bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictive equations for estimating resting energy expenditure in women with overweight and obesity at three postpartum stages
Authors: Halland Nesse Siri , Ottestad Inger , Winkvist Anna , Bertz Fredrik , Ellegård Lars , Brekke Hilde K.
Published: August 2020

The objective was to investigate which predictive equations provide the best estimates of resting energy expenditure (REE) in postpartum women with overweight and obesity. Lactating women with overweight or obesity underwent REE measurement by indirect calorimetry, and fat-free mass (FFM) was assessed by dual-energy X-ray absorptiometry at three postpartum stages. Predictive equations based on body weight and FFM were obtained from the literature. Performance of the predictive equations were analysed as the percentage of women whose REE was accurately predicted, defined as a predicted REE within ±10 % of measured REE. REE data were available for women at 10 weeks (n 71), 24 weeks (n 64) and 15 months (n 57) postpartum. Thirty-six predictive equations (twenty-five weight-based and eleven FFM-based) were validated. REE was accurately predicted in ≥80 % of women at all postpartum visits by six predictive equations (two weight-based and four FFM-based). The weight-based equation with the highest performance was that of Henry (weight, height, age 30–60 years) (HenryWH30−60), with an overall mean of 83 % accurate predictions. The HenryWH30−60 equation was highly suitable for predicting REE at all postpartum visits (irrespective of the women's actual age), and the performance was sustained across changes in weight and lactation status. No FFM-based equation was remarkably superior to HenryWH30−60 for the total postpartum period.
“Our Sisters in China Are Free”: Visual Representations of Chinese and Chinese American Suffragists
Authors: Cahill Cathleen D.
Published: August 2020

Both white and Chinese American suffragists in the United States closely watched and discussed the events of the Chinese Revolution of 1911 and the establishment of the Chinese Republic (1912–1949). They were aware of the republican revolutionaries’ support for women's rights, which conflicted with American stereotypes of China as a backward nation, especially in its treatment of women. Chinese suffragists, real and imagined, became a major talking point in debates over women's voting rights in the United States as white suffragists and national newspapers championed their stories. This led to prominent visual depictions of Chinese suffragists in the press, but also their participation in public events such as suffrage parades. For a brief time, the transnational nature of suffrage conversations was highly visible as was the suffrage activism of women in U.S. Chinese communities. However, because Chinese immigrants were barred from citizenship by U.S. immigration law, white activists tended to depict Chinese suffragists as foreign, resulting in the erasure of their memory in the U.S. suffrage movement.
The Ostroms and the contestable nature of goods: beyond taxonomies and toward institutional polycentricity
Authors: Rayamajhee Veeshan , Paniagua Pablo
Published: August 2020

This paper builds on the Ostroms' oeuvre to suggest that the binary Samuelsonian taxonomy of goods – or the ‘sterile dichotomy’, as Elinor Ostrom calls it – cannot serve as a reliable guide for public policy. Using the Ostroms' insights on co-production, institutional matching, and polycentricity, we argue that the ‘inherent’ nature of goods and their specific taxonomy are not static and definitive concepts but are instead contestable and dynamic features that are institutionally contingent. We explore four crucial mechanisms and/or contexts, not altogether unrelated, whereby the nature of goods becomes contestable and malleable: namely, (1) technological and geographical factors, (2) coproduction and entrepreneurial ingenuity, (3) bundling and unbundling of services, and (4) ideologies and regime shifts. This exercise has twofold purposes. First, we generalize the notion that there is nothing ‘inherent’ in the nature of goods and services and that they are fluid, heterogeneous, and malleable concepts. Second, we contribute to the debate on the provision of public goods and the role of civil society by highlighting the need for institutional malleability and diversity adaptive to changing technology, contexts, and institutional conditions.
Gendered accountability: when and why do women’s policy priorities get implemented?
Authors: Mechkova Valeriya , Carlitz Ruth
Published: August 2020

Recent decades have seen a surge in women occupying positions of political power. This has been welcomed in part as a means of achieving better policy outcomes for women. We interrogate this proposition, developing a “gendered accountability” framework to explain when and how female representation promotes the implementation of policies that women prioritize. Our empirical analysis applies this framework to sub-Saharan Africa, home to the largest recent expansion in women’s political representation. We find that increased female representation in the legislature is robustly associated with reduced infant and child mortality as well as greater spending on health. Effects are magnified when women are more active in civil society and appear primarily in countries that have gender quotas and proportional electoral systems. Thus, while female representation can lead to improved policy outcomes for women, the process is not automatic and is unlikely to occur absent key institutional and societal conditions.
Controls on Dissolved Silicon Isotopes Along the U.S. GEOTRACES Eastern Pacific Zonal Transect (GP16)
Authors: Grasse P. , Closset I. , Jones J. L. , Geilert S. , Brzezinski M. A.
Published: August 2020

