bluuebunny/crossref_metadata_2025 huggingface dataset:
LncRNA CDKN2B-AS1 stabilized by IGF2BP3 drives the malignancy of renal clear cell carcinoma through epigenetically activating NUF2 transcription
Authors: Xie Xina , Lin Jiatian , Fan Xiaoqin , Zhong Yuantang , Chen Yequn , Liu Kaiqing , Ren Yonggang , Chen Xiangling , Lai Daihuan , Li Xuyi , Li Zesong , Tang Aifa
Published: February 2021

Because of the lack of sensitivity to radiotherapy and chemotherapy, therapeutic options for renal clear cell carcinoma (KIRC) are scarce. Long noncoding RNAs (lncRNAs) play crucial roles in the progression of cancer. However, their functional roles and upstream mechanisms in KIRC remain largely unknown. Exploring the functions of potential essential lncRNAs may lead to the discovery of novel targets for the diagnosis and treatment of KIRC. Here, according to the integrated analysis of RNA sequencing and survival data in TCGA-KIRC datasets, cyclin-dependent kinase inhibitor 2B antisense lncRNA (CDKN2B-AS1) was discovered to be the most upregulated among the 14 lncRNAs that were significantly overexpressed in KIRC and related to shorter survival. Functionally, CDKN2B-AS1 depletion suppressed cell proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, CDKN2B-AS1 exerted its oncogenic activity by recruiting the CREB-binding protein and SET and MYND domain-containing 3 epigenetic-modifying complex to the promoter region of Ndc80 kinetochore complex component (NUF2), where it epigenetically activated NUF2 transcription by augmenting local H3K27ac and H3K4me3 modifications. Moreover, we also showed that CDKN2B-AS1 interacted with and was stabilized by insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal protein showing increased levels in KIRC. The Kaplan–Meier method and receiver operating curve analysis revealed that patients whose IGF2BP3, CDKN2B-AS1 and NUF2 are all elevated showed the shortest survival time, and the combined panel (containing IGF2BP3, CDKN2B-AS1, and NUF2) possessed the highest accuracy in discriminating high-risk from low-risk KIRC patients. Thus, we conclude that the stabilization of CDKN2B-AS1 by IGF2BP3 drives the malignancy of KIRC through epigenetically activating NUF2 transcription and that the IGF2BP3/CDKN2B-AS1/NUF2 axis may be an ideal prognostic and diagnostic biomarker and therapeutic target for KIRC.
Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan
Authors: Ling Shenglong , Shi Pan , Liu Sanling , Meng Xianyu , Zhou Yingxin , Sun Wenjing , Chang Shenghai , Zhang Xing , Zhang Longhua , Shi Chaowei , Sun Demeng , Liu Lei , Tian Changlin
Published: February 2021

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
Formative pluripotent stem cells show features of epiblast cells poised for gastrulation
Authors: Wang Xiaoxiao , Xiang Yunlong , Yu Yang , Wang Ran , Zhang Yu , Xu Qianhua , Sun Hao , Zhao Zhen-Ao , Jiang Xiangxiang , Wang Xiaoqing , Lu Xukun , Qin Dandan , Quan Yujun , Zhang Jiaqi , Shyh-Chang Ng , Wang Hongmei , Jing Naihe , Xie Wei , Li Lei
Published: February 2021

The pluripotency of mammalian early and late epiblast could be recapitulated by naïve embryonic stem cells (ESCs) and primed epiblast stem cells (EpiSCs), respectively. However, these two states of pluripotency may not be sufficient to reflect the full complexity and developmental potency of the epiblast during mammalian early development. Here we report the establishment of self-renewing formative pluripotent stem cells (fPSCs) which manifest features of epiblast cells poised for gastrulation. fPSCs can be established from different mouse ESCs, pre-/early-gastrula epiblasts and induced PSCs. Similar to pre-/early-gastrula epiblasts, fPSCs show the transcriptomic features of formative pluripotency, which are distinct from naïve ESCs and primed EpiSCs. fPSCs show the unique epigenetic states of E6.5 epiblast, including the super-bivalency of a large set of developmental genes. Just like epiblast cells immediately before gastrulation, fPSCs can efficiently differentiate into three germ layers and primordial germ cells (PGCs) in vitro. Thus, fPSCs highlight the feasibility of using PSCs to explore the development of mammalian epiblast.
The effect of oat β-glucan on postprandial blood glucose and insulin responses: a systematic review and meta-analysis
Authors: Zurbau Andreea , Noronha Jarvis C. , Khan Tauseef A. , Sievenpiper John L. , Wolever Thomas M. S.
Published: February 2021

