M. , Hussey Daniel S. , Jacobson David L. , Jin Yan
Published: April 2018

Enhancement of plant drought stress tolerance by plant growth‐promoting rhizobacteria (PGPR) has been increasingly documented in the literature. However, most studies to date have focused on PGPR‐root/plant interactions; very little is known about PGPR's role in mediating physiochemical and hydrological changes in the rhizospheric soil that may impact plant drought stress tolerance. Our study aimed to advance mechanistic understanding of PGPR‐mediated biophysical changes in the rhizospheric soil that may contribute to plant drought stress tolerance in addition to plant responses. We measured soil water retention characteristics, hydraulic conductivity, and water evaporation in soils with various textures (i.e., pure sand, sandy soil, and clay) as influenced by a representative PGPR (Bacillus subtilis strain UD1022) using the HYPROP system. We found that all PGPR‐treated soils held more water and had reduced hydraulic conductivity and accumulative evaporation, compared to their corresponding controls. We discuss three mechanisms, due to B. subtilis incubation or production of extracellular polymeric substances (EPS), that are potentially responsible for the changes in hydraulic properties and soil evaporation: (i) EPS have a large water holding capacity; (ii) EPS alter soil matrix structure and connectivity of pore space; (iii) EPS modify the physicochemical properties of water (surface tension and viscosity). These results clearly demonstrate PGPR's ability to increase water availability to plants by slowing down evaporation and by increasing the time available for plants to make metabolic adjustments to drought stress.
Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia
Authors: Kang Insung , Lee Byung-Chul , Choi Soon Won , Lee Jin Young , Kim Jae-Jun , Kim Bo-Eun , Kim Da-Hyun , Lee Seung Eun , Shin Nari , Seo Yoojin , Kim Hyung-Sik , Kim Dong-Ik , Kang Kyung-Sun
Published: April 2018

With the rapidly growing demand for mesenchymal stem cell (MSC) therapy, numerous strategies using MSCs for different diseases have been studied and reported. Because of their immunosuppressive properties, MSCs are commonly used as an allogeneic treatment. However, for the many donors who could potentially be used, it is important to understand the capacity for therapeutic usage with donor-to-donor heterogeneity. In this study, we aimed to investigate MSCs as a promising therapeutic strategy for critical limb ischemia. We evaluated MSCs from two donors (#55 and #64) and analyzed the capacity for angiogenesis through in vivo and in vitro assays to compare the therapeutic effect between different donors. We emphasized the importance of intra-population heterogeneity of MSCs on therapeutic usage by evaluating the effects of hypoxia on activating cellular angiogenesis in MSCs. The precondition of hypoxia in MSCs is known to enhance therapeutic efficacy. Our study suggests that sensitivity to hypoxic conditions is different between cells originating from different donors, and this difference affects the contribution to angiogenesis. The bioinformatics analysis of different donors under hypoxic culture conditions identified intrinsic variability in gene expression patterns and suggests alternative potential genetic factors ANGPTL4, ADM, SLC2A3, and CDON as guaranteed general indicators for further stem cell therapy.
Pan-CDK inhibition augments cisplatin lethality in nasopharyngeal carcinoma cell lines and xenograft models
Authors: Syn Nicholas L. , Lim Pei Li , Kong Li Ren , Wang Lingzhi , Wong Andrea Li-Ann , Lim Chwee Ming , Loh Thomas Kwok Seng , Siemeister Gerhard , Goh Boon Cher , Hsieh Wen-Son
Published: April 2018

In addition to their canonical roles in regulating cell cycle transition and transcription, cyclin-dependent kinases (CDKs) have been shown to coordinate DNA damage response pathways, suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies. Here, we report that roniciclib (BAY1000394), a potent pan-CDK inhibitor, displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma (NPC) models. Proliferation of the NPC cell lines HONE-1, CNE-2, C666-1, and HK-1 was effectively curbed by roniciclib treatment, with IC50 values between 11 and 38 nmol/L. These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1, 2, 3, and 4 and transcriptional CDKs 7 and 9, ultimately resulting in arrest at G1/S and G2/M, downregulation of the transcriptional apparatus, and repression of anti-apoptotic proteins. Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0 μmol/L cisplatin; this combination therapy achieved a response over 250% greater than either drug alone. Although roniciclib chemosensitized NPC cells to cisplatin, it did not sensitize untransformed (NP69) cells. The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin, whereas combining these two agents produced far greater tumor suppression than either of the monotherapies. In summary, these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses, thus justifying further evaluation of this combinatorial approach in clinical settings.
THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders
Authors: Guennewig Boris , Bitar Maina , Obiorah Ifeanyi , Hanks James , O’Brien Elizabeth A. , Kaczorowski Dominik C. , Hurd Yasmin L. , Roussos Panos , Brennand Kristen J. , Barry Guy
Published: April 2018

