bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-resolution characterization of gene function using single-cell CRISPR tiling screen
Authors: Yang Lu , Chan Anthony K. N. , Miyashita Kazuya , Delaney Christopher D. , Wang Xi , Li Hongzhi , Pokharel Sheela Pangeni , Li Sandra , Li Mingli , Xu Xiaobao , Lu Wei , Liu Qiao , Mattson Nicole , Chen Kevin Yining , Wang Jinhui , Yuan Yate-Ching , Horne David , Rosen Steven T. , Soto-Feliciano Yadira , Feng Zhaohui , Hoshii Takayuki , Xiao Gang , Müschen Markus , Chen Jianjun , Armstrong Scott A. , Chen Chun-Wei 
Published: July 2021

AbstractIdentification of novel functional domains and characterization of detailed regulatory mechanisms in cancer-driving genes is critical for advanced cancer therapy. To date, CRISPR gene editing has primarily been applied to defining the role of individual genes. Recently, high-density mutagenesis via CRISPR tiling of gene-coding exons has been demonstrated to identify functional regions in genes. Furthermore, breakthroughs in combining CRISPR library screens with single-cell droplet RNA sequencing (sc-RNAseq) platforms have revealed the capacity to monitor gene expression changes upon genetic perturbations at single-cell resolution. Here, we present “sc-Tiling,” which integrates a CRISPR gene-tiling screen with single-cell transcriptomic and protein structural analyses. Distinct from other reported single-cell CRISPR screens focused on observing gene function and gene-to-gene/enhancer-to-gene regulation, sc-Tiling enables the capacity to identify regulatory mechanisms within a gene-coding region that dictate gene activity and therapeutic response.
Binding of guide piRNA triggers methylation of the unstructured N-terminal region of Aub leading to assembly of the piRNA amplification complex
Authors: Huang Xiawei , Hu Hongmiao , Webster Alexandre , Zou Fan , Du Jiamu , Patel Dinshaw J. , Sachidanandam Ravi , Toth Katalin Fejes , Aravin Alexei A. , Li Sisi 
Published: July 2021

AbstractPIWI proteins use guide piRNAs to repress selfish genomic elements, protecting the genomic integrity of gametes and ensuring the fertility of animal species. Efficient transposon repression depends on amplification of piRNA guides in the ping-pong cycle, which in Drosophila entails tight cooperation between two PIWI proteins, Aub and Ago3. Here we show that post-translational modification, symmetric dimethylarginine (sDMA), of Aub is essential for piRNA biogenesis, transposon silencing and fertility. Methylation is triggered by loading of a piRNA guide into Aub, which exposes its unstructured N-terminal region to the PRMT5 methylosome complex. Thus, sDMA modification is a signal that Aub is loaded with piRNA guide. Amplification of piRNA in the ping-pong cycle requires assembly of a tertiary complex scaffolded by Krimper, which simultaneously binds the N-terminal regions of Aub and Ago3. To promote generation of new piRNA, Krimper uses its two Tudor domains to bind Aub and Ago3 in opposite modification and piRNA-loading states. Our results reveal that post-translational modifications in unstructured regions of PIWI proteins and their binding by Tudor domains that are capable of discriminating between modification states is essential for piRNA biogenesis and silencing.
Serine-linked PARP1 auto-modification controls PARP inhibitor response
Authors: Prokhorova Evgeniia , Zobel Florian , Smith Rebecca , Zentout Siham , Gibbs-Seymour Ian , Schützenhofer Kira , Peters Alessandra , Groslambert Joséphine , Zorzini Valentina , Agnew Thomas , Brognard John , Nielsen Michael L. , Ahel Dragana , Huet Sébastien , Suskiewicz Marcin J. , Ahel Ivan 
Published: July 2021

AbstractPoly(ADP-ribose) polymerase 1 (PARP1) and PARP2 are recruited and activated by DNA damage, resulting in ADP-ribosylation at numerous sites, both within PARP1 itself and in other proteins. Several PARP1 and PARP2 inhibitors are currently employed in the clinic or undergoing trials for treatment of various cancers. These drugs act primarily by trapping PARP1 on damaged chromatin, which can lead to cell death, especially in cells with DNA repair defects. Although PARP1 trapping is thought to be caused primarily by the catalytic inhibition of PARP-dependent modification, implying that ADP-ribosylation (ADPr) can counteract trapping, it is not known which exact sites are important for this process. Following recent findings that PARP1- or PARP2-mediated modification is predominantly serine-linked, we demonstrate here that serine ADPr plays a vital role in cellular responses to PARP1/PARP2 inhibitors. Specifically, we identify three serine residues within PARP1 (499, 507, and 519) as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance. Our data implicate genes that encode serine-specific ADPr regulators, HPF1 and ARH3, as potential PARP1/PARP2 inhibitor therapy biomarkers.
Structural basis of the activation of c-MET receptor
Authors: Uchikawa Emiko , Chen Zhiming , Xiao Guan-Yu , Zhang Xuewu , Bai Xiao-chen 
Published: July 2021