To determine the effect of oat β‑glucan (OBG) on acute glucose and insulin responses and identify significant effect modifiers we searched the MEDLINE, EMBASE, and Cochrane databases through October 27, 2020 for acute, crossover, controlled feeding trials investigating the effect of adding OBG (concentrate or oat-bran) to carbohydrate-containing test-meals compared to comparable or different carbohydrate-matched control-meals in humans regardless of health status. The primary outcome was glucose incremental area-under-the-curve (iAUC). Secondary outcomes were insulin iAUC, and glucose and insulin incremental peak-rise (iPeak). Two reviewers extracted the data and assessed risk-of-bias and certainty-of-evidence (GRADE). Data were pooled using generic inverse-variance with random-effects model and expressed as ratio-of-means with [95% CIs]. We included 103 trial comparisons (N = 538). OBG reduced glucose iAUC and iPeak by 23% (0.77 [0.74, 0.81]) and 28% (0.72 [0.64, 0.76]) and insulin by 22% (0.78 [0.72, 0.85]) and 24% (0.76 [0.65, 0.88]), respectively. Dose, molecular-weight, and comparator were significant effect modifiers of glucose iAUC and iPeak. Significant linear dose-response relationships were observed for all outcomes. OBG molecular-weight >300 kg/mol significantly reduced glucose iAUC and iPeak, whereas molecular-weight <300 kg/mol did not. Reductions in glucose iAUC (27 vs 20%, p = 0.03) and iPeak (39 vs 25%, p < 0.01) were significantly larger with different vs comparable control-meals. Outcomes were similar in participants with and without diabetes. All outcomes had high certainty-of-evidence. In conclusion, current evidence indicates that adding OBG to carbohydrate-containing meals reduces glycaemic and insulinaemic responses. However, the magnitude of glucose reduction depends on OBG dose, molecular-weight, and the comparator.
Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies
Authors: Gripp Karen W. , Smithson Sarah F. , Scurr Ingrid J. , Baptista Julia , Majumdar Anirban , Pierre Germaine , Williams Maggie , Henderson Lindsay B. , Wentzensen Ingrid M. , McLaughlin Heather , Leeuwen Lisette , Simon Marleen E. H. , van Binsbergen Ellen , Dinulos Mary Beth P. , Kaplan Julie D. , McRae Anne , Superti-Furga Andrea , Good Jean-Marc , Kutsche Kerstin
Published: February 2021

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann–Laband and Temple–Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
A unifying framework for mean-field theories of asymmetric kinetic Ising systems
Authors: Aguilera Miguel , Moosavi S. Amin , Shimazaki Hideaki
Published: February 2021

Kinetic Ising models are powerful tools for studying the non-equilibrium dynamics of complex systems. As their behavior is not tractable for large networks, many mean-field methods have been proposed for their analysis, each based on unique assumptions about the system’s temporal evolution. This disparity of approaches makes it challenging to systematically advance mean-field methods beyond previous contributions. Here, we propose a unifying framework for mean-field theories of asymmetric kinetic Ising systems from an information geometry perspective. The framework is built on Plefka expansions of a system around a simplified model obtained by an orthogonal projection to a sub-manifold of tractable probability distributions. This view not only unifies previous methods but also allows us to develop novel methods that, in contrast with traditional approaches, preserve the system’s correlations. We show that these new methods can outperform previous ones in predicting and assessing network properties near maximally fluctuating regimes.
Efficient overall water splitting in acid with anisotropic metal nanosheets
Authors: Wu Dongshuang , Kusada Kohei , Yoshioka Satoru , Yamamoto Tomokazu , Toriyama Takaaki , Matsumura Syo , Chen Yanna , Seo Okkyun , Kim Jaemyung , Song Chulho , Hiroi Satoshi , Sakata Osami , Ina Toshiaki , Kawaguchi Shogo , Kubota Yoshiki , Kobayashi Hirokazu , Kitagawa Hiroshi
Published: February 2021

Water is the only available fossil-free source of hydrogen. Splitting water electrochemically is among the most used techniques, however, it accounts for only 4% of global hydrogen production. One of the reasons is the high cost and low performance of catalysts promoting the oxygen evolution reaction (OER). Here, we report a highly efficient catalyst in acid, that is, solid-solution Ru‒Ir nanosized-coral (RuIr-NC) consisting of 3 nm-thick sheets with only 6 at.% Ir. Among OER catalysts, RuIr-NC shows the highest intrinsic activity and stability. A home-made overall water splitting cell using RuIr-NC as both electrodes can reach 10 mA cm−2geo at 1.485 V for 120 h without noticeable degradation, which outperforms known cells. Operando spectroscopy and atomic-resolution electron microscopy indicate that the high-performance results from the ability of the preferentially exposed {0001} facets to resist the formation of dissolvable metal oxides and to transform ephemeral Ru into a long-lived catalyst.
Exploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity
Authors: Becker Matthias , Strengert Monika , Junker Daniel , Kaiser Philipp D. , Kerrinnes Tobias , Traenkle Bjoern , Dinter Heiko , Häring Julia , Ghozzi Stéphane , Zeck Anne , Weise Frank , Peter Andreas , Hörber Sebastian , Fink Simon , Ruoff Felix , Dulovic Alex , Bakchoul Tamam , Baillot Armin , Lohse Stefan , Cornberg Markus , Illig Thomas , Gottlieb Jens , Smola Sigrun , Karch André , Berger Klaus , Rammensee Hans-Georg , Schenke-Layland Katja , Nelde Annika , Märklin Melanie , Heitmann Jonas S. , Walz Juliane S. , Templin Markus , Joos Thomas O. , Rothbauer Ulrich , Krause Gérard , Schneiderhan-Marra Nicole
Published: February 2021

