bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptative Machine Translation between paired Single-Cell Multi-Omics Data
Authors: Martinez-de-Morentin Xabier , Khan Sumeer A. , Lehmann Robert , Qu Sisi , Maillo Alberto , Kiani Narsis A. , Prosper Felipe , Tegner Jesper , Gomez-Cabrero David 
Published: January 2021

AbstractBackgroundSingle-cell multi-omics technologies allow the profiling of different data modalities from the same cell. However, while isolated modalities only capture one view of the total information of a biological cell, an integrative analysis capturing the different modalities is challenging. In response, bioinformatics and machine learning methodologies have been developed for multi-omics single-cell analysis. Nevertheless, it is unclear if current tools can address the dual aspect of modality integration and prediction across modalities without requiring extensive parameter finetuning.ResultsWe designed LIBRA, a Neural Network based framework, to learn a translation between paired multi-omics profiles such that a shared latent space is constructed. LIBRA is a state-of-the-art tool when evaluating the ability to increase cell-type (clustering) resolution in the latent space. When assessing the predictive power across data modalities, LIBRA outperforms existing tools. Finally, considering the importance of hyperparameters, we implemented anadaptative-tuningstrategy, labelled aLIBRA, in the LIBRA package. As expected, adaptive parameter optimization significantly boosts the performance of learning predictive models from paired datasets. Additionally, aLIBRA provides parameter combinations balancing the integrative and predictive tasks.ConclusionsLIBRA is a versatile tool, uniquely targeting both integration and prediction tasks of Single-cell multi-omics data. LIBRA is a data-driven robust platform that includes an adaptive learning scheme. Furthermore, LIBRA is freely available as R and Python libraries (https://github.com/TranslationalBioinformaticsUnit/LIBRA).
Microbiome-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer
Authors: Overacre-Delgoffe Abigail E. , Cillo Anthony R. , Bumgarner Hannah J. , Burr Ansen H.P. , Tometich Justin T. , Bhattacharjee Amrita , Bruno Tullia C. , Vignali Dario A.A. , Hand Timothy W. 
Published: January 2021

SummaryColorectal cancer (CRC) is a common and deadly disease, and patients with metastatic tumors often fail to respond to therapy. While select members of the microbiome are associated with improved anti-tumor immunity, mechanistic understanding of how the microbiome provides a benefit is lacking. We show that modification of the CRC-associated microbiome with a single immunogenic commensal bacteria can alter T cell differentiation, inhibit tumor growth, and increase survival. Microbiome-driven control of CRC required the formation of colonic tertiary lymphoid structures (TLS) and increased infiltration of the tumor with cytotoxic immune cells. In the context of CRC, CD4+T cells specific to the newly introduced commensals differentiated into T follicular helper cells and were necessary for the formation of TLS, immune infiltration of the tumor, and control over CRC. Thus, modification of the intestinal T cell response by the microbiome can be used to augment anti-tumor immunity in colorectal cancer.
Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia
Authors: Niu Mengyuan , Song Shiyu , Su Zhonglan , Wei Lulu , Li Li , Pu Wenyuan , Zhao Chen , Ding Yibing , Cao Wangsen , Gao Qian , Wang Hongwei 
Published: January 2021

AbstractCancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.
Transcription activation is enhanced by multivalent interactions independent of phase separation
Authors: Trojanowski Jorge , Frank Lukas , Rademacher Anne , Grigaitis Pranas , Rippe Karsten 
Published: January 2021

SummaryTranscription factors (TFs) consist of a DNA binding and an activation domain (AD) that are considered to be independent and exchangeable modules. However, recent studies conclude that also the physico-chemical properties of the AD can control TF assembly at chromatin by driving a phase separation into transcriptional condensates. Here, we dissected transcription activation by comparing different synthetic TFs at a reporter gene array with real-time single-cell fluorescence microscopy readouts. In these experiments, binding site occupancy, residence time and co-activator recruitment in relation to multivalent TF interactions were compared. While phase separation propensity and activation strength of the AD were correlated, the actual formation of liquid-like TF droplets had a neutral or inhibitory effect on transcription activation. Rather, we conclude that multivalent AD mediated interactions increase the transcription activation capacity of a TF by stabilizing chromatin binding and mediating the recruitment of co-activators independent of phase separation.
Development of white matter tracts between and within the dorsal and ventral streams
Authors: Vinci-Booher S. , Caron B. , Bullock D. , James K. , Pestilli F. 
Published: January 2021

