bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subcellular localization of biomolecules and drug distribution by high-definition ion beam imaging
Authors: Rovira-Clavé Xavier , Jiang Sizun , Bai Yunhao , Zhu Bokai , Barlow Graham , Bhate Salil , Coskun Ahmet F. , Han Guojun , Ho Chin-Min Kimmy , Hitzman Chuck , Chen Shih-Yu , Bava Felice-Alessio , Nolan Garry P. 
Published: July 2021

AbstractSimultaneous visualization of the relationship between multiple biomolecules and their ligands or small molecules at the nanometer scale in cells will enable greater understanding of how biological processes operate. We present here high-definition multiplex ion beam imaging (HD-MIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added structurally-unmodified small molecules. With this technology, the atomic constituents of the biomolecules themselves can be used in our system as the “tag” and we demonstrate measurements down to ~30 nm lateral resolution. We correlated the subcellular localization of the chemotherapy drug cisplatin simultaneously with five subnuclear structures. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. Unexpectedly, cells surviving multi-drug treatment with cisplatin and the BET inhibitor JQ1 demonstrated near total cisplatin exclusion from the nucleus, suggesting that selective subcellular drug relocalization may modulate resistance to this important chemotherapeutic treatment. Multiplexed high-resolution imaging techniques, such as HD-MIBI, will enable studies of biomolecules and drug distributions in biologically relevant subcellular microenvironments by visualizing the processes themselves in concert, rather than inferring mechanism through surrogate analyses.
Differentiating induced versus spontaneous subduction initiation using thermomechanical models and metamorphic soles
Authors: Zhou Xin , Wada Ikuko 
Published: July 2021

AbstractDespite the critical role of subduction in plate tectonics, the dynamics of its initiation remains unclear. High-temperature low-pressure metamorphic soles are vestiges of subduction initiation, providing records of the pressure and temperature conditions along the subducting slab surface during subduction initiation that can possibly differentiate the two end-member subduction initiation modes: spontaneous and induced. Here, using numerical models, we show that the slab surface temperature reaches 800–900 °C at ~1 GPa over a wide range of parameter values for spontaneous subduction initiation whereas for induced subduction initiation, such conditions can be reached only if the age of the overriding plate is <5 Ma. These modeling results indicate that spontaneous subduction initiation would be more favorable for creating high-temperature conditions. However, the synthesis of our modeling results and geological observations indicate that the majority of the metamorphic soles likely formed during induced subduction initiation that involved a young overriding plate.
Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Authors: Schützmann Marie P. , Hasecke Filip , Bachmann Sarah , Zielinski Mara , Hänsch Sebastian , Schröder Gunnar F. , Zempel Hans , Hoyer Wolfgang 
Published: July 2021

AbstractAmyloid-β peptide (Aβ) forms metastable oligomers >50 kDa, termed AβOs, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.
A synthetic nanobody targeting RBD protects hamsters from SARS-CoV-2 infection
Authors: Li Tingting , Cai Hongmin , Yao Hebang , Zhou Bingjie , Zhang Ning , van Vlissingen Martje Fentener , Kuiken Thijs , Han Wenyu , GeurtsvanKessel Corine H. , Gong Yuhuan , Zhao Yapei , Shen Quan , Qin Wenming , Tian Xiao-Xu , Peng Chao , Lai Yanling , Wang Yanxing , Hutter Cedric A. J. , Kuo Shu-Ming , Bao Juan , Liu Caixuan , Wang Yifan , Richard Audrey S. , Raoul Hervé , Lan Jiaming , Seeger Markus A. , Cong Yao , Rockx Barry , Wong Gary , Bi Yuhai , Lavillette Dimitri , Li Dianfan 
Published: July 2021

AbstractSARS-CoV-2, the causative agent of COVID-191, features a receptor-binding domain (RBD) for binding to the host cell ACE2 protein1–6. Neutralizing antibodies that block RBD-ACE2 interaction are candidates for the development of targeted therapeutics7–17. Llama-derived single-domain antibodies (nanobodies, ~15 kDa) offer advantages in bioavailability, amenability, and production and storage owing to their small sizes and high stability. Here, we report the rapid selection of 99 synthetic nanobodies (sybodies) against RBD by in vitro selection using three libraries. The best sybody, MR3 binds to RBD with high affinity (KD = 1.0 nM) and displays high neutralization activity against SARS-CoV-2 pseudoviruses (IC50 = 0.42 μg mL−1). Structural, biochemical, and biological characterization suggests a common neutralizing mechanism, in which the RBD-ACE2 interaction is competitively inhibited by sybodies. Various forms of sybodies with improved potency have been generated by structure-based design, biparatopic construction, and divalent engineering. Two divalent forms of MR3 protect hamsters from clinical signs after live virus challenge and a single dose of the Fc-fusion construct of MR3 reduces viral RNA load by 6 Log10. Our results pave the way for the development of therapeutic nanobodies against COVID-19 and present a strategy for rapid development of targeted medical interventions during an outbreak.
Memory and decision making interact to shape the value of unchosen options
Authors: Biderman Natalie , Shohamy Daphna 
Published: July 2021

