bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selecting Indicators and Optimizing Decision Rules for Long‐Term Water Resources Planning
Authors: Murgatroyd A. , Hall J. W. 
Published: April 2021

AbstractDecision rules provide an intuitive framework for water resources planning. Having adopted a rule‐based plan, decision makers can monitor critical variables to trigger timely adaptation actions when the variables pass their predetermined thresholds. However, establishing a strategy that is comprised of a set of decision rules raises methodological challenges: (i) to identify observable indicators that provide reliable information about current and future change, (ii) to choose suitable statistics to characterize nonstationary time series that are germane to system performance, and (iii) to optimize threshold levels that trigger interventions. We propose a methodology that addresses these methodological challenges whilst explicitly balancing expected risks of water shortages with the costs of intervention in the water supply system. The four‐step framework uses a multiobjective evolutionary algorithm to search for and to identify the combinations of indicator‐informed decision rules that govern if, when, and what supply options should be included in the water resource system. The rule‐based strategies are dynamically tested against an extensive ensemble of future climate and demand scenarios to examine the trade‐offs between strategy cost and level of service. The framework is applied to the London water system (England) using regional climate simulations to identify strategic rules for a 60‐year planning period. The results demonstrate the utility of the framework, identifying observable indicators and decision thresholds that are used in optimal rule‐based planning strategies. In key areas of the solution space, rule‐based strategies reduce expected restriction costs on average by 13.1%, and as much as 24.1%, for a given intervention cost.
PiAutoStage: An Open‐Source 3D Printed Tool for the Automatic Collection of High‐Resolution Microscope Imagery
Authors: Steiner R. Alex , Rooney Tyrone O. 
Published: April 2021

AbstractWe have created an open‐source 3D printable microscope automatic stage and integrated camera system capable of providing a means for imaging microscope slides—the PiAutoStage. The PiAutoStage was developed to interface with the high‐quality optics of existing microscopes by creating an adaptable system that can be used in conjunction with a range of microscope configurations. The PiAutoStage automatically captures the entire area of a microscope slide in a series of overlapping high‐resolution images, which can then be stitched into a single panoramic image. We have demonstrated the utility of the PiAutoStage when attached to a transmitted light microscope by creating high‐fidelity image stacks of rock specimens in plane polarized and cross‐polarized light. We have shown that the PiAutoStage is compatible with microscopes that do not currently have a camera attachment by using two different optical trains within the same microscope: one set of imagery collected through the photography tube of a trinocular microscope, and a second set through a camera mounted to an ocular. We furthermore establish the broad adaptability of the PiAutoStage system by attaching it to a reflected light stereo dissection microscope to capture images of microfossils. We discuss strategies for the online delivery of these large‐sized images in a data efficient manner through the application of tiled imagery and open‐source Java‐based web viewers. The low cost of the PiAutoStage system, combined with the data‐efficient mechanisms of online delivery make this system an important tool in promoting the universal accessibility of high‐resolution microscope imagery.
Statistical Study of Foreshock Transients in the Midtail Foreshock
Authors: Liu Terry Z. , Zhang Hui , Wang Chih‐Ping , Angelopoulos Vassilis , Vu Andrew , Wang Xueyi , Lin Yu 
Published: April 2021

AbstractIn the dayside foreshock, many foreshock transients have been observed and simulated. Because of their strong dynamic pressure perturbations, foreshock transients can disturb the local bow shock, magnetosheath, magnetopause, and thus the magnetosphere‐ionosphere system. They can also accelerate particles contributing to shock acceleration. Recent observations and simulations showed that foreshock transients also exist in the midtail foreshock, which can continuously disturb the nightside bow shock, magnetosheath, and magnetopause while propagating tailward for tens of minutes. To further understand the characteristics of midtail foreshock transients, we studied them statistically using Acceleration Reconnection Turbulence & Electrodynamics of Moon’s Interaction with the Sun observations. We selected 111 events that have dynamic pressure decrease along the local bow shock normal by more than 50%. We show that the dynamic pressure decrease is contributed by both density decrease and speed decrease. Around 90% of the events have electron temperature increase by more than 10% with a temperature change ratio proportional to the solar wind speed. Midtail foreshock transients more likely occur at the dawnside than the duskside. They are more significant closer to the bow shock and rather stable along the tailward direction. They have similar formation conditions compared to the dayside foreshock transients, except the ones related to the bow shock geometry. Our study indicates that the characteristics of foreshock transients based on dayside observations need to be generalized. Our study also implies that foreshock transients can exist for tens of minutes (even longer for larger planar shocks), continuously disturbing the local shock and accelerating/heating particles.
On the origin and evolution of SARS-CoV-2
Authors: Singh Devika , Yi Soojin V. 
Published: April 2021