AbstractThe c-MET receptor is a receptor tyrosine kinase (RTK) that plays essential roles in normal cell development and motility. Aberrant activation of c-MET can lead to both tumors growth and metastatic progression of cancer cells. C-MET can be activated by either hepatocyte growth factor (HGF), or its natural isoform NK1. Here, we report the cryo-EM structures of c-MET/HGF and c-MET/NK1 complexes in the active state. The c-MET/HGF complex structure reveals that, by utilizing two distinct interfaces, one HGF molecule is sufficient to induce a specific dimerization mode of c-MET for receptor activation. The binding of heparin as well as a second HGF to the 2:1 c-MET:HGF complex further stabilize this active conformation. Distinct to HGF, NK1 forms a stable dimer, and bridges two c-METs in a symmetrical manner for activation. Collectively, our studies provide structural insights into the activation mechanisms of c-MET, and reveal how two isoforms of the same ligand use dramatically different mechanisms to activate the receptor.
Xanthomonas effector XopR hijacks host actin cytoskeleton via complex coacervation
Authors: Sun He , Zhu Xinlu , Li Chuanxi , Ma Zhiming , Han Xiao , Luo Yuanyuan , Yang Liang , Yu Jing , Miao Yansong 
Published: July 2021

AbstractThe intrinsically disordered region (IDR) is a preserved signature of phytobacterial type III effectors (T3Es). The T3E IDR is thought to mediate unfolding during translocation into the host cell and to avoid host defense by sequence diversification. Here, we demonstrate a mechanism of host subversion via the T3E IDR. We report that the Xanthomonas campestris T3E XopR undergoes liquid-liquid phase separation (LLPS) via multivalent IDR-mediated interactions that hijack the Arabidopsis actin cytoskeleton. XopR is gradually translocated into host cells during infection and forms a macromolecular complex with actin-binding proteins at the cell cortex. By tuning the physical-chemical properties of XopR-complex coacervates, XopR progressively manipulates multiple steps of actin assembly, including formin-mediated nucleation, crosslinking of F-actin, and actin depolymerization, which occurs through competition for actin-depolymerizing factor and depends on constituent stoichiometry. Our findings unravel a sophisticated strategy in which bacterial T3E subverts the host actin cytoskeleton via protein complex coacervation.
A regulatory network involving Rpo, Gac and Rsm for nitrogen-fixing biofilm formation by Pseudomonas stutzeri
Authors: Shang Liguo , Yan Yongliang , Zhan Yuhua , Ke Xiubin , Shao Yahui , Liu Yaqun , Yang Hua , Wang Shanshan , Dai Shuling , Lu Jiasi , Yan Ning , Yang Zhimin , Lu Wei , Liu Zhu , Chen Shanchun , Elmerich Claudine , Lin Min 
Published: July 2021

AbstractBiofilm and nitrogen fixation are two competitive strategies used by many plant-associated bacteria; however, the mechanisms underlying the formation of nitrogen-fixing biofilms remain largely unknown. Here, we examined the roles of multiple signalling systems in the regulation of biofilm formation by root-associated diazotrophicP. stutzeriA1501. Physiological analysis, construction of mutant strains and microscale thermophoresis experiments showed that RpoN is a regulatory hub coupling nitrogen fixation and biofilm formation by directly activating the transcription ofpslA, a major gene involved in the synthesis of the Psl exopolysaccharide component of the biofilm matrix andnifA, the transcriptional activator ofnifgene expression. Genetic complementation studies and determination of the copy number of transcripts by droplet digital PCR confirmed that the regulatory ncRNA RsmZ serves as a signal amplifier to trigger biofilm formation by sequestering the translational repressor protein RsmA away frompslAandsadCmRNAs, the latter of which encodes a diguanylate cyclase that synthesises c-di-GMP. Moreover, RpoS exerts a braking effect on biofilm formation by transcriptionally downregulating RsmZ expression, while RpoS expression is repressed posttranscriptionally by RsmA. These findings provide mechanistic insights into how the Rpo/Gac/Rsm regulatory networks fine-tune nitrogen-fixing biofilm formation in response to the availability of nutrients.
Teaching solid mechanics to artificial intelligence—a fast solver for heterogeneous materials
Authors: Mianroodi Jaber Rezaei , H. Siboni Nima , Raabe Dierk 
Published: July 2021