AbstractThe goal of deliberation is to separate between options so that we can commit to one and leave the other behind. However, deliberation can, paradoxically, also form an association in memory between the chosen and unchosen options. Here, we consider this possibility and examine its consequences for how outcomes affect not only the value of the options we chose, but also, by association, the value of options we did not choose. In five experiments (totaln= 612), including a preregistered experiment (n= 235), we found that the value assigned to unchosen options is inversely related to their chosen counterparts. Moreover, this inverse relationship was associated with participants’ memory of the pairs they chose between. Our findings suggest that deciding between options does not end the competition between them. Deliberation binds choice options together in memory such that the learned value of one can affect the inferred value of the other.
Site-specific Umpolung amidation of carboxylic acids via triplet synergistic catalysis
Authors: Ning Yunyun , Wang Shuaishuai , Li Muzi , Han Jie , Zhu Chengjian , Xie Jin 
Published: July 2021

AbstractDevelopment of catalytic amide bond-forming methods is important because they could potentially address the existing limitations of classical methods using superstoichiometric activating reagents. In this paper, we disclose an Umpolung amidation reaction of carboxylic acids with nitroarenes and nitroalkanes enabled by the triplet synergistic catalysis of FeI2, P(V)/P(III) and photoredox catalysis, which avoids the production of byproducts from stoichiometric coupling reagents. A wide range of carboxylic acids, including aliphatic, aromatic and alkenyl acids participate smoothly in such reactions, generating structurally diverse amides in good yields (86 examples, up to 97% yield). This Umpolung amidation strategy opens a method to address challenging regioselectivity issues between nucleophilic functional groups, and complements the functional group compatibility of the classical amidation protocols. The synthetic robustness of the reaction is demonstrated by late-stage modification of complex molecules and gram-scale applications.
Identification of the cross-strand chimeric RNAs generated by fusions of bi-directional transcripts
Authors: Wang Yuting , Zou Qin , Li Fajin , Zhao Wenwei , Xu Hui , Zhang Wenhao , Deng Haiteng , Yang Xuerui 
Published: July 2021

AbstractA major part of the transcriptome complexity is attributed to multiple types of DNA or RNA fusion events, which take place within a gene such as alternative splicing or between different genes such as DNA rearrangement and trans-splicing. In the present study, using the RNA deep sequencing data, we systematically survey a type of non-canonical fusions between the RNA transcripts from the two opposite DNA strands. We name the products of such fusion events cross-strand chimeric RNA (cscRNA). Hundreds to thousands of cscRNAs can be found in human normal tissues, primary cells, and cancerous cells, and in other species as well. Although cscRNAs exhibit strong tissue-specificity, our analysis identifies thousands of recurrent cscRNAs found in multiple different samples. cscRNAs are mostly originated from convergent transcriptions of the annotated genes and their anti-sense DNA. The machinery of cscRNA biogenesis is unclear, but the cross-strand junction events show some features related to RNA splicing. The present study is a comprehensive survey of the non-canonical cross-strand RNA junction events, a resource for further characterization of the originations and functions of the cscRNAs.
Structural basis for +1 ribosomal frameshifting during EF-G-catalyzed translocation
Authors: Demo Gabriel , Gamper Howard B. , Loveland Anna B. , Masuda Isao , Carbone Christine E. , Svidritskiy Egor , Hou Ya-Ming , Korostelev Andrei A. 
Published: July 2021

AbstractFrameshifting of mRNA during translation provides a strategy to expand the coding repertoire of cells and viruses. How and where in the elongation cycle +1-frameshifting occurs remains poorly understood. We describe seven ~3.5-Å-resolution cryo-EM structures of 70S ribosome complexes, allowing visualization of elongation and translocation by the GTPase elongation factor G (EF-G). Four structures with a + 1-frameshifting-prone mRNA reveal that frameshifting takes place during translocation of tRNA and mRNA. Prior to EF-G binding, the pre-translocation complex features an in-frame tRNA-mRNA pairing in the A site. In the partially translocated structure with EF-G•GDPCP, the tRNA shifts to the +1-frame near the P site, rendering the freed mRNA base to bulge between the P and E sites and to stack on the 16S rRNA nucleotide G926. The ribosome remains frameshifted in the nearly post-translocation state. Our findings demonstrate that the ribosome and EF-G cooperate to induce +1 frameshifting during tRNA-mRNA translocation.
Structural evidence for extracellular silica formation by diatoms
Authors: Mayzel Boaz , Aram Lior , Varsano Neta , Wolf Sharon G. , Gal Assaf 
Published: July 2021

