bluuebunny/crossref_metadata_2025 huggingface dataset:
Two‐Moment Bulk Cloud Microphysics With Prognostic Precipitation in GFDL's Atmosphere Model AM4.0: Configuration and Performance
Authors: Guo Huan , Ming Yi , Fan Songmiao , Zhou Linjiong , Harris Lucas , Zhao Ming
Published: May 2021

A two‐moment Morrison‐Gettelman bulk cloud microphysics with prognostic precipitation (MG2), together with a mineral dust and temperature‐dependent ice nucleation scheme, have been implemented into the Geophysical Fluid Dynamics Laboratory's Atmosphere Model version 4.0 (AM4.0). We refer to this configuration as AM4‐MG2. This paper describes the configuration of AM4‐MG2, evaluates its performance, and compares it with AM4.0. It is shown that the global simulations with AM4‐MG2 compare favorably with observations and reanalyses. The model skill scores are close to AM4.0. Compared to AM4.0, improvements in AM4‐MG2 include (a) better coastal marine stratocumulus and seasonal cycles, (b) more realistic ice fraction, and (c) dominant accretion over autoconversion. Sensitivity tests indicate that nucleation and sedimentation schemes have significant impacts on cloud liquid and ice water fields, but higher horizontal resolution (about 50 km instead of 100 km) does not.
The Annual Cycle of Energy Input, Modal Excitation and Physical Plus Biogenic Turbulent Dissipation in a Temperate Lake
Authors: Simpson John H. , Woolway R. Iestyn , Scannell Brian , Austin Martin J. , Powell Ben , Maberly Stephen C.
Published: May 2021

A year of measurements by Doppler Current Profilers, a chain of temperature sensors and a suite of meteorological instruments has been analyzed to elucidate the seasonal cycle of the dynamical response of a temperate lake (Windermere) to surface forcing. The efficiency of energy input to the lake (Eff) was determined by comparing the rate of working by the surface wind‐stress RWy with the downward flux of momentum in the atmosphere. Eff was found to increase from values of ∼0.3% in winter mixed conditions, up to ∼1.2% during summer stratification, when internal seiches were present. Water column kinetic energy was similarly enhanced during stratification. Spectral analysis of the axial velocity showed that the first vertical mode was dominant during most of the stratified period with a less prominent second mode appearing in the early part of the summer. The observed periods and vertical structure of these modes generally accorded with estimates from internal wave theory based on density profiles. During stratification, pycnocline dissipation exhibited high variability linked to the surface forcing with an average, depth‐integrated, pycnocline dissipation rate of 2.5 × 10−5 W m−2 corresponding to ∼3%–4% of RWy. Over the same period, the dissipation rate in the bottom boundary layer (BBL) exhibited a marked diurnal variation unrelated to physical forcing. Acoustic backscatter indicated the presence of vertically migrating organisms with peak aggregation in the BBL around midday coinciding with maximum dissipation. During stratification, biogenic dissipation contributed an average of ∼36% of the total BBL dissipation rate of ∼5.7 × 10−5 W m−2.
A Closer Look at the Creation of a Metamorphic Sole
Authors: Rehnberg Morgan
Published: May 2021

Detailing the development of the metamorphic sole beneath the Oman–United Arab Emirates ophiolite provides insight into subduction zone processes.
Divergent Evolution of Glaciation Across High‐Mountain Asia During the Last Four Glacial‐Interglacial Cycles
Authors: Yan Qing , Owen Lewis A. , Zhang Zhongshi , Wang Huijun , Wei Ting , Jiang Nanxuan , Zhang Ran
Published: May 2021

Glaciers over High‐Mountain Asia (HMA) provide a critical window into past climate change and the linkage between high and low‐latitude glaciation, but how glaciers may have varied during past glacial‐interglacial cycles remains elusive. Here, we reconstruct the timing and extent of glaciations for the last 425 kyr over HMA, using a climate‐glaciation simulation constrained by observations and glacial geologic evidence. We illustrate that there were multiple alpine‐style glaciations comparable in extent to those during the last glacial maximum during the last four glacial‐interglacial cycles. The extent and timing of glaciations vary across HMA, especially between the westerly influenced northern and the monsoonal‐influenced southern HMA. The ∼23‐kyr periodicity dominates HMA glaciation due to the critical role of precession in regulating summer temperature and precipitation. Our results, in addition to helping to fill the incomplete glacial geologic record, provide a framework to test hypotheses linking orbital‐scale climate, glaciation, and landscape evolution over HMA.
Magnetosphere‐Ionosphere Coupling of Precipitated Electrons in Diffuse Aurora Driven by Time Domain Structures
Authors: Khazanov George V. , Shen Yangyang , Vasko Ivan Y. , Artemyev Anton V. , Chu Mike
Published: May 2021