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global outbreak of a coronavirus disease (herein referred to as COVID-19). Other viruses in the same phylogenetic group have been responsible for previous regional outbreaks, including SARS and MERS. SARS-CoV-2 has a zoonotic origin, similar to the causative viruses of these previous outbreaks. The repetitive introduction of animal viruses into human populations resulting in disease outbreaks suggests that similar future epidemics are inevitable. Therefore, understanding the molecular origin and ongoing evolution of SARS-CoV-2 will provide critical insights for preparing for and preventing future outbreaks. A key feature of SARS-CoV-2 is its propensity for genetic recombination across host species boundaries. Consequently, the genome of SARS-CoV-2 harbors signatures of multiple recombination events, likely encompassing multiple species and broad geographic regions. Other regions of the SARS-CoV-2 genome show the impact of purifying selection. The spike (S) protein of SARS-CoV-2, which enables the virus to enter host cells, exhibits signatures of both purifying selection and ancestral recombination events, leading to an effective S protein capable of infecting human and many other mammalian cells. The global spread and explosive growth of the SARS-CoV-2 population (within human hosts) has contributed additional mutational variability into this genome, increasing opportunities for future recombination.
Brain cells derived from Alzheimer’s disease patients have multiple specific innate abnormalities in energy metabolism
Authors: Ryu Woo-In , Bormann Mariana K. , Shen Minqi , Kim Dohoon , Forester Brent , Park Yeongwon , So Jisun , Seo Hyemyung , Sonntag Kai-C. , Cohen Bruce M. 
Published: April 2021

AbstractAltered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer’s disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a “multi-hit” disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.
Incerto-thalamic modulation of fear via GABA and dopamine
Authors: Venkataraman Archana , Hunter Sarah C. , Dhinojwala Maria , Ghebrezadik Diana , Guo JiDong , Inoue Kiyoshi , Young Larry J. , Dias Brian George 
Published: April 2021

AbstractFear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.
Precision radiogenomics: fusion biopsies to target tumour habitats in vivo
Authors: Crispin-Ortuzar Mireia , Sala Evis 
Published: April 2021

SummaryHigh-grade serous ovarian cancer lesions display a high degree of heterogeneity on CT scans. We have recently shown that regions with distinct imaging profiles can be accurately biopsied in vivo using a technique based on the fusion of CT and ultrasound scans.
Matrix stiffness changes affect astrocyte phenotype in an in vitro injury model
Authors: Hu Yan , Huang Guoyou , Tian Jin , Qiu Jinbin , Jia Yuanbo , Feng Dayun , Wei Zhao , Li Sidi , Xu Feng 
Published: April 2021

AbstractInjury to the central nervous system (CNS) usually leads to the activation of astrocytes, followed by glial scar formation. The formation of glial scars from active astrocytes in vivo has been found to be dependent on the cell microenvironment. However, how astrocytes respond to different microenvironmental cues during scar formation, such as changes in matrix stiffness, remains elusive. In this work, we established an in vitro model to assess the responses of astrocytes to matrix stiffness changes that may be related to pathophysiology. The investigated hydrogel backbones are composed of collagen type I and alginate. The stiffness of these hybrid hydrogels can be dynamically changed by association or dissociation of alginate chains through adding crosslinkers of calcium chloride or a decrosslinker of sodium citrate, respectively. We found that astrocytes obtain different phenotypes when cultured in hydrogels of different stiffnesses. The obtained phenotypes can be switched in situ when changing matrix stiffness in the presence of cells. Specifically, matrix stiffening reverts astrogliosis, whereas matrix softening initiates astrocytic activation in 3D. Moreover, the effect of matrix stiffness on astrocytic activation is mediated by Yes-associated protein (YAP), where YAP inhibition enhances the upregulation of GFAP and contributes to astrogliosis. To investigate the underlying mechanism of matrix stiffness-dependent GFAP expression, we also developed a mathematical model to describe the time-dependent dynamics of biomolecules involved in the matrix stiffness mechanotransduction process of astrocytes. The modeling results further indicate that the effect of matrix stiffness on cell fate and behavior may be related to changes in the cytoskeleton and subsequent activity of YAP. The results from this study will guide researchers to re-examine the role of matrix stiffness in reactive astrogliosis in vivo and inspire the development of a novel therapeutic approach for controlling glial scar formation following injury, enabling axonal regrowth and improving functional recovery by exploiting the benefits of mechanobiology studies.
Hollow medium-entropy alloy nanolattices with ultrahigh energy absorption and resilience
Authors: Surjadi James Utama , Feng Xiaobin , Fan Rong , Lin Weitong , Li Xiaocui , Lu Yang 
Published: April 2021

