bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Arabidopsisvenosa4-0supports the role of VENOSA4 in dNTP homeostasis
Authors: Sarmiento-Mañús Raquel , González-Bayón Rebeca , Fontcuberta-Cervera Sara , Hannah Matthew A. , Álvarez-Martínez Francisco Javier , Barrajón-Catalán Enrique , Micol Vicente , Quesada Víctor , Ponce María Rosa , Micol José Luis 
Published: April 2023

ABSTRACTAn imbalance in the deoxyribonucleoside triphosphate (dNTP) pool caused by an increase or decrease in the levels of any of the four dNTPs leads to increased DNA mutations, overloading DNA repair mechanisms. The human protein SAMHD1 (Sterile alpha motif and histidine-aspartate domain containing protein 1) functions as a dNTPase to maintain the balance of the dNTP pool, as well as in DNA repair. In eukaryotes, the limiting step inde novodNTP synthesis is catalyzed by RIBONUCLEOTIDE REDUCTASE (RNR), which consists of two R1 and two R2 subunits. In Arabidopsis, RNR1 is encoded byCRINKLED LEAVES 8(CLS8) and RNR2 by three paralogous genes, includingTSO2(TSO MEANING ’UGLY’ IN CHINESE 2). In plants, thede novobiosynthesis of purines occurs within the chloroplast, and DOV1 (DIFFERENTIAL DEVELOPMENT OF VASCULAR ASSOCIATED CELLS 1) catalyzes the first step of this pathway. Here, to explore the role ofVENOSA4(VEN4), the most likely Arabidopsis ortholog of humanSAMHD1, we studied theven4-0mutant. The mutant leaf phenotype caused by theven4-0point mutation was stronger than those of T-DNA insertionalven4mutations. Structural predictions suggested that the E249L amino acid substitution in the mutated VEN4-0 protein rigidifies its 3D structure compared to wild-type VEN4. The morphological phenotypes of theven4,cls8, anddov1single mutants were similar, and those of theven4 tso2andven4 dov1double mutants were synergistic. Theven4-0mutant had reduced levels of four amino acids related to dNTP biosynthesis, including glutamine and glycine, which are precursors in thede novopurine biosynthesis pathway. Finally, despite its annotation in some databases, At5g40290, a paralog ofVEN4, is likely a pseudogene. These observations support the previously proposed role of VEN4 in dNTP metabolism. Our results reveal a high degree of cross-kingdom functional conservation between VEN4 and SAMHD1 in dNTP homeostasis.
Determining epitope specificity of T-cell receptors with transformers
Authors: Khan Abdul Rehman , Reinders Marcel JT , Khatri Indu 
Published: April 2023

AbstractMotivationT-cell receptors (TCR) on T cells recognize and bind to epitopes presented by the major histocompatibility complex (MHC) in case of an infection or cancer. However, the high diversity of TCRs, as well as their unique and complex binding mechanisms underlying epitope recognition, make it difficult to predict the binding between TCR and epitope. Here, we present the utility of transformers, a deep learning strategy that incorporates an attention mechanism that learns the informative features, and show that these models pretrained on a large set of protein sequences outperform current strategies.MethodWe compared three pre-trained auto-encoder transformer models (ProtBERT, ProtAlbert, ProtElectra) and one pre-trained auto-regressive transformer model (ProtXLNet) to predict the binding specificity of TCRs to 25 epitopes from the VDJdb database (human and murine). Two additional modifications were performed to incorporate gene usage of the TCRs in the four transformer models.ResultsOf all 12 transformer implementations (4 models with 3 different modifications), a modified version of the ProtXLNet model could predict TCR-epitope pairs with the highest accuracy (weighted F1 score 0.55 simultaneously considering all 25 epitopes). The modification included additional features representing the gene names for the TCRs. We also showed that the basic implementation of transformers outperformed the previously available methods, i.e. TCRGP, TCRDist and DeepTCR, developed for the same biological problem, especially for the hard-to-classify labels.ConclusionWe show that the proficiency of transformers in attention learning can indeed be made operational in a complex biological setting like TCR binding prediction. Further ingenuity in utilizing the full potential of transformers, either through attention head visualization or introducing additional features, can further extend T-cell research avenues.AvailabilityData and code are available onhttps://github.com/InduKhatri/tcrformer
The positioning mechanics of microtubule asters inDrosophilaembryo explants
Authors: de-Carvalho Jorge , Tlili Sham , Saunders Timothy E. , Telley Ivo A. 
Published: April 2023