The distribution of dissolved silicon isotopes (δ30Si) was examined along the U.S. GEOTRACES East Pacific Zonal Transect (GP16) extending from Peru to Tahiti (10°S and 15°S latitude). Surface waters in the subtropical gyre displayed high δ30Si due to strong utilization of silicic acid (DSi). In contrast, surface waters close to the Peruvian coast where upwelling prevailed were less depleted and only moderately fractionated. δ30Si of water masses along the transect was compared with the results of an Optimum Multiparameter Analysis that quantified the fractional contributions of end‐member water masses in each sample. Strong admixture of intermediate waters obscured the expected heavy isotopic signatures of Subantarctic Mode Water and Antarctic Intermediate Water. Isotope values were nearly homogenous below 2,000 m (average: +1.3 ± 0.1‰, 1 s.d.) despite the 25 μmol kg−1 range in the DSi content among water masses. This homogeneity confirms prior observations and model results that predict nearly constant δ30Si values of +1.0‰ to +1.2‰ for Pacific deep waters with [DSi] > 100 μmol kg−1. Waters above the East Pacific Rise (EPR) influenced by hydrothermal activity showed a small increase in [DSi] together with dissolved iron, but overall stations close to the EPR were slightly depleted in [DSi] (3 to 6 μmol kg−1) with no significant shift in δ30Si compared to adjacent waters. Hydrothermal [DSi] appears to precipitate within the conduit of the EPR or upon contact with cold seawater resulting in a negligible influence of hydrothermal fluids on δ30Si in deep water.
Variations in Nightside Magnetic Field Topology at Mars
Authors: Brain D. A. , Weber T. , Xu S. , Mitchell D. L. , Lillis R. J. , Halekas J. S. , Espley J. , Jakosky B. M.
Published: August 2020

The Martian plasma environment contains a complex magnetic topology, with contributions from the interplanetary magnetic field (IMF) and crustal magnetic fields. The topology can control how plasma is exchanged between the solar wind and the Martian ionosphere. Here we use 7 years of suprathermal electron pitch angle distributions recorded by the Mars Global Surveyor (MGS) spacecraft to determine the topology at 2 am and 400 km on the Martian nightside as a function of geographic location and external drivers. Observations show that topology statistically varies with IMF direction, solar wind pressure, solar extreme ultraviolet (EUV) flux, and season. Changes in topology with IMF direction and season are consistent with changes in the likelihood of magnetic reconnection between individual crustal fields and the draped IMF. Changes in topology at a given location with solar wind pressure and solar EUV flux are consistent with reconfiguration of topological structures in the plasma environment.
Abrupt Freshening Since the Early Little Ice Age in Lake Sayram of Arid Central Asia Inferred From an Alkenone Isomer Proxy
Authors: Yao Yuan , Lan Jianghu , Zhao Jiaju , Vachula Richard S. , Xu Hai , Cai Yanjun , Cheng Hai , Huang Yongsong
Published: August 2020

Hydroclimatic variations of arid central Asia (ACA) significantly impact regional ecosystems and human civilizations. Here we present a lake water salinity record of the last 3,000 years from Lake Sayram in the core area of ACA using a new alkenone isomer‐based RIK37 index. Our record shows an abrupt decrease in salinity by more than 5‰ since the “early” Little Ice Age (LIA) (about CE 1150), which can be attributed to the combined effect of regional wetting, cooling, and topographic features. Combined with other moisture records in the region, we find two periods of relatively wet conditions during CE 1150–1550 and 1850 to present, which may be linked to Arctic sea ice expansion due to natural variability and, from CE 1950, anthropogenically induced warming. The wet conditions during CE 1206–1260 may have favored the spread of the Mongol Empire across the entire core area of ACA.
Internal Structure and Hydrothermal Fluid Circulation of Parícutin Volcano, Mexico: Insights Gained From Near‐Surface Geophysics
Authors: Bolós Xavier , Delgado‐Torres Alexander , Cifuentes Gerardo , Macías José Luis , Boijseauneau‐López Mario , Tinoco Claudio , Salguero David
Published: August 2020

