bluuebunny/crossref_metadata_2025 huggingface dataset:
Advanced InSAR Tropospheric Corrections From Global Atmospheric Models that Incorporate Spatial Stochastic Properties of the Troposphere
Authors: Cao Yunmeng , Jónsson Sigurjón , Li Zhiwei
Published: April 2021

Tropospheric delays are still the main error source of satellite‐based Interferometric Synthetic Aperture Radar (InSAR) mapping of Earth’s surface movements. Recent studies have demonstrated the potential of global atmospheric models (GAMs) in reducing InSAR tropospheric delays. However, the importance of appropriate interpolation and weighting strategies in GAM corrections has largely been overlooked. Here we present a new GAM‐based tropospheric correction method that incorporates spatial stochastic models of the troposphere into the weighting strategy of the correction. The method determines the correlation between a pixel of interest and neighboring GAM grid locations (3D) according to the spatial variability of the tropospheric random field, instead of subjectively using an inverse distance method, a local spline function, or other standard interpolation scheme. Also, our new method considers horizontal heterogeneities of the tropospheric field by estimating the integral of the tropospheric delays along the satellite line‐of‐sight (LOS) direction, instead of calculating projected zenith‐delays. The method can be used with any GAM, but we here implement it with the latest ECMWF (European Center for Medium‐Range Weather Forecasts) ERA5 reanalysis products. We validate the new method with hundreds of Sentinel‐1 images from 2015 to 2020 over the island of Hawaii, a location with variable topography, surface conditions, local climate, and deformation, and explore the tropospheric corrections for both interferograms and time‐series analysis products (deformation velocities and time‐series solutions). Compared with other GAM corrections (PyAPS, d‐LOS, and GACOS), our new method yields a larger reduction of the average standard deviation of the corrected interferograms, i.e., from 2.55  to 1.91 cm, instead of 2.47 cm (PyAPS), 2.44 cm (d‐LOS), and 2.10 cm (GACOS). Also, a larger fraction of 87% of the interferograms (243 out of 280) is improved, compared with 52%, 53%, and 66% for the other GAM corrections, respectively. These results demonstrate the importance of considering (1) tropospheric stochastic models in GAM corrections, (2) horizontal heterogeneities when estimating the LOS delays, and (3) tropospheric delays when mapping long‐wavelength or small‐magnitude deformations using InSAR.
Constraints on Mantle Viscosity From Intermediate‐Wavelength Geoid Anomalies in Mantle Convection Models With Plate Motion History
Authors: Mao Wei , Zhong Shijie
Published: April 2021

The Earth's long‐ and intermediate‐wavelength geoid anomalies are surface expressions of mantle convection and are sensitive to mantle viscosity. While previous studies of the geoid provide important constraints on the mantle radial viscosity variations, the mantle buoyancy in these studies, as derived from either seismic tomography or slab density models, may suffer significant uncertainties. In this study, we formulate 3‐D spherical mantle convection models with plate motion history since the Cretaceous that generate dynamically self‐consistent mantle thermal and buoyancy structures, and for the first time, use the dynamically generated slab structures and the observed geoid to place important constraints on the mantle viscosity. We found that non‐uniform weak plate margins and strong plate interiors are critical in reproducing the observed geoid and surface plate motion, especially the net lithosphere rotation (i.e., degree‐1 toroidal plate motion). In the best‐fit model, which leads to correlation of 0.61 between the modeled and observed geoid at degrees 4–12, the lower mantle viscosity is ∼1.3–2.5 × 1022 Pa⋅s and is ∼30 and ∼600–1,000 times higher than that in the transition zone and asthenosphere, respectively. Slab structures and the geoid are also strongly affected by slab strength, and the observations prefer moderately strong slabs that are ∼10–100 times stronger than the ambient mantle. Finally, a thin weak layer below the 670‐km phase change on a regional scale only in subduction zones produces stagnant slabs in the mantle transition zone as effectively as a weak layer on a global scale.
More than Skin Deep: Sea Surface Temperature as a Means of Inferring Atlantic Water Variability on the Southeast Greenland Continental Shelf Near Helheim Glacier
Authors: Snow T. , Straneo F. , Holte J. , Grigsby S. , Abdalati W. , Scambos T.
Published: April 2021