AbstractThe degree of interaction between the ventral and dorsal visual streams has been discussed in multiple scientific domains for decades. Recently, several white matter tracts that directly connect cortical regions associated with the dorsal and ventral streams have become possible to study due to advancements in automated and reproducible methods. The developmental trajectory of this set of tracts, here referred to as the posterior vertical pathway (PVP), has yet to be described. We propose an input-driven model of white matter development and provide evidence for the model by focusing on the development of the PVP. We used reproducible, cloud-computing methods and diffusion imaging from adults and children (ages 5-8 years) to compare PVP development to that of tracts within the ventral and dorsal pathways. PVP microstructure was more adult-like than dorsal stream microstructure, but less adult-like than ventral stream microstructure. Additionally, PVP microstructure was more similar to the microstructure of the ventral than the dorsal stream and was predicted by performance on a perceptual task in children. Overall, results suggest a potential role for the PVP in the development of the dorsal visual stream that may be related to its ability to facilitate interactions between ventral and dorsal streams during learning. Our results are consistent with the proposed model, suggesting that the microstructural development of major white matter pathways is related, at least in part, to the propagation of sensory information within the visual system.Significance StatementUnderstanding white matter development is important to building predictive models that can inform interventions and targeted educational methods. We propose and provide evidence for an input-driven model of white matter development. We tested an uncharacterized aspect of human brain development. Namely, how the recently described posterior vertical white matter tracts develop. Our results suggest a developmental progression along the known, direct anatomical connections from posterior visual areas to anterior ventral and dorsal areas. Our results suggest fundamental biological mechanisms that clarify the role of white matter in predicting human learning and behavior.
Inhibition of BMP and FGF signaling prior to wound epithelium formation leads to an aberrant regenerative response in teleost fishPoecilia latipinna
Authors: Ranadive Isha , Patel Sonam , Pai Siddharth , Khaire Kashmira , Balakrishnan Suresh 
Published: January 2021

AbstractThe BMP and FGF pathways play a pivotal role in the successful regeneration of caudal fin of teleost fish. Individual inhibition of these pathways led to impaired caudal fin regeneration until the pharmacologic inhibitor of FGF (SU5402) and BMP (LDN193189) were metabolized off. Therefore, in the current study both these pathways were inhibited collectively wherein inhibition of BMP and FGF during the wound epithelium formation led to stalling of the process by bringing down the established levels ofshhandrunx2. In members of the treatment group, it was observed that, each blastema grows crouched rather than linear and the regrown lepidotrichia therefore remain tilted down. Amongst the other irregularities observed, the transition from epithelial to mesenchymal cells was found hindered due to down-regulation ofsnailandtwist, brought about by BMP and FGF inhibition. Compromised expression ofSnailandtwistderanged the normal levels of cadherins causing disruption in the transition of cells. Lastly, blocking BMP and FGF delayed blastema formation and proliferation due to diminished levels offgf2, fgf8, fgf10andbmp6, whilecasp3andcasp9levels remained heightened causing accelerated cell death. This study not only highlights the axial role of BMP and FGF pathways in regeneration but also accentuates the collaboration amongst the two. This ingenious coordination of signalling further reinforces the involvement of relaying messenger molecules between these crucial pathways.Summary StatementBMP and FGF collectively control the process of blastema formation in fish and inhibiting them prior to wound epithelium stage leads to irrevocable damage to the regenerating caudal fin.
Structural insight intoPichia pastorisfatty acid synthase
Authors: Snowden Joseph S. , Alzahrani Jehad , Sherry Lee , Stacey Martin , Rowlands David J. , Ranson Neil A. , Stonehouse Nicola J. 
Published: January 2021