AbstractWe propose a deep neural network (DNN) as a fast surrogate model for local stress calculations in inhomogeneous non-linear materials. We show that the DNN predicts the local stresses with 3.8% mean absolute percentage error (MAPE) for the case of heterogeneous elastic media and a mechanical contrast of up to factor of 1.5 among neighboring domains, while performing 103 times faster than spectral solvers. The DNN model proves suited for reproducing the stress distribution in geometries different from those used for training. In the case of elasto-plastic materials with up to 4 times mechanical contrast in yield stress among adjacent regions, the trained model simulates the micromechanics with a MAPE of 6.4% in one single forward evaluation of the network, without any iteration. The results reveal an efficient approach to solve non-linear mechanical problems, with an acceleration up to a factor of 8300 for elastic-plastic materials compared to typical solvers.
Statistical learning occurs during practice while high-order rule learning during rest period
Authors: Quentin Romain , Fanuel Lison , Kiss Mariann , Vernet Marine , Vékony Teodóra , Janacsek Karolina , Cohen Leonardo G. , Nemeth Dezso 
Published: July 2021

AbstractKnowing when the brain learns is crucial for both the comprehension of memory formation and consolidation and for developing new training and neurorehabilitation strategies in healthy and patient populations. Recently, a rapid form of offline learning developing during short rest periods has been shown to account for most of procedural learning, leading to the hypothesis that the brain mainly learns during rest between practice periods. Nonetheless, procedural learning has several subcomponents not disentangled in previous studies investigating learning dynamics, such as acquiring the statistical regularities of the task, or else the high-order rules that regulate its organization. Here we analyzed 506 behavioral sessions of implicit visuomotor deterministic and probabilistic sequence learning tasks, allowing the distinction between general skill learning, statistical learning, and high-order rule learning. Our results show that the temporal dynamics of apparently simultaneous learning processes differ. While high-order rule learning is acquired offline, statistical learning is evidenced online. These findings open new avenues on the short-scale temporal dynamics of learning and memory consolidation and reveal a fundamental distinction between statistical and high-order rule learning, the former benefiting from online evidence accumulation and the latter requiring short rest periods for rapid consolidation.
How young children integrate information sources to infer the meaning of words
Authors: Bohn Manuel , Tessler Michael Henry , Merrick Megan , Frank Michael C. 
Published: July 2021

AbstractBefore formal education begins, children typically acquire a vocabulary of thousands of words. This learning process requires the use of many different information sources in their social environment, including their current state of knowledge and the context in which they hear words used. How is this information integrated? We specify a developmental model according to which children consider information sources in an age-specific way and integrate them via Bayesian inference. This model accurately predicted 2–5-year-old children’s word learning across a range of experimental conditions in which they had to integrate three information sources. Model comparison suggests that the central locus of development is an increased sensitivity to individual information sources, rather than changes in integration ability. This work presents a developmental theory of information integration during language learning and illustrates how formal models can be used to make a quantitative test of the predictive and explanatory power of competing theories.
Nonlinear second-order photonic topological insulators
Authors: Kirsch Marco S. , Zhang Yiqi , Kremer Mark , Maczewsky Lukas J. , Ivanov Sergey K. , Kartashov Yaroslav V. , Torner Lluis , Bauer Dieter , Szameit Alexander , Heinrich Matthias 
Published: July 2021