There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to Δ9-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC.
Increased functional connectivity of the posterior cingulate cortex with the lateral orbitofrontal cortex in depression
Authors: Cheng Wei , Rolls Edmund T. , Qiu Jiang , Xie Xiongfei , Wei Dongtao , Huang Chu-Chung , Yang Albert C. , Tsai Shih-Jen , Li Qi , Meng Jie , Lin Ching-Po , Xie Peng , Feng Jianfeng
Published: April 2018

To analyze the functioning of the posterior cingulate cortex (PCC) in depression, we performed the first fully voxel-level resting state functional-connectivity neuroimaging analysis of depression of the PCC, with 336 patients with major depressive disorder and 350 controls. Voxels in the PCC had significantly increased functional connectivity with the lateral orbitofrontal cortex, a region implicated in non-reward and which is thereby implicated in depression. In patients receiving medication, the functional connectivity between the lateral orbitofrontal cortex and PCC was decreased back towards that in the controls. In the 350 controls, it was shown that the PCC has high functional connectivity with the parahippocampal regions which are involved in memory. The findings support the theory that the non-reward system in the lateral orbitofrontal cortex has increased effects on memory systems, which contribute to the rumination about sad memories and events in depression. These new findings provide evidence that a key target to ameliorate depression is the lateral orbitofrontal cortex.
Exosomal circRNA_100284 from arsenite-transformed cells, via microRNA-217 regulation of EZH2, is involved in the malignant transformation of human hepatic cells by accelerating the cell cycle and promoting cell proliferation
Authors: Dai Xiangyu , Chen Chao , Yang Qianlei , Xue Junchao , Chen Xiong , Sun Baofei , Luo Fei , Liu Xinlu , Xiao Tian , Xu Hui , Sun Qian , Zhang Aihua , Liu Qizhan
Published: April 2018

Intercellular communication between malignant cells and neighboring nonmalignant cells is involved in carcinogenesis. In the progression of carcinogenesis, exosomes are messengers for intercellular communication. Circular RNAs (circRNAs) are noncoding RNAs with functions that include regulation of the cell cycle and proliferation. However, the functions of exosomal circRNAs are not clear. The present research aimed to determine whether circRNAs secreted from arsenite-transformed human hepatic epithelial (L-02) cells are transferred into normal L-02 cells and become functionally active in the normal cells. The results showed that circRNA_100284 is involved in the malignant transformation of L-02 cells induced by arsenite. The medium from transformed L-02 cells induced upregulation of circRNA_100284, accelerated the cell cycle, and promoted proliferation of normal L-02 cells. Transformed cells transferred circRNA_100284 into normal L-02 cells via exosomes and led to the malignant transformation of the non-transformed cells. Knockdown of circRNA_100284, which reduced circRNA_100284 levels in exosomes derived from transformed L-02 cells, blocked the accelerated cell cycle and reduced proliferation and malignancy. In addition, in normal L-02 cells, exosomal circRNA_100284 derived from arsenite-transformed L-02 cells induced acceleration of the cell cycle and promoted proliferation via acting as a sponge of microRNA-217. Further, exosomal circRNA_100284 was upregulated in the sera of people exposed to arsenite. Thus, exosomes derived from transformed L-02 cells transferred circRNA_100284 to surrounding cells, which induced an accelerated cell cycle and promoted proliferation of normal liver cells and led to the malignant transformation of the non-transformed cells. The findings support the concept that exosomal circRNAs are involved in cell–cell communication during carcinogenesis induced by arsenite.
Characterization of the enhancer and promoter landscape of inflammatory bowel disease from human colon biopsies
Authors: Boyd Mette , Thodberg Malte , Vitezic Morana , Bornholdt Jette , Vitting-Seerup Kristoffer , Chen Yun , Coskun Mehmet , Li Yuan , Lo Bobby Zhao Sheng , Klausen Pia , Jan Schweiger Pawel , Pedersen Anders Gorm , Rapin Nicolas , Skovgaard Kerstin , Dahlgaard Katja , Andersson Robin , Terkelsen Thilde Bagger , Lilje Berit , Troelsen Jesper Thorvald , Petersen Andreas Munk , Jensen Kim Bak , Gögenur Ismail , Thielsen Peter , Seidelin Jakob Benedict , Nielsen Ole Haagen , Bjerrum Jacob Tveiten , Sandelin Albin
Published: April 2018