Enhanced outlet glacier discharge accounts for almost half of the Greenland Ice Sheet's mass loss since 1990. Warming subsurface Atlantic Water (AW) has been implicated in much of that loss, particularly along Greenland's southeastern coast. However, oceanographic observations are sparse prior to the last decade, making it difficult to diagnose changes in AW properties reaching the glaciers. Here, we investigate the use of sea surface temperature (SST) measurements to quantify ocean temperature variability on the continental shelf near Sermilik Fjord and Helheim Glacier. We find that after removing the short‐term, atmospheric‐driven variability in non‐winter months, regional SSTs provide a reliable upper ocean (surface mixed layer) temperature record. In the trough region near Sermilik Fjord, the adjusted SSTs correlate well with moored ocean measurements of the water entering the fjord at depth and driving glacier melting. Using this relationship, we reconstruct the AW variability on the shelf dating back to 2000, 8 years before the first mooring deployments. Across the 19‐year record, the AW temperatures in the trough do not always track properties in the source waters of the Irminger Current, which flows along the continental break. Instead, the properties of the waters found at the fjord mouth depend on variations in the source AW and, also, in the Polar Water that flows into the region from the Arctic Ocean. Satellite‐derived SSTs, when combined with local oceanography considerations, have the potential to improve understanding around previously unanswered glacier‐ocean questions in areas surrounding Greenland.
An Aerosol Climatology and Implications for Clouds at a Remote Marine Site: Case Study Over Bermuda
Authors: Aldhaif Abdulmonam M. , Lopez David H. , Dadashazar Hossein , Painemal David , Peters Andrew J. , Sorooshian Armin
Published: April 2021

Aerosol characteristics and aerosol–cloud interactions remain uncertain in remote marine regions. We use over a decade of data (2000–2012) from the NASA AErosol RObotic NETwork, aerosol and wet deposition samples, satellite remote sensors, and models to examine aerosol and cloud droplet number characteristics at a representative open ocean site (Bermuda) over the Western North Atlantic Ocean (WNAO). Annual mean values were as follows: aerosol optical depth (AOD) = 0.12, Ångström Exponent (440/870 nm) = 0.95, fine mode fraction = 0.51, asymmetry factor = 0.72 (440 nm) and 0.68 (1020 nm), and Aqua‐MODIS cloud droplet number concentrations = 51.3 cm−3. The winter season (December–February) was characterized by high sea salt optical thickness and the highest aerosol extinction in the lowest 2 km. Extensive precipitation over the WNAO in winter helps contribute to the low FMFs in winter (∼0.40–0.50) even though air trajectories often originate over North America. Spring and summer had more pronounced influence from sulfate, dust, organic carbon, and black carbon. Volume size distributions were bimodal with a dominant coarse mode (effective radii: 1.85–2.09 µm) and less pronounced fine mode (0.14–0.16 µm), with variability in the coarse mode likely due to different characteristic sizes for transported dust (smaller) versus regional sea salt (larger). Extreme pollution events highlight the sensitivity of this site to long‐range transport of urban emissions, dust, and smoke. Differing annual cycles are identified between AOD and cloud droplet number concentrations, motivating a deeper look into aerosol–cloud interactions at this site.
Joint Influence Mechanism of Phenology and Climate on the Dynamics of Gross Primary Productivity: Insights From Temperate Deciduous Broadleaf Forests in North America
Authors: Xie Zhiying , Zhu Wenquan , Qiao Kun , Li Peixian , Liu Hao
Published: April 2021

Understanding the influence mechanism of biotic and abiotic factors on the dynamics of gross primary productivity (GPP) is crucial to accurately simulate the terrestrial carbon cycle. Based on the carbon flux data, meteorological data (i.e., temperature, precipitation, vapor pressure deficit, and radiation) and phenological metrics (i.e., the date of greenup, maturity, senescence, and dormancy) collected from six North America temperate deciduous broadleaf forests (NAT‐DBF) sites, this study investigated the joint influence mechanism of phenology and climate on the dynamics of GPP by using commonality analysis and structural equation modeling. The results showed that precipitation, the date of maturity and senescence jointly dominated the dynamics of annual GPP in NAT‐DBF. The date of maturity and senescence rather than the date of greenup and dormancy were crucial phenological metrics that directly influenced the dynamics of annual GPP. There existed an important indirect influence path of temperature on the dynamics of annual GPP through regulating the date of maturity, while the direct influence of temperature on the dynamics of annual GPP was negligible. Precipitation not only directly influenced the dynamics of annual GPP, but also indirectly influenced the dynamics of annual GPP through regulating the date of senescence. Our study provides a process‐based understanding for the joint influence mechanism of meteorological factors and phenology on the dynamics of annual GPP, which is helpful for understanding the vegetation responses to climate change and improving the process‐based ecosystem models.
Constant Slip Rate on the Doruneh Strike‐Slip Fault, Iran, Averaged Over Late Pleistocene, Holocene, and Decadal Timescales
Authors: Mousavi Zahra , Fattahi Morteza , Khatib Mohammad , Talebian Morteza , Pathier Erwan , Walpersdorf Andrea , Sloan R. Alastair , Thomas Alexander L. , Rhodes Ed , Clive Fynn , Dodds Nicholas , Walker Richard T.
Published: April 2021