AbstractHollow micro/nanolattices have emerged in recent years as a premium solution compared to conventional foams or aerogels for mechanically robust lightweight structures. However, existing hollow metallic micro/nanolattices often cannot exhibit high toughness due to the intrinsic brittleness from localized strut fractures, limiting their broad applications. Here, we report the development of hollow CoCrNi medium-entropy alloy (MEA) nanolattices, which exhibit high specific energy absorption (up to 25 J g−1) and resilience (over 90% recoverability) by leveraging size-induced ductility and rationally engineered MEA microstructural defects. This strategy provides a pathway for the development of ultralight, damage-resistant metallic metamaterials for a myriad of structural and functional applications.
High-yield, wafer-scale fabrication of ultralow-loss, dispersion-engineered silicon nitride photonic circuits
Authors: Liu Junqiu , Huang Guanhao , Wang Rui Ning , He Jijun , Raja Arslan S. , Liu Tianyi , Engelsen Nils J. , Kippenberg Tobias J. 
Published: April 2021

AbstractLow-loss photonic integrated circuits and microresonators have enabled a wide range of applications, such as narrow-linewidth lasers and chip-scale frequency combs. To translate these into a widespread technology, attaining ultralow optical losses with established foundry manufacturing is critical. Recent advances in integrated Si3N4 photonics have shown that ultralow-loss, dispersion-engineered microresonators with quality factors Q > 10 × 106 can be attained at die-level throughput. Yet, current fabrication techniques do not have sufficiently high yield and performance for existing and emerging applications, such as integrated travelling-wave parametric amplifiers that require meter-long photonic circuits. Here we demonstrate a fabrication technology that meets all requirements on wafer-level yield, performance and length scale. Photonic microresonators with a mean Q factor exceeding 30 × 106, corresponding to 1.0 dB m−1 optical loss, are obtained over full 4-inch wafers, as determined from a statistical analysis of tens of thousands of optical resonances, and confirmed via cavity ringdown with 19 ns photon storage time. The process operates over large areas with high yield, enabling 1-meter-long spiral waveguides with 2.4 dB m−1 loss in dies of only 5 × 5 mm2 size. Using a response measurement self-calibrated via the Kerr nonlinearity, we reveal that the intrinsic absorption-limited Q factor of our Si3N4 microresonators can exceed 2 × 108. This absorption loss is sufficiently low such that the Kerr nonlinearity dominates the microresonator’s response even in the audio frequency band. Transferring this Si3N4 technology to commercial foundries can significantly improve the performance and capabilities of integrated photonics.
An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
Authors: Lindskrog Sia Viborg , Prip Frederik , Lamy Philippe , Taber Ann , Groeneveld Clarice S. , Birkenkamp-Demtröder Karin , Jensen Jørgen Bjerggaard , Strandgaard Trine , Nordentoft Iver , Christensen Emil , Sokac Mateo , Birkbak Nicolai J. , Maretty Lasse , Hermann Gregers G. , Petersen Astrid C. , Weyerer Veronika , Grimm Marc-Oliver , Horstmann Marcus , Sjödahl Gottfrid , Höglund Mattias , Steiniche Torben , Mogensen Karin , de Reyniès Aurélien , Nawroth Roman , Jordan Brian , Lin Xiaoqi , Dragicevic Dejan , Ward Douglas G. , Goel Anshita , Hurst Carolyn D. , Raman Jay D. , Warrick Joshua I. , Segersten Ulrika , Sikic Danijel , van Kessel Kim E. M. , Maurer Tobias , Meeks Joshua J. , DeGraff David J. , Bryan Richard T. , Knowles Margaret A. , Simic Tatjana , Hartmann Arndt , Zwarthoff Ellen C. , Malmström Per-Uno , Malats Núria , Real Francisco X. , Dyrskjøt Lars 
Published: April 2021