Numerous investigations of Parícutin volcano have been made since its formation during 1943–1952, but none has utilized geophysical techniques until now. This report summarizes the results of near‐surface geophysical surveys conducted during 2017–2019, involving self‐potential, ground‐temperature measurements, and a 3D resistivity model of the scoria cone. Interpretation of the integrated data enabled the definition of the geometry of the eruption's feeder dyke and a better understanding of the near‐surface spatter facies. These geophysical data also better characterized the buried morphology of a horseshoe‐shaped crater produced by a cone collapse early in the eruption, as well as the contact between lava flows and overlying pyroclastic fallout deposits. Moreover, the measured conductivities detected several meter‐scale zones of convective hydrothermal fluid circulation within the cone. Collectively, the data of this study demonstrate a powerful approach to discern the relationship between the internal structure of a monogenetic cone and its associated hydrothermal system.
Toward Near‐Field Tsunami Forecasting Along the Cascadia Subduction Zone Using Rapid GNSS Source Models
Authors: Williamson Amy L. , Melgar Diego , Crowell Brendan W. , Arcas Diego , Melbourne Timothy I. , Wei Yong , Kwong Kevin
Published: August 2020

Over the past 15 years and through multiple large and devastating earthquakes, tsunami warning systems have grown considerably in their efficacy in providing timely and accurate forecasts to affected communities. However, one part of tsunami warning that still needs improvement is forecasts catered to local, near‐field communities in the time after an earthquake rupture but before coastal inundation. In this study, we test a rapid, Global Navigation Satellite Systems (GNSS)‐driven earthquake characterization model using a large data set of synthetic megathrust ruptures for its near‐field tsunami forecasting potential. We also provide a framework for tsunami forecasting that focuses on the likelihood of exceedance of user‐defined coastal amplitudes that may be of use in the first 15 min following an earthquake. Specifically, we can estimate the earthquake magnitude, without saturation, for 82% of tested ruptures. We can also identify test ruptures as dominantly thrust events, without analyst guidance for 92% of tested thrust ruptures. Finally, modeling the tsunami component of our rapidly estimated fault rupture leads to greater than 80% accuracy in identifying tsunami impact at key coastal amplitude thresholds. This is promising for near‐field warning when the time prior to inundation is limited to tens of minutes. We focus this study on large megathrust ruptures along the quiescent Cascadia subduction zone where there is already a dense GNSS network.
Evaluation of Stratospheric Intrusions and Biomass Burning Plumes on the Vertical Distribution of Tropospheric Ozone Over the Midwestern United States
Authors: Wilkins J. L. , de Foy B. , Thompson A. M. , Peterson D. A. , Hyer E. J. , Graves C. , Fishman J. , Morris G. A.
Published: August 2020

Naturally occurring ozone‐rich stratosphere‐to‐troposphere transport (STT) intrusions and biomass burning (BB) plumes reaching the surface can contribute to exceedances of the U.S. National Ambient Air Quality Standards for ground‐level ozone (70 ppbv implemented in 2015). Additionally, fires can inject significant pollution into the free troposphere where it can be transported long distances. The combined air quality impacts from these sources on ozone have only been analyzed in a few case studies for the Midwest United States. Here we study ozone impacts in a Midwestern city, for the first time in St. Louis, Missouri, using a series of ozonesonde profiles taken during the Studies of Emissions and Atmospheric Composition, Clouds and Climate Coupling by Regional Surveys (SEAC4RS) field campaign in August–September 2013. All ozonesondes showed enhancements above the background profile levels (~55 ppbv) throughout each tropospheric column. Two models were used to estimate ozone origins in columns. A chemical transport model identified STT enhancements equivalent to 10 to 15 ppbv over the background with a 10% to 15% contribution overall to the column. Two FLEXPART‐WRF simulations, one with smoke in the boundary layer and another with smoke above, identified BB enhancements equivalent to 10 to 80 ppbv. Overall, the total BB contribution is 15% to 30% of the total column. Five ozonesondes showed signatures of mixed BB plumes and STT intrusions. During this study period, BB in the western United States contributed 70% to ozone enhancements in the total column compared to 3% from the central United States and 27% from other areas.
Snowfall and Water Stable Isotope Variability in East Antarctica Controlled by Warm Synoptic Events
Authors: Servettaz Aymeric P. M. , Orsi Anais J. , Curran Mark A. J. , Moy Andrew D. , Landais Amaelle , Agosta Cécile , Winton V. Holly L. , Touzeau Alexandra , McConnell Joseph R. , Werner Martin , Baroni Mélanie
Published: August 2020

