bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Programmable Ontology Encompassing the Functional Logic of the Drosophila Brain
Authors: Lazar Aurel A. , Turkcan Mehmet Kerem , Zhou Yiyin 
Published: December 2021

AbstractThe Drosophila brain has only a fraction of the number of neurons of higher organisms such as mice and humans. Yet the sheer complexity of its neural circuits recently revealed by large connectomics datasets suggests that computationally modeling the function of fruit fly brain circuits at this scale posits significant challenges.To address these challenges, we present here a programmable ontology that expands the scope of the current Drosophila brain anatomy ontologies to encompass the functional logic of the fly brain. The programmable ontology provides a language not only for modeling circuit motifs but also for programmatically exploring their functional logic. To achieve this goal, we tightly integrated the programmable ontology with the workflow of the interactive FlyBrainLab computing platform. As part of the programmable ontology, we developed NeuroNLP++, a web application that supports free-form English queries for constructing functional brain circuits fully anchored on the available connectome/synaptome datasets, and the published worldwide literature.In addition, we present a methodology for including a model of the space of odorants into the programmable ontology, and for modeling olfactory sensory circuits of the antenna of the fruit fly brain that detect odorant sources. Furthermore, we describe a methodology for modeling the functional logic of the antennal lobe circuit consisting of massive local feedback loops, a characteristic feature observed across Drosophila brain regions. Finally, using a circuit library, we demonstrate the power of our methodology for interactively exploring the functional logic of the massive number of feedback loops in the antennal lobe.
Landscape of human spinal cord cell type diversity at midgestation
Authors: Andersen Jimena , Thom Nicholas , Shadrach Jennifer L. , Chen Xiaoyu , Amin Neal D. , Yoon Se-Jin , Greenleaf William J. , Müller Fabian , Pașca Anca M. , Kaltschmidt Julia A. , Pașca Sergiu 
Published: December 2021

AbstractUnderstanding spinal cord generation and assembly is essential to elucidate how motor behavior is controlled and how disorders arise. The cellular landscape of the human spinal cord remains, however, insufficiently explored. Here, we profiled the midgestation human spinal cord with single cell-resolution and discovered, even at this fetal stage, remarkable heterogeneity across and within cell types. Glia displayed diversity related to positional identity along the dorso-ventral and rostro-caudal axes, while astrocytes with specialized transcriptional programs mapped onto distinct histological domains. We discovered a surprisingly early diversification of alpha (α) and gamma (γ) motor neurons that control and modulate contraction of muscle fibers, which was suggestive of accelerated developmental timing in human spinal cord compared to rodents. Together with mapping of disease-related genes, this transcriptional profile of the developing human spinal cord opens new avenues for interrogating the cellular basis of motor control and related disorders in humans.
An automated microfluidic platform integrating functional vascularized organoids-on-chip
Authors: Quintard Clément , Jonsson Gustav , Laporte Camille , Bissardon Caroline , Pitaval Amandine , Werschler Nicolas , Leopoldi Alexandra , Hagelkrüys Astrid , Blandin Pierre , Achard Jean-Luc , Navarro Fabrice , Fouillet Yves , Penninger Josef M. , Gidrol Xavier 
Published: December 2021

ABSTRACTThe development of vascular networks on-chip is crucial for the long-term culture of three-dimensional cell aggregates such as organoids, spheroids, tumoroids, and tissue explants. Despite the rapid advancement of microvascular network systems and organoid technology, vascularizing organoids-on-chips remains a challenge in tissue engineering. Moreover, most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical settings to operate. Considering these constraints, we developed an innovative platform to establish and monitor the formation of endothelial networks around model spheroids of mesenchymal and endothelial cells as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 15 days on-chip. Importantly, these networks were functional, demonstrating intravascular perfusion within the spheroids or vascular organoids connected to neighbouring endothelial beds. This microphysiological system thus represents a viable organ-on-chip model to vascularize biological tissues and should allow to establish perfusion into organoids using advanced microfluidics.
Deciphering sex-specific miRNAs as heat-recorders in zebrafish
Authors: van Gelderen T.A. , Montfort J. , Álvarez-Dios J.A. , Thermes V. , Piferrer F. , Bobe J. , Ribas L. 
Published: December 2021

AbstractMicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in a wide variety of physiological processes, including those related to the reproductive system. Although in the last decade a plethora of miRNAs has been reported, the miRNA alterations occurred by environmental cues and their biological functions have not yet been elucidated. With the aim to identify epigenetic regulations mediated by miRNAs in the gonads in a climate change scenario, zebrafish (Danio rerio) were subjected to high temperatures during sex differentiation (18-32 days post fertilization, dpf), a treatment that results in male-skewed sex ratios. Once the fish reached adulthood (90 dpf), ovaries and testes were sequenced by high-throughput technologies. About 101 million high-quality reads were obtained from gonadal samples. Analyses of the expression levels of the miRNAs identified a total of 23 and 1 differentially expressed (DE) miRNAs in ovaries and testes, respectively, two months after the heat treatment. Most of the identified miRNAs were involved in human sex-related cancer. After retrieving 3’ UTR regions, ~400 predicted targets of the 24 DE miRNAs were obtained, some with reproduction-related functions. Their synteny in the zebrafish genome was, for more than half of them, in the chromosomes 7, 2, 4, 3 and 11 in the ovaries, chromosome 4 being the place where the predicted sex-associated-region (sar) is localized in wild zebrafish. Further, spatial localization in the gonads of two selected miRNAs (miR-122-5p and miR-146-5p) showed exclusive expression in the ovarian germ cells. The present study expands the catalog of sex-specific miRNAs and deciphers, for the first time, thermosensitive miRNAs in the zebrafish gonads that might be used as potential epimarkers to predict environmental past events.
Stable m7G Cap-Distal 5′UTR Hairpin Structure Mediates Distinct 40S and 60S Binding Dynamics
Authors: Wang Hongyun , Gaba Anthony , Qu Xiaohui 
Published: December 2021

ABSTRACTThe 5′ untranslated region (UTR) of diverse mRNAs contains secondary structures that can influence protein synthesis by modulating the initiation step of translation. Studies support the ability of these structures to inhibit 40S subunit recruitment and scanning, but the dynamics of ribosomal subunit interactions with mRNA remain poorly understood. Here, we developed a reconstitutedSaccharomyces cerevisiaecell-free translation system with fluorescently labeled ribosomal subunits. We applied this extract and single-molecule fluorescence microscopy to monitor, in real time, individual 40S and 60S interactions with mRNAs containing 5’ UTR hairpin structures with varying thermostability. In comparison to mRNAs containing no or weak 5′UTR hairpins (ΔG >= -5.4 kcal/mol), mRNAs with stable hairpins (ΔG <= -16.5 kcal/mol) showed reduced numbers of 60S recruitment to mRNA, consistent with the expectation of reduced translation efficiency for such mRNAs. Interestingly, such mRNAs showed increased numbers of 40S recruitment events to individual mRNAs but with shortened duration on mRNA. Correlation analysis showed that these unstable 40S binding events were nonproductive for 60S recruitment. Furthermore, although the mRNA sequence is long enough to accommodate multiple 40S, individual mRNAs are predominantly observed to engage with a single 40S at a time, indicating the sequestering of mRNA 5’ end by initiating 40S. Altogether, these observations suggest that stable cap-distal hairpins in 5’ UTR reduce initiation and translation efficiency by destabilizing 40S-mRNA interactions and promoting 40S dissociation from mRNA. The premature 40S dissociation frees mRNA 5′-end accessibility for new initiation events, but the increased rate of 40S recruitment is insufficient to compensate for the reduction of initiation efficiency due to premature 40S dissociation. This study provides the first single-molecule kinetic characterization of 40S/60S interactions with mRNA during cap-dependent initiation and the modulation of such interactions by cap-distal 5’ UTR hairpin structures.
The EBNA2-EBF1 complex promotes oncogenic MYC expression levels and metabolic processes required for cell cycle progression of Epstein-Barr virus-infected B cells
Authors: Beer Sophie , Wange Lucas E. , Zhang Xiang , Kuklik-Roos Cornelia , Enard Wolfgang , Hammerschmidt Wolfgang , Scialdone Antonio , Kempkes Bettina 
Published: December 2021

ABSTRACTEpstein-Barr virus (EBV) is a human tumor virus, which preferentially infects resting human B cells. Upon infection in vitro, EBV activates and immortalizes these cells. The viral latent protein EBV nuclear antigen (EBNA) 2 is essential for B cell activation and immortalization; it targets and binds the cellular and ubiquitously expressed DNA binding protein CBF1, thereby transactivating a plethora of viral and cellular genes. In addition, EBNA2 uses its N-terminal dimerization (END) domain to bind early B cell factor (EBF) 1, a pioneer transcription factor specifying the B cell lineage. We found that EBNA2 exploits EBF1 to support key metabolic processes and to foster cell cycle progression of infected B cells in their first cell cycles upon activation. An α1-helix within the END domain was found to promote EBF1 binding. EBV mutants lacking the α1-helix in EBNA2 can infect and activate B cells efficiently, but the activated cells fail to complete the early S phase of their initial cell cycle. Expression of MYC, target genes of MYC and E2F as well as multiple metabolic processes linked to cell cycle progression are impaired in EBVΔα1 infected B cells. Our findings indicate that EBF1 controls B cell activation via EBNA2 and, thus, has a critical role in regulating the cell cycle of EBV infected B cells. This is a function of EBF1 going beyond its well-known contribution to B cell lineage specification.Significance statementEpstein-Barr virus (EBV) infects primary B cells and establishes life-long latent infection in these cells. EBV nuclear antigen (EBNA) 2 drives early processes of B cell activation and cell cycle entry. The surface of the N-terminal dimerization domain of EBNA2 exposes a five amino acid α-helix (α1) that recruits EBF1 to activate MYC and downstream targets of both MYC and E2F to support critical metabolic processes in infected B cells and to drive them through S phase in the first cell cycle post-infection. Our study demonstrates how EBNA2 exploits EBF1, a key factor of B cell lineage specification to initiate proliferation and high-lights the α1-helix as a potential Achilles heel of the virus at the stage when latent infection is established.
Age-associated B cells are long-lasting effectors that restrain reactivation of latent γHV68
Authors: Mouat Isobel C. , Shanina Iryna , Horwitz Marc S. 
Published: December 2021

