bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spike Protein Targeting “Nano-Glue” that Captures and Promotes SARS-CoV-2 Elimination
Authors: Zhang Guofang , Cong Yalin , Cao Guoli , Li Liang , Yu Peng , Song Qingle , Liu Ke , Qu Jing , Wang Jing , Xu Wei , Liao Shumin , Fan Yunping , Li Yufeng , Wang Guocheng , Fang Lijing , Chang Yanzhong , Zhao Yuliang , Boraschi Diana , Li Hongchang , Chen Chunying , Wang Liming , Li Yang 
Published: April 2021

AbstractThe global emergency caused by the SARS-CoV-2 pandemics can only be solved with adequate preventive and therapeutic strategies, both currently missing. The electropositive Receptor Binding Domain (RBD) of SARS-CoV-2 spike protein with abundant β-sheet structure serves as target for COVID-19 therapeutic drug design. Here, we discovered that ultrathin 2D CuInP2S6(CIPS) nanosheets as a new agent against SARS-CoV-2 infection, which also able to promote viral host elimination. CIPS exhibits extremely high and selective binding capacity with the RBD of SARS-CoV-2 spike protein, with consequent inhibition of virus entry and infection in ACE2-bearing cells and human airway epithelial organoids. CIPS displays nano-viscous properties in selectively binding with spike protein (KD< 1 pM) with negligible toxicityin vitroandin vivo. Further, the CIPS-bound SARS-CoV-2 was quickly phagocytosed and eliminated by macrophages, suggesting CIPS could be successfully used to capture and facilitate the virus host elimination with possibility of triggering anti-viral immunization. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, as well as for use as disinfection agent and surface coating material to constrain the SARS-CoV-2 spreading.
Transferable representations of single-cell transcriptomic data
Authors: Weinberger Ethan , Lee Su-In 
Published: April 2021

AbstractAdvances in single-cell RNA-seq (scRNA-seq) technologies are enabling the construction of large-scale, human-annotated reference cell atlases, creating unprecedented opportunities to accelerate future research. However, effectively leveraging information from these atlases, such as clustering labels or cell type annotations, remains challenging due to substantial technical noise and sparsity in scRNA-seq measurements. To address this problem, we present HD-AE, a deep autoencoder designed to extract integrated low-dimensional representations of scRNA-seq measurements across datasets from different labs and experimental conditions (https://github.com/suinleelab/HD-AE). Unlike previous approaches, HD-AE’s representations successfully transfer to new query datasets without needing to retrain the model. Researchers without substantial computational resources or machine learning expertise can thus leverage the robust representations learned by pretrained HD-AE models to compare embeddings of their own data with previously generated sets of reference embeddings.
Examination of gene loss in the DNA mismatch repair pathway and its mutational consequences in a fungal phylum
Authors: Phillips Megan A , Steenwyk Jacob L , Shen Xing-Xing , Rokas Antonis 
Published: April 2021

AbstractThe DNA mismatch repair (MMR) pathway corrects mismatched bases produced during DNA replication and is highly conserved across the tree of life, reflecting its fundamental importance for genome integrity. Loss of function in one or a few MMR genes can lead to increased mutation rates and microsatellite instability, as seen in some human cancers. While loss of MMR genes has been documented in the context of human disease and in hypermutant strains of pathogens, examples of entire species and species lineages that have experienced substantial MMR gene loss are lacking. We examined the genomes of 1,107 species in the fungal phylum Ascomycota for the presence of 52 genes known to be involved in the MMR pathway of fungi. We found that the median ascomycete genome contained 49 / 52 MMR genes. In contrast, four closely related species of obligate plant parasites from the powdery mildew generaErysipheandBlumeria, have lost between 5 and 21 MMR genes, includingMLH3,EXO1, andDPB11. The lost genes span MMR functions, include genes that are conserved in all other ascomycetes, and loss of function of any of these genes alone has been previously linked to increased mutation rate. Consistent with the hypothesis that loss of these genes impairs MMR pathway function, we found that powdery mildew genomes with higher levels of MMR gene loss exhibit increased numbers of mononucleotide runs, longer microsatellites, accelerated sequence evolution, elevated mutational bias in the A|T direction, and decreased GC content. These results identify a striking example of macroevolutionary loss of multiple MMR pathway genes in a eukaryotic lineage, even though the mutational outcomes of these losses appear to resemble those associated with detrimental MMR dysfunction in other organisms.Significance StatementThe DNA mismatch repair pathway corrects nucleotide base errors that occur during the replication of DNA; loss of these genes leads to cancer. We examined the conservation of the DNA mismatch repair pathway’s genes across more than 1,000 species in a fungal phylum and found a lineage of powdery mildews, a group of fungi that infect the leaves of plants, which have experienced extensive loss of multiple, otherwise highly conserved, genes. The genomes of these powdery mildews show elevated rates of diverse types of mutation, raising the hypothesis that these organisms have diversified while lacking genes thought to be essential for the accurate replication of DNA.
Selective Chemical Labeling and Sequencing of 5-Hydroxymethylcytosine in DNA at Single-Base Resolution
Authors: Li Xiaogang , Shi Xinxin , Gong Yin , Guo Wenting , Liu Yuanrui , Peng Chunwei , Xu Yingchun 
Published: April 2021