Varying estimates of both present‐day strain accumulation and long‐term slip rate on the Doruneh left‐lateral strike‐slip fault, NE Iran, have led to suggestions that it exhibits large along‐strike and/or temporal changes in activity. In this study, we make and compare estimates of slip rate measured using both geodesy and geomorphology, and spanning time periods ranging from decadal to 100 ka. To image the present‐day accumulation of strain, we process 7 years (2003–2010) of data from six ENVISAT tracks covering the fault, with interferograms produced for 400‐km‐long strips of data to image the long‐wavelength signals associated with interseismic strain accumulation across the locked fault. Our analysis shows that less than 4 mm/yr—and likely only 1–3 mm/yr—of slip accumulates across the fault. Using high‐resolution optical satellite imagery, we make reconstructions of displacement across six alluvial fans whose surfaces cross the fault, in four separate river catchments. We determine the ages of these fans using infra‐red‐stimulated luminescence dating combined with U‐series dating of pedogenic carbonates. The six fans vary in age from ∼10– to 100 kyr, and a regression line fitted to four of these yields a slip rate of 2.5 ± 0.3 mm/yr. We conclude that within the uncertainty of our measurements, the slip rate has remained constant over the last ∼100 ka and is representative of the strain accumulation at the present‐day. The slip rate that we measure is consistent with the E‐W left‐lateral Doruneh fault accommodating N‐S right‐lateral faulting by “bookshelf” faulting, with clockwise rotation about a vertical axis.
Inheritance of Penetrative Basement Anisotropies by Extension‐Oblique Faults: Insights From Analogue Experiments
Authors: Samsu Anindita , Cruden Alexander R. , Molnar Nicolas E. , Weinberg Roberto F.
Published: April 2021

During rifting, pre‐existing penetrative basement fabrics can affect new faults in cover rocks by a mechanism that does not appear to involve reactivation. This subtle form of inheritance can significantly impact fault network architecture in rift basins above laterally variable basement domains with geomechanical anisotropies. Here we use multi‐layer, brittle‐ductile, crustal‐scale analogue experiments to study the influence of penetrative basement anisotropies on fault patterns in the overlying cover during a single phase of orthogonal rifting. The experiments were designed to test whether basement anisotropies, oriented 45° to the extension direction, can lead to the formation of rift faults that are oblique to both the imposed extension direction and basement anisotropies. Our experiments show that a penetrative, vertically layered, mm‐wide basement anisotropy creates extension‐oblique faults in the overlying cover. We interpret this to arise when local strike‐slip kinematics along the interfaces of mechanically contrasting materials in the basement combine with the regional imposed orthogonal extension, creating a transtensional regime. The width and spacing of alternating “strong” and “weak” basement zones interact with rift kinematics, impacting the orientation, kinematics and spacing of new faults in the cover. New insights on the influence of penetrative, pre‐existing basement fabrics on localized re‐orientation of 3D strain in the cover have implications for understanding complex fault systems in rift basins and transfer zones.
Exploration and Visualization of Patterns Underlying Multistakeholder Preferences in Watershed Conservation Decisions Generated by an Interactive Genetic Algorithm
Authors: Piemonti Adriana Debora , Guizani Mariam , Babbar‐Sebens Meghna , Zhang Eugene , Mukhopadhyay Snehasis
Published: April 2021

In multiple watershed planning and design problems, such as conservation planning, quantitative estimates of costs, and environmental benefits of proposed conservation decisions may not be the only criteria that influence stakeholders' preferences for those decisions. Their preferences may also be influenced by the conservation decision itself—specifically, the type of practice, where it is being proposed, existing biases, and previous experiences with the practice. While human‐in‐the‐loop type search techniques, such as Interactive Genetic Algorithms (IGA), provide opportunities for stakeholders to incorporate their preferences in the design of alternatives, examination of user‐preferred conservation design alternatives for patterns in Decision Space can provide insights into which local decisions have higher or lower agreement among stakeholders. In this paper, we explore and compare spatial patterns in conservation decisions (specifically involving cover crops and filter strips) within design alternatives generated by IGA and noninteractive GA. Methods for comparing patterns include nonvisual as well as visualization approaches, including a novel visual analytics technique. Results for the study site show that user‐preferred designs generated by all participants had strong bias for cover crops in a majority (50%–83%) of the subbasins. Further, exploration with heat maps visualization indicate that IGA‐based search yielded very different spatial patterns of user‐preferred decisions in subbasins in comparison to decisions within design alternatives that were generated without the human‐in‐the‐loop. Finally, the proposed coincident‐nodes, multiedge graph visualization was helpful in visualizing disagreement among participants in local subbasin scale decisions, and for visualizing spatial patterns in local subbasin scale costs and benefits.
Rare Wintertime Thunderstorms Recorded over the U.S. Gulf Coast
Authors: Kornei Katherine
Published: April 2021

“Thundersnow”—thunderstorm activity accompanying a winter storm—was spotted near southern Texas earlier this year.
Preadult polytoxicomania—strong environmental underpinnings and first genetic hints
Authors: Steixner-Kumar Agnes A. , Daguano Gastaldi Vinicius , Seidel Jan , Rosenberger Albert , Begemann Martin , Ehrenreich Hannelore
Published: April 2021