Inflammatory bowel disease (IBD) is a chronic intestinal disorder, with two main types: Crohn’s disease (CD) and ulcerative colitis (UC), whose molecular pathology is not well understood. The majority of IBD-associated SNPs are located in non-coding regions and are hard to characterize since regulatory regions in IBD are not known. Here we profile transcription start sites (TSSs) and enhancers in the descending colon of 94 IBD patients and controls. IBD-upregulated promoters and enhancers are highly enriched for IBD-associated SNPs and are bound by the same transcription factors. IBD-specific TSSs are associated to genes with roles in both inflammatory cascades and gut epithelia while TSSs distinguishing UC and CD are associated to gut epithelia functions. We find that as few as 35 TSSs can distinguish active CD, UC, and controls with 85% accuracy in an independent cohort. Our data constitute a foundation for understanding the molecular pathology, gene regulation, and genetics of IBD.
Uncovering inherent cellular plasticity of multiciliated ependyma leading to ventricular wall transformation and hydrocephalus
Authors: Abdi Khadar , Lai Chun-Hsiang , Paez-Gonzalez Patricia , Lay Mark , Pyun Joon , Kuo Chay T.
Published: April 2018

Specialized, differentiated cells often perform unique tasks that require them to maintain a stable phenotype. Multiciliated ependymal cells (ECs) are unique glial cells lining the brain ventricles, important for cerebral spinal fluid circulation. While functional ECs are needed to prevent hydrocephalus, they have also been reported to generate new neurons: whether ECs represent a stable cellular population remains unclear. Via a chemical screen we found that mature ECs are inherently plastic, with their multiciliated state needing constant maintenance by the Foxj1 transcription factor, which paradoxically is rapidly turned over by the ubiquitin-proteasome system leading to cellular de-differentiation. Mechanistic analyses revealed a novel NF-κB-independent IKK2 activity stabilizing Foxj1 in mature ECs, and we found that known IKK2 inhibitors including viruses and growth factors robustly induced Foxj1 degradation, EC de-differentiation, and hydrocephalus. Although mature ECs upon de-differentiation can divide and regenerate multiciliated ECs, we did not detect evidence supporting EC’s neurogenic potential.
Gold-catalyzed stereoselective cycloisomerization of allenoic acids for two types of common natural γ-butyrolactones
Authors: Zhou Jing , Fu Chunling , Ma Shengming
Published: April 2018

γ-(E)-Vinylic and γ-alkylic γ-butyrolactones are two different types of lactones existing extensively in animals and plants and many of them show interesting biological activities. Nature makes alkylic γ-butyrolactones by many different enzymatic lactonization processes. Scientists have been mimicking the natural strategy by developing new catalysts. However, direct and efficient access to γ-(E)-vinylic γ-butyrolactones is still extremely limited. Here, we wish to present our modular allene approach, which provides an efficient asymmetric approach to (E)-vinylic γ-butyrolactones from allenoic acids by identifying a new gold complex as the catalyst. Based on this cycloisomerization strategy, the first syntheses of racemic xestospongiene and xestospongienes E, F, G, and H have been realized and the absolute configurations of the chiral centers in xestospongienes E and F have been revised. In addition, by applying a C–O bond cleavage-free hydrogenation, the syntheses of naturally occurring γ-alkylic γ-lactones, (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-γ-palmitolactone, and (R)-4-decalactone, have also been achieved.
Correlation of the Dzyaloshinskii–Moriya interaction with Heisenberg exchange and orbital asphericity
Authors: Kim Sanghoon , Ueda Kohei , Go Gyungchoon , Jang Peong-Hwa , Lee Kyung-Jin , Belabbes Abderrezak , Manchon Aurelien , Suzuki Motohiro , Kotani Yoshinori , Nakamura Tetsuya , Nakamura Kohji , Koyama Tomohiro , Chiba Daichi , Yamada Kihiro. T. , Kim Duck-Ho , Moriyama Takahiro , Kim Kab-Jin , Ono Teruo
Published: April 2018

