bluuebunny/crossref_metadata_2025 huggingface dataset:
Argentine Danish Grammatical Gender: Stability with Strongly Patterned Variation
Authors: Kühl Karoline , Heegård Petersen Jan
Published: February 2021

This paper investigates the expression of grammatical gender in Heritage Argentine Danish. We examine a subset of the Corpus of South American Danish of approximately 20,500 tokens of gender marking produced by 90 speakers. The results show that Argentine Danish gender marking in general complies with the Standard Denmark Danish rules. However, there is also systematic variation: While there is hardly any difference compared to Standard Denmark Danish with respect to the definite suffix, gender marking on prenominal determiners differs from that in Standard Danish. More specifically, the less frequent neuter gender is more vulnerable, and common gender tends to be overgeneralized. Further, complex NPs with attributive adjectives show more variation in gender marking on prenominal determiners than simple NPs. As to sociolinguistic variation, the analysis shows that tokens produced by older speakers and speakers from settlements with a higher degree of language maintenance are consistent to a higher degree with Standard Danish gender marking. The paper compares these results with the results of studies of gender marking variation in other Germanic heritage languages. We conclude that the overall stability of grammatical gender in the Germanic heritage languages is a general pattern that only partly relates to social or societal factors.*
From Pennsylvania to Transylvania: August Ludwig Schlözer and the decentering of Enlightenment
Authors: Varga Benedek M.
Published: February 2021

This article analyzes the historical and political thinking of the eighteenth-century German historian August Ludwig Schlözer, in the context of the American War of Independence and the French Revolution. The article argues that Schlözer's disillusionment with these transformative events led him to identify the German settlers in medieval Transylvania as agents of a better Enlightenment. In doing so, Schlözer constructed the history of the Transylvanian German colony as an antithesis to American colonial endeavors, while redefining the frameworks and history of enlightened progress in both time and space. In this way, Schlözer translated the history of a marginal East–Central European region into a world-historical narrative.
Institutional quality and the capital structure of microfinance institutions: the moderating role of board gender diversity
Authors: Adusei Michael , Sarpong-Danquah Beatrice
Published: February 2021

We test the effect of institutional quality on capital structure in the microfinance setting. In doing this, we rely on data from 532 microfinance institutions (MFIs) located in 73 countries dotted across the six microfinance regions in the world. We observe that institutional quality exhibits a robust negative and statistically significant relationship with capital structure in both the short and long run, implying that MFIs in countries with a better institutional environment are less likely to utilize more debt. Our moderation analysis furnishes us with evidence that the presence of women on the board of an MFI significantly moderates the relationship between institutional quality and its capital structure. We show that in the presence of more female representation on the boards of MFIs, the tendency of MFIs using less debt is higher.
Characteristics of Train Stations Where Railway Suicides Have Occurred and Locations Within the Stations
Authors: Sueki Hajime
Published: February 2021

Abstract. Background: To devise effective railway suicide countermeasures, it is necessary to identify stations where suicide is likely to occur. Aim: We explored the characteristics of stations where railway suicides have occurred and locations within the stations. Method: (Study 1) Using suicide data from between April 2014 and September 2019 provided by a major railway company in Japan, station-specific suicide was modeled as an outcome variable in a multivariate Poisson regression model. (Study 2) With railway company staff, we visited stations where suicide frequently occurs and conducted fieldwork. Results: (Study 1) Our estimation using a Poisson regression model revealed that railway suicides were more frequent when stations were serviced by passing trains, had a large number of passengers, and were located near psychiatric hospitals. (Study 2) Of 50 suicides, 48.0% occurred in front of benches or waiting rooms, 26.0% occurred at the front end of the platform, 24.0% occurred at the entrance to the platform, and 22.0% occurred at a blind spot for the train driver. Limitations: All data were provided by one railway company in Japan, limiting the generalizability of the results. Conclusion: Stations where suicide occurs frequently have distinct characteristics. Focusing on suicide hotspots may aid suicide prevention.
Simulating the Ion Precipitation From the Inner Magnetosphere by H‐Band and He‐Band Electro Magnetic Ion Cyclotron Waves
Authors: Shreedevi P. R. , Yu Yiqun , Ni Binbin , Saikin Anthony , Jordanova Vania K.
Published: February 2021