Considering the immense societal and personal costs and suffering associated with multiple drug use or “polytoxicomania”, better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p  = 1.5 × 10−45; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10−33) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10−24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS–PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.
Lithium: a potential therapeutic strategy in obsessive–compulsive disorder by targeting the canonical WNT/β pathway
Authors: Vallée Alexandre , Vallée Jean-Noël , Lecarpentier Yves
Published: April 2021

Obsessive–compulsive disorder (OCD) is a neuropsychiatric disorder characterized b–y recurrent and distinctive obsessions and/or compulsions. The etiologies remain unclear. Recent findings have shown that oxidative stress, inflammation, and the glutamatergic pathway play key roles in the causes of OCD. However, first-line therapies include cognitive–behavioral therapy but only 40% of the patients respond to this first-line therapy. Research for a new treatment is mandatory. This review focuses on the potential effects of lithium, as a potential therapeutic strategy, on OCD and some of the presumed mechanisms by which lithium provides its benefit properties. Lithium medication downregulates GSK-3β, the main inhibitor of the WNT/β-catenin pathway. The activation of the WNT/β-catenin could be associated with the control of oxidative stress, inflammation, and glutamatergic pathway. Future prospective clinical trials could focus on lithium and its different and multiple interactions in OCD.
The effect of geriatric intervention in frail older patients receiving chemotherapy for colorectal cancer: a randomised trial (GERICO)
Authors: Lund Cecilia Margareta , Vistisen Kirsten Kjeldgaard , Olsen Anne Pries , Bardal Pernille , Schultz Martin , Dolin Troels Gammeltoft , Rønholt Finn , Johansen Julia Sidenius , Nielsen Dorte Lisbeth
Published: April 2021

Background

Older patients with colorectal cancer (CRC) experience chemotherapy dose reductions or discontinuation. Comprehensive geriatric assessment (CGA) predicts survival and chemotherapy completion in patients with cancer, but the benefit of geriatric interventions remains unexplored.

Methods

The GERICO study is a randomised Phase 3 trial including patients ≥70 years receiving adjuvant or first-line palliative chemotherapy for CRC. Vulnerable patients (G8 questionnaire ≤14 points) were randomised 1:1 to CGA-based interventions or standard care, along with guideline-based chemotherapy. The primary outcome was chemotherapy completion without dose reductions or delays. Secondary outcomes were toxicity, survival and quality of life (QoL).

Results

Of 142 patients, 58% received adjuvant and 42% received first-line palliative chemotherapy. Interventions included medication changes (62%), nutritional therapy (51%) and physiotherapy (39%). More interventional patients completed scheduled chemotherapy compared with controls (45% vs. 28%, P = 0.0366). Severe toxicity occurred in 39% of controls and 28% of interventional patients (P = 0.156). QoL improved in interventional patients compared with controls with the decreased burden of illness (P = 0.048) and improved mobility (P = 0.008).

Conclusion

Geriatric interventions compared with standard care increased the number of older, vulnerable patients with CRC completing adjuvant chemotherapy, and may improve the burden of illness and mobility.

Trial registration

ClinicalTrials.gov ID: NCT 02748811.
NDUFA4L2 promotes glioblastoma progression, is associated with poor survival, and can be effectively targeted by apatinib
Authors: Chen Zheng , Wei Xiangyu , Wang Xueyi , Zheng Xuan , Chang Bowen , Shen Lin , Zhu Hanshuo , Yang Min , Li Shiting , Zheng Xuesheng
Published: April 2021

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) is a subunit of Complex I of the mitochondrial respiratory chain, which is important in metabolic reprogramming and oxidative stress in multiple cancers. However, the biological role and molecular regulation of NDUFA4L2 in glioblastoma (GBM) are poorly understood. Here, we found that NDUFA4L2 was significantly upregulated in GBM; the elevated levels were correlated with reduced patient survival. Gene knockdown of NDUFA4L2 inhibited tumor cell proliferation and enhanced apoptosis, while tumor cells initiated protective mitophagy in vitro and in vivo. We used lentivirus to reduce expression levels of NDUFA4L2 protein in GBM cells exposed to mitophagy blockers, which led to a significant enhancement of tumor cell apoptosis in vitro and inhibited the development of xenografted tumors in vivo. In contrast to other tumor types, NDUFA4L2 expression in GBM may not be directly regulated by hypoxia-inducible factor (HIF)-1α, because HIF-1α inhibitors failed to inhibit NDUFA4L2 in GBM. Apatinib was able to effectively target NDUFA4L2 in GBM, presenting an alternative to the use of lentiviruses, which currently cannot be used in humans. Taken together, our data suggest the use of NDUFA4L2 as a potential therapeutic target in GBM and demonstrate a practical treatment approach.
Fangchinoline suppresses conjunctival melanoma by directly binding FUBP2 and inhibiting the homologous recombination pathway
Authors: Bao Keting , Li Yongyun , Wei Jinlian , Li Ruoxi , Yang Jie , Shi Jiahao , Li Baoli , Zhu Jin , Mao Fei , Jia Renbing , Li Jian
Published: April 2021