AbstractHigher-order topological insulators are a novel topological phase beyond the framework of conventional bulk–boundary correspondence1,2. In these peculiar systems, the topologically non-trivial boundary modes are characterized by a co-dimension of at least two3,4. Despite several promising preliminary considerations regarding the impact of nonlinearity in such systems5,6, the flourishing field of experimental higher-order topological insulator research has thus far been confined to the linear evolution of topological states. As such, the observation of the interplay between nonlinearity and the dynamics of higher-order topological phases in conservative systems remains elusive. Here we experimentally demonstrate nonlinear higher-order topological corner states. Our photonic platform enables us to observe nonlinear topological corner states as well as the formation of solitons in such topological structures. Our work paves the way towards the exploration of topological properties of matter in the nonlinear regime, and may herald a new class of compact devices that harnesses the intriguing features of topology in an on-demand fashion.
Eight soybean reference genome resources from varying latitudes and agronomic traits
Authors: Chu Jeffrey Shih-Chieh , Peng Bo , Tang Kuanqiang , Yi Xingxing , Zhou Huangkai , Wang Huan , Li Guang , Leng Jiantian , Chen Nansheng , Feng Xianzhong 
Published: July 2021

AbstractComparative analysis of multiple reference genomes representing diverse genetic backgrounds is critical for understanding the role of key alleles important in domestication and genetic breeding of important crops such as soybean. To enrich the genetic resources for soybean, we describe the generation, technical assessment, and preliminary genomic variation analysis of eight de novo reference-grade soybean genome assemblies from wild and cultivated accessions. These resources represent soybeans cultured at different latitudes and exhibiting different agronomical traits. Of these eight soybeans, five are from new accessions that have not been sequenced before. We demonstrate the usage of these genomes to identify small and large genomic variations affecting known genes as well as screening for genic PAV regions for identifying candidates for further functional studies.
Phytotoxic effects of invasive Ageratina adenophora on two native subtropical shrubs in Nepal
Authors: Darji Tej Bahadur , Adhikari Barsha , Pathak Seeta , Neupane Shristi , Thapa Lal B. , Bhatt Tara Datt , Pant Ramesh Raj , Pant Gunanand , Pal Khadka Bahadur , Bishwakarma Kiran 
Published: July 2021

AbstractThe response of native plants to allelopathic interference of invasive species may differ from species to species. In this study, the phytotoxic effects ofAgeratina adenophorawere tested on two native shrubs (Osbeckia stellataandElsholtzia blanda) of Nepal. Both the shrubs were grown in pots under treatments ofA. adenophorafresh leaves and root leachates, and litter. Then, the seedling length and biomass were compared among the treatments. The results show thatA. adenophoralitter has stimulatory effects but the leachates from fresh leaves and root are phytotoxic to the growth and development of native shrubs. Infrared Spectroscopy (IR) analysis confirmed the presence of O–H (Hydroxyl), N–H (Amines), C≡C (Alkynes), and C–H stretching (Aromatic) or C–O–C stretching (Ethers) in the leachates representing harmful allelochemicals. The invaded soil byA. adenophorahad low pH and a high amount of organic matter, total nitrogen, phosphorus, and potassium than the uninvaded soil. The results indicate that the nativeO. stellataandE. blandaare harmed byA. adenophorain nature by leaching of allelochemicals and probably by reducing the soil pH. Overall, this study has provided valuable insights regarding the effects ofA. adenophorainvasion on native shrubs and revealing the potential mechanism of its invasiveness.
Visualization and modeling of inhibition of IL-1β and TNF-α mRNA transcription at the single-cell level
Authors: Kalb Daniel , Vo Huy D. , Adikari Samantha , Hong-Geller Elizabeth , Munsky Brian , Werner James 
Published: July 2021

AbstractIL-1β and TNF-α are canonical immune response mediators that play key regulatory roles in a wide range of inflammatory responses to both chronic and acute conditions. Here we employ an automated microscopy platform for the analysis of messenger RNA (mRNA) expression of IL-1β and TNF-α at the single-cell level. The amount of IL-1β and TNF-α mRNA expressed in a human monocytic leukemia cell line (THP-1) is visualized and counted using single-molecule fluorescent in-situ hybridization (smFISH) following exposure of the cells to lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria. We show that the small molecule inhibitors MG132 (a 26S proteasome inhibitor used to block NF-κB signaling) and U0126 (a MAPK Kinase inhibitor used to block CCAAT-enhancer-binding proteins C/EBP) successfully block IL-1β and TNF-α mRNA expression. Based upon this single-cell mRNA expression data, we screened 36 different mathematical models of gene expression, and found two similar models that capture the effects by which the drugs U0126 and MG132 affect the rates at which the genes transition into highly activated states. When their parameters were informed by the action of each drug independently, both models were able to predict the effects of the combined drug treatment. From our data and models, we postulate that IL-1β is activated by both NF-κB and C/EBP, while TNF-α is predominantly activated by NF-κB. Our combined single-cell experimental and modeling efforts show the interconnection between these two genes and demonstrates how the single-cell responses, including the distribution shapes, mean expression, and kinetics of gene expression, change with inhibition.
Angle change of the A-domain in a single SERCA1a molecule detected by defocused orientation imaging
Authors: Katoh Takanobu A. , Daiho Takashi , Yamasaki Kazuo , Danko Stefania , Fujimura Shoko , Suzuki Hiroshi 
Published: July 2021