Abstract5-Hydroxymethylcytosine (5hmC), the oxidative product of 5-methylcytosine (5mC) catalyzed by ten-eleven translocation (TET) enzymes, plays an important role in many biological processes as an epigenetic mediator. Prior studies have shown that 5hmC can be selectively labeled with chemically-modified glucose moieties and enriched using click chemistry with biotin affinity approaches. Besides, DNA deaminases of the AID/APOBEC family can discriminate modified 5hmC bases from cytosine (C)or 5-methylcytosine (5mC). Herein, we developed a method based on ESC whole-genome analysis which could enrich 5hmC-containing DNA by selective chemical labeling and locate 5hmC sites at single-base resolution with enzyme-based deamination. The combination experimental design is an extension of previous methods, and we hope that this cost-effective single base resolution 5hmC sequencing method could be used to promote the mechanism and diagnosis research of 5hmC.
Phylogenomic analyses of the East Asian endemicAbelia(Caprifoliaceae) shed insights into the temporal and spatial diversification history with widespread hybridizations
Authors: Sun Qing-Hui , Morales-Briones Diego F. , Wang Hong-Xin , Landis Jacob B. , Wen Jun , Wang Hua-Feng 
Published: April 2021

AbstractBackground and AimsAbelia(Caprifoliaceae) is a small genus with five species, including one man-made hybrid and several natural hybrids. The genus has a discontinuous distribution in mainland China, Taiwan Island, and the Ryukyu islands, providing a model system to explore mechanisms of species dispersal in the East Asian flora. However, the current phylogenetic relationships withinAbeliaremain uncertain.MethodsIn this study, we reconstructed phylogenetic relationships withinAbeliausing nuclear loci generated by target enrichment and plastomes from genome skimming. Divergence time estimation, ancestral area reconstruction, and ecological niche modelling (ENM) were used to examine the diversification history ofAbelia.Key ResultsWe found extensive cytonuclear discordance across the genus. By integrating lines of evidence from molecular phylogenies, divergence times, and morphology, we propose to mergeA. macroteravar.zabelioidesintoA. uniflora.Network analyses suggested that there have been widespread and multiple hybridization events amongAbeliaspecies. These hybridization events may have contributed to the speciation mechanism and resulted in a high observed morphological diversity. The diversification ofAbeliabegan in the early Eocene, followed byA. chinensisvar.ionandracolonizing the island of Taiwan in the Middle Miocene. The ENM results suggested an expansion of climatically suitable areas during the Last Glacial Maximum and range contraction during the Last Interglacial. Disjunction between the Himalayan-Hengduan Mountain region (HHM) and the island of Taiwan is most likely the consequence of topographic isolation and postglacial contraction.ConclusionsWe used genomic data to reconstruct the phylogeny ofAbeliaand found a clear pattern of reticulate evolution in the group. In addition, our results support shrinkage of postglacial range and the heterogeneity of the terrain have led to the disjunction of the mainland China-Taiwan island. This study provides important new insights into the speciation process and taxonomy ofAbelia.
Dynamic Profiling of Binding and Allosteric Propensities of the SARS-CoV-2 Spike Protein with Different Classes of Antibodies: Mutational and Perturbation-Based Scanning Reveal Allosteric Duality of Functionally Adaptable Hotspots
Authors: Verkhivker Gennady M. , Agajanian Steve , Oztas Deniz Yazar , Gupta Grace 
Published: April 2021