AbstractThe silica cell wall of diatoms, a widespread group of unicellular microalgae, is an exquisite example for the ability of organisms to finely sculpt minerals under strict biological control. The prevailing paradigm for diatom silicification is that this is invariably an intracellular process, occurring inside specialized silica deposition vesicles that are responsible for silica precipitation and morphogenesis. Here, we study the formation of long silicified extensions that characterize many diatom species. We use cryo-electron tomography to image silica formation in situ, in 3D, and at a nanometer-scale resolution. Remarkably, our data suggest that, contradictory to the ruling paradigm, these intricate structures form outside the cytoplasm. In addition, the formation of these silica extensions is halted at low silicon concentrations that still support the formation of other cell wall elements, further alluding to a different silicification mechanism. The identification of this unconventional strategy expands the suite of mechanisms that diatoms use for silicification.
A fructose/H+ symporter controlled by a LacI-type regulator promotes survival of pandemic Vibrio cholerae in seawater
Authors: Liu Yutao , Liu Bin , Xu Tingting , Wang Qian , Li Wendi , Wu Jialin , Zheng Xiaoyu , Liu Bin , Liu Ruiying , Liu Xingmei , Guo Xi , Feng Lu , Wang Lei 
Published: July 2021

AbstractThe bacterium Vibrio cholerae can colonize the human intestine and cause cholera, but spends much of its life cycle in seawater. The pathogen must adapt to substantial environmental changes when moving between seawater and the human intestine, including different availability of carbon sources such as fructose. Here, we use in vitro experiments as well as mouse intestinal colonization assays to study the mechanisms used by pandemic V. cholerae to adapt to these environmental changes. We show that a LacI-type regulator (FruI) and a fructose/H+ symporter (FruT) are important for fructose uptake at low fructose concentrations, as those found in seawater. FruT is downregulated by FruI, which is upregulated when O2 concentrations are low (as in the intestine) by ArcAB, a two-component system known to respond to changes in oxygen levels. As a result, the bacteria predominantly use FruT for fructose uptake under seawater conditions (low fructose, high O2), and use a known fructose phosphotransferase system (PTS, Fpr) for fructose uptake under conditions found in the intestine. PTS activity leads to reduced levels of intracellular cAMP, which in turn upregulate virulence genes. Our results indicate that the FruT/FruI system may be important for survival of pandemic V. cholerae in seawater.
Extensive variation in the intelectin gene family in laboratory and wild mouse strains
Authors: Almalki Faisal , Nonnecke Eric B. , Castillo Patricia A. , Bevin-Holder Alex , Ullrich Kristian K. , Lönnerdal Bo , Odenthal-Hesse Linda , Bevins Charles L. , Hollox Edward J. 
Published: July 2021

AbstractIntelectins are a family of multimeric secreted proteins that bind microbe-specific glycans. Both genetic and functional studies have suggested that intelectins have an important role in innate immunity and are involved in the etiology of various human diseases, including inflammatory bowel disease. Experiments investigating the role of intelectins in human disease using mouse models are limited by the fact that there is not a clear one-to-one relationship between intelectin genes in humans and mice, and that the number of intelectin genes varies between different mouse strains. In this study we show by gene sequence and gene expression analysis that human intelectin-1 (ITLN1) has multiple orthologues in mice, including a functional homologue Itln1; however, human intelectin-2 has no such orthologue or homologue. We confirm that all sub-strains of the C57 mouse strain have a large deletion resulting in retention of only one intelectin gene, Itln1. The majority of laboratory strains have a full complement of six intelectin genes, except CAST, SPRET, SKIVE, MOLF and PANCEVO strains, which are derived from different mouse species/subspecies and encode different complements of intelectin genes. In wild mice, intelectin deletions are polymorphic in Mus musculus castaneus and Mus musculus domesticus. Further sequence analysis shows that Itln3 and Itln5 are polymorphic pseudogenes due to premature truncating mutations, and that mouse Itln1 has undergone recent adaptive evolution. Taken together, our study shows extensive diversity in intelectin genes in both laboratory and wild-mice, suggesting a pattern of birth-and-death evolution. In addition, our data provide a foundation for further experimental investigation of the role of intelectins in disease.
Intact fibroblast growth factor 23 levels and outcome prediction in patients with acute heart failure
Authors: Cornelissen Anne , Florescu Roberta , Kneizeh Kinan , Cornelissen Christian , Brandenburg Vincent , Liehn Elisa , Schuh Alexander 
Published: July 2021