Recent theoretical studies and the spacecraft conjugate observations between the Time History of Events and Macroscale Interactions during Substorms (THEMIS) mission and the low‐altitude Enhanced Polar Outflow Probe (e‐POP) spacecraft demonstrated the connections between broadband electrostatic fluctuations, the so called time domain structures (TDSs), and electron precipitation in the region of diffuse aurora. In this letter, we used the SuperThermal Electron Transport (STET) code to implement these theoretical and experimental results and analyze magnetosphere‐ionosphere energy interplay of the precipitated electrons that are driven by TDSs. To put TDSs electron scattering processes in the context with other wave scattering activities, ECH and whistler chorus waves are taken into account. Integrated electron energy fluxes in the diffuse aurora driven by TDSs are comparable to those driven by whistler waves. We find that including Magnetosphere‐Ionosphere coupling processes increases the integrated electron energy fluxes by more than two times than only driven by TDSs.
The First Detection of an Earthquake From a Balloon Using Its Acoustic Signature
Authors: Brissaud Quentin , Krishnamoorthy Siddharth , Jackson Jennifer M. , Bowman Daniel C. , Komjathy Attila , Cutts James A. , Zhan Zhongwen , Pauken Michael T. , Izraelevitz Jacob S. , Walsh Gerald J.
Published: May 2021

Extreme temperature and pressure conditions on the surface of Venus present formidable technological challenges against performing ground‐based seismology. Efficient coupling between the Venusian atmosphere and the solid planet theoretically allows the study of seismically generated acoustic waves using balloons in the upper atmosphere, where conditions are far more clement. However, earthquake detection from a balloon has never been demonstrated. We present the first detection of an earthquake from a balloon‐borne microbarometer near Ridgecrest, CA in July 2019 and include a detailed analysis of the dependence of seismic infrasound, as measured from a balloon on earthquake source parameters, topography, and crustal and atmospheric structure. Our comprehensive analysis of seismo‐acoustic phenomenology demonstrates that seismic activity is detectable from a high‐altitude platform on Earth, and that Rayleigh wave‐induced infrasound can be used to constrain subsurface velocities, paving the way for the detection and characterization of such signals on Venus.
Network‐Synchronization Analysis Reveals the Weakening Tropical Circulations
Authors: Geng Zijin , Zhang Yongwen , Lu Bo , Fan Jingfang , Zhao Ziming , Chen Xiaosong
Published: May 2021

The impact of climate change on extreme weather is one of the most concerning problems. Climate change could cause more frequent and unexpected extreme weather. Still, synchronization features of extreme weather under climate change are not fully understood. Here, we develop a climate network approach to study global synchronization patterns of extreme events based on the 500‐hPa geopotential field. We find that a positive event synchronization (PES) network is associated with the tropical circulations in the tropics; a negative event synchronization network is associated with the large‐scale atmospheric Rossby waves in mid‐latitudes. By studying temporal evolution of the PES network, we find that the synchronization strengths in the tropics are weakening under climate change in relation to the slowing down of tropical circulations. Furthermore, our results show that the strength of synchronization in Africa and the Atlantic Ocean decrease faster than other regions.
Investigating the Link Between Outer Radiation Belt Losses and Energetic Electron Escape at the Magnetopause: A Case Study Using Multi‐Mission Observations and Simulations
Authors: Cohen I. J. , Turner D. L. , Michael A. T. , Sorathia K. A. , Ukhorskiy A. Y.
Published: May 2021

Radiation belt flux dropout events are sudden and often significant reductions in high‐energy electrons from Earth's outer radiation belts. These losses are theorized to be due to interactions with the dayside magnetopause and possibly connected to observations of escaping magnetospheric particles. This study focuses on radiation belt losses during a moderate‐strength, nonstorm dropout event on November 21, 2016. The potential loss mechanisms and the linkage to dayside escape are investigated using combined energetic electron observations throughout the dayside magnetosphere from the Magnetospheric Multiscale and Van Allen Probes spacecraft along with global magnetohydrodynamic and test particle simulations. In particular, this nonstorm‐time event simplifies the magnetospheric conditions and removes ambiguity in the interpretation of results, allowing focus on subsequent losses from enhanced outward radial transport that can occur after initial compression and relaxation of the magnetopause boundary. The evolution of measured phase space density profiles suggest a total loss of approximately 60% of the initial radiation belt content during the event. Together the in situ observations and high‐resolution simulations help to characterize the loss by bounding the following parameters: (a) the duration of the loss, (b) the relative distribution of losses and surface area of the magnetopause over which loss occurs, and (c) the escaping flux (i.e., loss) rate across the magnetopause. In particular, this study is able to estimate the surface area of loss to less than 2.9 × 106 RE2 and the duration of loss to greater than 6 h, while also demonstrating the magnetic local time‐dependence of the escaping flux and energy spectrum.
Rectified Effects of Interannual Chlorophyll Variability on the Tropical Pacific Climate Revealed by a Hybrid Coupled Physics‐Biology Model
Authors: Tian Feng , Zhang Rong‐Hua , Wang Xiujun , Zhi Hai
Published: May 2021