During geomagnetic storms, magnetospheric wave activity drives the ion precipitation which can become an important source of energy flux into the ionosphere and strongly affect the dynamics of the magnetosphere‐ionosphere coupling. In this study, we investigate the role of Electro Magnetic Ion Cyclotron (EMIC) waves in causing ion precipitation into the ionosphere using simulations from the RAM‐SCBE model with and without EMIC waves included. The global distribution of H‐band and He‐band EMIC wave intensity in the model is based on three different EMIC wave models statistically derived from satellite measurements. Comparisons among the simulations and with observations suggest that the EMIC wave model based on recent Van Allen Probes observations is the best in reproducing the realistic ion precipitation into the ionosphere. Specifically, the maximum precipitating proton fluxes appear at L = 4–5 in the afternoon‐to‐night sector which is in good agreement with statistical results, and the temporal evolution of integrated proton energy fluxes at auroral latitudes is consistent with earlier studies of the stormtime precipitating proton energy fluxes and vary in close relation to the SYM‐H index. Besides, the simulations with this wave model can account for the enhanced precipitation of < 20 keV proton energy fluxes at regions closer to Earth (L < 5) as measured by NOAA/POES satellites, and reproduce reasonably well the intensity of <30 keV proton energy fluxes measured by DMSP satellites. It is suggested that the inclusion of H‐band EMIC waves improves the intensity of precipitation in the model leading to better agreement with the NOAA/POES data.
The Effects of Inductive Electric Field on the Spatial and Temporal Evolution of the Inner Magnetospheric Ring Current
Authors: Liu Jianghuai , Ilie Raluca
Published: February 2021

Charged particles are observed to be injected into the inner magnetosphere from the plasma sheet and energized up to high energies over short distance and time, during both geomagnetic storms and substorms. Numerous studies suggest that it is the short‐duration and high‐speed plasma flows, which are closely associated with the global effects of magnetic reconnection and inductive effects, rather than the slow and steady convection that control the earthward transport of plasma and magnetic flux from the magnetotail, especially during geomagnetic activities. In order to include the effect of the inductive electric field produced by the temporal change of magnetic field on the dynamics of ring current, we implemented both theoretical and numerical modifications to an inner magnetosphere kinetic model—Hot Electron‐Ion Drift Integrator. New drift terms associated with the inductive electric field are incorporated into the calculation of bounce‐averaged coefficients for the distribution function, and their numerical implementations and the associated effects on total drift and energization rate are discussed. Numerical simulations show that the local particle drifts are significantly altered by the presence of inductive electric fields, in addition to the changing magnetic gradient‐curvature drift due to the distortion of magnetic field, and at certain locations, the inductive drift dominates both the potential and the magnetic gradient‐curvature drift. The presence of a self‐consistent inductive electric field alters the overall particle trajectories, energization, and pitch angle, resulting in significant changes in the topology and the strength of the ring current.
On the Generation of an Unseasonal EPB Over South East Asia
Authors: Currie J. L. , Carter B. A. , Retterer J. , Dao T. , Pradipta R. , Caton R. , Groves K. , Otsuka Y. , Yokoyama T. , Hozumi K. , Le Truong T. , Terkildsen M.
Published: February 2021

An unseasonal equatorial plasma bubble (EPB) event over South‐East Asia was observed on July 22, 2014 that has not been studied before. An investigation into this event is presented with the 26th July, 2014 as a comparison, non‐bubble day. The 22nd July EPB event occurred in the late post‐sunset sector and was associated with a small upward plasma drift. This event was highlighted using a new filter on the SCINDA S4 data. Ionosonde data show that sporadic E was present during the growth period for the EPB event. Modeling results from Thermosphere‐Ionosphere Electrodynamics (TEC) Global Circulation Model were used to conduct a numerical experiment investigating the direct effect of sporadic E on the linear R‐T growth rate. It was shown that sporadic E located in the correct latitude and local time can increase the linear growth rate. The seeding conditions were investigated using TEC data from Patumwan, Thailand. Wave‐like structures were observed for both days of interest, with larger amplitudes on 22nd July compared with the 26th July. Finally, simulations using the high‐resolution model PBMOD showed that for forcing from above conditions similar to the days of interest, EPBs would form in the presence of large seed perturbations. Therefore, it is likely that this unseasonal event was caused by large seed perturbations in TEC.
Automatic Detection of the Thermal Electron Density From the WHISPER Experiment Onboard CLUSTER‐II Mission With Neural Networks
Authors: Gilet N. , De Leon E. , Gallé R. , Vallières X. , Rauch J.‐L. , Jegou K. , Bucciantini L. , Savreux V. , Décréau P. , Henri P.
Published: February 2021

The Waves of HIgh frequency and Sounder for Probing Electron density by Relaxation (WHISPER) instrument has been monitoring the bulk properties of the plasma environment around Earth for more than 20 years. Onboard the 3‐D Earth magnetospheric CLUSTER‐II mission, this experiment delivers active and natural electric field spectra, in a frequency interval ranging respectively from 3.5 to 82 kHz, and from 2 to 80 kHz. The thermal electron density, a key parameter of scientific interest and major driver for the calibration of particles instrument, is derived from spectra. Until recently, the extraction of the thermal electron density required a manual intervention. To automate this process, self‐learning algorithms based on Multilayer Neural Networks have been implemented. The evaluation of the thermal electron density from WHISPER spectra depends on the plasma region encountered by the spacecraft. First, a fully connected neural network has been implemented to predict the plasma region, using only the active spectra measured by the WHISPER instrument. Second, a specific neural network has been implemented to predict the thermal electron density for each plasma region. The model reaches up to 98% prediction accuracy for some plasma regimes. Two thermal electron density prediction models were trained, a first one to process data from the free solar wind and magnetosheath regions, and a second one for the plasmasphere region. The prediction accuracy can reach up to 95% in the free solar wind and magnetosheath regimes, and 75% in the plasmasphere.
Seismic Structure, Gravity Anomalies and Flexure Along the Emperor Seamount Chain
Authors: Watts A. B. , Grevemeyer I. , Shillington D. J. , Dunn R. A. , Boston B. , Gómez de la Peña L.
Published: February 2021