AbstractAge-associated B cells (ABCs; CD19+CD11c+T-bet+) are a unique population that are increased in an array of viral infections, though their role during latent infection is largely unexplored. Here, we use murine gammaherpesvirus 68 (γHV68) to demonstrate that ABCs remain elevated long-term during latent infection and express IFNγ and TNF. Using a strain of γHV68 that is cleared following acute infection, we show that ABCs persist in the absence of latent virus, though their expression of IFNγ and TNF is decreased. With a fluorescent virus we demonstrate that ABCs are infected with γHV68 at similar rates to other previously activated B cells. We find that mice without ABCs display defects in anti-viral IgG2a/c antibodies and are more susceptible to γHV68 reactivation when challenged with heterologous infection. Together, these results indicate that ABCs are a persistent effector subset during latent viral infection that restrains γHV68 reactivation.
Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation
Authors: Viberti Bianca , Branca Lisa , Bellini Simone , Bassetti Claudio LA , Adamantidis Antoine , Schmidt Markus 
Published: December 2021

AbstractNarcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previous demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation.Statement of SignificanceCataplexy and the loss of muscle tone has historically been viewed as a component of REM sleep that inappropriately intrudes into wakefulness. In addition to fragmented sleep, the intrusion of REM-like events into wakefulness has led to the hypothesis that narcolepsy represents a dysregulation of boundary state control. We show that REM sleep and cataplexy can be dissociated during the dark (active) phase through Ta manipulation. Such dissociation may provide clues regarding the cause of boundary state instability in Hcrt-KO mice, as well as provide a new method to interrogate mechanisms of REM sleep and cataplexy.
Molecular probes of spike ectodomain and its subdomains for SARS-CoV-2 variants, Alpha through Omicron
Authors: Teng I-Ting , Nazzari Alexandra F. , Choe Misook , Liu Tracy , de Souza Matheus Oliveira , Petrova Yuliya , Tsybovsky Yaroslav , Wang Shuishu , Zhang Baoshan , Artamonov Mykhaylo , Madan Bharat , Huang Aric , Lopez Acevedo Sheila N. , Pan Xiaoli , Ruckwardt Tracy J. , DeKosky Brandon J. , Mascola John R. , Misasi John , Sullivan Nancy J. , Zhou Tongqing , Kwong Peter D. 
Published: December 2021

AbstractSince the outbreak of the COVID-19 pandemic, widespread infections have allowed SARS-CoV-2 to evolve in human, leading to the emergence of multiple circulating variants. Some of these variants show increased resistance to vaccines, convalescent plasma, or monoclonal antibodies. In particular, mutations in the SARS-CoV-2 spike have drawn attention. To facilitate the isolation of neutralizing antibodies and the monitoring the vaccine effectiveness against these variants, we designed and produced biotin-labeled molecular probes of variant SARS-CoV-2 spikes and their subdomains, using a structure-based construct design that incorporated an N-terminal purification tag, a specific amino acid sequence for protease cleavage, the variant spike-based region of interest, and a C-terminal sequence targeted by biotin ligase. These probes could be produced by a single step using in-process biotinylation and purification. We characterized the physical properties and antigenicity of these probes, comprising the N-terminal domain (NTD), the receptor-binding domain (RBD), the RBD and subdomain 1 (RBD-SD1), and the prefusion-stabilized spike ectodomain (S2P) with sequences from SARS-CoV-2 variants of concern or of interest, including variants Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta, Lambda, Mu, and Omicron. We functionally validated probes by using yeast expressing a panel of nine SARS-CoV-2 spike-binding antibodies and confirmed sorting capabilities of variant probes using yeast displaying libraries of plasma antibodies from COVID-19 convalescent donors. We deposited these constructs to Addgene to enable their dissemination. Overall, this study describes a matrix of SARS-CoV-2 variant molecular probes that allow for assessment of immune responses, identification of serum antibody specificity, and isolation and characterization of neutralizing antibodies.
Viral population genomics reveals host and infectivity impact on SARS-CoV-2 adaptive landscape
Authors: Gayvert Kaitlyn , Copin Richard , McKay Sheldon , Setliff Ian , Lim Wei Keat , Baum Alina , Kyratsous Christos A. , Atwal Gurinder S. 
Published: December 2021