The humoral immune response to SARS-CoV-2 is a benchmark for immunity and detailed analysis is required to understand the manifestation and progression of COVID-19, monitor seroconversion within the general population, and support vaccine development. The majority of currently available commercial serological assays only quantify the SARS-CoV-2 antibody response against individual antigens, limiting our understanding of the immune response. To overcome this, we have developed a multiplex immunoassay (MultiCoV-Ab) including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses. Compared to three broadly used commercial in vitro diagnostic tests, our MultiCoV-Ab achieves a higher sensitivity and specificity when analyzing a well-characterized sample set of SARS-CoV-2 infected and uninfected individuals. We find a high response against endemic coronaviruses in our sample set, but no consistent cross-reactive IgG response patterns against SARS-CoV-2. Here we show a robust, high-content-enabled, antigen-saving multiplex assay suited to both monitoring vaccination studies and facilitating epidemiologic screenings for humoral immunity towards pandemic and endemic coronaviruses.
AI-based mobile application to fight antibiotic resistance
Authors: Pascucci Marco , Royer Guilhem , Adamek Jakub , Asmar Mai Al , Aristizabal David , Blanche Laetitia , Bezzarga Amine , Boniface-Chang Guillaume , Brunner Alex , Curel Christian , Dulac-Arnold Gabriel , Fakhri Rasheed M. , Malou Nada , Nordon Clara , Runge Vincent , Samson Franck , Sebastian Ellen , Soukieh Dena , Vert Jean-Philippe , Ambroise Christophe , Madoui Mohammed-Amin
Published: February 2021

Antimicrobial resistance is a major global health threat and its development is promoted by antibiotic misuse. While disk diffusion antibiotic susceptibility testing (AST, also called antibiogram) is broadly used to test for antibiotic resistance in bacterial infections, it faces strong criticism because of inter-operator variability and the complexity of interpretative reading. Automatic reading systems address these issues, but are not always adapted or available to resource-limited settings. We present an artificial intelligence (AI)-based, offline smartphone application for antibiogram analysis. The application captures images with the phone’s camera, and the user is guided throughout the analysis on the same device by a user-friendly graphical interface. An embedded expert system validates the coherence of the antibiogram data and provides interpreted results. The fully automatic measurement procedure of our application’s reading system achieves an overall agreement of 90% on susceptibility categorization against a hospital-standard automatic system and 98% against manual measurement (gold standard), with reduced inter-operator variability. The application’s performance showed that the automatic reading of antibiotic resistance testing is entirely feasible on a smartphone. Moreover our application is suited for resource-limited settings, and therefore has the potential to significantly increase patients’ access to AST worldwide.
Cas12a-assisted precise targeted cloning using in vivo Cre-lox recombination
Authors: Enghiad Behnam , Huang Chunshuai , Guo Fang , Jiang Guangde , Wang Bin , Tabatabaei S. Kasra , Martin Teresa A. , Zhao Huimin
Published: February 2021