The Hawaiian‐Emperor seamount chain in the Pacific Ocean has provided fundamental insights into hotspot generated intraplate volcanism and the long‐term strength of oceanic lithosphere. However, only a few seismic experiments to determine crustal and upper mantle structure have been carried out on the Hawaiian Ridge, and no deep imaging has ever been carried out along the Emperor seamounts. Here, we present the results of an active source seismic experiment using 29 Ocean‐Bottom Seismometers (OBS) carried out along a strike profile of the seamounts in the region of Jimmu and Suiko guyots. Joint reflection and refraction tomographic inversion of the OBS data show the upper crust is highly heterogeneous withPwave velocities <4–5 km s−1, which are attributed to extrusive lavas and clastics. In contrast, the lower crust is remarkably homogeneous with velocities of 6.5–7.2 km s−1, which we attribute to oceanic crust and mafic intrusions. Moho is identified by a strongPmParrival at offsets of 20–80 km, yielding depths of 13–16 km. The underlying mantle is generally homogeneous with velocities in the range 7.9–8.0 km s−1. The crust and mantle velocity structure has been verified by gravity modeling. While top of oceanic crust prior to volcano loading is not recognized as a seismic or gravity discontinuity, flexural modeling reveals a ∼5.0–5.5 km thick preexisting oceanic crust that is overlain by a ∼8 km thick volcanic edifice. Unlike at the Hawaiian Ridge, we find no evidence of magmatic underplating.
A Two‐Phase Model for the Evolution of Planetary Embryos With Implications for the Formation of Mars
Authors: Zhang Zhongtian , Bercovici David , Jordan Jacob S.
Published: February 2021

Attempts to constrain the accretion history of Mars using geochemical observations have focused on the chronology of core formation. However, given the possibility of incomplete metal‐silicate equilibration, most previous results cannot distinguish between the following two scenarios: (1) Mars was formed early through gradual accretion and remained isolated as a “planetary embryo” and (2) Mars underwent relatively protracted accretion involving collisions between planetary embryos. Here we use a two‐phase model to demonstrate that, despite strong heating from the short‐lived radionuclide 26Al, the mantle of a Mars‐sized planetary embryo may stay effectively solid because the generation and migration of melts in relatively small fractions leads to efficient heat transport. In this scenario, the effectively solid mantle would have undergone substantial differentiation before the extinction of 26Al, and the disparate planetary building blocks would not have been homogenized within the embryo. Hence, features of very early silicate differentiation (within the first few million years of the solar system) and significant nucleosynthetic isotope heterogeneity would be expected to exist in stranded planetary embryos. In contrast, meteorite observations suggest that the crust‐mantle system of Mars is homogeneous in nucleosynthetic isotope anomalies and the onset of silicate differentiation was no earlier than ∼15 Myr after solar system formation. This discrepancy implies that Mars is not a stranded planetary embryo. Instead, we suggest that the accretion of Mars involved at least one collision between planetary embryos with comparable sizes that caused complete melting and homogenization during the giant‐impact stage of planetary growth.
Why are ELEvoHI CME Arrival Predictions Different if Based on STEREO‐A or STEREO‐B Heliospheric Imager Observations?
Authors: Hinterreiter Jürgen , Amerstorfer Tanja , Reiss Martin A. , Möstl Christian , Temmer Manuela , Bauer Maike , Amerstorfer Ute V. , Bailey Rachel L. , Weiss Andreas J. , Davies Jackie A. , Barnard Luke A. , Owens Mathew J.
Published: February 2021

Accurate forecasting of the arrival time and arrival speed of coronal mass ejections (CMEs) is an unsolved problem in space weather research. In this study, a comparison of the predicted arrival times and speeds for each CME based, independently, on the inputs from the two STEREO vantage points is carried out. We perform hindcasts using ELlipse Evolution model based on Heliospheric Imager observations (ELEvoHI) ensemble modeling. An estimate of the ambient solar wind conditions is obtained by the Wang‐Sheeley‐Arge/Heliospheric Upwind eXtrapolation (WSA/HUX) model combination that serves as input to ELEvoHI. We carefully select 12 CMEs between February 2010 and July 2012 that show clear signatures in both STEREO‐A and STEREO‐B HI time‐elongation maps, that propagate close to the ecliptic plane, and that have corresponding in situ signatures at Earth. We find a mean arrival time difference of 6.5 h between predictions from the two different viewpoints, which can reach up to 9.5 h for individual CMEs, while the mean arrival speed difference is 63 km s−1. An ambient solar wind with a large speed variance leads to larger differences in the STEREO‐A and STEREO‐B CME arrival time predictions (cc = 0.92). Additionally, we compare the predicted arrivals, from both spacecraft, to the actual in situ arrivals at Earth and find a mean absolute error of 7.5 ± 9.5 h for the arrival time and 87 ± 111 km s−1 for the arrival speed. There is no tendency for one spacecraft to provide more accurate arrival predictions than the other.
The electrochemical detection of bioterrorism agents: a review of the detection, diagnostics, and implementation of sensors in biosafety programs for Class A bioweapons
Authors: O’Brien Connor , Varty Kathleen , Ignaszak Anna
Published: February 2021