Conjunctival melanoma (CM) is a rare and fatal ocular tumour with poor prognosis. There is an urgent need of effective therapeutic drugs against CM. Here, we reported the discovery of a novel potential therapeutic target for CM. Through phenotypic screening of our in-house library, fangchinoline was discovered to significantly inhibit the growth of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1. Further mechanistic experiments indicated that fangchinoline suppressed the homologous recombination (HR)-directed DNA repair by binding with far upstream element binding protein 2 (FUBP2) and downregulating the expression of HR factors BRCA1 and RAD51. In vitro and in vivo antitumour experiments revealed that fangchinoline increased the efficacy of cisplatin by blocking HR factors and reduced the drug dose and toxicity. In conclusion, our work provides a promising therapeutic strategy for the treatment of CM that is worthy of extensive preclinical investigation.
The chromosome-level Hemerocallis citrina Borani genome provides new insights into the rutin biosynthesis and the lack of colchicine
Authors: Qing Zhixing , Liu Jinghong , Yi Xinxin , Liu Xiubin , Hu Guoan , Lao Jia , He Wei , Yang Zihui , Zou Xiaoyan , Sun Mengshan , Huang Peng , Zeng Jianguo
Published: April 2021

Hemerocallis citrina Borani (huang hua cai in Chinese) is an important horticultural crop whose flower buds are widely consumed as a delicious vegetable in Asia. Here we assembled a high-quality reference genome of H. citrina using single-molecule sequencing and Hi-C technologies. The genome assembly was 3.77 Gb and consisted of 3183 contigs with a contig N50 of 2.09 Mb, which were further clustered into 11 pseudochromosomes. A larger portion (3.25 Gb or 86.20%) was annotated as a repetitive content and 54,295 protein-coding genes were annotated in the genome. Genome evolution analysis showed that H. citrina experienced a recent whole-genome duplication (WGD) event at ~15.73 million years ago (Mya), which was the main factor leading to many multiple copies of orthologous genes. We used this reference genome to predict 20 genes involved in the rutin biosynthesis pathway. Moreover, our metabolomics data revealed neither colchicine nor its precursors in H. citrina, challenging the long-standing belief that this alkaloid causes poisoning by the plant. The results of our disruptive research are further substantiated by our genomic finding that H. citrina does not contain any genes involved in colchicine biosynthesis. The high-quality genome lays a solid foundation for genetic research and molecular breeding of H. citrina.
VESPER: global and local cryo-EM map alignment using local density vectors
Authors: Han Xusi , Terashi Genki , Christoffer Charles , Chen Siyang , Kihara Daisuke
Published: April 2021

An increasing number of density maps of biological macromolecules have been determined by cryo-electron microscopy (cryo-EM) and stored in the public database, EMDB. To interpret the structural information contained in EM density maps, alignment of maps is an essential step for structure modeling, comparison of maps, and for database search. Here, we developed VESPER, which captures the similarity of underlying molecular structures embedded in density maps by taking local gradient directions into consideration. Compared to existing methods, VESPER achieved substantially more accurate global and local alignment of maps as well as database retrieval.
Cryo-EM structure of the human histamine H1 receptor/Gq complex
Authors: Xia Ruixue , Wang Na , Xu Zhenmei , Lu Yang , Song Jing , Zhang Anqi , Guo Changyou , He Yuanzheng
Published: April 2021

Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human H1R in complex with a Gq protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for Gq engagement in a model of “squash to activate and expand to deactivate”. The structure also reveals features for Gq coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of Gq/11 protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.
Intracellular trafficking of Notch orchestrates temporal dynamics of Notch activity in the fly brain
Authors: Wang Miaoxing , Han Xujun , Liu Chuyan , Takayama Rie , Yasugi Tetsuo , Ei Shin-Ichiro , Nagayama Masaharu , Tanaka Yoshitaro , Sato Makoto
Published: April 2021