Direct cloning represents the most efficient strategy to access the vast number of uncharacterized natural product biosynthetic gene clusters (BGCs) for the discovery of novel bioactive compounds. However, due to their large size, repetitive nature, or high GC-content, large-scale cloning of these BGCs remains an overwhelming challenge. Here, we report a scalable direct cloning method named Cas12a-assisted precise targeted cloning using in vivo Cre-lox recombination (CAPTURE) which consists of Cas12a digestion, a DNA assembly approach termed T4 polymerase exo + fill-in DNA assembly, and Cre-lox in vivo DNA circularization. We apply this method to clone 47 BGCs ranging from 10 to 113 kb from both Actinomycetes and Bacilli with ~100% efficiency. Heterologous expression of cloned BGCs leads to the discovery of 15 previously uncharacterized natural products including six cyclic head-to-tail heterodimers with a unique 5/6/6/6/5 pentacyclic carbon skeleton, designated as bipentaromycins A–F. Four of the bipentaromycins show strong antimicrobial activity to both Gram-positive and Gram-negative bacteria such as methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus faecium, and bioweapon Bacillus anthracis. Due to its robustness and efficiency, our direct cloning method coupled with heterologous expression provides an effective strategy for large-scale discovery of novel natural products.
POLRMT mutations impair mitochondrial transcription causing neurological disease
Authors: Oláhová Monika , Peter Bradley , Szilagyi Zsolt , Diaz-Maldonado Hector , Singh Meenakshi , Sommerville Ewen W. , Blakely Emma L. , Collier Jack J. , Hoberg Emily , Stránecký Viktor , Hartmannová Hana , Bleyer Anthony J. , McBride Kim L. , Bowden Sasigarn A. , Korandová Zuzana , Pecinová Alena , Ropers Hans-Hilger , Kahrizi Kimia , Najmabadi Hossein , Tarnopolsky Mark A. , Brady Lauren I. , Weaver K. Nicole , Prada Carlos E. , Õunap Katrin , Wojcik Monica H. , Pajusalu Sander , Syeda Safoora B. , Pais Lynn , Estrella Elicia A. , Bruels Christine C. , Kunkel Louis M. , Kang Peter B. , Bonnen Penelope E. , Mráček Tomáš , Kmoch Stanislav , Gorman Gráinne S. , Falkenberg Maria , Gustafsson Claes M. , Taylor Robert W.
Published: February 2021

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.
Symmetry breaking propulsion of magnetic microspheres in nonlinearly viscoelastic fluids
Authors: Rogowski Louis William , Ali Jamel , Zhang Xiao , Wilking James N. , Fu Henry C. , Kim Min Jun
Published: February 2021

Microscale propulsion impacts a diverse array of fields ranging from biology and ecology to health applications, such as infection, fertility, drug delivery, and microsurgery. However, propulsion in such viscous drag-dominated fluid environments is highly constrained, with time-reversal and geometric symmetries ruling out entire classes of propulsion. Here, we report the spontaneous symmetry-breaking propulsion of rotating spherical microparticles within non-Newtonian fluids. While symmetry analysis suggests that propulsion is not possible along the fore-aft directions, we demonstrate the existence of two equal and opposite propulsion states along the sphere’s rotation axis. We propose and experimentally corroborate a propulsion mechanism for these spherical microparticles, the simplest microswimmers to date, arising from nonlinear viscoelastic effects in rotating flows similar to the rod-climbing effect. Similar possibilities of spontaneous symmetry-breaking could be used to circumvent other restrictions on propulsion, revising notions of microrobotic design and control, drug delivery, microscale pumping, and locomotion of microorganisms.
Highly active alkyne metathesis catalysts operating under open air condition
Authors: Ge Yanqing , Huang Shaofeng , Hu Yiming , Zhang Lei , He Ling , Krajewski Sebastian , Ortiz Michael , Jin Yinghua , Zhang Wei
Published: February 2021

Alkyne metathesis represents a rapidly emerging synthetic method that has shown great potential in small molecule and polymer synthesis. However, its practical use has been impeded by the limited availability of user-friendly catalysts and their generally high moisture/air sensitivity. Herein, we report an alkyne metathesis catalyst system that can operate under open-air conditions with a broad substrate scope and excellent yields. These catalysts are composed of simple multidentate tris(2-hydroxyphenyl)methane ligands, which can be easily prepared in multi-gram scale. The catalyst substituted with electron withdrawing cyano groups exhibits the highest activity at room temperature with excellent functional group tolerance (-OH, -CHO, -NO2, pyridyl). More importantly, the catalyst provides excellent yields (typically >90%) in open air, comparable to those operating under argon. When dispersed in paraffin wax, the active catalyst can be stored on a benchtop under ambient conditions without any decrease in activity for one day (retain 88% after 3 days). This work opens many possibilities for developing highly active user-friendly alkyne metathesis catalysts that can function in open air.
Genome-wide association studies provide insights into the genetic determination of fruit traits of pear
Authors: Zhang Ming-Yue , Xue Cheng , Hu Hongju , Li Jiaming , Xue Yongsong , Wang Runze , Fan Jing , Zou Cheng , Tao Shutian , Qin Mengfan , Bai Bing , Li Xiaolong , Gu Chao , Wu Shan , Chen Xu , Yang Guangyan , Liu Yueyuan , Sun Manyi , Fei Zhangjun , Zhang Shaoling , Wu Jun
Published: February 2021