AbstractStructural and biochemical studies of the SARS-CoV-2 spike complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes and a broad range of recognition modes linked to different neutralization responses In this study, we combined atomistic simulations with mutational and perturbation-based scanning approaches to perform in silico profiling of binding and allosteric propensities of the SARS-CoV-2 spike protein residues in complexes with B38, P2B-2F6, EY6A and S304 antibodies representing three different classes. Conformational dynamics analysis revealed that binding-induced modulation of soft modes can elicit the unique protein response to different classes of antibodies. Mutational scanning heatmaps and sensitivity analysis revealed the binding energy hotspots for different classes of antibodies that are consistent with the experimental deep mutagenesis, showing that differences in the binding affinity caused by global circulating variants in spike positions K417, E484 and N501 are relatively moderate and may not fully account for the observed antibody resistance effects. Through functional dynamics analysis and perturbation-response scanning of the SARS-CoV-2 spike protein residues in the unbound form and antibody-bound forms, we examine how antibody binding can modulate allosteric propensities of spike protein residues and determine allosteric hotspots that control signal transmission and global conformational changes. These results show that residues K417, E484, and N501 targeted by circulating mutations correspond to a group of versatile allosteric centers in which small perturbations can modulate collective motions, alter the global allosteric response and elicit binding resistance. We suggest that SARS-CoV-2 S protein may exploit plasticity of specific allosteric hotspots to generate escape mutants that alter response to antibody binding without compromising activity of the spike protein.
Jointex vivoMRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies
Authors: Tisdall M. Dylan , Ohm Daniel T. , Lobrovich Rebecca , Das Sandhitsu R. , Mizsei Gabor , Prabhakaran Karthik , Ittyerah Ranjit , Lim Sydney , McMillan Corey T. , Wolk David A. , Gee James , Trojanowski John Q. , Lee Edward B. , Detre John A. , Yushkevich Paul , Grossman Murray , Irwin David J. 
Published: April 2021

ABSTRACTFrontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w)ex vivoMRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease (AD). However, an integrated,ex vivoMRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphereex vivoMRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach revealsex vivoMRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted toin vivoapplication at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.
A divergent nonsense-mediated decay machinery inPlasmodium falciparumis inefficient and non-essential
Authors: McHugh Emma , Bulloch Michaela S. , Batinovic Steven , Sarna Drishti K. , Ralph Stuart A. 
Published: April 2021

ABSTRACTNonsense-mediated decay (NMD) is a conserved mRNA quality control process that eliminates transcripts bearing a premature termination codon. In addition to its role in removing erroneous transcripts, NMD is involved in post-transcriptional regulation of gene expression via programmed intron retention in metazoans. The apicomplexan parasitePlasmodium falciparumshows relatively high levels of intron retention, but it is unclear whether these variant transcripts are functional targets of NMD. In this study, we use CRISPR-Cas9 to disrupt and epitope-tag two core NMD components:PfUPF1 (PF3D7_1005500) andPfUPF2 (PF3D7_0925800). Using RNA-seq, we find that NMD inP. falciparumis highly derived and requires UPF2, but not UPF1 for transcript degradation. Furthermore, our work suggests that the majority of intron retention inP. falciparumhas no functional role and that NMD is not required for parasite growthex vivo. We localise bothPfUPF1 andPfUPF2 to puncta within the parasite cytoplasm, which may represent processing bodies - ribonucleoparticles that are sites of cytoplasmic mRNA decay. Finally, we identify a number of mRNA-binding proteins that co-immunoprecipitate with the NMD core complex and propose a model for a divergent NMD that does not requirePfUPF1 and incorporates novel accessory proteins to elicit mRNA decay.
Sodium accumulation in breast cancer predicts malignancy and treatment response
Authors: James Andrew D , Leslie Theresa K , Kaggie Joshua D , Wiggins Laura , Patten Lewis , O’Duinn John Murphy , Langer Swen , Labarthe Marie-Christine , Riemer Frank , Baxter Gabrielle , McLean Mary A. , Gilbert Fiona J , Kennerley Aneurin J , Brackenbury William J 
Published: April 2021