During the past year, disease has shown us the iron grip it can hold over a population of people. Health systems can be overwhelmed, economies can be brought into recession, and many people can be harmed or killed. When weaponized, diseases can be manipulated to create a detriment to health while becoming an economic burden on any society. It is consequently prudent that easy detection of bioweapons is available to governments for protecting their people. Electrochemical sensing displays many distinct advantages, such as its low limit of detection, low cost to run, rapid generation of results, and in many instances portability. We therefore present a wide array of electrochemical sensing platforms currently being fabricated, a brief summary of Class A bioweapons, and the potential future of bioweapon detection and biosafety.
Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder
Authors: Liu Fatao , Li Yongsheng , Ying Dongjian , Qiu Shimei , He Yong , Li Maolan , Liu Yun , Zhang Yijian , Zhu Qin , Hu Yunping , Liu Liguo , Li Guoqiang , Pan Weihua , Jin Wei , Mu Jiasheng , Cao Yang , Liu Yingbin
Published: February 2021

Neuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.
Cognitive reflection correlates with behavior on Twitter
Authors: Mosleh Mohsen , Pennycook Gordon , Arechar Antonio A. , Rand David G.
Published: February 2021

We investigate the relationship between individual differences in cognitive reflection and behavior on the social media platform Twitter, using a convenience sample ofN = 1,901 individuals from Prolific. We find that people who score higher on the Cognitive Reflection Test—a widely used measure of reflective thinking—were more discerning in their social media use, as evidenced by the types and number of accounts followed, and by the reliability of the news sources they shared. Furthermore, a network analysis indicates that the phenomenon of echo chambers, in which discourse is more likely with like-minded others, is not limited to politics: people who scored lower in cognitive reflection tended to follow a set of accounts which are avoided by people who scored higher in cognitive reflection. Our results help to illuminate the drivers of behavior on social media platforms and challenge intuitionist notions that reflective thinking is unimportant for everyday judgment and decision-making.
Dissociable roles of cortical excitation-inhibition balance during patch-leaving versus value-guided decisions
Authors: Kaiser Luca F. , Gruendler Theo O. J. , Speck Oliver , Luettgau Lennart , Jocham Gerhard
Published: February 2021

In a dynamic world, it is essential to decide when to leave an exploited resource. Such patch-leaving decisions involve balancing the cost of moving against the gain expected from the alternative patch. This contrasts with value-guided decisions that typically involve maximizing reward by selecting the current best option. Patterns of neuronal activity pertaining to patch-leaving decisions have been reported in dorsal anterior cingulate cortex (dACC), whereas competition via mutual inhibition in ventromedial prefrontal cortex (vmPFC) is thought to underlie value-guided choice. Here, we show that the balance between cortical excitation and inhibition (E/I balance), measured by the ratio of GABA and glutamate concentrations, plays a dissociable role for the two kinds of decisions. Patch-leaving decision behaviour relates to E/I balance in dACC. In contrast, value-guided decision-making relates to E/I balance in vmPFC. These results support mechanistic accounts of value-guided choice and provide evidence for a role of dACC E/I balance in patch-leaving decisions.
The docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition
Authors: Man Wing K. , Tahirbegi Bogachan , Vrettas Michail D. , Preet Swapan , Ying Liming , Vendruscolo Michele , De Simone Alfonso , Fusco Giuliana
Published: February 2021

α-Synuclein (αS) is a presynaptic disordered protein whose aberrant aggregation is associated with Parkinson’s disease. The functional role of αS is still debated, although it has been involved in the regulation of neurotransmitter release via the interaction with synaptic vesicles (SVs). We report here a detailed characterisation of the conformational properties of αS bound to the inner and outer leaflets of the presynaptic plasma membrane (PM), using small unilamellar vesicles. Our results suggest that αS preferentially binds the inner PM leaflet. On the basis of these studies we characterise in vitro a mechanism by which αS stabilises, in a concentration-dependent manner, the docking of SVs on the PM by establishing a dynamic link between the two membranes. The study then provides evidence that changes in the lipid composition of the PM, typically associated with neurodegenerative diseases, alter the modes of binding of αS, specifically in a segment of the sequence overlapping with the non-amyloid component region. Taken together, these results reveal how lipid composition modulates the interaction of αS with the PM and underlie its functional and pathological behaviours in vitro.
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
Authors: Tillu Vikas A. , Rae James , Gao Ya , Ariotti Nicholas , Floetenmeyer Matthias , Kovtun Oleksiy , McMahon Kerrie-Ann , Chaudhary Natasha , Parton Robert G. , Collins Brett M.
Published: February 2021