Understanding climate proxy records that preserve physical characteristics of past climate is a prerequisite to reconstruct long‐term climatic conditions. Water stable isotope ratios (δ18O) constitute a widely used proxy in ice cores to reconstruct temperature and climate. However, the original climate signal is altered between the formation of precipitation and the ice, especially in low‐accumulation areas such as the East Antarctic Plateau. Atmospheric conditions under which the isotopic signal is acquired at Aurora Basin North (ABN), East Antarctica, are characterized with the regional atmospheric model Modèle Atmosphérique Régional (MAR). The model shows that 50% of the snow is accumulated in less than 24 days year−1. Snowfall occurs throughout the year and intensifies during winter, with 64% of total accumulation between April and September, leading to a cold bias of −0.86°C in temperatures above inversion compared to the annual mean of −29.7°C. Large snowfall events are associated with high‐pressure systems forcing warm oceanic air masses toward the Antarctic interior, which causes a warm bias of +2.83°C. The temperature‐δ18O relationship, assessed with the global atmospheric model ECHAM5‐wiso, is primarily constrained by the winter variability, but the observed slope is valid year‐round. Three snow δ18O records covering 2004–2014 indicate that the anomalies recorded in the ice core are attributable to the occurrence of warm winter storms bringing precipitation to ABN and support the interpretation of δ18O in this region as a marker of temperature changes related to large‐scale atmospheric conditions, particularly blocking events and variations in the Southern Annular Mode.
Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network
Authors: Gu Xiaorong , Tohme Rita , Tomlinson Benjamin , Sakre Nneha , Hasipek Metis , Durkin Lisa , Schuerger Caroline , Grabowski Dale , Zidan Asmaa M. , Radivoyevitch Tomas , Hong Changjin , Carraway Hetty , Hamilton Betty , Sobecks Ronald , Patel Bhumika , Jha Babal K. , Hsi Eric D. , Maciejewski Jaroslaw , Saunthararajah Yogen
Published: August 2020

Mechanisms-of-resistance to decitabine and 5-azacytidine, mainstay treatments for myeloid malignancies, require investigation and countermeasures. Both are nucleoside analog pro-drugs processed by pyrimidine metabolism into a deoxynucleotide analog that depletes the key epigenetic regulator DNA methyltranseferase 1 (DNMT1). Here, upon serial analyses of DNMT1 levels in patients’ bone marrows on-therapy, we found DNMT1 was not depleted at relapse. Showing why, bone marrows at relapse exhibited shifts in expression of key pyrimidine metabolism enzymes in directions adverse to pro-drug activation. Further investigation revealed the origin of these shifts. Pyrimidine metabolism is a network that senses and regulates deoxynucleotide amounts. Deoxynucleotide amounts were disturbed by single exposures to decitabine or 5-azacytidine, via off-target depletion of thymidylate synthase and ribonucleotide reductase respectively. Compensating pyrimidine metabolism shifts peaked 72–96 h later. Continuous pro-drug exposures stabilized these adaptive metabolic responses to thereby prevent DNMT1-depletion and permit exponential leukemia out-growth as soon as day 40. The consistency of the acute metabolic responses enabled exploitation: simple treatment modifications in xenotransplant models of chemorefractory leukemia extended noncytotoxic DNMT1-depletion and leukemia control by several months. In sum, resistance to decitabine and 5-azacytidine originates from adaptive responses of the pyrimidine metabolism network; these responses can be anticipated and thus exploited.
Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: outcomes by disease burden
Authors: DeAngelo Daniel J. , Advani Anjali S. , Marks David I. , Stelljes Matthias , Liedtke Michaela , Stock Wendy , Gökbuget Nicola , Jabbour Elias , Merchant Akil , Wang Tao , Vandendries Erik , Neuhof Alexander , Kantarjian Hagop , O’Brien Susan
Published: August 2020

Adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) have a poor prognosis, especially if disease burden is high. This post hoc analysis of the phase 3 INO-VATE trial examined the efficacy and safety of inotuzumab ozogamicin (InO) vs. standard of care chemotherapy (SC) among R/R ALL patients with low, moderate, or high disease burden, respectively, defined as bone marrow blasts (BMB) < 50% (n = 53 vs. 48), 50–90% (n = 79 vs. 83), and >90% (n = 30 vs. 30). Patients in the InO vs. SC arm with low, moderate, and high BMB%, respectively, had improved rates of complete remission/complete remission with incomplete hematologic recovery (74% vs. 46% [p = 0.0022], 75 vs. 27% [p < 0.0001], and 70 vs. 17% [p < 0.0001]), and improved overall survival (hazard ratio: 0.64 [p = 0.0260], 0.81 [p = 0.1109], and 0.60 [p = 0.0335]). Irrespective of BMB%, cytopenias were the most common treatment-emergent adverse events, and post-transplant veno-occlusive disease was more common with InO vs. SC. Patients with extramedullary disease or lymphoblastic lymphoma showed similar efficacy and safety outcomes. This favorable benefit-to-risk ratio of InO treatment irrespective of disease burden supports its use in challenging and high disease burden subpopulations. INO-VATE is registered at www.clinicaltrials.gov: #NCT01564784.
DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain
Authors: Zhang Jing , Bellani Marina A. , James Ryan C. , Pokharel Durga , Zhang Yongqing , Reynolds John J. , McNee Gavin S. , Jackson Andrew P. , Stewart Grant S. , Seidman Michael M.
Published: August 2020