AbstractMicrotubule asters are essential in localizing the action of microtubules in processes including mitosis and organelle positioning. In large cells, such as the one-cell sea urchin embryo, aster dynamics are dominated by hydrodynamic pulling forces. However, in systems with more densely positioned nuclei such as the earlyDrosophilaembryo, which packs around 6000 nuclei within the syncytium in a crystalline-like order, it is unclear what processes dominate aster dynamics. Here, we take advantage of a cell cycle regulationDrosophilamutant to generate embryos with multiple asters, independent from nuclei. We use anex vivoassay to further simplify this biological system to explore the forces generated by and between asters. Through live imaging, drug and optical perturbations, and theoretical modelling, we demonstrate that these asters likely generate an effective pushing force over short distances.Significance StatementUsing cytosolic explants fromDrosophilasyncytial embryos combined with quantitative microscopy and perturbations, de-Carvalhoet al., reveal the mechanical forces separatingDrosophilamicrotubule asters. Aster separation drives precise nuclear positioning in multinucleated embryo cells, a vital process for tissue formation and gene expression during subsequent embryo development.
Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy
Authors: Mistretta Maxime , Cimino Mena , Campagne Pascal , Volant Stevenn , Kornobis Etienne , Hebert Olivier , Rochais Christophe , Dallemagne Patrick , Lecoutey Cédric , Tisnerat Camille , Lepailleur Alban , Ayotte Yann , LaPlante Steven R. , Gangneux Nicolas , Záhorszká Monika , Korduláková Jana , Vichier-Guerre Sophie , Bonhomme Frédéric , Pokorny Laura , Albert Marvin , Tinevez Jean-Yves , Manina Giulia 
Published: April 2023

AbstractDrug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective anti-microbial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. To address this, we developed a flow-controlled multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells, compressed inside separate microchambers by a soft hydro-pneumatic membrane. With this platform, we implemented a dynamic single-cell screening for compounds that induce a phenotypic change while decreasing cell-to-cell variation, aiming to undermine the bacterial population, making it more vulnerable to other drugs. We first applied this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our top hit impairsMycobacterium tuberculosisvia a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that pheno-tuning compounds represent a successful approach to tackle pathogens that are increasingly difficult to treat.
The diversity of splicing modifiers acting on A-1bulged 5’-splice sites reveals rules to guide rational design
Authors: Florian Malard , Wolter Antje , Marquevielle Julien , Morvan Estelle , Allain Frédéric HT. , Sebastien Campagne 
Published: April 2023

ABSTRACTNon-physiological alternative splicing patterns are associated with numerous human diseases. Among the strategies developed to treat these diseases, small molecule splicing modifiers are emerging as a new class of RNA therapeutics. TheSMN2splicing modifier SMN-C5 was used as a prototype to understand their mode of action and discover the concept of 5’-splice site bulge repair. However, different small molecules harbouring a similar activity were also identified. In this study, we combined NMR spectroscopy and computational approaches to determine the binding modes of otherSMN2andHTTsplicing modifiers at the interface between U1 snRNP and an A-1bulged 5’-splice site. Our results show that the other splicing modifiers interact with the intermolecular RNA helix epitope containing an unpaired adenine within a G-2A-1G+1U+2motif, which is essential for their biological activity. We also determined structural models of risdiplam, SMN-CX, and branaplam bound to RNA, and solved the solution structure of the most divergentSMN2splicing modifier, SMN-CY, in complex with the RNA helix. These findings not only deepen our understanding of the chemical diversity of splicing modifiers that target A-1bulged 5’-splice sites, but also identify common pharmacophores required for modulating 5’-splice site selection with small molecules.
A rapid and robust leaf ablation method to visualize bundle sheath cell chloroplasts in C3species
Authors: Billakurthi Kumari , Hibberd Julian M 
Published: April 2023