Caveolae are spherically shaped nanodomains of the plasma membrane, generated by cooperative assembly of caveolin and cavin proteins. Cavins are cytosolic peripheral membrane proteins with negatively charged intrinsically disordered regions that flank positively charged α-helical regions. Here, we show that the three disordered domains of Cavin1 are essential for caveola formation and dynamic trafficking of caveolae. Electrostatic interactions between disordered regions and α-helical regions promote liquid-liquid phase separation behaviour of Cavin1 in vitro, assembly of Cavin1 oligomers in solution, generation of membrane curvature, association with caveolin-1, and Cavin1 recruitment to caveolae in cells. Removal of the first disordered region causes irreversible gel formation in vitro and results in aberrant caveola trafficking through the endosomal system. We propose a model for caveola assembly whereby fuzzy electrostatic interactions between Cavin1 and caveolin-1 proteins, combined with membrane lipid interactions, are required to generate membrane curvature and a metastable caveola coat.
A pediatric brain tumor atlas of genes deregulated by somatic genomic rearrangement
Authors: Zhang Yiqun , Chen Fengju , Donehower Lawrence A. , Scheurer Michael E. , Creighton Chad J.
Published: February 2021

The global impact of somatic structural variants (SSVs) on gene expression in pediatric brain tumors has not been thoroughly characterised. Here, using whole-genome and RNA sequencing from 854 tumors of more than 30 different types from the Children’s Brain Tumor Tissue Consortium, we report the altered expression of hundreds of genes in association with the presence of nearby SSV breakpoints. SSV-mediated expression changes involve gene fusions, altered cis-regulation, or gene disruption. SSVs considerably extend the numbers of patients with tumors somatically altered for critical pathways, including receptor tyrosine kinases (KRAS, MET, EGFR, NF1), Rb pathway (CDK4), TERT, MYC family (MYC, MYCN, MYB), and HIPPO (NF2). Compared to initial tumors, progressive or recurrent tumors involve a distinct set of SSV-gene associations. High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes. Compared to adult cancers, pediatric brain tumors would involve a different set of genes with SSV-altered cis-regulation. Our comprehensive and pan-histology genomic analyses reveal SSVs to play a major role in shaping the transcriptome of pediatric brain tumors.
Ni-catalyzed regio- and stereo-defined intermolecular cross-electrophile dialkylation of alkynes without directing group
Authors: Zhan Yi-Zhou , Xiao Nan , Shu Wei
Published: February 2021

The development of straightforward synthesis of regio- and stereodefined alkenes with multiple aliphatic substituents under mild conditions is an unmet challenge owing to competitive β-hydride elimination and selectivity issues. Herein, we report the nickel-catalyzed intermolecular cross-dialkylation of alkynes devoid of directing or activating groups to afford multiple aliphatic substituted alkenes in a syn-selective fashion at room temperature. The combination of two-electron oxidative cyclometallation and single-electron cross-electrophile coupling of nickel enables the syn-cross-dialkylation of alkynes at room temperature. This reductive protocol enables the sequential installation of two different alkyl substituents onto alkynes in a regio- and stereo-selective manner, circumventing the tedious preformation of sensitive organometallic reagents. The synthetic utility of this protocol is demonstrated by efficient synthesis of multi-substituted unfunctionalized alkenes and diverse transformations of the product.
Combined quantum tunnelling and dielectrophoretic trapping for molecular analysis at ultra-low analyte concentrations
Authors: Tang Longhua , Nadappuram Binoy Paulose , Cadinu Paolo , Zhao Zhiyu , Xue Liang , Yi Long , Ren Ren , Wang Jiangwei , Ivanov Aleksandar P. , Edel Joshua B.
Published: February 2021

Quantum tunnelling offers a unique opportunity to study nanoscale objects with atomic resolution using electrical readout. However, practical implementation is impeded by the lack of simple, stable probes, that are required for successful operation. Existing platforms offer low throughput and operate in a limited range of analyte concentrations, as there is no active control to transport molecules to the sensor. We report on a standalone tunnelling probe based on double-barrelled capillary nanoelectrodes that do not require a conductive substrate to operate unlike other techniques, such as scanning tunnelling microscopy. These probes can be used to efficiently operate in solution environments and detect single molecules, including mononucleotides, oligonucleotides, and proteins. The probes are simple to fabricate, exhibit remarkable stability, and can be combined with dielectrophoretic trapping, enabling active analyte transport to the tunnelling sensor. The latter allows for up to 5-orders of magnitude increase in event detection rates and sub-femtomolar sensitivity.
Dynamic structure of active sites in ceria-supported Pt catalysts for the water gas shift reaction
Authors: Li Yuanyuan , Kottwitz Matthew , Vincent Joshua L. , Enright Michael J. , Liu Zongyuan , Zhang Lihua , Huang Jiahao , Senanayake Sanjaya D. , Yang Wei-Chang D. , Crozier Peter A. , Nuzzo Ralph G. , Frenkel Anatoly I.
Published: February 2021