Duplication of mammalian genomes requires replisomes to overcome numerous impediments during passage through open (eu) and condensed (hetero) chromatin. Typically, studies of replication stress characterize mixed populations of challenged and unchallenged replication forks, averaged across S phase, and model a single species of “stressed” replisome. Here, in cells containing potent obstacles to replication, we find two different lesion proximal replisomes. One is bound by the DONSON protein and is more frequent in early S phase, in regions marked by euchromatin. The other interacts with the FANCM DNA translocase, is more prominent in late S phase, and favors heterochromatin. The two forms can also be detected in unstressed cells. ChIP-seq of DNA associated with DONSON or FANCM confirms the bias of the former towards regions that replicate early and the skew of the latter towards regions that replicate late.
GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
Authors: Zhou Wei , Brumpton Ben , Kabil Omer , Gudmundsson Julius , Thorleifsson Gudmar , Weinstock Josh , Zawistowski Matthew , Nielsen Jonas B. , Chaker Layal , Medici Marco , Teumer Alexander , Naitza Silvia , Sanna Serena , Schultheiss Ulla T. , Cappola Anne , Karjalainen Juha , Kurki Mitja , Oneka Morgan , Taylor Peter , Fritsche Lars G. , Graham Sarah E. , Wolford Brooke N. , Overton William , Rasheed Humaira , Haug Eirin B. , Gabrielsen Maiken E. , Skogholt Anne Heidi , Surakka Ida , Davey Smith George , Pandit Anita , Roychowdhury Tanmoy , Hornsby Whitney E. , Jonasson Jon G. , Senter Leigha , Liyanarachchi Sandya , Ringel Matthew D. , Xu Li , Kiemeney Lambertus A. , He Huiling , Netea-Maier Romana T. , Mayordomo Jose I. , Plantinga Theo S. , Hrafnkelsson Jon , Hjartarson Hannes , Sturgis Erich M. , Palotie Aarno , Daly Mark , Citterio Cintia E. , Arvan Peter , Brummett Chad M. , Boehnke Michael , de la Chapelle Albert , Stefansson Kari , Hveem Kristian , Willer Cristen J. , Åsvold Bjørn Olav
Published: August 2020

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates
Authors: Papkou Andrei , Hedge Jessica , Kapel Natalia , Young Bernadette , MacLean R. Craig
Published: August 2020

The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates ofStaphylococcus aureuswith the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump,norA, causes widespread variation in evolvability across isolates. ElevatednorAexpression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification ofnorAprovides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.
Quantitative evaluation of protective antibody response induced by hepatitis E vaccine in humans
Authors: Wen Gui-Ping , He Linling , Tang Zi-Min , Wang Si-Ling , Zhang Xu , Chen Yuan-Zhi , Lin Xiaohe , Liu Chang , Chen Jia-Xin , Ying Dong , Chen Zi-Hao , Wang Ying-Bin , Luo Wen-Xin , Huang Shou-Jie , Li Shao-Wei , Zhang Jun , Zheng Zi-Zheng , Zhu Jiang , Xia Ning-Shao
Published: August 2020

Efficacy evaluation through human trials is crucial for advancing a vaccine candidate to clinics. Next-generation sequencing (NGS) can be used to quantify B cell repertoire response and trace antibody lineages during vaccination. Here, we demonstrate this application with a case study of Hecolin®, the licensed vaccine for hepatitis E virus (HEV). Four subjects are administered the vaccine following a standard three-dose schedule. Vaccine-induced antibodies exhibit a high degree of clonal diversity, recognize five conformational antigenic sites of the genotype 1 HEV p239 antigen, and cross-react with other genotypes. Unbiased repertoire sequencing is performed for seven time points over six months of vaccination, with maturation pathways characterize for a set of vaccine-induced antibodies. In addition to dynamic repertoire profiles, NGS analysis reveals differential patterns of HEV-specific antibody lineages and highlights the necessity of the long vaccine boost. Together, our study presents a quantitative strategy for vaccine evaluation in small-scale human studies.
Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions
Authors: Sijbesma Eline , Visser Emira , Plitzko Kathrin , Thiel Philipp , Milroy Lech-Gustav , Kaiser Markus , Brunsveld Luc , Ottmann Christian
Published: August 2020