El Niño‐Southern Oscillation (ENSO) induces large interannual chlorophyll variability (ICV) in the tropical Pacific, which modulates shortwave penetration in the upper ocean. However, the extent to which ICV can have rectified effect (higher‐frequency process impacts low‐frequency climate variability (i.e., ENSO) and mean state) in the tropical Pacific remains unclear. Here, a hybrid coupled physics‐biogeochemistry model with tunable coupling ocean‐atmosphere intensity (α) is used to examine this rectified effect. The simulations consist of a control run in which the ICV effect is represented in the model and the other with the ICV effect being purposely excluded by only reserving the climatological chlorophyll field. Results show that the ICV effect depends on α; ENSO amplitude is reduced by 12%–40% with decreased annual mean sea surface temperature by 0.05–0.4°C in the eastern equatorial Pacific when taking α = 0.8–1.15. A stability analysis reveals that the ICV effect on ENSO exhibits two feedback loops. (a) Positive (negative) chlorophyll anomalies during La Niña (El Niño) act to increase (decrease) shortwave absorption within the mixed layer, which enhances thermodynamic damping (slightly weakening ENSO amplitude). (b) Chlorophyll anomalies modulate vertical redistribution of penetrative shortwave radiation between the mixed layer and subsurface layers; this differential heating affects ocean stratification and vertical mixing, which weakens the thermocline and Ekman feedback (predominantly weakening ENSO amplitude). Additionally, ICV exhibits asymmetric effects on ENSO evolution, with the El Niño amplitude being damped stronger than La Nina; this residual effect leads to a net cooling condition in the eastern tropical Pacific.
The Mixed Layer Salinity Budget in the Central Equatorial Indian Ocean
Authors: Chi Nan‐Hsun , Lien Ren‐Chieh , D'Asaro Eric A.
Published: May 2021

The oceanic surface mixed layer salinity (MLS) budget of the central and eastern equatorial Indian Ocean during boreal fall and winter is studied using in situ and remote sensing measurements. Budgets on roughly 100 km scale were constructed using data from two DYNAmics of the Madden–Julian Oscillation and two Research Moored Array for African‐Asian‐Australian Monsoon Analysis and Prediction moorings near 79°E during September 2011 to January 2012. The horizontal advective salinity flux plays a significant role in the seasonal variation of equatorial MLS. In boreal fall, the equatorial and 1.5°S MLS increases due to horizontal advection and turbulent mixing, despite the freshening surface flux associated with MJOs. In boreal winter, with larger sub‐monthly variation and uncertainties, the decreasing of equatorial MLS is accounted by freshening zonal advection and surface flux, abated by salty meridional advection; the 1.5°S MLS is explained by the combination of freshening meridional advection and surface flux, and salty zonal advection. Budgets between 2011 and 2015 are investigated using data products from Tropical Rainfall Measuring Mission, Aquarius, Ocean Surface Current Analyses Real‐time, Objectively Analyzed air‐sea Fluxes, and Argo mixed layers over a wider region. The eastward development of the equatorial salinity tongue in the central to eastern Indian Ocean in boreal fall and the westward retreat in boreal winter are largely determined by the equatorial zonal current. The meridional migration of ITCZ rainfall plays a secondary role. In order to improve model prediction skills of MLS changes in the equatorial Indian Ocean, both zonal and meridional salinity advective fluxes, at a spatial scale of 1° longitude and latitude and a timescale less than days, need to be properly simulated.
Secondary Formation of Aerosols Under Typical High‐Humidity Conditions in Wintertime Sichuan Basin, China: A Contrast to the North China Plain
Authors: Wang Yujue , Hu Min , Hu Wei , Zheng Jing , Niu Hongya , Fang Xin , Xu Nan , Wu Zhijun , Guo Song , Wu Yusheng , Chen Wentai , Lu Sihua , Shao Min , Xie Shaodong , Luo Bin , Zhang Yuanhang
Published: May 2021

The Sichuan Basin is one of the regions suffering from severe haze pollution in southwest China. However, the secondary aerosol formation in this region is poorly understood. In this study, the chemical compositions of PM2.5 and molecular compositions of water‐soluble organics in wintertime Sichuan were measured to investigate the aerosol sources and formation under typical high relative humidity (RH) conditions. Strong correlations between PM2.5, carbonaceous aerosols and K+ suggested the influence of biomass burning. The impacts of biomass burning were also supported by the dominance of primarily emitted reduced/less oxidized nitrogen‐containing organics as well as the high peak intensities of secondarily formed nitrocatechols and methyl‐nitrocatechols. High humidity (average RH = 80%) and aerosol liquid water (ALW) in Sichuan facilitated the secondary formation of sulfate, nitrate, and secondary organic aerosols (SOA). The average sulfate oxidation ratio and nitrogen oxidation ratio in Sichuan were 2.5 and 3.1 times of those in winter Beijing (average RH = 27%). This suggested higher potentials of SO2 and NOx to form sulfate and nitrate under high‐RH conditions. The abundant aqueous‐SOA formation in Sichuan was supported by the dominance of organosulfates (OSs) and nitrooxy‐OSs in mass spectra of water‐soluble organics, while the OSs in winter Beijing were quite limited. The more abundant OS formation in Sichuan was attributed to the much higher RH, ALW, aerosol acidity, and sulfate, which favored the acidic sulfate‐catalyzed aqueous‐phase reactions for OS formation. Higher concentrations of biogenic volatile organic compounds were additional reasons for the more abundant OSs in Sichuan than in Beijing.
RBM24 exacerbates bladder cancer progression by forming a Runx1t1/TCF4/miR-625-5p feedback loop
Authors: Yin Yue-Wei , Liu Kai-Long , Lu Bao-Sai , Li Wei , Niu Ya-Lin , Zhao Chen-Ming , Yang Zhan , Guo Ping-Ying , Qi Jin-Chun
Published: May 2021