SummaryType I fatty acid synthases (FASs) are critical metabolic enzymes which are common targets for bioengineering in the production of biofuels and other products. Serendipitously, we identified FAS as a contaminant in a cryoEM dataset of virus-like particles (VLPs) purified fromP. pastoris, an important model organism and common expression system used in protein production. From these data, we determined the structure ofP. pastorisFAS to 3.1 Å resolution. While the overall organisation of the complex was typical of type I FASs, we identified several differences in both structural and enzymatic domains through comparison with the prototypical yeast FAS fromS. cerevisiae. Using focussed classification, we were also able to resolve and model the mobile acyl-carrier protein (ACP) domain, which is key for function. Ultimately, the structure reported here will be a useful resource for further efforts to engineer yeast FAS for synthesis of alternate products.
SpatialExperiment: infrastructure for spatially resolved transcriptomics data in R using Bioconductor
Authors: Righelli Dario , Weber Lukas M. , Crowell Helena L. , Pardo Brenda , Collado-Torres Leonardo , Ghazanfar Shila , Lun Aaron T. L. , Hicks Stephanie C. , Risso Davide 
Published: January 2021

AbstractSummarySpatialExperimentis a new data infrastructure for storing and accessing spatially resolved transcriptomics data, implemented within the R/Bioconductor framework, which provides advantages of modularity, interoperability, standardized operations, and comprehensive documentation. Here, we demonstrate the structure and user interface with examples from the 10x Genomics Visium and seqFISH platforms, and provide access to example datasets and visualization tools in theSTexampleData,TENxVisiumData, andggspavispackages.Availability and ImplementationTheSpatialExperiment,STexampleData,TENxVisiumData, andggspavispackages are available from Bioconductor. The package versions described in this manuscript are available in Bioconductor version 3.15 onwards.Contactrisso.davide@gmail.com,shicks19@jhu.eduSupplementary InformationSupplementary Tables and Figures are available online.
Maternal transfer of neutralizing antibodies to OspA after oral vaccination of the rodent reservoir
Authors: O’Connell Kathryn , Nair Nisha , Samanta Kamalika , Azevedo Jose F. , Brown Grant D. , Petersen Christine A. , Gomes-Solecki Maria 
Published: January 2021

AbstractLyme Disease presents unique challenges for public health efforts. We hypothesized that transfer of protective antibodies between mothers and offspring should occur after oral vaccination of C3H-HeN mice withE. colioverexpressing OspA. We present new evidence for maternal transfer of vaccine induced neutralizing anti-OspA IgG antibodies to mouse pups through ingestion of colostrum. Protective levels of OspA antibodies in pups were present from 2-5 weeks after birth and they persisted in some mice until 9 weeks of age. This was corroborated by detection of neutralizing antibodies in the serum of all pups at 2-3 weeks after birth and in some mice at 9 weeks of age. A clear association was found between robust antibody responses in mothers and the length of antibody persistence in the respective pups using a novel longitudinal Bayesian model. These factors are likely to impact the enzootic cycle ofB. burgdorferiwhen reservoir targeted OspA-based vaccination interventions are implemented.
MOLECULAR LANDSCAPE OF OLD AGE MELANOMA BY SURVIVAL AND IMMUNOTHERAPY RESPONSE
Authors: Smith Stephen P. , Nagore Eduardo , Budden Timothy , Kumar Rajiv , Marais Richard , Gaudy-Marqueste Caroline , Virós Amaya 
Published: January 2021

AbstractMelanoma mortality particularly affects older patients, and age is a powerful independent predictor of death. The pathogenic mutations and transcriptomic changes associated with poor survival in aged patients are not known.We analyzed 5 cohorts of metastatic (N=324, N=18, N=66) and primary melanomas (N=103, N=30) to establish the effect of age on prognosis, identify age-specific driver genes and transcriptomic changes linked to survival and immunotherapy response.We identify the pathogenic mutations and transcriptomic changes associated with poor survival by age, and show mutations inBRAF, NRAS, CDKN2AorIDH1identify metastatic and primary melanoma aged patients with worse outcome. In contrast, activation of immune-regulatory pathways is a hallmark of long-term survival. We tested if mutations in genes linked to poor outcome are associated to immunotherapy responders, exploring combinations of agespecific mutations in metastatic immune checkpoint inhibitor aged responders. Strikingly, aged patients withBRAF, NRAS, CDKN2AorIDH1mutations and high tumor mutation burden treated with immunotherapy have an improved median survival of 12 months. These data highlight the molecular landscape of melanoma varies by age, and age stratification can refine prognosis and therapy rationales. A set of mutations identifies patients at highest risk of death who are likely immunotherapy responders.
Tau aggregates are RNA-protein assemblies that mis-localize multiple nuclear speckle components
Authors: Lester Evan , Ooi Felicia K. , Bakkar Nadine , Ayers Jacob , Woerman Amanda L. , Wheeler Joshua , Bowser Robert , Carlson George A. , Prusiner Stanley B. , Parker Roy 
Published: January 2021