AbstractBackgroundIt has been proposed that engineering the C4photosynthetic pathway into C3crops could significantly increase yield. This goal requires an increase in the chloroplast compartment of bundle sheath cells in C3species. To facilitate large-scale testing of candidate regulators of chloroplast development in the rice bundle sheath, a simple and robust method to phenotype this tissue in C3species is required.ResultsWe established a leaf ablation method to accelerate phenotyping of rice bundle sheath cells. The approach allowed bundle sheath cell dimensions, chloroplast area and chloroplast number per cell to be measured. Using this method, bundle sheath cell dimensions of maize were also measured and compared with rice. Our data show that bundle sheath width but not length significantly differed between C3rice and C4maize. Comparison of paradermal versus transverse bundle sheath cell width indicated that bundle sheath cells were intact after leaf ablation. Moreover, comparisons of planar chloroplast areas and chloroplast numbers per bundle sheath cell between wild-type and transgenic rice lines expressing the maizeGOLDEN-2(ZmG2) showed that the leaf ablation method allowed differences in chloroplast parameters to be detected.ConclusionsLeaf ablation is a simple approach to accessing bundle sheath cell files in C3species. We show that this method is suitable for obtaining parameters associated with bundle sheath cell size, chloroplast area and chloroplast number per cell.
TCR2vec: a deep representation learning framework of T-cell receptor sequence and function
Authors: Jiang Yuepeng , Huo Miaozhe , Zhang Pingping , Zou Yiping , Li Shuai Cheng 
Published: April 2023

AbstractThe T-cell receptor (TCR) repertoires are critical components of the adaptive immune system, and machine learning methods were proposed to analyze the TCR repertoire data. However, most methods work solely on the hypervariable CDR3 regions of TCRs, overlooking the information encoded in other domains. Representing full TCRs as informative vectors can be indispensable for developing reliable and effective machine learning models. We introduce TCR2vec, a deep representation learning framework with 12 layers of transformer blocks, to pave the way for downstream modelings of full TCRs. Together with masked language modeling (MLM), we propose a novel pretraining task named similarity preservation modeling (SPM) to capture the sequence similarities of TCRs. Through a multi-task pretraining procedure on MLM and SPM, TCR2vec learns a contextual understanding of TCRs within a similarity-preserved vector space. We first verify the effectiveness of TCR2vec in predicting TCR’s binding specificity and TCR clustering through comparison with three other embedding approaches. TCR2vec can be finetuned on small task-specific labeled data for enhanced performance, which outperforms state-of-the-art models by 2-25% in predicting TCR’s binding specificity. Next, we compare the performance of two versions of TCR2vec pretrained on full TCRs (TCR2vec) or CDR3s (CDR3vec) and demonstrate that TCR2vec consistently outperforms CDR3vec by 12-14%. Further analysis of attention maps reveals that residues outside CDR3 also make notable contributions to the recognition of antigens. TCR2vec is available athttps://github.com/jiangdada1221/TCR2vec.
PanKmer:k-mer based and reference-free pangenome analysis
Authors: Aylward Anthony J. , Petrus Semar , Mamerto Allen , Hartwick Nolan T. , Michael Todd P. 
Published: April 2023

AbstractSummaryPangenomes are replacing single reference genomes as the definitive representation of DNA sequence within a species or clade. Pangenome analysis predominantly leverages graph-based methods that require computationally intensive multiple genome alignments, do not scale to highly complex eukaryotic genomes, limit their scope to identifying structural variants (SVs), or incur bias by relying on a reference genome. Here, we present PanKmer, a toolkit designed for reference-free analysis of pangenome datasets consisting of dozens to thou-sands of individual genomes. PanKmer decomposes a set of input genomes into a table of observedk-mers and their presence-absence values in each genome. These are stored in an efficientk-mer index data format that encodes SNPs, INDELs, and SVs. It also includes functions for downstream analysis of thek-mer index, such as calculating sequence similarity statistics between individuals at whole-genome or local scales. For example,k-mers can be “anchored” in any individual genome to quantify sequence variability or conservation at a specific locus. This facilitates workflows with various biological applications, e.g. identifying cases of hybridization between plant species. PanKmer provides researchers with a valuable and convenient means to explore the full scope of genetic variation in a population, without reference bias.Availability and implementationPanKmer is implemented as a Python package with components written in Rust, released under a BSD license. The source code is available from the Python Package Index (PyPI) athttps://pypi.org/project/pankmer/as well as Gitlab athttps://gitlab.com/salk-tm/pankmer. Full documentation is available athttps://salk-tm.gitlab.io/pankmer/.Supplementary informationSupplementary data are available online
Increase in primary cilia number and length upon VDAC1 depletion contributes to attenuated proliferation of cancer cells
Authors: Dutta Arpita , Halder Priyadarshini , Gayen Anakshi , Mukherjee Avik , Mukherjee Chandrama , Majumder Shubhra 
Published: April 2023