AbstractThe sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ ions across the membrane coupled with ATP hydrolysis. Crystal structures of ligand-stabilized molecules indicate that the movement of actuator (A) domain plays a crucial role in Ca2+ translocation. However, the actual structural movements during the transitions between intermediates remain uncertain, in particular, the structure of E2PCa2 has not been solved. Here, the angle of the A-domain was measured by defocused orientation imaging using isotropic total internal reflection fluorescence microscopy. A single SERCA1a molecule, labeled with fluorophore ReAsH on the A-domain in fixed orientation, was embedded in a nanodisc, and stabilized on Ni–NTA glass. Activation with ATP and Ca2+ caused angle changes of the fluorophore and therefore the A-domain, motions lost by inhibitor, thapsigargin. Our high-speed set-up captured the motion during EP isomerization, and suggests that the A-domain rapidly rotates back and forth from an E1PCa2 position to a position close to the E2P state. This is the first report of the detection in the movement of the A-domain as an angle change. Our method provides a powerful tool to investigate the conformational change of a membrane protein in real-time.
A pan-cancer transcriptomic study showing tumor specific alterations in central metabolism
Authors: Sheraj Ilir , Guray N. Tulin , Banerjee Sreeparna 
Published: July 2021

AbstractRecently, there has been a resurgence of interest in metabolic rewiring of tumors to identify clinically relevant genes. However, most of these studies have had either focused on individual tumors, or are too general, providing a broad outlook on overall changes. In this study, we have first curated an extensive list of genes encoding metabolic enzymes and metabolite transporters relevant to carbohydrate, fatty acid and amino acid oxidation and biosynthesis. Next, we have used publicly available transcriptomic data for 20 different tumor types from The Cancer Genome Atlas Network (TCGA) and focused on differential expression of these genes between tumor and adjacent normal tissue. Our study revealed major transcriptional alterations in genes that are involved in central metabolism. Most tumors exhibit upregulation in carbohydrate and amino acid transporters, increased glycolysis and pentose phosphate pathway, and decreased fatty acid and amino acid oxidation. On the other hand, the expression of genes of the tricarboxylic acid cycle, anaplerotic reactions and electron transport chain differed between tumors. Although most transcriptomic alterations were conserved across many tumor types suggesting the initiation of common regulatory programs, expression changes unique to specific tumors were also identified, which can provide gene expression fingerprints as potential biomarkers or drug targets. Our study also emphasizes the value of transcriptomic data in the deeper understanding of metabolic changes in diseases.
Spatiotemporal analysis of COVID-19 outbreaks in Wuhan, China
Authors: Liu Wei , Wang Dongming , Hua Shuiqiong , Xie Cong , Wang Bin , Qiu Weihong , Xu Tao , Ye Zi , Yu Linling , Yang Meng , Xiao Yang , Feng Xiaobing , Shi Tingming , Li Mingyan , Chen Weihong 
Published: July 2021

AbstractFew study has revealed spatial transmission characteristics of COVID-19 in Wuhan, China. We aimed to analyze the spatiotemporal spread of COVID-19 in Wuhan and its influence factors. Information of 32,682 COVID-19 cases reported through March 18 were extracted from the national infectious disease surveillance system. Geographic information system methods were applied to analysis transmission of COVID-19 and its influence factors in different periods. We found decrease in effective reproduction number (Rt) and COVID-19 related indicators through taking a series of effective public health measures including restricting traffic, centralized quarantine and strict stay-at home policy. The distribution of COVID-19 cases number in Wuhan showed obvious global aggregation and local aggregation. In addition, the analysis at streets-level suggested population density and the number of hospitals were associated with COVID-19 cases number. The epidemic situation showed obvious global and local spatial aggregations. High population density with larger number of hospitals may account for the aggregations. The epidemic in Wuhan was under control in a short time after strong quarantine measures and restrictions on movement of residents were implanted.