Oxide-supported noble metal catalysts have been extensively studied for decades for the water gas shift (WGS) reaction, a catalytic transformation central to a host of large volume processes that variously utilize or produce hydrogen. There remains considerable uncertainty as to how the specific features of the active metal-support interfacial bonding—perhaps most importantly the temporal dynamic changes occurring therein—serve to enable high activity and selectivity. Here we report the dynamic characteristics of a Pt/CeO2 system at the atomic level for the WGS reaction and specifically reveal the synergistic effects of metal-support bonding at the perimeter region. We find that the perimeter Pt0 − O vacancy−Ce3+ sites are formed in the active structure, transformed at working temperatures and their appearance regulates the adsorbate behaviors. We find that the dynamic nature of this site is a key mechanistic step for the WGS reaction.
Autocatalytic photoredox Chan-Lam coupling of free diaryl sulfoximines with arylboronic acids
Authors: Wang Cong , Zhang Hui , Wells Lucille A. , Liu Tian , Meng Tingting , Liu Qingchao , Walsh Patrick J. , Kozlowski Marisa C. , Jia Tiezheng
Published: February 2021

N-Arylation of NH-sulfoximines represents an appealing approach to access N-aryl sulfoximines, but has not been successfully applied to NH-diaryl sulfoximines. Herein, a copper-catalyzed photoredox dehydrogenative Chan-Lam coupling of free diaryl sulfoximines and arylboronic acids is described. This neutral and ligand-free coupling is initiated by ambient light-induced copper-catalyzed single-electron reduction of NH-sulfoximines. This electron transfer route circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions, increasing the environmental friendliness of this process. Instead, dihydrogen gas forms as a byproduct of this reaction. Mechanistic investigations also reveal a unique autocatalysis process. The C–N coupling products, N-arylated sulfoximines, serve as ligands along with NH-sulfoximine to bind to the copper species, generating the photocatalyst. DFT calculations reveal that both the NH-sulfoximine substrate and the N-aryl product can ligate the copper accounting for the observed autocatalysis. Two energetically viable stepwise pathways were located wherein the copper facilitates hydrogen atom abstraction from the NH-sulfoximine and the ethanol solvent to produce dihydrogen. The protocol described herein represents an appealing alternative strategy to the classic oxidative Chan-Lam reaction, allowing greater substrate generality as well as the elimination of byproduct formation from oxidants.
Mutant-selective degradation by BRAF-targeting PROTACs
Authors: Alabi Shanique , Jaime-Figueroa Saul , Yao Zhan , Gao Yijun , Hines John , Samarasinghe Kusal T. G. , Vogt Lea , Rosen Neal , Crews Craig M.
Published: February 2021

Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low  nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window.
Functional and structural characterization of a flavoprotein monooxygenase essential for biogenesis of tryptophylquinone cofactor
Authors: Oozeki Toshinori , Nakai Tadashi , Kozakai Kazuki , Okamoto Kazuki , Kuroda Shun’ichi , Kobayashi Kazuo , Tanizawa Katsuyuki , Okajima Toshihide
Published: February 2021

Bioconversion of peptidyl amino acids into enzyme cofactors is an important post-translational modification. Here, we report a flavoprotein, essential for biosynthesis of a protein-derived quinone cofactor, cysteine tryptophylquinone, contained in a widely distributed bacterial enzyme, quinohemoprotein amine dehydrogenase. The purified flavoprotein catalyzes the single-turnover dihydroxylation of the tryptophylquinone-precursor, tryptophan, in the protein substrate containing triple intra-peptidyl crosslinks that are pre-formed by a radical S-adenosylmethionine enzyme within the ternary complex of these proteins. Crystal structure of the peptidyl tryptophan dihydroxylase reveals a large pocket that may dock the protein substrate with the bound flavin adenine dinucleotide situated close to the precursor tryptophan. Based on the enzyme-protein substrate docking model, we propose a chemical reaction mechanism of peptidyl tryptophan dihydroxylation catalyzed by the flavoprotein monooxygenase. The diversity of the tryptophylquinone-generating systems suggests convergent evolution of the peptidyl tryptophan-derived cofactors in different proteins.
422 Million intrinsic quality factor planar integrated all-waveguide resonator with sub-MHz linewidth
Authors: Puckett Matthew W. , Liu Kaikai , Chauhan Nitesh , Zhao Qiancheng , Jin Naijun , Cheng Haotian , Wu Jianfeng , Behunin Ryan O. , Rakich Peter T. , Nelson Karl D. , Blumenthal Daniel J.
Published: February 2021