RNA–binding motif protein 24 (RBM24) acts as a multifunctional determinant of cell fate, proliferation, apoptosis, and differentiation during development by regulating premRNA splicing and mRNA stability. It is also implicated in carcinogenesis, but the functions of RBM24 in bladder cancer (BC) remain unclear. In the present study, we revealed that RBM24 was upregulated in BC tissues. Importantly, we found that a higher level of RBM24 was correlated with poor prognosis in BC patients. Overexpression of RBM24 promoted BC cell proliferation, while depletion of RBM24 inhibited BC cell proliferation in vivo and in vitro. Mechanistically, RBM24 positively regulated Runx1t1 expression in BC cells by binding to and enhancing Runx1t1 mRNA stability. Furthermore, Runx1t1 in turn promoted RBM24 expression by interacting with the transcription factor TCF4 and suppressing the transcription of miR-625-5p, which directly targets RBM24 and suppresses RBM24 expression. RBM24-regulated BC cell proliferation was moderated via the Runx1t1/TCF4/miR-625-5p feedback loop. These results indicate that the RBM24/Runx1t1/TCF4/miR-625-5p positive feedback loop participates in BC progression. Disruption of this pathway may be a potential therapeutic strategy for BC treatment.
Imbalanced post- and extrasynaptic SHANK2A functions during development affect social behavior in SHANK2-mediated neuropsychiatric disorders
Authors: Eltokhi Ahmed , Gonzalez-Lozano Miguel A. , Oettl Lars-Lennart , Rozov Andrey , Pitzer Claudia , Röth Ralph , Berkel Simone , Hüser Markus , Harten Aliona , Kelsch Wolfgang , Smit August B. , Rappold Gudrun A. , Sprengel Rolf
Published: May 2021

Mutations inSHANKgenes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported inShankKO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK proteins, but these remain poorly defined. In this study, we examined how SHANK2 can mediate electrophysiological, molecular, and behavioral effects by conditionally overexpressing either wild-type SHANK2A or the extrasynaptic SHANK2A(R462X) variant. SHANK2A overexpression affected pre- and postsynaptic targets and revealed a reversible, development-dependent autism spectrum disorder-like behavior. SHANK2A also mediated redistribution of Ca2+-permeable AMPA receptors between apical and basal hippocampal CA1 dendrites, leading to impaired synaptic plasticity in the basal dendrites. Moreover, SHANK2A overexpression reduced social interaction and increased the excitatory noise in the olfactory cortex during odor processing. In contrast, overexpression of the extrasynaptic SHANK2A(R462X) variant did not impair hippocampal synaptic plasticity, but still altered the expression of presynaptic/axonal signaling proteins. We also observed an attention-deficit/hyperactivity-like behavior and improved social interaction along with enhanced signal-to-noise ratio in cortical odor processing. Our results suggest that the disruption of pre- and postsynaptic SHANK2 functions caused bySHANK2mutations has a strong impact on social behavior. These findings indicate that pre- and postsynaptic SHANK2 actions cooperate for normal neuronal function, and that an imbalance between these functions may lead to different neuropsychiatric disorders.
Creating robotic intelligence using multistimuli-responsive cobalt-doped manganese oxide
Authors: Wu Runni , Kwan Kin Wa , Mak Chi Hin , Ngan Alfonso Hing Wan
Published: May 2021

Compact material constructs possessing some degree of built-in intelligence via the exhibition of complex functionalities in response to easily deliverable stimuli are highly desirable for material-powered robots. We report here a visible light-driven, dual-responsive material of cobalt-doped manganese dioxide (Co-MnO2), which exhibits high actuation performance in terms of speed and power requirement and decreased electrical resistivity under light illumination. The actuation properties are fine-tunable by controlling the amount of Co doping, followed by an electrochemical treatment to activate the actuation, and the resistance change conveniently serves as a built-in feedback signal for controlling the actuation. Utilizing these properties, compact microrobotic devices capable of self-sensing visible light intensities of ~4 mW/cm2to perform complex motions along multiple selectable configurational pathways are fabricated. Intelligent robotic functions, including self-adapting load lifting, object sorting, and on-demand structural stiffening, are demonstrated in these devices. The concept demonstrated here opens up a perspective of creating robotic intelligence using multistimuli-responsive materials.
Permutation-based identification of important biomarkers for complex diseases via machine learning models
Authors: Mi Xinlei , Zou Baiming , Zou Fei , Hu Jianhua
Published: May 2021

Study of human disease remains challenging due to convoluted disease etiologies and complex molecular mechanisms at genetic, genomic, and proteomic levels. Many machine learning-based methods have been developed and widely used to alleviate some analytic challenges in complex human disease studies. While enjoying the modeling flexibility and robustness, these model frameworks suffer from non-transparency and difficulty in interpreting each individual feature due to their sophisticated algorithms. However, identifying important biomarkers is a critical pursuit towards assisting researchers to establish novel hypotheses regarding prevention, diagnosis and treatment of complex human diseases. Herein, we propose a Permutation-based Feature Importance Test (PermFIT) for estimating and testing the feature importance, and for assisting interpretation of individual feature in complex frameworks, including deep neural networks, random forests, and support vector machines. PermFIT (available athttps://github.com/SkadiEye/deepTL) is implemented in a computationally efficient manner, without model refitting. We conduct extensive numerical studies under various scenarios, and show that PermFIT not only yields valid statistical inference, but also improves the prediction accuracy of machine learning models. With the application to the Cancer Genome Atlas kidney tumor data and the HITChip atlas data, PermFIT demonstrates its practical usage in identifying important biomarkers and boosting model prediction performance.
Robot-assisted, source-camera-coupled multi-view broadband imagers for ubiquitous sensing platform
Authors: Li Kou , Yuasa Ryoichi , Utaki Ryogo , Sun Meiling , Tokumoto Yu , Suzuki Daichi , Kawano Yukio
Published: May 2021