AbstractTau aggregates contribute to neurodegenerative diseases including frontotemporal dementia and Alzheimer’s disease (AD). Although RNA promotes tau aggregationin vitro, whether tau aggregates in cells contain RNA is unknown. We demonstrate in cell culture and mouse brains that both cytosolic and nuclear tau aggregates contain RNA, with enrichment for snRNAs and snoRNAs. Nuclear tau aggregates colocalize with and alter the composition, dynamics, and organization of nuclear speckles, which are membraneless organelles involved in pre-mRNA splicing. Moreover, several nuclear speckle components, including SRRM2, mislocalize to cytosolic tau aggregates in cells, mouse brains, and patient brains with AD, frontotemporal dementia (FTD), and corticobasal degeneration (CBD). Consistent with these alterations we observe the presence of tau aggregates is sufficient to alter pre-mRNA splicing. This work identifies tau alteration of nuclear speckles as a feature of tau aggregation that may contribute to the pathology of tau aggregates.
UNC-2 CaV2 channel localization at presynaptic active zones depends on UNC-10/RIM and SYD-2/Liprin-α inCaenorhabditis elegans
Authors: Oh Kelly H. , Krout Mia , Richmond Janet E. , Kim Hongkyun 
Published: January 2021

AbstractPresynaptic active zone proteins couple calcium influx with synaptic vesicle exocytosis. However, the control of presynaptic calcium channel clustering by active zone proteins is not completely understood. In aC. elegansforward genetic screen, we find that UNC-10/RIM (Rab3-interacting molecule) and SYD-2/Liprin-αregulate presynaptic clustering of UNC-2, the CaV2 channel ortholog. We further quantitatively analyzed live animals using endogenously GFP-tagged UNC-2 and active zone components. Consistent with the interaction between RIM and CaV2 in mammals, the intensity and number of UNC-2 channel clusters at presynaptic terminals were greatly reduced inunc-10mutant animals. To understand how SYD-2 regulates presynaptic UNC-2 channel clustering, we analyzed presynaptic localization of endogenous SYD-2, UNC-10, RIMB-1/RIM-BP (RIM binding protein), and ELKS-1. Our analysis revealed that while SYD-2 is the most critical for active zone assembly, loss of SYD-2 function does not completely abolish presynaptic localization of UNC-10, RIMB-1, and ELKS-1, suggesting an existence of SYD-2-independent active zone assembly. UNC-2 localization analysis in double and triple mutants of active zone components show that SYD-2 promotes UNC-2 clustering by partially controlling UNC-10 localization, and ELKS-1 and RIMB-1 also contribute to UNC-2 channel clustering. In addition, we find that core active zone proteins are unequal in their abundance. While the abundance of UNC-10 at the active zone is comparable to UNC-2, SYD-2 and ELKS-1 are twice more and RIMB-1 four times more abundant than UNC-2. Together our data show that UNC-10, SYD-2, RIMB-1, and ELKS-1 control presynaptic UNC-2 channel clustering in redundant yet distinct manners.Significance StatementPrecise control of neurotransmission is dependent on the tight coupling of the calcium influx through voltage-gated calcium channels (VGCCs) to the exocytosis machinery at the presynaptic active zones. However, how these VGCCs are tethered to the active zone is incompletely understood. To understand the mechanism of presynaptic VGCC localization, we performed aC. elegansforward genetic screen and quantitatively analyzed endogenous active zones and presynaptic VGCCs. In addition to RIM (Rab3-interacting molecule), our study finds that SYD-2/Liprin-αis critical for presynaptic localization of VGCCs. Yet, the loss of SYD-2, the master active zone scaffolding protein, does not completely abolish the presynaptic localization of the VGCC, showing that the active zone is a resilient structure assembled by redundant mechanisms.
Structure and Function of an in vivo Assembled Type III-A CRISPR-Cas Complex Reveal Critical Roles of Dynamics in Activity Control
Authors: Sridhara Sagar , Rai Jay , Whyms Charlisa , Woodside Walter , Terns Michael P , Li Hong 
Published: January 2021