While Delta non-autonomously activates Notch in neighboring cells, it autonomously inactivates Notch through cis-inhibition, the molecular mechanism and biological roles of which remain elusive. The wave of differentiation in the Drosophila brain, the ‘proneural wave’, is an excellent model for studying Notch signaling in vivo. Here, we show that strong nonlinearity in cis-inhibition reproduces the second peak of Notch activity behind the proneural wave in silico. Based on this, we demonstrate that Delta expression induces a quick degradation of Notch in late endosomes and the formation of the twin peaks of Notch activity in vivo. Indeed, the amount of Notch is upregulated and the twin peaks are fused forming a single peak when the function of Delta or late endosomes is compromised. Additionally, we show that the second Notch peak behind the wavefront controls neurogenesis. Thus, intracellular trafficking of Notch orchestrates the temporal dynamics of Notch activity and the temporal patterning of neurogenesis.
Publisher Correction: Topological optical differentiator
Authors: Zhu Tengfeng , Guo Cheng , Huang Junyi , Wang Haiwen , Orenstein Meir , Ruan Zhichao , Fan Shanhui
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22493-6
The NIH Somatic Cell Genome Editing program
Authors:   The SCGE Consortium, Saha Krishanu , Sontheimer Erik J. , Brooks P. J. , Dwinell Melinda R. , Gersbach Charles A. , Liu David R. , Murray Stephen A. , Tsai Shengdar Q. , Wilson Ross C. , Anderson Daniel G. , Asokan Aravind , Banfield Jillian F. , Bankiewicz Krystof S. , Bao Gang , Bulte Jeff W. M. , Bursac Nenad , Campbell Jarryd M. , Carlson Daniel F. , Chaikof Elliot L. , Chen Zheng-Yi , Cheng R. Holland , Clark Karl J. , Curiel David T. , Dahlman James E. , Deverman Benjamin E. , Dickinson Mary E. , Doudna Jennifer A. , Ekker Stephen C. , Emborg Marina E. , Feng Guoping , Freedman Benjamin S. , Gamm David M. , Gao Guangping , Ghiran Ionita C. , Glazer Peter M. , Gong Shaoqin , Heaney Jason D. , Hennebold Jon D. , Hinson John T. , Khvorova Anastasia , Kiani Samira , Lagor William R. , Lam Kit S. , Leong Kam W. , Levine Jon E. , Lewis Jennifer A. , Lutz Cathleen M. , Ly Danith H. , Maragh Samantha , McCray Paul B. , McDevitt Todd C. , Mirochnitchenko Oleg , Morizane Ryuji , Murthy Niren , Prather Randall S. , Ronald John A. , Roy Subhojit , Roy Sushmita , Sabbisetti Venkata , Saltzman W. Mark , Santangelo Philip J. , Segal David J. , Shimoyama Mary , Skala Melissa C. , Tarantal Alice F. , Tilton John C. , Truskey George A. , Vandsburger Moriel , Watts Jonathan K. , Wells Kevin D. , Wolfe Scot A. , Xu Qiaobing , Xue Wen , Yi Guohua , Zhou Jiangbing
Published: April 2021

The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tissues that are difficult to reach. Here we discuss the consortium’s plans to develop and benchmark approaches to induce and measure genome modifications, and to define downstream functional consequences of genome editing within human cells. Central to this effort is a rigorous and innovative approach that requires validation of the technology through third-party testing in small and large animals. New genome editors, delivery technologies and methods for tracking edited cells in vivo, as well as newly developed animal models and human biological systems, will be assembled—along with validated datasets—into an SCGE Toolkit, which will be disseminated widely to the biomedical research community. We visualize this toolkit—and the knowledge generated by its applications—as a means to accelerate the clinical development of new therapies for a wide range of conditions.
Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry
Authors: Hajdinjak Mateja , Mafessoni Fabrizio , Skov Laurits , Vernot Benjamin , Hübner Alexander , Fu Qiaomei , Essel Elena , Nagel Sarah , Nickel Birgit , Richter Julia , Moldovan Oana Teodora , Constantin Silviu , Endarova Elena , Zahariev Nikolay , Spasov Rosen , Welker Frido , Smith Geoff M. , Sinet-Mathiot Virginie , Paskulin Lindsey , Fewlass Helen , Talamo Sahra , Rezek Zeljko , Sirakova Svoboda , Sirakov Nikolay , McPherron Shannon P. , Tsanova Tsenka , Hublin Jean-Jacques , Peter Benjamin M. , Meyer Matthias , Skoglund Pontus , Kelso Janet , Pääbo Svante
Published: April 2021

Modern humans appeared in Europe by at least 45,000 years ago1–5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.
Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and 18F-FMISO PET
Authors: Huang Shiliang , Michalek Joel E. , Reardon David A. , Wen Patrick Y. , Floyd John R. , Fox Peter T. , Clarke Geoffrey D. , Jerabek Paul A. , Schmainda Kathleen M. , Muzi Mark , Hyun Hyewon , Lee Eudocia Quant , Brenner Andrew J.
Published: April 2021

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and 18F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and 18F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (rs = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (rs = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
Phylogeography and morphological evolution of Pseudechiniscus (Heterotardigrada: Echiniscidae)
Authors: Gąsiorek Piotr , Vončina Katarzyna , Zając Krzysztof , Michalczyk Łukasz
Published: April 2021