High quality-factor (Q) optical resonators are a key component for ultra-narrow linewidth lasers, frequency stabilization, precision spectroscopy and quantum applications. Integration in a photonic waveguide platform is key to reducing cost, size, power and sensitivity to environmental disturbances. However, to date, the Q of all-waveguide resonators has been relegated to below 260 Million. Here, we report a Si3N4 resonator with 422 Million intrinsic and 3.4 Billion absorption-limited Qs. The resonator has 453 kHz intrinsic, 906 kHz loaded, and 57 kHz absorption-limited linewidths and the corresponding 0.060 dB m−1 loss is the lowest reported to date for waveguides with deposited oxide upper cladding. These results are achieved through a careful reduction of scattering and absorption losses that we simulate, quantify and correlate to measurements. This advancement in waveguide resonator technology paves the way to all-waveguide Billion Q cavities for applications including nonlinear optics, atomic clocks, quantum photonics and high-capacity fiber communications.
LETR1 is a lymphatic endothelial-specific lncRNA governing cell proliferation and migration through KLF4 and SEMA3C
Authors: Ducoli Luca , Agrawal Saumya , Sibler Eliane , Kouno Tsukasa , Tacconi Carlotta , Hon Chung-Chao , Berger Simone D. , Müllhaupt Daniela , He Yuliang , Kim Jihye , D’Addio Marco , Dieterich Lothar C. , Carninci Piero , de Hoon Michiel J. L. , Shin Jay W. , Detmar Michael
Published: February 2021

Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, includingKLF4andSEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.
Simple physical mixing of zeolite prevents sulfur deactivation of vanadia catalysts for NOx removal
Authors: Song Inhak , Lee Hwangho , Jeon Se Won , Ibrahim Ismail A. M. , Kim Joonwoo , Byun Youngchul , Koh Dong Jun , Han Jeong Woo , Kim Do Heui
Published: February 2021

NOx abatement has been an indispensable part of environmental catalysis for decades. Selective catalytic reduction with ammonia using V2O5/TiO2 is an important technology for removing NOx emitted from industrial facilities. However, it has been a huge challenge for the catalyst to operate at low temperatures, because ammonium bisulfate (ABS) forms and causes deactivation by blocking the pores of the catalyst. Here, we report that physically mixed H-Y zeolite effectively protects vanadium active sites by trapping ABS in micropores. The mixed catalysts operate stably at a low temperature of 220 °C, which is below the dew point of ABS. The sulfur resistance of this system is fully maintained during repeated aging/regeneration cycles because the trapped ABS easily decomposes at 350 °C. Further investigations reveal that the pore structure and the amount of framework Al determined the trapping ability of various zeolites.
Arachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation
Authors: Ye Zhongde , Shen Yi , Jin Ke , Qiu Jingtao , Hu Bin , Jadhav Rohit R. , Sheth Khushboo , Weyand Cornelia M. , Goronzy Jörg J.
Published: February 2021

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two distinct autoimmune diseases that manifest with chronic synovial inflammation. Here, we show that CD4+ T cells from patients with RA and PsA have increased expression of the pore-forming calcium channel component ORAI3, thereby increasing the activity of the arachidonic acid-regulated calcium-selective (ARC) channel and making T cells sensitive to arachidonic acid. A similar increase does not occur in T cells from patients with systemic lupus erythematosus. Increased ORAI3 transcription in RA and PsA T cells is caused by reduced IKAROS expression, a transcriptional repressor of the ORAI3 promoter. Stimulation of the ARC channel with arachidonic acid induces not only a calcium influx, but also the phosphorylation of components of the T cell receptor signaling cascade. In a human synovium chimeric mouse model, silencing ORAI3 expression in adoptively transferred T cells from patients with RA attenuates tissue inflammation, while adoptive transfer of T cells from healthy individuals with reduced expression of IKAROS induces synovitis. We propose that increased ARC activity due to reduced IKAROS expression makes T cells more responsive and contributes to chronic inflammation in RA and PsA.
Plasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes
Authors: Weiner Adam B. , Vidotto Thiago , Liu Yang , Mendes Adrianna A. , Salles Daniela C. , Faisal Farzana A. , Murali Sanjana , McFarlane Matthew , Imada Eddie L. , Zhao Xin , Li Ziwen , Davicioni Elai , Marchionni Luigi , Chinnaiyan Arul M. , Freedland Stephen J. , Spratt Daniel E. , Wu Jennifer D. , Lotan Tamara L. , Schaeffer Edward M.
Published: February 2021