AbstractElevated fibroblast growth factor 23 (FGF23) levels are associated with adverse outcome in populations with cardiovascular disease and chronic kidney failure. It is unclear if FGF23 has significance in prognosis estimation in patients with acute heart failure (HF) when compared to traditional risk estimation tools. Serum levels of intact FGF23 were assessed in 139 patients admitted to the Intermediate Care Unit of a tertiary hospital for acute HF. Patients were followed-up for one year. After exclusion of patients who were lost to follow-up, data outliers, and patients with sampling errors, the final study cohort comprised 133 patients. The Seattle Heart Failure (SHF) Model was used to estimate one-year survival. FGF23 levels correlated with HF severity and were strongly associated with one-year mortality. Associations between one-year outcome and FGF23, assessed on day 1 after admission, were still evident after multivariable adjustment (OR 15.07; 95%CI 1.75–129.79; p = 0.014). FGF23 levels predicted the one-year outcome with similar accuracy as the SHF Model, both if assessed on day 1 and on day 2 after admission (FGF23d1: AUC 0.784; 95%CI 0.669–0.899; FGF23d2: AUC 0.766; 95%CI 0.631–0.901; SHF: AUC 0.771; 95%CI 0.651–0.891). The assessment of FGF23 in patients with acute HF might help identify high-risk patients that are more prone to complications, need a closer follow-up and more aggressive treatment.
A model of the evolution of equitable offers in n-person dictator games with interbirth intervals
Authors: Schank Jeffrey C. 
Published: July 2021

AbstractPeople are often generous even when it is not in their apparent self-interest to do so as demonstrated by numerous experiments using the dictator game (DG). More recent research using DGs has varied the number of dictators and recipients and used these games to investigate the bystander effect and congestible altruism. These studies have found that people are less generous when there are others who could be generous (the bystander effect) and also less generous when there are multiple recipients (congestible altruism) though the sum of their generosity to all recipients increases. A working hypothesis is proposed that the context-sensitive generosity observed in n-person DGs can be explained as equitable behavior. From an evolutionary perspective, explaining the evolution of equitable behavior is challenging at best. To provide an evolutionary explanation, a second working hypothesis is proposed: equitable offers evolve because they reduce resource deficits produced by variability in the accumulation of resources and thereby minimize the length of interbirth intervals (IBIs) and increase fitness. Based on this working hypothesis, an evolutionary model was developed for n-person DGs to investigate the evolution of equitable offers as a resource allocation problem when reproduction is constrained by IBIs. Simulations demonstrated that equitable offers could evolve in group-structured populations when there is a cost (i.e., longer IBIs) to running resource deficits. Mean evolved offers also varied as a function of the number of dictators and recipients in patterns consistent with the bystander effect and congestible altruism. Equitable offers evolved because they reduced resource variability among group members and thereby reduced resource deficits, which insured higher average rates of reproduction for more equitable groups of agents. Implications of these results are discussed.
Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach
Authors: Bennion Brian J. , Malfatti Michael A. , Be Nicholas A. , Enright Heather A. , Hok Saphon , Cadieux C. Linn , Carpenter Timothy S. , Lao Victoria , Kuhn Edward A. , McNerney M. Windy , Lightstone Felice C. , Nguyen Tuan H. , Valdez Carlos A. 
Published: July 2021

AbstractNerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.
Boron rich nanotube drug carrier system is suited for boron neutron capture therapy
Authors: Heide Fabian , McDougall Matthew , Harder-Viddal Candice , Roshko Roy , Davidson David , Wu Jiandong , Aprosoff Camila , Moya-Torres Aniel , Lin Francis , Stetefeld Jörg 
Published: July 2021

AbstractBoron neutron capture therapy (BNCT) is a two-step therapeutic process that utilizes Boron-10 in combination with low energy neutrons to effectively eliminate targeted cells. This therapy is primarily used for difficult to treat head and neck carcinomas; recent advances have expanded this method to cover a broader range of carcinomas. However, it still remains an unconventional therapy where one of the barriers for widespread adoption is the adequate delivery of Boron-10 to target cells. In an effort to address this issue, we examined a unique nanoparticle drug delivery system based on a highly stable and modular proteinaceous nanotube. Initially, we confirmed and structurally analyzed ortho-carborane binding into the cavities of the nanotube. The high ratio of Boron to proteinaceous mass and excellent thermal stability suggest the nanotube system as a suitable candidate for drug delivery into cancer cells. The full physicochemical characterization of the nanotube then allowed for further mechanistic molecular dynamic studies of the ortho-carborane uptake and calculations of corresponding energy profiles. Visualization of the binding event highlighted the protein dynamics and the importance of the interhelical channel formation to allow movement of the boron cluster into the nanotube. Additionally, cell assays showed that the nanotube can penetrate outer membranes of cancer cells followed by localization around the cells’ nuclei. This work uses an integrative approach combining experimental data from structural, molecular dynamics simulations and biological experiments to thoroughly present an alternative drug delivery device for BNCT which offers additional benefits over current delivery methods.