AbstractThe small RNA-mediated immunity in bacteria depends on foreign RNA-activated and self RNA-inhibited enzymatic activities. The multi-subunit Type III-A CRISPR-Cas effector complex (Csm) exemplifies this principle, but its molecular basis for regulation remains unexplained. Recognition of the foreign RNA, or cognate target RNA (CTR), triggers its single-stranded deoxyribonuclease (DNase) and cyclic oligoadenylate (cOA) synthesis activities. The same activities remain dormant in the presence of the self-RNA, or noncognate target RNA (NTR) that differs from CTR only in its 3’-protospacer flanking sequence. Here we captured four structures ofin vivoassembledLactococcus lactisCsm (LlCsm) by electron cryomicroscopy representing both the active and the inactive states. Surprisingly, in absence of bound RNA, LlCsm largely forms a minimal assembly lacking the Csm2 subunit with a stably bound catalytic subunit Csm1. Comparison of the minimal LlCsm structure and activities, both in vitro and in vivo, with those of fully assembled LlCsm reveals a molecular mechanism responsible for the viral RNA-activated and self RNA-inhibited activity of Csm1 through protein dynamics.Graphic Art Summary
Synthetic nanobody–SARS-CoV-2 receptor-binding domain structures identify distinct epitopes
Authors: Ahmad Javeed , Jiang Jiansheng , Boyd Lisa F. , Natarajan Kannan , Margulies David H. 
Published: January 2021

AbstractThe worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demands unprecedented attention. We report four X-ray crystal structures of three synthetic nanobodies (sybodies) (Sb16, Sb45 and Sb68) bind to the receptor-binding domain (RBD) of SARS-CoV-2: binary complexes of Sb16–RBD and Sb45–RBD; a ternary complex of Sb45–RBD–Sb68; and Sb16 unliganded. Sb16 and Sb45 bind the RBD at the ACE2 interface, positioning their CDR2 and CDR3 loops diametrically. Sb16 reveals a large CDR2 shift when binding the RBD. Sb68 interacts peripherally at the ACE2 interface; steric clashes with glycans explain its mechanism of viral neutralization. Superposing these structures onto trimeric spike (S) protein models indicates these sybodies bind conformations of the mature S protein differently, which may aid therapeutic design.One Sentence SummaryX-ray structures of synthetic nanobodies complexed with the receptor-binding domain of the spike protein of SARS-CoV-2 reveal details of CDR loop interactions in recognition of distinct epitopic sites.
MrHAMER yields highly accurate single molecule viral sequences enabling analysis of intra-host evolution
Authors: Gallardo CM , Wang S , Montiel-Garcia DJ , Little SJ , Smith DM , Routh AL , Torbett BE 
Published: January 2021

AbstractTechnical challenges remain in the sequencing of RNA viruses due to their high intra-host diversity. This bottleneck is particularly pronounced when interrogating long-range co-evolution given the read-length limitations of next-generation sequencing platforms. This has hampered the direct observation of long-range genetic interactions that code for protein-protein interfaces with relevance in both drug and vaccine development. Here we overcome these technical limitations by developing a nanopore-based long-range viral sequencing pipeline that yields accurate single molecule sequences of circulating virions from clinical samples. We demonstrate its utility in observing the evolution of individual HIV Gag-Pol genomes in response to antiviral pressure. Our pipeline, called Multi-read Hairpin Mediated Error-correction Reaction (MrHAMER), yields >1000s viral genomes per sample at 99.9% accuracy, maintains the original proportion of sequenced virions present in a complex mixture, and allows the detection of rare viral genomes with their associated mutations present at <1% frequency. This method facilitates scalable investigation of genetic correlates of resistance to both antiviral therapy and immune pressure, and enable the identification of novel host-viral and viral-viral interfaces that can be modulated for therapeutic benefit.