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia
Authors: Ushiki Aki , Zhang Yichi , Xiong Chenling , Zhao Jingjing , Georgakopoulos-Soares Ilias , Kane Lauren , Jamieson Kirsty , Bamshad Michael J. , Nickerson Deborah A. ,   University of Washington Center for Mendelian Genomics, Shen Yin , Lettice Laura A. , Silveira-Lucas Elizabeth Lemos , Petit Florence , Ahituv Nadav 
Published: April 2021

AbstractAcheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer–promoter interactions.
Structure-guided engineering of adenine base editor with minimized RNA off-targeting activity
Authors: Li Jianan , Yu Wenxia , Huang Shisheng , Wu Susu , Li Liping , Zhou Jiankui , Cao Yu , Huang Xingxu , Qiao Yunbo 
Published: April 2021

AbstractBoth adenine base editors (ABEs) and cytosine base editors (CBEs) have been recently revealed to induce transcriptome-wide RNA off-target editing in a guide RNA-independent manner. Here we construct a reporter system containing E.coli Hokb gene with a tRNA-like motif for robust detection of RNA editing activities as the optimized ABE, ABEmax, induces highly efficient A-to-I (inosine) editing within an E.coli tRNA-like structure. Then, we design mutations to disrupt the potential interaction between TadA and tRNAs in structure-guided principles and find that Arginine 153 (R153) within TadA is essential for deaminating RNAs with core tRNA-like structures. Two ABEmax or mini ABEmax variants (TadA* fused with Cas9n) with deletion of R153 within TadA and/or TadA* (named as del153/del153* and mini del153) are successfully engineered, showing minimized RNA off-targeting, but comparable DNA on-targeting activities. Moreover, R153 deletion in recently reported ABE8e or ABE8s can also largely reduce their RNA off-targeting activities. Taken together, we develop a strategy to generate engineered ABEs (eABEs) with minimized RNA off-targeting activities.
Nanoscale magnonic Fabry-Pérot resonator for low-loss spin-wave manipulation
Authors: Qin Huajun , Holländer Rasmus B. , Flajšman Lukáš , Hermann Felix , Dreyer Rouven , Woltersdorf Georg , van Dijken Sebastiaan 
Published: April 2021

AbstractActive control of propagating spin waves on the nanoscale is essential for beyond-CMOS magnonic computing. Here, we experimentally demonstrate reconfigurable spin-wave transport in a hybrid YIG-based material structure that operates as a Fabry-Pérot nanoresonator. The magnonic resonator is formed by a local frequency downshift of the spin-wave dispersion relation in a continuous YIG film caused by dynamic dipolar coupling to a ferromagnetic metal nanostripe. Drastic downscaling of the spin-wave wavelength within the bilayer region enables programmable control of propagating spin waves on a length scale that is only a fraction of their wavelength. Depending on the stripe width, the device structure offers full nonreciprocity, tunable spin-wave filtering, and nearly zero transmission loss at allowed frequencies. Our results provide a practical route for the implementation of low-loss YIG-based magnonic devices with controllable transport properties.
The molecular pH-response mechanism of the plant light-stress sensor PsbS
Authors: Krishnan-Schmieden Maithili , Konold Patrick E. , Kennis John T. M. , Pandit Anjali 
Published: April 2021

AbstractPlants need to protect themselves from excess light, which causes photo-oxidative damage and lowers the efficiency of photosynthesis. Photosystem II subunit S (PsbS) is a pH sensor protein that plays a crucial role in plant photoprotection by detecting thylakoid lumen acidification in excess light conditions via two lumen-faced glutamates. However, how PsbS is activated under low-pH conditions is unknown. To reveal the molecular response of PsbS to low pH, here we perform an NMR, FTIR and 2DIR spectroscopic analysis of Physcomitrella patens PsbS and of the E176Q mutant in which an active glutamate has been replaced. The PsbS response mechanism at low pH involves the concerted action of repositioning of a short amphipathic helix containing E176 facing the lumen and folding of the luminal loop fragment adjacent to E71 to a 310-helix, providing clear evidence of a conformational pH switch. We propose that this concerted mechanism is a shared motif of proteins of the light-harvesting family that may control thylakoid inter-protein interactions driving photoregulatory responses.