Tardigrades constitute a micrometazoan phylum usually considered as taxonomically challenging and therefore difficult for biogeographic analyses. The genus Pseudechiniscus, the second most speciose member of the family Echiniscidae, is commonly regarded as a particularly difficult taxon for studying due to its rarity and homogenous sculpturing of the dorsal plates. Recently, wide geographic ranges for some representatives of this genus and a new hypothesis on the subgeneric classification have been suggested. In order to test these hypotheses, we sequenced 65 Pseudechiniscus populations extracted from samples collected in 19 countries distributed on 5 continents, representing the Neotropical, Afrotropical, Holarctic, and Oriental realms. The deep subdivision of the genus into the cosmopolitan suillus-facettalis clade and the mostly tropical-Gondwanan novaezeelandiae clade is demonstrated. Meridioniscus subgen. nov. is erected to accommodate the species belonging to the novaezeelandiae lineage characterised by dactyloid cephalic papillae that are typical for the great majority of echiniscids (in contrast to pseudohemispherical papillae in the suillus-facettalis clade, corresponding to the subgenus Pseudechiniscus). Moreover, the evolution of morphological traits (striae between dorsal pillars, projections on the pseudosegmental plate IV’, ventral sculpturing pattern) crucial in the Pseudechiniscus taxonomy is reconstructed. Furthermore, broad distributions are emphasised as characteristic of some taxa. Finally, the Malay Archipelago and Indochina are argued to be the place of origin and extensive radiation of Pseudechiniscus.
Drastic improvement of Curie temperature by chemical pressure in N-type diluted magnetic semiconductor Ba(Zn,Co)$$_{2}$$As$$_{2}$$
Authors: Fu Licheng , Gu Yilun , Zhi Guoxiang , Zhang Haojie , Zhang Rufei , Dong Jinou , Zhao Xueqin , Xie Lingfeng , Ning Fanlong
Published: April 2021

We report the effect of chemical pressure on the ferromagnetic ordering of the recently reported n-type diluted magnetic semiconductor Ba(Zn$$_{1-x}$$

1
-
x

Co$$_{x}$$

x

)$$_{2}$$

2

As$$_{2}$$

2

which has a maximum $$T_C$$

T
C

$$\sim$$
∼
45 K. Doping Sb into As-site and Sr into Ba-site induces negative and positive chemical pressure, respectively. While conserving the tetragonal crystal structure and n-type carriers, the unit cell volume shrink by $$\sim$$
∼
0.3$$\%$$
%
with 15$$\%$$
%
Sr doping, but drastically increase the ferromagnetic transition temperature by 18$$\%$$
%
to 53 K. Our experiment unequivocally demonstrate that the parameters of Zn(Co)As$$_{4}$$

4

tetrahedra play a vital role in the formation of ferromagnetic ordering in the Ba(Zn,Co)$$_{2}$$

2

As$$_{2}$$

2

DMS.
Cooperation in spatial public good games depends on the locality effects of game, adaptation, and punishment
Authors: Okada Isamu , Yamamoto Hitoshi , Akiyama Eizo , Toriumi Fujio
Published: April 2021

Despite intensive studies on the evolution of cooperation in spatial public goods games, there have been few investigations into locality effects in interaction games, adaptation, and punishment. Here we analyze locality effects using an agent-based model of a regular graph. Our simulation shows that a situation containing a local game, local punishment, and global adaptation leads to the most robustly cooperative regime. Further, we show an interesting feature in local punishment. Previous studies showed that a local game and global adaptation are likely to generate cooperation. However, they did not consider punishment. We show that if local punishment is introduced in spatial public goods games, a situation satisfying either local game or local adaptation is likely to generate cooperation. We thus propose two principles. One is if interactions in games can be restricted locally, it is likely to generate cooperation independent of the interaction situations on punishment and adaptation. The other is if the games must be played globally, a cooperative regime requires both local punishment and local adaptation.
Methods for tuning plasmonic and photonic optical resonances in high surface area porous electrodes
Authors: Otto Lauren M. , Gaulding E. Ashley , Chen Christopher T. , Kuykendall Tevye R. , Hammack Aeron T. , Toma Francesca M. , Ogletree D. Frank , Aloni Shaul , Stadler Bethanie J. H. , Schwartzberg Adam M.
Published: April 2021

Surface plasmons have found a wide range of applications in plasmonic and nanophotonic devices. The combination of plasmonics with three-dimensional photonic crystals has enormous potential for the efficient localization of light in high surface area photoelectrodes. However, the metals traditionally used for plasmonics are difficult to form into three-dimensional periodic structures and have limited optical penetration depth at operational frequencies, which limits their use in nanofabricated photonic crystal devices. The recent decade has seen an expansion of the plasmonic material portfolio into conducting ceramics, driven by their potential for improved stability, and their conformal growth via atomic layer deposition has been established. In this work, we have created three-dimensional photonic crystals with an ultrathin plasmonic titanium nitride coating that preserves photonic activity. Plasmonic titanium nitride enhances optical fields within the photonic electrode while maintaining sufficient light penetration. Additionally, we show that post-growth annealing can tune the plasmonic resonance of titanium nitride to overlap with the photonic resonance, potentially enabling coupled-phenomena applications for these three-dimensional nanophotonic systems. Through characterization of the tuning knobs of bead size, deposition temperature and cycle count, and annealing conditions, we can create an electrically- and plasmonically-active photonic crystal as-desired for a particular application of choice.
Evaluation of practical experiences of German speaking radiation oncologists in combining radiation therapy with checkpoint blockade
Authors: Kraus Kim M. , Fischer Julius C. , Borm Kai J. , Vogel Marco M. E. , Pigorsch Steffi. U. , Devečka Michal , Combs Stephanie E.
Published: April 2021