Black men die more often of prostate cancer yet, interestingly, may derive greater survival benefits from immune-based treatment with sipuleucel-T. Since no signatures of immune-responsiveness exist for prostate cancer, we explored race-based immune-profiles to identify vulnerabilities. Here we show in multiple independent cohorts comprised of over 1,300 patient samples annotated with either self-identified race or genetic ancestry, prostate tumors from Black men or men of African ancestry have increases in plasma cell infiltrate and augmented markers of NK cell activity and IgG expression. These findings are associated with improved recurrence-free survival following surgery and nominate plasma cells as drivers of prostate cancer immune-responsiveness.
Microbial nitrification and acidification of lacustrine sediments deduced from the nature of a sedimentary kaolin deposit in central Japan
Authors: Takagi Tetsuichi , Shin Ki-Cheol , Jige Mayumi , Hoshino Mihoko , Tsukimura Katsuhiro
Published: February 2021

Kaolin deposits in the Seto-Tono district, central Japan, were formed by intense kaolinization of lacustrine arkose sediments deposited in small and shallow inland lakes in the late Miocene. Based on mineralogical and stable isotopic (Fe, C, N) studies of Motoyama kaolin deposit in the Seto area, we concluded that it was formed by microbial nitrification and acidification of lacustrine sediments underneath an inland lake. Small amounts of Fe–Ti oxides and Fe-hydroxide in the kaolin clay indicated that iron was oxidized and leached during the kaolinization. The field occurrences indicate that leached ferric iron precipitated on the bottom of the kaolin deposit as limonite crusts, and their significantly fractionated Fe isotope compositions suggest the involvement of microbial activity. The C/N ratios of most of the kaolin clay are distinctly higher than those of modern lacustrine sediment. Although, the possibility of a low-temperature hydrothermal origin of the kaolin deposit cannot be completely ruled out, it is more likely that acidification by dilute nitric acid formed from plant-derived ammonia could have caused the kaolinization, Fe oxidation and leaching. The nitrate-dependent microbial Fe oxidation is consistent with dilute nitric acid being the predominant oxidant.
An arylthiazyne derivative is a potent inhibitor of lipid peroxidation and ferroptosis providing neuroprotection in vitro and in vivo
Authors: Keuters Meike Hedwig , Keksa-Goldsteine Velta , Dhungana Hiramani , Huuskonen Mikko T. , Pomeshchik Yuriy , Savchenko Ekaterina , Korhonen Paula K. , Singh Yajuvinder , Wojciechowski Sara , Lehtonen Šárka , Kanninen Katja M. , Malm Tarja , Sirviö Jouni , Muona Anu , Koistinaho Milla , Goldsteins Gundars , Koistinaho Jari
Published: February 2021

Lipid peroxidation-initiated ferroptosis is an iron-dependent mechanism of programmed cell death taking place in neurological diseases. Here we show that a condensed benzo[b]thiazine derivative small molecule with an arylthiazine backbone (ADA-409-052) inhibits tert-Butyl hydroperoxide (TBHP)-induced lipid peroxidation (LP) and protects against ferroptotic cell death triggered by glutathione (GSH) depletion or glutathione peroxidase 4 (GPx4) inhibition in neuronal cell lines. In addition, ADA-409-052 suppresses pro-inflammatory activation of BV2 microglia and protects N2a neuronal cells from cell death induced by pro-inflammatory RAW 264.7 macrophages. Moreover, ADA-409-052 efficiently reduces infarct volume, edema and expression of pro-inflammatory genes in a mouse model of thromboembolic stroke. Targeting ferroptosis may be a promising therapeutic strategy in neurological diseases involving severe neuronal death and neuroinflammation.
Nanodomain structure of single crystalline nickel oxide
Authors: Walls B. , Mazilkin A. A. , Mukhamedov B. O. , Ionov A. , Smirnova I. A. , Ponomareva A. V. , Fleischer K. , Kozlovskaya N. A. , Shulyatev D. A. , Abrikosov I. A. , Shvets I. V. , Bozhko S. I.
Published: February 2021

In this work we present a comprehensive study of the domain structure of a nickel oxide single crystal grown by floating zone melting and suggest a correlation between point defects and the observed domain structure. The properties and structure of domains dictate the dynamics of resistive switching, water splitting and gas sensing, to name but a few. Investigating the correlation between point defects and domain structure can provide a deeper understanding of their formation and structure, which potentially allows one to tailor domain structure and the dynamics of the aforementioned applications. A range of inhomogeneities are observed by diffraction and microscopy techniques. X-ray and low-energy electron diffraction reveal domains on the submicron- and nanometer-scales, respectively. In turn, these domains are visualised by atomic force and scanning tunneling microscopy (STM), respectively. A comprehensive transmission electron microscopy (TEM) study reveals inhomogeneities ranging from domains of varying size, misorientation of domains, variation of the lattice constant and bending of lattice planes. X-ray photoelectron spectroscopy and electron energy-loss spectroscopy indicate the crystal is Ni deficient. Density functional theory calculations—considering the spatial and electronic disturbance induced by the favourable nickel vacancy—reveal a nanoscale distortion comparable to STM and TEM observations. The different inhomogeneities are understood in terms of the structural relaxation induced by ordering of nickel vacancies, which is predicted to be favourable.