AbstractPrimary cilia (PCs) that are present in most human cells and perform sensory function or signal transduction are lost in many solid tumors. Previously, we identified VDAC1, best known to regulate mitochondrial bioenergetics, to negatively regulate ciliogenesis. Here, we show that downregulation of VDAC1 in pancreatic cancer-derived Panc1 and glioblastoma-derived U-87 cells significantly increased ciliation. Those PCs were remarkably longer than the control cells. Such increased ciliation inhibited cell cycle, which contributed to reduced proliferation of these cells. VDAC1-depletion also led to longer PCs in quiescent RPE1 cells. Therefore, serum-induced PC disassembly was slower in VDAC1-depleted RPE1 cells. Overall, this study reiterates the importance of VDAC1 in modulating tumorigenesis, due to its novel role in regulating PC length and disassembly.
Anti-nucleolin aptamer, iSN04, inhibits the inflammatory responses in myoblasts by modulating the β-catenin/NF-κB signaling pathway
Authors: Yamamoto Machi , Miyoshi Mana , Morioka Kamino , Mitani Takakazu , Takaya Tomohide 
Published: April 2023

AbstractA myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to be a nucleic acid drug for the muscle wasting associated with chronic diseases. The present study investigated the anti-inflammatory mechanism of iSN04 in the murine myoblast cell line C2C12. Tumor necrosis factor-α (TNF-α) or Toll-like receptor (TLR) ligands (Pam3CSK4and FSL-1) induced nuclear translocation and transcriptional activity of nuclear factor-κB (NF-κB), resulting in upregulated expression of TNF-α and interleukin-6. Pre-treatment with iSN04 significantly suppressed these inflammatory responses by inhibiting the nuclear accumulation of β-catenin induced by TNF-α or TLR ligands. These results demonstrate that antagonizing nucleolin with iSN04 downregulates the inflammatory effect mediated by the β-catenin/NF-κB signaling pathway in myoblasts. In addition, the anti-inflammatory effects of iSN04 were also observed in smooth muscle cells and pre-adipocytes, suggesting that iSN04 may be useful in preventing inflammation induced by metabolic disorders.
Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants
Authors: Zhang Pei-Pei , Benske Taylor M. , Paton James C. , Paton Adrienne W. , Mu Ting-Wei , Wang Ya-Juan 
Published: April 2023

AbstractTheGRINgenes encoding N-methyl-D-aspartate receptor (NMDAR) subunits are remarkably intolerant to variation. Many pathogenic NMDAR variants result in their protein misfolding, inefficient assembly, reduced surface expression, and impaired functionality at the plasma membrane, causing neurological disorders including epilepsy and intellectual disability. Here, we concentrate on the proteostasis maintenance of NMDARs containing epilepsy-associated variations in the GluN2A (or NR2A) subunit, including M705V and A727T. We showed that these two variants are targeted to the proteasome for degradation and have reduced functional surface expression. We demonstrated that the application of BIX, a known small molecule activator of an HSP70 family chaperone BiP (Binding immunoglobulinProtein) in the endoplasmic reticulum (ER), significantly increases total and surface protein levels, and thus the function of the M705V and A727T variants in HEK293T cells. Mechanistic studies revealed that BIX promotes folding, inhibits degradation, and enhances anterograde trafficking of the M705V variant by modest activation of the IRE1 pathway of the unfolded protein response. Our results showed that adapting the ER proteostasis network restores the folding, trafficking, and function of pathogenic NMDAR variants, representing a potential treatment for neurological disorders resulting from NMDAR dysfunction.
Cascading failure in guarantee networks from the perspective of equilibrium
Authors: Ren Chao , Liu Xiaoxing , Zhu Ziyan 
Published: April 2023