AbstractBreast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models.Ex vivoSBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by1H diffusion-weighted imaging (DWI). Moreover, combining23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.
MG132 induces progerin clearance and improves disease phenotypes in fibroblasts of patients affected with Hutchinson-Gilford Progeria-like syndromes
Authors: Harhouri Karim , Cau Pierre , Casey Frank , Mawuse Guedenon Koffi , Doubaj Yassamine , Van Maldergem Lionel , Mejia-Baltodano Gerardo , Bartoli Catherine , De Sandre-Giovannoli Annachiara , Lévy Nicolas 
Published: April 2021

ABSTRACTProgeroid Syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging that clinically resemble some aspects of advancing physiological aging. Most classical HGPS patients carry ade novopoint mutation within exon 11 of theLMNAgene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry otherLMNAmutations affecting exon 11 splicing, leading to defects in nuclear A-type Lamins and are named “HGPS-like” patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90). We recently found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patient cells. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
Glucose regulates expression of pro-inflammatory genesIL-1βandIL-12through a mechanism involving hexosamine biosynthesis pathway dependent regulation of α-E catenin in the RAW 264.7 macrophage cell line
Authors: Dissanayake Waruni C. , Oh Jin Kyo , Sorrenson Brie , Shepherd Peter R. 
Published: April 2021

AbstractHigh glucose levels are associated with changes in macrophage polarization and evidence indicates that the sustained or even short-term high glucose levels modulate inflammatory responses in macrophages. However, the mechanism by which macrophages can sense the changes in glucose levels are not clearly understood. We find that high glucose levels rapidly increase the α-E catenin protein level in RAW264.7 macrophages. We also find an attenuation of glucose induced increase of α-E catenin when hexosamine biosynthesis pathway is inhibited either with glutamine depletion or with the drugs azaserine and tunicamycin. This indicates the involvement of hexosamine biosynthesis pathway in this process. Then, we investigated the potential role of α-E catenin in glucose induced macrophage polarization. We find that the reduction of α-E catenin level using siRNA attenuates the glucose induced change of IL-1β mRNA level under LPS stimulated condition. Further, we identified that the depletion of α-E catenin also decreases theIL-12gene expression in basal glucose conditions leading to a reduction of glucose induced changes inIL-12. Together this indicates that α-E catenin can sense the changes in glucose levels in macrophagesviahexosamine biosynthesis pathway and also can modulate the glucose induced gene expression of inflammatory markers such asIL-1-βandIL-12. This identifies a new part of the mechanism by which macrophages are able to respond to changes in glucose levels.
Convergent selection on hormone signaling shaped social evolution in bees
Authors: Jones Beryl M. , Rubin Benjamin E.R. , Dudchenko Olga , Kingwell Callum J. , Traniello Ian M. , Wang Z. Yan , Kapheim Karen M. , Wyman Eli S. , Adastra Per A. , Liu Weijie , Parsons Lance R. , Jackson S. RaElle , Goodwin Katharine , Davidson Shawn M. , McBride Matthew J. , Webb Andrew E. , Omufwoko Kennedy S. , Van Dorp Nikki , Otárola Mauricio Fernández , Pham Melanie , Omer Arina D. , Weisz David , Schraiber Joshua , Villanea Fernando , Wcislo William T. , Paxton Robert J. , Hunt Brendan G. , Aiden Erez Lieberman , Kocher Sarah D. 
Published: April 2021

AbstractSweat bees have repeatedly gained and lost eusociality, a transition from individual to group reproduction. Here, we generate chromosome-length genome assemblies for 17 species and identify genomic signatures of evolutionary trade-offs associated with transitions between social and solitary living. Both young genes and regulatory regions show enrichment for these molecular patterns. We also identify loci that show evidence of complementary signals of positive and relaxed selection linked specifically to the convergent gains and losses of eusociality in sweat bees. This includes two proteins that bind and transport juvenile hormone (JH) – a key regulator of insect development and reproduction. We find one of these JH binding proteins is primarily expressed in subperineurial glial cells that form the insect blood-brain barrier and that brain levels of JH vary by sociality. Our findings are consistent with a role of JH in modulating social behavior and suggest eusocial evolution was facilitated by alteration of the proteins that bind and transport JH, revealing how an ancestral, developmental hormone may have been co-opted during one of life’s major transitions. More broadly, our results highlight how trade-offs have structured the molecular basis of eusociality in these bees and demonstrate how both directional selection and release from constraint can shape trait evolution.