Chiral spin textures of a ferromagnetic layer in contact to a heavy non-magnetic metal, such as Néel-type domain walls and skyrmions, have been studied intensively because of their potential for future nanomagnetic devices. The Dyzaloshinskii–Moriya interaction (DMI) is an essential phenomenon for the formation of such chiral spin textures. In spite of recent theoretical progress aiming at understanding the microscopic origin of the DMI, an experimental investigation unravelling the physics at stake is still required. Here we experimentally demonstrate the close correlation of the DMI with the anisotropy of the orbital magnetic moment and with the magnetic dipole moment of the ferromagnetic metal in addition to Heisenberg exchange. The density functional theory and the tight-binding model calculations reveal that inversion symmetry breaking with spin–orbit coupling gives rise to the orbital-related correlation. Our study provides the experimental connection between the orbital physics and the spin–orbit-related phenomena, such as DMI.
Blackbody radiation shift assessment for a lutetium ion clock
Authors: Arnold K. J. , Kaewuam R. , Roy A. , Tan T. R. , Barrett M. D.
Published: April 2018

The accuracy of state-of-the-art atomic clocks is derived from the insensitivity of narrow optical atomic resonances to environmental perturbations. Two such resonances in singly ionized lutetium have been identified with potentially lower sensitivities compared to other clock candidates. Here we report measurement of the most significant unknown atomic property of both transitions, the static differential scalar polarizability. From this, the fractional blackbody radiation shift for one of the transitions is found to be −1.36(9) × 10−18 at 300 K, the lowest of any established optical atomic clock. In consideration of leading systematic effects common to all ion clocks, both transitions compare favorably to the most accurate ion-based clocks reported to date. This work firmly establishes Lu+ as a promising candidate for a future generation of more accurate optical atomic clocks.
The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression
Authors: Ali Mina , Ajore Ram , Wihlborg Anna-Karin , Niroula Abhishek , Swaminathan Bhairavi , Johnsson Ellinor , Stephens Owen W , Morgan Gareth , Meissner Tobias , Turesson Ingemar , Goldschmidt Hartmut , Mellqvist Ulf-Henrik , Gullberg Urban , Hansson Markus , Hemminki Kari , Nahi Hareth , Waage Anders , Weinhold Niels , Nilsson Björn
Published: April 2018

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined = 2.5 × 10−27; βcombined = −0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause–effect relationship. Our results provide mechanistic insight into MM predisposition.
Magnetically tunable bidirectional locomotion of a self-assembled nanorod-sphere propeller
Authors: García-Torres José , Calero Carles , Sagués Francesc , Pagonabarraga Ignacio , Tierno Pietro
Published: April 2018

Field-driven direct assembly of nanoscale matter has impact in disparate fields of science. In microscale systems, such concept has been recently exploited to optimize propulsion in viscous fluids. Despite the great potential offered by miniaturization, using self-assembly to achieve transport at the nanoscale remains an elusive task. Here we show that a hybrid propeller, composed by a ferromagnetic nanorod and a paramagnetic microsphere, can be steered in a fluid in a variety of modes, from pusher to puller, when the pair is dynamically actuated by a simple oscillating magnetic field. We exploit this unique design to build more complex structures capable of carrying several colloidal cargos as microscopic trains that quickly disassemble at will under magnetic command. In addition, our prototype can be extended to smaller nanorods below the diffraction limit, but still dynamically reconfigurable by the applied magnetic field.
Stochastic system identification without an a priori chosen kinetic model—exploring feasible cell regulation with piecewise linear functions
Authors: Hoffmann Martin , Galle Jörg
Published: April 2018

Kinetic models are at the heart of system identification. A priori chosen rate functions may, however, be unfitting or too restrictive for complex or previously unanticipated regulation. We applied general purpose piecewise linear functions for stochastic system identification in one dimension using published flow cytometry data on E.coli and report on identification results for equilibrium state and dynamic time series. In metabolic labelling experiments during yeast osmotic stress response, we find mRNA production and degradation to be strongly co-regulated. In addition, mRNA degradation appears overall uncorrelated with mRNA level. Comparison of different system identification approaches using semi-empirical synthetic data revealed the superiority of single-cell tracking for parameter identification. Generally, we find that even within restrictive error bounds for deviation from experimental data, the number of viable regulation types may be large. Indeed, distinct regulation can lead to similar expression behaviour over time. Our results demonstrate that molecule production and degradation rates may often differ from classical constant, linear or Michaelis–Menten type kinetics.
Author Correction: Introduced ascidians harbor highly diverse and host-specific symbiotic microbial assemblages
Authors: Evans James S. , Erwin Patrick M. , Shenkar Noa , López-Legentil Susanna
Published: April 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources
Authors: Huang Liang-Chin , Ross Karen E. , Baffi Timothy R. , Drabkin Harold , Kochut Krzysztof J. , Ruan Zheng , D’Eustachio Peter , McSkimming Daniel , Arighi Cecilia , Chen Chuming , Natale Darren A. , Smith Cynthia , Gaudet Pascale , Newton Alexandra C. , Wu Cathy , Kannan Natarajan
Published: April 2018