The systematic stabilization of protein–protein interactions (PPI) has great potential as innovative drug discovery strategy to target novel and hard-to-drug protein classes. The current lack of chemical starting points and focused screening opportunities limits the identification of small molecule stabilizers that engage two proteins simultaneously. Starting from our previously described virtual screening strategy to identify inhibitors of 14-3-3 proteins, we report a conceptual molecular docking approach providing concrete entries for discovery and rational optimization of stabilizers for the interaction of 14-3-3 with the carbohydrate-response element-binding protein (ChREBP). X-ray crystallography reveals a distinct difference in the binding modes between weak and general inhibitors of 14-3-3 complexes and a specific, potent stabilizer of the 14-3-3/ChREBP complex. Structure-guided stabilizer optimization results in selective, up to 26-fold enhancement of the 14-3-3/ChREBP interaction. This study demonstrates the potential of rational design approaches for the development of selective PPI stabilizers starting from weak, promiscuous PPI inhibitors.
Enhancing myocardial repair with CardioClusters
Authors: Monsanto Megan M. , Wang Bingyan J. , Ehrenberg Zach R. , Echeagaray Oscar , White Kevin S. , Alvarez Roberto , Fisher Kristina , Sengphanith Sharon , Muliono Alvin , Gude Natalie A. , Sussman Mark A.
Published: August 2020

Cellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such ‘next generation’ implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit+cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed CardioClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.
A nature-inspired hydrogen-bonded supramolecular complex for selective copper ion removal from water
Authors: Bui Ngoc T. , Kang Hyungmook , Teat Simon J. , Su Gregory M. , Pao Chih-Wen , Liu Yi-Sheng , Zaia Edmond W. , Guo Jinghua , Chen Jeng-Lung , Meihaus Katie R. , Dun Chaochao , Mattox Tracy M. , Long Jeffrey R. , Fiske Peter , Kostecki Robert , Urban Jeffrey J.
Published: August 2020

Herein, we present a scalable approach for the synthesis of a hydrogen-bonded organic–inorganic framework via coordination-driven supramolecular chemistry, for efficient remediation of trace heavy metal ions from water. In particular, using copper as our model ion of interest and inspired by nature’s use of histidine residues within the active sites of various copper binding proteins, we design a framework featuring pendant imidazole rings and copper-chelating salicylaldoxime, known as zinc imidazole salicylaldoxime supramolecule. This material is water-stable and exhibits unprecedented adsorption kinetics, up to 50 times faster than state-of-the-art materials for selective copper ion capture from water. Furthermore, selective copper removal is achieved using this material in a pH range that was proven ineffective with previously reported metal–organic frameworks. Molecular dynamics simulations show that this supramolecule can reversibly breathe water through lattice expansion and contraction, and that water is initially transported into the lattice through hopping between hydrogen-bond sites.
Artificial van der Waals hybrid synapse and its application to acoustic pattern recognition
Authors: Seo Seunghwan , Kang Beom-Seok , Lee Je-Jun , Ryu Hyo-Jun , Kim Sungjun , Kim Hyeongjun , Oh Seyong , Shim Jaewoo , Heo Keun , Oh Saeroonter , Park Jin-Hong
Published: August 2020

Brain-inspired parallel computing, which is typically performed using a hardware neural-network platform consisting of numerous artificial synapses, is a promising technology for effectively handling large amounts of informational data. However, the reported nonlinear and asymmetric conductance-update characteristics of artificial synapses prevent a hardware neural-network from delivering the same high-level training and inference accuracies as those delivered by a software neural-network. Here, we developed an artificial van-der-Waals hybrid synapse that features linear and symmetric conductance-update characteristics. Tungsten diselenide and molybdenum disulfide channels were used selectively to potentiate and depress conductance. Subsequently, via training and inference simulation, we demonstrated the feasibility of our hybrid synapse toward a hardware neural-network and also delivered high recognition rates that were comparable to those delivered using a software neural-network. This simulation involving the use of acoustic patterns was performed with a neural network that was theoretically formed with the characteristics of the hybrid synapses.
Author Correction: Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy
Authors: Couturier Charles P. , Ayyadhury Shamini , Le Phuong U. , Nadaf Javad , Monlong Jean , Riva Gabriele , Allache Redouane , Baig Salma , Yan Xiaohua , Bourgey Mathieu , Lee Changseok , Wang Yu Chang David , Yong V. Wee , Guiot Marie-Christine , Najafabadi Hamed , Misic Bratislav , Antel Jack , Bourque Guillaume , Ragoussis Jiannis , Petrecca Kevin
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher Correction: Integrated analysis of a compendium of RNA-Seq datasets for splicing factors
Authors: Yu Peng , Li Jin , Deng Su-Ping , Zhang Feiran , Grozdanov Petar N. , Chin Eunice W. M. , Martin Sheree D. , Vergnes Laurent , Islam M. Saharul , Sun Deqiang , LaSalle Janine M. , McGee Sean L. , Goh Eyleen , MacDonald Clinton C. , Jin Peng
Published: August 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Neuronal adenosine A2A receptors signal ergogenic effects of caffeine
Authors: Aguiar Aderbal S. , Speck Ana Elisa , Canas Paula M. , Cunha Rodrigo A.
Published: August 2020

Caffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A1 and A2A receptors. We now investigated A2AR as a possible ergogenic mechanism through pharmacological and genetic inactivation. Forty-two adult females (20.0 ± 0.2 g) and 40 male mice (23.9 ± 0.4 g) from a global and forebrain A2AR knockout (KO) colony ran an incremental exercise test with indirect calorimetry (V̇O2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A2AR antagonist) 15 min before the open field and exercise tests. We also evaluated the estrous cycle and infrared temperature immediately at the end of the exercise test. Caffeine and SCH 58621 were psychostimulant. Moreover, Caffeine and SCH 58621 were ergogenic, that is, they increased V̇O2max, running power, and critical power, showing that A2AR antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A2AR KO mice, showing that the antagonism of A2AR in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A2AR-dependent manner, and A2AR was paramount for exercise thermoregulation.
Modeling and scale-bridging using machine learning: nanoconfinement effects in porous media
Authors: Lubbers Nicholas , Agarwal Animesh , Chen Yu , Son Soyoun , Mehana Mohamed , Kang Qinjun , Karra Satish , Junghans Christoph , Germann Timothy C. , Viswanathan Hari S.
Published: August 2020

Fine-scale models that represent first-principles physics are challenging to represent at larger scales of interest in many application areas. In nanoporous media such as tight-shale formations, where the typical pore size is less than 50 nm, confinement effects play a significant role in how fluids behave. At these scales, fluids are under confinement, affecting key properties such as density, viscosity, adsorption, etc. Pore-scale Lattice Boltzmann Methods (LBM) can simulate flow in complex pore structures relevant to predicting hydrocarbon production, but must be corrected to account for confinement effects. Molecular dynamics (MD) can model confinement effects but is computationally expensive in comparison. The hurdle to bridging MD with LBM is the computational expense of MD simulations needed to perform this correction. Here, we build a Machine Learning (ML) surrogate model that captures adsorption effects across a wide range of parameter space and bridges the MD and LBM scales using a relatively small number of MD calculations. The model computes upscaled adsorption parameters across varying density, temperature, and pore width. The ML model is 7 orders of magnitude faster than brute force MD. This workflow is agnostic to the physical system and could be generalized to further scale-bridging applications.
Understanding the spatial–temporal variation of human footprint in Jiangsu Province, China, its anthropogenic and natural drivers and potential implications
Authors: Shen Feixue , Yang Lin , He Xianglin , Zhou Chenghu , Adams Jonathan M.
Published: August 2020

Understanding the spatial and temporal patterns of human pressures provides a foundation for understanding interactions between human and environment and managing human activities for a sustainable development. This study is the first attempt focused within China at calculating the spatial–temporal human footprint and its driving forces in a highly urbanized area with intensive human activities. Population, land use, night-time lights, and road impacts were used to generate human footprint maps of Jiangsu Province for 2000, 2010 and 2015 with a resolution of 1 km * 1 km. Five natural drivers and four anthropogenic drivers were employed to construct generalized additive models for explaining the spatial variation of human footprint and its change. It shows that a large difference is between the human footprint in northern and southern Jiangsu, and the pattern of human pressures conforms to the “Matthew effect”, with spatial aggregation of high human footprint areas accelerating. Slope, industrialization level are significant in explaining the spatial variation of human footprint in 2000, 2010 and 2015. The effect of natural drivers decreases for explaining the human footprint over time. Furthermore, annual precipitation, mean annual temperature and urban per capita disposable income are also significant drivers for human footprint in 2010 and 2015. And the increasing of human footprint slows with increasing of industrialization level. The difference of industrialization level and urban income between northern and southern Jiangsu mainly caused different driving pattern for human footprint and its change. Our study has generated new insights on the interaction pattern between human and nature in highly developed regions based on the human footprint concept, and can provide references for managing human activities in similar regions rapid socioeconomic development.
Validation of a patient-specific system for mandible-first bimaxillary surgery: ramus and implant positioning precision assessment and guide design comparison
Authors: Badiali Giovanni , Bevini Mirko , Ruggiero Federica , Cercenelli Laura , Lovero Elisa , De Simone Elisabetta , Rucci Paola , Bianchi Alberto , Marchetti Claudio
Published: August 2020