Pear is a major fruit tree crop distributed worldwide, yet its breeding is a very time-consuming process. To facilitate molecular breeding and gene identification, here we have performed genome-wide association studies (GWAS) on eleven fruit traits. We identify 37 loci associated with eight fruit quality traits and five loci associated with three fruit phenological traits. Scans for selective sweeps indicate that traits including fruit stone cell content, organic acid and sugar contents might have been under continuous selection during breeding improvement. One candidate gene, PbrSTONE, identified in GWAS, has been functionally verified to be involved in the regulation of stone cell formation, one of the most important fruit quality traits in pear. Our study provides insights into the complex fruit related biology and identifies genes controlling important traits in pear through GWAS, which extends the genetic resources and basis for facilitating molecular breeding in perennial trees.
Harnessing peak transmission around symptom onset for non-pharmaceutical intervention and containment of the COVID-19 pandemic
Authors: Tian Liang , Li Xuefei , Qi Fei , Tang Qian-Yuan , Tang Viola , Liu Jiang , Li Zhiyuan , Cheng Xingye , Li Xuanxuan , Shi Yingchen , Liu Haiguang , Tang Lei-Han
Published: February 2021

Within a short period of time, COVID-19 grew into a world-wide pandemic. Transmission by pre-symptomatic and asymptomatic viral carriers rendered intervention and containment of the disease extremely challenging. Based on reported infection case studies, we construct an epidemiological model that focuses on transmission around the symptom onset. The model is calibrated against incubation period and pairwise transmission statistics during the initial outbreaks of the pandemic outside Wuhan with minimal non-pharmaceutical interventions. Mathematical treatment of the model yields explicit expressions for the size of latent and pre-symptomatic subpopulations during the exponential growth phase, with the local epidemic growth rate as input. We then explore reduction of the basic reproduction number R0 through specific transmission control measures such as contact tracing, testing, social distancing, wearing masks and sheltering in place. When these measures are implemented in combination, their effects on R0 multiply. We also compare our model behaviour to the first wave of the COVID-19 spreading in various affected regions and highlight generic and less generic features of the pandemic development.
Dopaminergic mechanism underlying reward-encoding of punishment omission during reversal learning in Drosophila
Authors: McCurdy Li Yan , Sareen Preeti , Davoudian Pasha A. , Nitabach Michael N.
Published: February 2021

Animals form and update learned associations between otherwise neutral sensory cues and aversive outcomes (i.e., punishment) to predict and avoid danger in changing environments. When a cue later occurs without punishment, this unexpected omission of aversive outcome is encoded as reward via activation of reward-encoding dopaminergic neurons. How such activation occurs remains unknown. Using real-time in vivo functional imaging, optogenetics, behavioral analysis and synaptic reconstruction from electron microscopy data, we identify the neural circuit mechanism through which Drosophila reward-encoding dopaminergic neurons are activated when an olfactory cue is unexpectedly no longer paired with electric shock punishment. Reduced activation of punishment-encoding dopaminergic neurons relieves depression of olfactory synaptic inputs to cholinergic neurons. Synaptic excitation by these cholinergic neurons of reward-encoding dopaminergic neurons increases their odor response, thus decreasing aversiveness of the odor. These studies reveal how an excitatory cholinergic relay from punishment- to reward-encoding dopaminergic neurons encodes the absence of punishment as reward, revealing a general circuit motif for updating aversive memories that could be present in mammals.
Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013–16 West Africa epidemic
Authors: Tipton T. R. W. , Hall Y. , Bore J. A. , White A. , Sibley L. S. , Sarfas C. , Yuki Y. , Martin M. , Longet S. , Mellors J. , Ewer K. , Günther S. , Carrington M. , Kondé M. K. , Carroll M. W.
Published: February 2021

Zaireebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013–16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.
A role for subducted albite in the water cycle and alkalinity of subduction fluids
Authors: Hwang Gil Chan , Hwang Huijeong , Bang Yoonah , Choi Jinhyuk , Park Yong , Jeon Tae-Yeol , Chae Boknam , Jung Haemyeong , Lee Yongjae
Published: February 2021

Albite is one of the major constituents in the crust. We report here that albite, when subjected to hydrous cold subduction conditions, undergoes hitherto unknown breakdown into hydrated smectite, moganite, and corundum, above 2.9 GPa and 290 °C or about 90 km depth conditions, followed by subsequent breakdown of smectite into jadeite above 4.3 GPa and 435 °C or near 135 km depth. Upon the hydration into smectite, the fluid volume of the system decreases by ~14 %, whereas it increases by ~8 % upon its dehydration into jadeite. Both the hydration and dehydration depths are correlated to increases in seismicity by 93 % and 104 %, respectively, along the South Mariana trench over the past 5 years. Moreover, the formation of smectite is accompanied by the release of OH− species, which would explain the formation of moganite and expected alkalinity of the subducting fluid. Thus, we shed new insights into the mechanism of water transport and related geochemical and geophysical activities in the contemporary global subduction system.
Observation of a quantum phase transition in the quantum Rabi model with a single trapped ion
Authors: Cai M.-L. , Liu Z.-D. , Zhao W.-D. , Wu Y.-K. , Mei Q.-X. , Jiang Y. , He L. , Zhang X. , Zhou Z.-C. , Duan L.-M.
Published: February 2021