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the ‘hydrophobic motif’ of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes.
Simultaneous lancet-free monitoring of alcohol and glucose from low-volumes of perspired human sweat
Authors: Bhide Ashlesha , Muthukumar Sriram , Saini Amreek , Prasad Shalini
Published: April 2018

A lancet-free, label-free biosensor for simultaneous detection of sweat glucose and alcohol was demonstrated using zinc oxide thin films integrated into a nanoporous flexible electrode system. Sensing was achieved from perspired human sweat at low volumes (1–3 μL), comparable to ambient conditions without external stimulation. Zinc oxide thin film electrodes were surface functionalized with alcohol oxidase enzyme and with glucose oxidase enzyme towards developing an affinity biosensor specific to the physiological relevant range of alcohol comprising of 0–2 drinks (0–50 mg/dl) and physiologically relevant range of glucose ranging from hypo- to hyper-glycaemia (50–130 mg/dl) in perspired human sweat. Sensing was achieved by measuring impedance changes associated with alcohol and glucose binding onto the sensor interface using electrochemical impedance spectroscopy with a dynamic range from 0.01–200 mg/dl and a limit of detection of 0.01 mg/dl for alcohol in human sweat. Sensor calibration in synthetic sweat containing interferents (25–200 mg/dl) and comparison using regression and Bland-Altman analysis of sweat sensor performance was done with BACtrack®. Combinatorial detection of glucose and ethanol in perspired human sweat and comparison of sweat sensor performance with Accu-Chek® blood glucose monitoring system that we expect would be relevant for pre-diabetics and diabetics for monitoring their glucose levels and alcohol consumption.
Functional and Morphological Changes in the Deep Lumbar Multifidus Using Electromyography and Ultrasound
Authors: Zhang Shanshan , Xu Yi , Han Xiulan , Wu Wen , Tang Yan , Wang Chuhuai
Published: April 2018

Surface electromyography (sEMG) studies have indicated that chronic low back pain (cLBP) involves altered electromyographic activity and morphological structure of the lumbar multifidus (LM) beyond pain perception; however, most studies have evaluated the superficial lumbar multifidus. It is difficult to record electromyography (EMG) signals from the deep multifidus (DM) to determine the neuromuscular activation patterns, making it difficult to determine the relationship between functional and structural changes in cLBP. We developed a novel method to record intramuscular EMG signals in the DM based on the sEMG system and fine-wire electrodes. We measured EMG signals of the DM in 24 cLBP patients and 26 pain-free healthy controls to identify changes in neuromuscular activation. We also used ultrasound to measure DM muscle thickness, cross-sectional area, and contraction activity to identify potential relationships between EMG activity and structural damage. cLBP patients had decreased average EMG and root mean square, but increased median frequency and mean power frequency. Average EMG was positively correlated with contractile activity, but not statistically correlated with noncontractile anatomical abnormalities. Our results suggest that cLBP alters the neuromuscular activation patterns and morphological structure of the contractile activity of the DM, providing insights into the mechanisms underlying pain perception.
East Asian Winter Monsoon Impacts the ENSO-related Teleconnections and North American Seasonal Air Temperature Prediction
Authors: Ma Tianjiao , Chen Wen , Nath Debashis , Graf Hans-F. , Wang Lin , Huangfu Jingliang
Published: April 2018

El Niño-Southern Oscillation (ENSO) is a key feature for seasonal weather and climate prediction in the extra-tropics since related sea surface temperature anomalies induce precipitation anomalies that generate poleward propagating Rossby waves and teleconnections. The East Asian winter monsoon (EAWM) is driven by processes originating over the Asian continent and, to a lesser degree, by ENSO-related tropical convection. EAWM also strongly affects convection and precipitation patterns over the western tropical Pacific by cold air outbreaks reaching equatorial latitudes. Hence, one can expect a modulating effect of EAWM on the generation of Rossby wave trains related to ENSO. By increasing the convective heating over the western Pacific, strong EAWM strengthens the Pacific Walker circulation, and weakens (strengthens) the El Niño (La Niña) related effects on the extra-tropics via a modulation of the Pacific North America teleconnection pattern. Our results indicate that, for seasonal prediction over North America, along with ENSO the variability of EAWM should also be taken into account. The climate anomalies over the North America for the same phase of ENSO are significantly different for strong and weak EAWM.