PurposeThe purpose of this paper is to test the invulnerability of the guarantee network at the equilibrium point.Design/methodology/approachThis paper introduces a tractable guarantee network model that captures the invulnerability of the network in terms of cascade-based attack. Furthermore, the equilibrium points are introduced for banks to determine loan origination.FindingsThe proposed approach not only develops equilibrium analysis as an extended perspective in the guarantee network, but also applies cascading failure method to construct the guarantee network. The equilibrium points are examined by simulating experiment. The invulnerability of the guarantee network is quantified by the survival of firms in the simulating progress.Research limitations/implicationsThere is less study in equilibrium analysis of the guarantee network. Additionally, cascading failure model is expressed in the presented approach. Moreover, agent-based model can be extended in generating the guarantee network in the future study.Originality/valueThe approach of this paper presents a framework to analyze the equilibrium of the guarantee network. For this, the systemic risk of the whole guarantee network and each node's contribution are measured to predict the probability of default on cascading failure. Focusing on cascade failure process based on equilibrium point, the invulnerability of the guarantee network can be quantified.
Development of an activated carbon‐geopolymer composite for treatment of Pb(II) polluted water and soil
Authors: He Panyang , Xin Kaineng , Zhang Xiaomin , Guo Zhonglin , Zheng Wei 
Published: April 2023

AbstractAn activated carbon‐geopolymer composite (ACGC) was prepared by using fly ash as raw materials via a simple geopolymerization process for treating the Pb(II) contaminant in wastewater and soil. The phase composition, microtopography, pore structure, and surface groups of the composites were studied by X‐ray diffractometer, field emission scanning electron microscopy, X‐ray photoelectron spectroscopy, N2 adsorption‐desorption isotherm, and Fourier transform infrared spectroscope. It was discovered that there was a synergistic effect between geopolymer matrix and activated carbon (AC), that is, addition of AC particles could increase the pores in geopolymer while strong alkalis condition provided by geopolymer enhanced the contents of oxygenic groups of AC. When the composite was used as the adsorbent, the sample containing 20 wt% AC (40ACGC) showed the maximum adsorption capacity (319.72 mg/g), and its adsorption isotherm fitted the Langmuir model well, suggesting the monolayer adsorption of Pb2+ on the 40ACGC. The kinetics of Pb2+ adsorption on the 40ACGC belonged to the pseudo‐second‐order model, indicating that Pb2+ adsorption on the composite followed chemical adsorption. In addition, the 40ACGC sample showed excellent stabilization performance for Pb2+ in soil. This work offered a new thinking to the application of geopolymers into remediation of heavy metal‐polluted soil.
Use of different ratios of by‐product from mung bean dry‐dehulling in pasta making: nutritional quality, textural and cooking attributes, overall acceptability and in‐vitro antioxidant release from the pasta
Authors: Le Thi Thuc Man , Nguyen Phuong Thao , Tran Thi Thu Tra , Ton Nu Minh Nguyet , Le Van Viet Man 
Published: April 2023

SummaryThe production of dehulled mung bean seeds generates a by‐product which includes husk particles and finely broken endosperm. In this study, the mung bean by‐product flour (MBBF) was used as an antioxidant dietary fibre ingredient for pasta formulation. Increase in MBBF ratio in the pasta recipe from 0% to 25% enhanced total dietary fibre and total phenolic of the product by 4.2 and 4.5 times, respectively; in addition, the cooking loss of pasta increased while its optimal cooking time and swelling index were reduced. The pasta samples supplemented with MFFB had increased hardness but decreased cohesiveness, tensile strength, and elongation rate. The pasta samples incorporated with 10–20% MFFB were accepted by consumers and could be considered as a high‐fibre food product since their total dietary fibre content was varied from 7.5 to 13.5 g/100 g. The pasta cooking decreased its chlorophyll content but improved the phenolic level. At 20% MFFB level, the 2,2‐diphenyl‐1‐picrylhydrazyl radical scavenging activity and ferric‐reducing antioxidant power of the product released at the in‐vitro intestinal step were 2.2 and 6.8 times, respectively, higher than those of the undigested cooked pasta. MBBF is a potential antioxidant dietary fibre ingredient to produce healthy pasta and the use of this by‐product would contribute to sustainable development of circular economy in the near future.