Quantum phase transitions (QPTs) are usually associated with many-body systems in the thermodynamic limit when their ground states show abrupt changes at zero temperature with variation of a parameter in the Hamiltonian. Recently it has been realized that a QPT can also occur in a system composed of only a two-level atom and a single-mode bosonic field, described by the quantum Rabi model (QRM). Here we report an experimental demonstration of a QPT in the QRM using a171Yb+ion in a Paul trap. We measure the spin-up state population and the average phonon number of the ion as two order parameters and observe clear evidence of the phase transition via adiabatic tuning of the coupling between the ion and its spatial motion. An experimental probe of the phase transition in a fundamental quantum optics model without imposing the thermodynamic limit opens up a window for controlled study of QPTs and quantum critical phenomena.
Capturing functional two-dimensional nanosheets from sandwich-structure vermiculite for cancer theranostics
Authors: Ji Xiaoyuan , Ge Lanlan , Liu Chuang , Tang Zhongmin , Xiao Yufen , Chen Wei , Lei Zhouyue , Gao Wei , Blake Sara , De Diba , Shi Bingyang , Zeng Xiaobing , Kong Na , Zhang Xingcai , Tao Wei
Published: February 2021

Clay-based nanomaterials, especially 2:1 aluminosilicates such as vermiculite, biotite, and illite, have demonstrated great potential in various fields. However, their characteristic sandwiched structures and the lack of effective methods to exfoliate two-dimensional (2D) functional core layers (FCLs) greatly limit their future applications. Herein, we present a universal wet-chemical exfoliation method based on alkali etching that can intelligently “capture” the ultrathin and biocompatible FCLs (MgO and Fe2O3) sandwiched between two identical tetrahedral layers (SiO2 and Al2O3) from vermiculite. Without the sandwich structures that shielded their active sites, the obtained FCL nanosheets (NSs) exhibit a tunable and appropriate electron band structure (with the bandgap decreased from 2.0 eV to 1.4 eV), a conductive band that increased from −0.4 eV to −0.6 eV, and excellent light response characteristics. The great properties of 2D FCL NSs endow them with exciting potential in diverse applications including energy, photocatalysis, and biomedical engineering. This study specifically highlights their application in cancer theranostics as an example, potentially serving as a prelude to future extensive studies of 2D FCL NSs.
Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19
Authors: Wheatley Adam K. , Juno Jennifer A. , Wang Jing J. , Selva Kevin J. , Reynaldi Arnold , Tan Hyon-Xhi , Lee Wen Shi , Wragg Kathleen M. , Kelly Hannah G. , Esterbauer Robyn , Davis Samantha K. , Kent Helen E. , Mordant Francesca L. , Schlub Timothy E. , Gordon David L. , Khoury David S. , Subbarao Kanta , Cromer Deborah , Gordon Tom P. , Chung Amy W. , Davenport Miles P. , Kent Stephen J.
Published: February 2021

The durability of infection-induced SARS-CoV-2 immunity has major implications for reinfection and vaccine development. Here, we show a comprehensive profile of antibody, B cell and T cell dynamics over time in a cohort of patients who have recovered from mild-moderate COVID-19. Binding and neutralising antibody responses, together with individual serum clonotypes, decay over the first 4 months post-infection. A similar decline in Spike-specific CD4+ and circulating T follicular helper frequencies occurs. By contrast, S-specific IgG+ memory B cells consistently accumulate over time, eventually comprising a substantial fraction of circulating the memory B cell pool. Modelling of the concomitant immune kinetics predicts maintenance of serological neutralising activity above a titre of 1:40 in 50% of convalescent participants to 74 days, although there is probably additive protection from B cell and T cell immunity. This study indicates that SARS-CoV-2 immunity after infection might be transiently protective at a population level. Therefore, SARS-CoV-2 vaccines might require greater immunogenicity and durability than natural infection to drive long-term protection.
Widespread signatures of natural selection across human complex traits and functional genomic categories
Authors: Zeng Jian , Xue Angli , Jiang Longda , Lloyd-Jones Luke R. , Wu Yang , Wang Huanwei , Zheng Zhili , Yengo Loic , Kemper Kathryn E. , Goddard Michael E. , Wray Naomi R. , Visscher Peter M. , Yang Jian
Published: February 2021