Multi-functional photo-imaging garners attention towards the development of universal safety-net sensor networks. Although there are urgent needs to comprehensively address the optical information from arbitrarily structured and located targets, investigations on multi-view sensitive broadband monitoring, being independent of the operating environment, are yet to be completed. This study presents a robot-assisted, photo-source and imager implanted, multi-view stereoscopic sensitive broadband photo-monitoring platform with reflective and transmissive switchable modes. A multifaceted photo-thermoelectric device design based on flexible carbon nanotube films facilitates the prototype demonstrations of non-destructive, target-structure-independent, free-form multi-view examinations on actual three-dimensional industrial components. Further functionalisation, namely, a portable system utilising three-dimensional printing and ultraviolet processing, achieves the unification of freely attachable photo-imagers and miniature photo-sources, enabling location-independent operation. Consequently, the non-destructive unmanned, remote, high-speed, omni-directional testing of a defective aerial miniature model winding road-bridge with a robot-assisted photo-source imager built into a multi-axis movable photo-thermoelectric monitor arm is demonstrated.
Catalytic asymmetric Nakamura reaction by gold(I)/chiral N,Nʹ-dioxide-indium(III) or nickel(II) synergistic catalysis
Authors: Hu Xinyue , Tang Xiaoxue , Zhang Xiying , Lin Lili , Feng Xiaoming
Published: May 2021

Intermolecular addition of enols and enolates to unactivated alkynes was proved to be a simple and powerful method for carbon-carbon bond formation. Up to date, a catalytic asymmetric version of alkyne with 1,3-dicarbonyl compound has not been realized. Herein, we achieve the catalytic asymmetric intermolecular addition of 1,3-dicarbonyl compounds to unactivated 1-alkynes attributing to the synergistic activation of chiral N,N′-dioxide-indium(III) or nickel(II) Lewis acid and achiral gold(I) π-acid. A range of β-ketoamides, β-ketoesters and 1,3-diketones transform to the corresponding products with a tetra-substituted chiral center in good yields with good e.r. values. Besides, a possible catalytic cycle and a transition state model are proposed to illustrate the reaction process and the origin of chiral induction based on the experimental investigations.
Co-development of central and peripheral neurons with trunk mesendoderm in human elongating multi-lineage organized gastruloids
Authors: Olmsted Zachary T. , Paluh Janet L.
Published: May 2021

Stem cell technologies including self-assembling 3D tissue models provide access to early human neurodevelopment and fundamental insights into neuropathologies. Gastruloid models have not been used to investigate co-developing central and peripheral neuronal systems with trunk mesendoderm which we achieve here in elongating multi-lineage organized (EMLO) gastruloids. We evaluate EMLOs over a forty-day period, applying immunofluorescence of multi-lineage and functional biomarkers, including day 16 single-cell RNA-Seq, and evaluation of ectodermal and non-ectodermal neural crest cells (NCCs). We identify NCCs that differentiate to form peripheral neurons integrated with an upstream spinal cord region after day 8. This follows initial EMLO polarization events that coordinate with endoderm differentiation and primitive gut tube formation during multicellular spatial reorganization. This combined human central-peripheral nervous system model of early organogenesis highlights developmental events of mesendoderm and neuromuscular trunk regions and enables systemic studies of tissue interactions and innervation of neuromuscular, enteric and cardiac relevance.
Chemically defined and xeno-free culture condition for human extended pluripotent stem cells
Authors: Liu Bei , Chen Shi , Xu Yaxing , Lyu Yulin , Wang Jinlin , Du Yuanyuan , Sun Yongcheng , Liu Heming , Zhou Haoying , Lai Weifeng , Xue Anqi , Yin Ming , Li Cheng , Bai Yun , Xu Jun , Deng Hongkui
Published: May 2021

Extended pluripotent stem (EPS) cells have shown great applicative potentials in generating synthetic embryos, directed differentiation and disease modeling. However, the lack of a xeno-free culture condition has significantly limited their applications. Here, we report a chemically defined and xeno-free culture system for culturing and deriving human EPS cells in vitro. Xeno-free human EPS cells can be long-term and genetically stably maintained in vitro, as well as preserve their embryonic and extraembryonic developmental potentials. Furthermore, the xeno-free culturing system also permits efficient derivation of human EPS cells from human fibroblast through reprogramming. Our study could have broad utility in future applications of human EPS cells in biomedicine.
Regioselective activation of benzocyclobutenones and dienamides lead to anti-Bredt bridged-ring systems by a [4+4] cycloaddition
Authors: Zhang Jianyu , Wang Xi , Xu Tao
Published: May 2021