ABSTRACTPublic health surveillance, drug treatment development, and optimization of immunological interventions all depend on understanding pathogen adaptation, which differ for specific pathogens. SARS-CoV-2 is an exceptionally successful human pathogen, yet complete understanding of the forces driving its evolution is lacking. Here, we leveraged almost four million SARS-CoV-2 sequences originating mostly from non-vaccinated naïve patients to investigate the impact of functional constraints and natural immune pressures on the sequence diversity of the SARS-CoV-2 genome. Overall, we showed that the SARS-CoV-2 genome is under strong and intensifying levels of purifying selection with a minority of sites under diversifying pressure. With a particular focus on the spike protein, we showed that sites under selection were critical for protein stability and virus fitness related to increased infectivity and/or reduced neutralization by convalescent sera. We investigated the genetic diversity of SARS-CoV-2 B and T cell epitopes and determined that the currently known T cell epitope sequences were highly conserved. Outside of the spike protein, we observed that mutations under selection in variants of concern can be associated to beneficial outcomes for the virus. Altogether, the results yielded a comprehensive map of all sites under selection across the entirety of SARS-CoV-2 genome, highlighting targets for future studies to better understand the virus spread, evolution and success.
That gut feeling: public perceptions of media coverage and science surrounding probiotic products
Authors: Vijaykumar Santosh , McCready Jemma , Graham Pamela Louise , Morris Daniel 
Published: December 2021

PurposeThe authors sought to unpack the paradox between increasing demand for probiotics products against inconclusive scientific evidence about the effectiveness. This paper investigated public understanding of the composition and benefits of probiotic products, measured trust in news media and scientists as sources of information about probiotic products and informational and attitudinal predictors of consumer trust in the news media and scientists.Design/methodology/approachA cross-sectional survey was conducted amongst a representative sample of 2000 UK consumers. Participants responded to multiple-choice questions and psychometric scales capturing probiotics knowledge, consumption, information seeking behaviour, attitudes to and confidence in the news media and probiotics scientists. Descriptive statistics, one-way ANOVA and hierarchical regression modelling were performed.FindingsInformation exposure to probiotics content was highest from traditional media followed by online channels. Levels of confidence in probiotics scientists were higher than in the news media, even though these levels were highest amongst current consumers and lowest amongst non-consumers. Conflicting information, health consciousness and trust in nutrition stakeholders were identified as important predictors of trust in news media and scientists.Originality/valueThis study provides a large-scale nationally representative overview of public attitudes and sentiments related to probiotic products with a focus on attitudes towards the news media and the scientific establishment. The findings suggest a need for better consumer awareness about the state of science around probiotic products, interventions that could enable consumers to discern conflicting evidence or news reports, and critical skills that can render them more resilient to online misinformation.
Politicised opinion leaders in the younger generation: to meat or not to meat?
Authors: Schulze Maureen , Spiller Achim , Jürkenbeck Kristin 
Published: December 2021

PurposeThe consumption of animal-based food products faces several sustainability challenges. To date, however, meat intake plays an important role in everyday food choices. With their ability to change the opinions of a critical mass, opinion leaders in food choices are assumed to play a predominant role in influencing future dietary styles. Thus, the objective of this study was to identify opinion leaders in food choices and their personal meat consumption behaviour as well as their attitude towards policy interventions aiming to meat reduction.Design/methodology/approachThe sample consisted of 1,479 German participants aged between 15 and 29 years who were online surveyed in autumn 2020. A latent profile analysis (LPA) identified three distinct groups of opinion leader in the younger generation labelled “non-opinion leaders”, “weak opinion leaders” and “opinion leaders”. The identified profiles were used to understand opinion leaders and their food choices by using chi-square tests as well as univariate ANOVA with Tukey or Games-Howell post hoc tests.FindingsOpinion leadership in food choices was associated with a higher interest in meat-reduced dietary styles and with more positive attitudes towards innovative food ideas. Moreover, opinion leaders were associated with politicised food decisions, indicating that their food choices align with their political and social interests.Originality/valueThe results contribute to a better understanding of the development of future dietary styles, provide evidence for a shift towards more sustainable dietary patterns in the near future and highlight that food decisions are no longer solely decisions on an individual basis but rather becoming of political relevance.