Understanding how natural selection has shaped genetic architecture of complex traits is of importance in medical and evolutionary genetics. Bayesian methods have been developed using individual-level GWAS data to estimate multiple genetic architecture parameters including selection signature. Here, we present a method (SBayesS) that only requires GWAS summary statistics. We analyse data for 155 complex traits (n = 27k–547k) and project the estimates onto those obtained from evolutionary simulations. We estimate that, on average across traits, about 1% of human genome sequence are mutational targets with a mean selection coefficient of ~0.001. Common diseases, on average, show a smaller number of mutational targets and have been under stronger selection, compared to other traits. SBayesS analyses incorporating functional annotations reveal that selection signatures vary across genomic regions, among which coding regions have the strongest selection signature and are enriched for both the number of associated variants and the magnitude of effect sizes.
Hologenome analysis reveals dual symbiosis in the deep-sea hydrothermal vent snail Gigantopelta aegis
Authors: Lan Yi , Sun Jin , Chen Chong , Sun Yanan , Zhou Yadong , Yang Yi , Zhang Weipeng , Li Runsheng , Zhou Kun , Wong Wai Chuen , Kwan Yick Hang , Cheng Aifang , Bougouffa Salim , Van Dover Cindy Lee , Qiu Jian-Wen , Qian Pei-Yuan
Published: February 2021

Animals endemic to deep-sea hydrothermal vents often form obligatory symbioses with bacteria, maintained by intricate host–symbiont interactions. Most genomic studies on holobionts have not investigated both sides to similar depths. Here, we report dual symbiosis in the peltospirid snail Gigantopelta aegis with two gammaproteobacterial endosymbionts: a sulfur oxidiser and a methane oxidiser. We assemble high-quality genomes for all three parties, including a chromosome-level host genome. Hologenomic analyses reveal mutualism with nutritional complementarity and metabolic co-dependency, highly versatile in transporting and using chemical energy. Gigantopelta aegis likely remodels its immune system to facilitate dual symbiosis. Comparisons with Chrysomallon squamiferum, a confamilial snail with a single sulfur-oxidising gammaproteobacterial endosymbiont, show that their sulfur-oxidising endosymbionts are phylogenetically distant. This is consistent with previous findings that they evolved endosymbiosis convergently. Notably, the two sulfur-oxidisers share the same capabilities in biosynthesising nutrients lacking in the host genomes, potentially a key criterion in symbiont selection.
Four-dimensional vibrational spectroscopy for nanoscale mapping of phonon dispersion in BN nanotubes
Authors: Qi Ruishi , Li Ning , Du Jinlong , Shi Ruochen , Huang Yang , Yang Xiaoxia , Liu Lei , Xu Zhi , Dai Qing , Yu Dapeng , Gao Peng
Published: February 2021

Directly mapping local phonon dispersion in individual nanostructures can advance our understanding of their thermal, optical, and mechanical properties. However, this requires high detection sensitivity and combined spatial, energy and momentum resolutions, thus has been elusive. Here, we demonstrate a four-dimensional electron energy loss spectroscopy technique, and present position-dependent phonon dispersion measurements in individual boron nitride nanotubes. By scanning the electron beam in real space while monitoring both the energy loss and the momentum transfer, we are able to reveal position- and momentum-dependent lattice vibrations at nanometer scale. Our measurements show that the phonon dispersion of multi-walled nanotubes is locally close to hexagonal-boron nitride crystals. Interestingly, acoustic phonons are sensitive to defect scattering, while optical modes are insensitive to small voids. This work not only provides insights into vibrational properties of boron nitride nanotubes, but also demonstrates potential of the developed technique in nanoscale phonon dispersion measurements.
Direct observation of charge separation in an organic light harvesting system by femtosecond time-resolved XPS
Authors: Roth Friedrich , Borgwardt Mario , Wenthaus Lukas , Mahl Johannes , Palutke Steffen , Brenner Günter , Mercurio Giuseppe , Molodtsov Serguei , Wurth Wilfried , Gessner Oliver , Eberhardt Wolfgang
Published: February 2021

The ultrafast dynamics of photon-to-charge conversion in an organic light-harvesting system is studied by femtosecond time-resolved X-ray photoemission spectroscopy (TR-XPS) at the free-electron laser FLASH. This novel experimental technique provides site-specific information about charge separation and enables the monitoring of free charge carrier generation dynamics on their natural timescale, here applied to the model donor-acceptor system CuPc:C60. A previously unobserved channel for exciton dissociation into mobile charge carriers is identified, providing the first direct, real-time characterization of the timescale and efficiency of charge generation from low-energy charge-transfer states in an organic heterojunction. The findings give strong support to the emerging realization that charge separation even from energetically disfavored excitonic states is contributing significantly, indicating new options for light harvesting in organic heterojunctions.
Mitochondrial DNA editing in mice with DddA-TALE fusion deaminases
Authors: Lee Hyunji , Lee Seonghyun , Baek Gayoung , Kim Annie , Kang Beum-Chang , Seo Huiyun , Kim Jin-Soo
Published: February 2021