To the best of our knowledge, bridgehead carbon benzofused-bridged ring systems have previously not been accessible to the synthetic community. Here, we describe a formal type-II [4 + 4] cycloaddition approach that provides fully sp2-carbon embedded anti-Bredt bicyclo[5.3.1] skeletons through the Rh-catalyzed C1–C8 activation of benzocyclobutenones (BCBs) and their coupling with pedant dienamides. Variously substituted dienamides have been coupled with BCBs to provide a range of complex bicyclo[5.3.1] scaffolds (>20 examples, up to 89% yield). The bridged rings were further converted to polyfused hydroquinoline-containing tetracycles via a serendipitously discovered transannular 1,5-hydride shift/Prins-like cyclization/Schmidt rearrangement cascade.
Towards a bioengineered uterus: bioactive sheep uterus scaffolds are effectively recellularized by enzymatic preconditioning
Authors: Padma Arvind Manikantan , Carrière Laura , Krokström Karlsson Frida , Sehic Edina , Bandstein Sara , Tiemann Tom Tristan , Oltean Mihai , Song Min Jong , Brännström Mats , Hellström Mats
Published: May 2021

Uterine factor infertility was considered incurable until recently when we reported the first successful live birth after uterus transplantation. However, risky donor surgery and immunosuppressive therapy are factors that may be avoided with bioengineering. For example, transplanted recellularized constructs derived from decellularized tissue restored fertility in rodent models and mandate translational studies. In this study, we decellularized whole sheep uterus with three different protocols using 0.5% sodium dodecyl sulfate, 2% sodium deoxycholate (SDC) or 2% SDC, and 1% Triton X-100. Scaffolds were then assessed for bioactivity using the dorsal root ganglion and chorioallantoic membrane assays, and we found that all the uterus scaffolds exhibited growth factor activity that promoted neurogenesis and angiogenesis. Extensive recellularization optimization was conducted using multipotent sheep fetal stem cells and we report results from the following three in vitro conditions; (a) standard cell culturing conditions, (b) constructs cultured in transwells, and (c) scaffolds preconditioned with matrix metalloproteinase 2 and 9. The recellularization efficiency was improved short-term when transwells were used compared with standard culturing conditions. However, the recellularization efficiency in scaffolds preconditioned with matrix metalloproteinases was 200–300% better than the other strategies evaluated herein, independent of decellularization protocol. Hence, a major recellularization hurdle has been overcome with the improved recellularization strategies and in vitro platforms described herein. These results are an important milestone and should facilitate the production of large bioengineered grafts suitable for future in vivo applications in the sheep, which is an essential step before considering these principles in a clinical setting.
International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers
Authors: Amar Laurence , Pacak Karel , Steichen Olivier , Akker Scott A. , Aylwin Simon J. B. , Baudin Eric , Buffet Alexandre , Burnichon Nelly , Clifton-Bligh Roderick J. , Dahia Patricia L. M. , Fassnacht Martin , Grossman Ashley B. , Herman Philippe , Hicks Rodney J. , Januszewicz Andrzej , Jimenez Camilo , Kunst Henricus P. M. , Lewis Dylan , Mannelli Massimo , Naruse Mitsuhide , Robledo Mercedes , Taïeb David , Taylor David R. , Timmers Henri J. L. M. , Treglia Giorgio , Tufton Nicola , Young William F. , Lenders Jacques W. M. , Gimenez-Roqueplo Anne-Paule , Lussey-Lepoutre Charlotte
Published: May 2021

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA,SDHB,SDHCandSDHD), which encode the four subunits of the SDH enzyme. When a pathogenicSDHxmutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carrySDHxmutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rareSDHx-related tumours and management of elderly people who have anSDHxmutation. This Consensus Statement focuses on the management of asymptomaticSDHxmutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
A computational model for predicting changes in infection dynamics due to leakage through N95 respirators
Authors: Hariharan Prasanna , Sharma Neha , Guha Suvajyoti , Banerjee Rupak K. , D’Souza Gavin , Myers Matthew R.
Published: May 2021

In the absence of fit-testing, leakage of aerosolized pathogens through the gaps between the face and N95 respirators could compromise the effectiveness of the device and increase the risk of infection for the exposed population. To address this issue, we have developed a model to estimate the increase in risk of infection resulting from aerosols leaking through gaps between the face and N95 respirators. The gaps between anthropometric face-geometry and N95 respirators were scanned using computed tomography. The gap profiles were subsequently input into CFD models. The amount of aerosol leakage was predicted by the CFD simulations. Leakage levels were validated using experimental data obtained using manikins. The computed amounts of aerosol transmitted to the respiratory system, with and without leaks, were then linked to a risk-assessment model to predict the infection risk for a sample population. An influenza outbreak in which 50% of the population deployed respirators was considered for risk assessment. Our results showed that the leakage predicted by the CFD model matched the experimental data within about 13%. Depending upon the fit between the headform and the respirator, the inward leakage for the aerosols ranged between 30 and 95%. In addition, the non-fit-tested respirator lowered the infection rate from 97% (for no protection) to between 42 and 80%, but not to the same level as the fit-tested respirators (12%). The CFD-based leakage model, combined with the risk-assessment model, can be useful in optimizing protection strategies for a given population exposed to a pathogenic aerosol.
The nature of Pu-bearing particles from the Maralinga nuclear testing site, Australia
Authors: Cook Megan , Etschmann Barbara , Ram Rahul , Ignatyev Konstantin , Gervinskas Gediminas , Conradson Steven D. , Cumberland Susan , Wong Vanessa N. L. , Brugger Joёl
Published: May 2021