The results of this survey reveal current clinical practice in the handling of combined radioimmunotherapy with Immune Checkpoint Inhibitors (RT + ICI). We aim to provide a basis to open a discussion for clinical application of RT + ICI by analyzation of experts’ assessment. We conducted a survey with 24 items with a focus on side effects of RT + ICI, common practice of scheduling and handling of adverse events. After pilot testing by radiation oncology experts the link to the online survey was sent to all members of the German Society of Radiation Oncology (DEGRO). In total, 51 radiation oncologists completed the questionnaire. Pulmonary toxicity under RT + ICI with ICIs was reported most frequently. Consensus was observed for bone and soft tissue RT of the limbs in favor for no interruption of ICIs. For cranial RT half of the participants do not suspend ICIs during normofractionated radiotherapy (nfRT) or stereotactic hypofractionated RT (SRT). More participants pause ICIs for central than for peripheral thoracic region. Maintenance therapy with ICIs is mostly not interrupted prior to RT. For management of RT associated pneumonitis under durvalumab the majority of 86.3% suggest corticosteroid therapy and 76.5% would postpone the next cycle of ICI therapy. The here obtained assessment and experiences by radiation oncologists reveal a large variability in practical handling of combined RT + ICI. Until scientific evidence is available a discussion for current clinical application of RT + ICI should be triggered. Interdisciplinary consensus guidelines with practical recommendations are required.
Electron transfer studies of a conventional redox probe in human sweat and saliva bio-mimicking conditions
Authors: Krishnaveni P. , Ganesh V.
Published: April 2021

Modern day hospital treatments aim at developing electrochemical biosensors for early diagnosis of diseases using unconventional human bio-fluids like sweat and saliva by monitoring the electron transfer reactions of target analytes. Such kinds of health care diagnostics primarily avoid the usage of human blood and urine samples. In this context, here we have investigated the electron transfer reaction of a well-known and commonly used redox probe namely, potassium ferro/ferri cyanide by employing artificially simulated bio-mimics of human sweat and saliva as unconventional electrolytes. Typically, electron transfer characteristics of the redox couple, [Fe(CN)6]3−/4− are investigated using electrochemical techniques like cyclic voltammetry and electrochemical impedance spectroscopy. Many different kinetic parameters are determined and compared with the conventional system. In addition, such electron transfer reactions have also been studied using a lyotropic liquid crystalline phase comprising of Triton X-100 and water in which the aqueous phase is replaced with either human sweat or saliva bio-mimics. From these studies, we find out the electron transfer reaction of [Fe(CN)6]3−/4− redox couple is completely diffusion controlled on both Au and Pt disc shaped electrodes in presence of sweat and saliva bio-mimic solutions. Moreover, the reaction is partially blocked by the presence of lyotropic liquid crystalline phase consisting of sweat and saliva bio-mimics indicating the predominant charge transfer controlled process for the redox probe. However, the rate constant values associated with the electron transfer reaction are drastically reduced in presence of liquid crystalline phase. These studies are essentially carried out to assess the effect of sweat and saliva on the electrochemistry of Fe2+/3+ redox couple.
Extracellular vesicles isolated from milk can improve gut barrier dysfunction induced by malnutrition
Authors: Maghraby Mohamed Karim , Li Bo , Chi Lijun , Ling Catriona , Benmoussa Abderrahim , Provost Patrick , Postmus Andrea C. , Abdi Abdirahman , Pierro Agostino , Bourdon Celine , Bandsma Robert H. J.
Published: April 2021

Malnutrition impacts approximately 50 million children worldwide and is linked to 45% of global mortality in children below the age of five. Severe acute malnutrition (SAM) is associated with intestinal barrier breakdown and epithelial atrophy. Extracellular vesicles including exosomes (EVs; 30–150 nm) can travel to distant target cells through biofluids including milk. Since milk-derived EVs are known to induce intestinal stem cell proliferation, this study aimed to examine their potential efficacy in improving malnutrition-induced atrophy of intestinal mucosa and barrier dysfunction. Mice were fed either a control (18%) or a low protein (1%) diet for 14 days to induce malnutrition. From day 10 to 14, they received either bovine milk EVs or control gavage and were sacrificed on day 15, 4 h after a Fluorescein Isothiocyanate (FITC) dose. Tissue and blood were collected for histological and epithelial barrier function analyses. Mice fed low protein diet developed intestinal villus atrophy and barrier dysfunction. Despite continued low protein diet feeding, milk EV treatment improved intestinal permeability, intestinal architecture and cellular proliferation. Our results suggest that EVs enriched from milk should be further explored as a valuable adjuvant therapy to standard clinical management of malnourished children with high risk of morbidity and mortality.