DddA-derived cytosine base editors (DdCBEs), composed of the split interbacterial toxin DddAtox, transcription activator-like effector (TALE), and uracil glycosylase inhibitor (UGI), enable targeted C-to-T base conversions in mitochondrial DNA (mtDNA). Here, we demonstrate highly efficient mtDNA editing in mouse embryos using custom-designed DdCBEs. We target the mitochondrial gene, MT-ND5 (ND5), which encodes a subunit of NADH dehydrogenase that catalyzes NADH dehydration and electron transfer to ubiquinone, to obtain several mtDNA mutations, including m.G12918A associated with human mitochondrial diseases and m.C12336T that incorporates a premature stop codon, creating mitochondrial disease models in mice and demonstrating a potential for the treatment of mitochondrial disorders.
Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis
Authors: Wipperman Matthew F. , Bhattarai Shakti K. , Vorkas Charles Kyriakos , Maringati Venkata Suhas , Taur Ying , Mathurin Laurent , McAulay Katherine , Vilbrun Stalz Charles , Francois Daphie , Bean James , Walsh Kathleen F. , Nathan Carl , Fitzgerald Daniel W. , Glickman Michael S. , Bucci Vanni
Published: February 2021

The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.
Author Correction: High-performance compliant thermoelectric generators with magnetically self-assembled soft heat conductors for self-powered wearable electronics
Authors: Lee Byeongmoon , Cho Hyeon , Park Kyung Tae , Kim Jin-Sang , Park Min , Kim Heesuk , Hong Yongtaek , Chung Seungjun
Published: February 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21629-y
Nuclear spin assisted magnetic field angle sensing
Authors: Qiu Ziwei , Vool Uri , Hamo Assaf , Yacoby Amir
Published: February 2021

Quantum sensing exploits the strong sensitivity of quantum systems to measure small external signals. The nitrogen-vacancy (NV) center in diamond is one of the most promising platforms for real-world quantum sensing applications, predominantly used as a magnetometer. However, its magnetic field sensitivity vanishes when a bias magnetic field acts perpendicular to the NV axis. Here, we introduce a different sensing strategy assisted by the nitrogen nuclear spin that uses the entanglement between the electron and nuclear spins to restore the magnetic field sensitivity. This, in turn, allows us to detect small changes in the magnetic field angle relative to the NV axis. Furthermore, based on the same underlying principle, we show that the NV coupling strength to magnetic noise, and hence its coherence time, exhibits a strong asymmetric angle dependence. This allows us to uncover the directional properties of the local magnetic environment and to realize maximal decoupling from anisotropic noise.
Berry curvature origin of the thickness-dependent anomalous Hall effect in a ferromagnetic Weyl semimetal
Authors: Zhang Yao , Yin Yuefeng , Dubuis Guy , Butler Tane , Medhekar Nikhil V. , Granville Simon
Published: February 2021

Magnetic Weyl semimetals with spontaneously broken time-reversal symmetry exhibit a large intrinsic anomalous Hall effect originating from the Berry curvature. To employ this large Hall current for room temperature topo-spintronics applications, it is necessary to fabricate these materials as thin or ultrathin films. Here, we experimentally demonstrate that Weyl semimetal Co2MnGa thin films (20–50 nm) show a large anomalous Hall angle ~11.4% at low temperature and ~9.7% at room temperature, which can be ascribed to the non-trivial topology of the band structure with large intrinsic Berry curvature. However, the anomalous Hall angle decreases significantly with thicknesses below 20 nm, which band structure calculations confirm is due to the reduction of the majority spin contribution to the Berry curvature. Our results suggest that Co2MnGa is an excellent material to realize room temperature topo-spintronics applications; however, the significant thickness dependence of the Berry curvature has important implications for thin-film device design.
Quantifying the impact of the COVID-19 lockdown on household water consumption patterns in England
Authors: Abu-Bakar Halidu , Williams Leon , Hallett Stephen H.
Published: February 2021

The COVID-19 lockdown has instigated significant changes in household behaviours across a variety of categories including water consumption, which in the south and east regions of England is at an all-time high. We analysed water consumption data from 11,528 households over 20 weeks from January 2020, revealing clusters of households with distinctive temporal patterns. We present a data-driven household water consumer segmentation characterising households’ unique consumption patterns and we demonstrate how the understanding of the impact of these patterns of behaviour on network demand during the COVID-19 pandemic lockdown can improve the accuracy of demand forecasting. Our results highlight those groupings with the highest and lowest impact on water demand across the network, revealing a significant quantifiable change in water consumption patterns during the COVID-19 lockdown period. The implications of the study to urban water demand forecasting strategies are discussed, along with proposed future research directions.