The high-energy release of plutonium (Pu) and uranium (U) during the Maralinga nuclear trials (1955–1963) in Australia, designed to simulate high temperature, non-critical nuclear accidents, resulted in wide dispersion µm-sized, radioactive, Pu–U-bearing ‘hot’ particles that persist in soils. By combining non-destructive, multi-technique synchrotron-based micro-characterization with the first nano-scale imagining of the composition and textures of six Maralinga particles, we find that all particles display intricate physical and chemical make-ups consistent with formation via condensation and cooling of polymetallic melts (immiscible Fe–Al–Pu–U; and Pb ± Pu–U) within the detonation plumes. Plutonium and U are present predominantly in micro- to nano-particulate forms, and most hot particles contain low valence Pu–U–C compounds; these chemically reactive phases are protected by their inclusion in metallic alloys. Plutonium reworking was observed within an oxidised rim in a Pb-rich particle; however overall Pu remained immobile in the studied particles, while small-scale oxidation and mobility of U is widespread. It is notoriously difficult to predict the long-term environmental behaviour of hot particles. Nano-scale characterization of the hot particles suggests that long-term, slow release of Pu from the hot particles may take place via a range of chemical and physical processes, likely contributing to on-going Pu uptake by wildlife at Maralinga.
Differentiation between multiple sclerosis and neuromyelitis optica spectrum disorder using optical coherence tomography angiography
Authors: Rogaczewska Małgorzata , Michalak Sławomir , Stopa Marcin
Published: May 2021

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are autoimmune demyelinating diseases of distinct etiology presenting with optic neuritis (ON). This study aimed to identify the macular and peripapillary neurovascular alterations that may facilitate the differentiation between NMOSD and MS eyes using spectral-domain optical coherence tomography (OCT) and OCT angiography (OCTA). A total of 13 NMOSD patients and 40 MS patients were evaluated. After ON, the radial peripapillary capillary (RPC) vessel density was significantly decreased in the superior (S) and inferior (I) sectors in NMOSD compared with MS eyes, whereas in non-ON eyes, the temporal (T) sector of RPC was reduced in MS group. In the ON eyes, the retinal nerve fiber layer in the I and T quadrants was thinner in NMOSD than in MS. Regarding ON and non-ON eyes, the macular capillary plexuses, and the ganglion cell complex thickness did not differ between NMOSD and MS. The ratios, based on the disease-specific intra-eye RPC vessel density reduction pattern, were the best discriminants between NMOSD and MS, i.e., inferior to nasal (I/N) and I/T ratios for ON eyes, and S/T and N/T ratios for non-ON eyes. Our results show that the OCTA-based simple ratios may be useful in distinguishing NMOSD and MS patients.
Assessment and optimization of respiratory syncytial virus prophylaxis in Connecticut, 1996–2013
Authors: Artin Ben , Pitzer Virginia E. , Weinberger Daniel M.
Published: May 2021

Respiratory syncytial virus (RSV) causes seasonal respiratory infection, with hospitalization rates of up to 50% in high-risk infants. Palivizumab provides safe and effective, yet costly, immunoprophylaxis. The American Academy of Pediatrics (AAP) recommends palivizumab only for high-risk infants and only during the RSV season. Outside of Florida, the current guidelines do not recommend regional adjustments to the timing of the immunoprophylaxis regimen. Our hypothesis is that adjusting the RSV prophylaxis regimen in Connecticut based on spatial variation in the timing of RSV incidence can reduce the disease burden compared to the current AAP-recommended prophylaxis regimen. We obtained weekly RSV-associated hospital admissions by ZIP-code in Connecticut between July 1996 and June 2013. We estimated the fraction of all Connecticut RSV cases occurring during the period of protection offered by immunoprophylaxis (“preventable fraction”) under the AAP guidelines. We then used the same model to estimate protection conferred by immunoprophylaxis regimens with alternate start dates, but unchanged duration. The fraction of RSV hospitalizations preventable by the AAP guidelines varies by county because of variations in epidemic timing. Prophylaxis regimens adjusted for state- or county-level variation in the timing of RSV seasons are superior to the AAP-recommended regimen. The best alternative strategy yielded a preventable fraction of 95.1% (95% CI 94.7–95.4%), compared to 94.1% (95% CI 93.7–94.5%) for the AAP recommendation. In Connecticut, county-level recommendations would provide only a minimal additional benefit while adding complexity. Initiating RSV prophylaxis based on state-level data may improve protection compared with the AAP recommendations.
Transcriptomic and metabolomic joint analysis reveals distinct flavonoid biosynthesis regulation for variegated testa color development in peanut (Arachis hypogaea L.)
Authors: Hu Mengdie , Li Jiawei , Hou Mingyu , Liu Xiaoqing , Cui Shunli , Yang Xinlei , Liu Lifeng , Jiang Xiaoxia , Mu Guojun
Published: May 2021