In orthognathic surgery, the use of patient-specific osteosynthesis devices is a novel approach used to transfer the virtual surgical plan to the patient. The aim of this study is to analyse the quality of mandibular anatomy reproduction using a mandible-first mandibular-PSI guided procedure on 22 patients. Three different positioning guide designs were compared in terms of osteosynthesis plate positioning and mandibular anatomical outcome. PSIs and positioning guides were designed according to virtual surgical plan and 3D printed using biocompatible materials. A CBCT scan was performed 1 month after surgery and postoperative mandibular models were segmented for comparison against the surgical plan. A precision comparison was carried out among the three groups. Correlations between obtained rami and plates discrepancies and between planned rami displacements and obtained rami discrepancies were calculated. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned mandibular anatomy reproduction. Different guide designs did not differ in mandibular outcome precision. Plate positional discrepancies influenced the corresponding ramus position, mainly in roll angle and vertical translation. Ramus planned displacement was found to be a further potential source of inaccuracy, possibly due to osteosynthesis surface interference.
Utilitarianism in minimal-group decision making is less common than equality-based morality, mostly harm-oriented, and rarely impartial
Authors: Roets Arne , Bostyn Dries H. , De keersmaecker Jonas , Haesevoets Tessa , Van Assche Jasper , Van Hiel Alain
Published: August 2020

In the study of utilitarian morality, the sacrificial dilemma paradigm has been the dominant approach for years. However, to address some of the most pressing issues in the current research literature, the present studies adopt an alternative approach by using a minimal group paradigm in which participants have to make decisions about the allocation of resources. This approach allows not only to pit utilitarianism against equality-based morality, but also to study these modes of morality for both harm and benefit, and to directly address the role of group identity affecting the (im)partial nature of ‘utilitarian’ (i.e., outcome maximizing) decisions. In our experiments, across four different samples (total N = 946), we demonstrate that although participants generally prefer equality-based allocations over maximizing distributions, outcome maximizing choices become more prevalent when they served to minimize harm compared to maximizing benefit. Furthermore, reducing the objective value of the equal distribution outcomes further prompts participants to adopt a more utilitarian approach in situations involving harm, but has little effect in situations where benefits have to be distributed. Finally, the introduction of (minimal) group identity consistently demonstrates that decisions that maximize the overall outcome are more likely if they also serve the ingroup compared to when they rather serve the outgroup. We discuss how these findings have meaningful implications that may be especially relevant for recent movements that advocate a utilitarian approach to charity, and for our understanding of (im)partiality in lay people’s ‘utilitarian’ decision making.
Lipid membrane templated misfolding and self-assembly of intrinsically disordered tau protein
Authors: Majewski Jaroslaw , Jones Emmalee M. , Vander Zanden Crystal M. , Biernat Jacek , Mandelkow Eckhard , Chi Eva Y.
Published: August 2020

The aggregation of the intrinsically disordered tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the lipid membrane plays in modulating the aggregation of three tau variants, the largest isoform hTau40, the truncated construct K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the tau proteins were also highly surface active and favorably interacted with anionic lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of ~ 40 proteins misfolded in a β-sheet conformation at the membrane surface, as detected by in situ synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau’s inherent surface activity and favorable interactions with anionic lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.
Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes
Authors: Lee Inn-Chi , Yang Jiann-Jou , Wong Swee-Hee , Liou Ying-Ming , Li Shuan-Yow
Published: August 2020

Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were “rescued” after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.
Precise 3D modulation of electro-optical parameters during neurotransmitter uncaging experiments with neurons in vitro
Authors: Cozzolino Marco , Bazzurro Virginia , Gatta Elena , Bianchini Paolo , Angeli Elena , Robello Mauro , Diaspro Alberto
Published: August 2020

Ruthenium–bipyridinetriphenylphosphine–GABA (RuBi–GABA) is a caged compound that allows studying the neuronal transmission in a specific region of a neuron. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is bound to a caged group that blocks the interaction of the neurotransmitter with its receptor site. Following linear—one-photon (1P)—and non-linear—multi-photon—absorption of light, the covalent bond of the caged molecule is broken, and GABA is released. Such a controlled release in time and space allows investigating the interaction with its receptor in four dimensions (X,Y,Z,t). Taking advantage of this strategy, we succeeded in addressing the modulation of GABAA in rat cerebellar neurons by coupling the photoactivation process, by confocal or two-photon excitation microscopy, with the electrophysiological technique of the patch-clamp in the whole-cell configuration. Key parameters have been comprehensively investigated and correlated in a temporally and spatially confined way, namely: photoactivation laser power, time of exposure, and distance of the uncaging point from the cell of interest along the X, Y, Z spatial coordinates. The goal of studying specific biological events as a function of controlled physical parameters has been achieved.