Peanut is one of the important oil and economic crops, among which the variegated testa peanut is a unique member. The molecular mechanisms underlying the pigment synthesis in variegated testa are still unclear. Differentially expressed genes (DEGs) in the flavonoid metabolism pathway in pigmented areas indicated that there were 27 DEGs highly related to the synthesis of variegated testa color among 1,050 DEGs. Of these 27, 13 were up-regulated and 14 were down-regulated, including 3 PALs, 1 C4H, 2 CHSs, 1 F3H, 1 F3'H, 2 DFRs, 2 LARs, 2 IAAs, 4 bHLHs, and 9 MYBs. GO (Gene Ontology) analysis indicated that DEGs were similarly enriched in three branches. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis suggested flavonoid biosynthesis is the most direct metabolic pathway for the synthesis of testa variegation. The liquid chromatography–tandem mass spectrometry (LC–MS/MS) results showed that cyanidin and delphinidin were the primary metabolites that caused the color differences between the pigmented and the non-pigmented areas. Through the verification of 20 DEGs via qPCR, the results were consistent with transcriptome sequencing in four comparison groups. The results in this study lay the foundation for revealing the molecular regulation mechanisms of flavonoid synthesis in variegated testa peanut.
Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target
Authors: Seligson Nathan D. , Maradiaga Richard D. , Stets Colin M. , Katzenstein Howard M. , Millis Sherri Z. , Rogers Alan , Hays John L. , Chen James L.
Published: May 2021

Sarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.
Collagen analogs with phosphorylcholine are inflammation-suppressing scaffolds for corneal regeneration from alkali burns in mini-pigs
Authors: Simpson Fiona C. , McTiernan Christopher D. , Islam Mohammad Mirazul , Buznyk Oleksiy , Lewis Philip N. , Meek Keith M. , Haagdorens Michel , Audiger Cindy , Lesage Sylvie , Gueriot François-Xavier , Brunette Isabelle , Robert Marie-Claude , Olsen David , Koivusalo Laura , Liszka Aneta , Fagerholm Per , Gonzalez-Andrades Miguel , Griffith May
Published: May 2021

The long-term survival of biomaterial implants is often hampered by surgery-induced inflammation that can lead to graft failure. Considering that most corneas receiving grafts are either pathological or inflamed before implantation, the risk of rejection is heightened. Here, we show that bioengineered, fully synthetic, and robust corneal implants can be manufactured from a collagen analog (collagen-like peptide-polyethylene glycol hybrid, CLP-PEG) and inflammation-suppressing polymeric 2-methacryloyloxyethyl phosphorylcholine (MPC) when stabilized with the triazine-based crosslinker 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. The resulting CLP-PEG-MPC implants led to reduced corneal swelling, haze, and neovascularization in comparison to CLP-PEG only implants when grafted into a mini-pig cornea alkali burn model of inflammation over 12 months. Implants incorporating MPC allowed for faster nerve regeneration and recovery of corneal sensation. CLP-PEG-MPC implants appear to be at a more advanced stage of regeneration than the CLP-PEG only implants, as evidenced by the presence of higher amounts of cornea-specific type V collagen, and a corresponding decrease in the presence of extracellular vesicles and exosomes in the corneal stroma, in keeping with the amounts present in healthy, unoperated corneas.
Top-down acetylcholine signaling via olfactory bulb vasopressin cells contributes to social discrimination in rats
Authors: Suyama Hajime , Egger Veronica , Lukas Michael
Published: May 2021

Social discrimination in rats requires activation of the intrinsic bulbar vasopressin system, but it is unclear how this system comes into operation, as olfactory nerve stimulation primarily inhibits bulbar vasopressin cells (VPCs). Here we show that stimulation with a conspecific can activate bulbar VPCs, indicating that VPC activation depends on more than olfactory cues during social interaction. A series of in vitro electrophysiology, pharmacology and immunohistochemistry experiments implies that acetylcholine, probably originating from centrifugal projections, can enable olfactory nerve-evoked action potentials in VPCs. Finally, cholinergic activation of the vasopressin system contributes to vasopressin-dependent social discrimination, since recognition of a known rat was blocked by bulbar infusion of the muscarinic acetylcholine receptor antagonist atropine and rescued by additional bulbar application of vasopressin. Thus, our results implicate that top-down cholinergic modulation of bulbar VPC activity is involved in social discrimination in rats.
Integrating molecular, histopathological, neuroimaging and clinical neuroscience data with NeuroPM-box
Authors: Iturria-Medina Yasser , Carbonell Félix , Assadi Atousa , Adewale Quadri , Khan Ahmed F. , Baumeister Tobias R. , Sanchez-Rodriguez Lazaro
Published: May 2021

Understanding and treating heterogeneous brain disorders requires specialized techniques spanning genetics, proteomics, and neuroimaging. Designed to meet this need,NeuroPM-boxis a user-friendly, open-access, multi-tool cross-platform software capable of characterizing multiscale and multifactorial neuropathological mechanisms. Using advanced analytical modeling for molecular, histopathological, brain-imaging and/or clinical evaluations, this framework has multiple applications, validated here with synthetic (N > 2900), in-vivo (N = 911) and post-mortem (N = 736) neurodegenerative data, and including the ability to characterize: (i) the series of sequential states (genetic, histopathological, imaging or clinical alterations) covering decades of disease progression, (ii) concurrent intra-brain spreading of pathological factors (e.g., amyloid, tau and alpha-synuclein proteins), (iii) synergistic interactions between multiple biological factors (e.g., toxic tau effects on brain atrophy), and (iv) biologically-defined patient stratification based on disease heterogeneity and/or therapeutic needs. This freely available toolbox (neuropm-lab.com/neuropm-box.html) could contribute significantly to a better understanding of complex brain processes and accelerating the implementation of Precision Medicine in Neurology.