bluuebunny/crossref_metadata_2025_split huggingface dataset:
Galectin-9 Regulates The Threshold of B Cell Activation and Autoimmunity
Authors: Smith Logan K. , Fawaz Kareem , Treanor Bebhinn 
Published: November 2020

ABSTRACTDespite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9 deficient mice have an expanded population of B1a cells and increased titers of B-1a derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate auto-antigen delivery to the spleen, driving autoimmune responses.
Analysing the Yeast Complexome - The Complex Portal rising to the challenge
Authors: Meldal Birgit H M , Pons Carles , Perfetto Livia , Del-Toro Noemi , Wong Edith , Aloy Patrick , Hermjakob Henning , Orchard Sandra , Porras Pablo 
Published: November 2020

AbstractThe EMBL-EBI Complex Portal is a knowledgebase of macromolecular complexes providing persistent stable identifiers. Entries are linked to literature evidence and provide details of complex membership, function, structure and complex-specific Gene Ontology annotations. Data is freely available and downloadable in HUPO-PSI community standards and missing entries can be requested for curation. In collaboration withSaccharomycesGenome Database and UniProt, the yeast complexome, a compendium of all known heteromeric assemblies from the model organismSaccharomyces cerevisiae, was curated. This expansion of knowledge and scope has led to a 50% increase in curated complexes compared to the previously published dataset, CYC2008. The yeast complexome is used as a reference resource for the analysis of complexes from large-scale experiments. Our analysis showed that genes coding for proteins in complexes tend to have more genetic interactions, are co-expressed with more genes, are multifunctional, localize more often in the nucleus, and are more often involved in nucleic acid-related metabolic processes and processes where large machineries are the predominant functional drivers. A comparison to genetic interactions showed that about 40% of expanded co-complex pairs also have genetic interactions, suggesting strong functional links between complex members.
Intracellular sterol sensing controls intestinal B cell differentiation
Authors: Trindade Bruno C. , Ceglia Simona , Berthelette Alyssa , Raso Fiona , Howley Kelsey , Muppidi Jagan R. , Reboldi Andrea 
Published: November 2020

AbstractIntestinal B cell responses are critical for the maintenance of gut homeostasis, yet environmental signals that control B cell metabolism and effector function remain poorly characterized. Here, we show that Peyer’s patches germinal center (GC) B cells are sensitive to 25-hydroxycholesterol (25-HC), an oxidized metabolite of cholesterol produced by the enzyme cholesterol 25-hydroxylase (CH25H). In mice lacking CH25H, antigen-specific GC B cells show an increased cholesterol metabolic signature and preferentially differentiate in plasma cells (PCs), thereby inducing a stronger intestinal IgA response upon immunization or infection. GC B cells express the sterol sensor SREBP2 and use it to sense 25-HC. Deletion of SREBP2 from GC B cells prevents PC differentiation and forces the maintenance of GC identity. GC localized oxysterol production by follicular dendritic cells is central in dictating GC metabolism and imposing B cell fate. Our findings show that the 25-HC-SREBP2 axis shapes B cell effector function in intestinal lymphoid organs and indicate that dietary cholesterol can instruct local B cell response.
The Correlation of Substitution Effects Across Populations and Generations in the Presence of Non-Additive Functional Gene Action
Authors: Legarra A. , Garcia-Baccino C.A. , Wientjes Y.C.J. , Vitezica Z.G. 
Published: November 2020

ABSTRACTAllele substitution effects at quantitative trait loci (QTL) are part of the basis of quantitative genetics theory and applications such as association analysis and genomic prediction. In the presence of non-additive functional gene action, substitution effects are not constant across populations. We develop an original approach to model the difference in substitution effects across populations as a first order Taylor series expansion from a “focal” population. This expansion involves the difference in allele frequencies and second-order statistical effects (additive by additive and dominance). The change in allele frequencies is a function of relationships (or genetic distances) across populations. As a result, it is possible to estimate the correlation of substitution effects across two populations using three elements: magnitudes of additive, dominance and additive by additive variances; relationships (Nei’s minimum distances or Fst indexes); and assumed heterozygosities. Similarly, the theory applies as well to distinct generations in a population, in which case the distance across generations is a function of increase of inbreeding. Simulation results confirmed our derivations. Slight biases were observed, depending on the non-additive mechanism and the reference allele. Our derivations are useful to understand and forecast the possibility of prediction across populations and the similarity of GWAS effects.
Contrast-enhanced sonography with biomimetic lung surfactant nanodrops
Authors: Thomas Alec N. , Song Kang-Ho , Upadhyay Awaneesh , Papadopoulou Virginie , Ramirez David , Benninger Richard K. P. , Lowerison Matthew , Song Pengfei , Murray Todd W. , Borden Mark A. 
Published: November 2020

AbstractNanodrops comprising a perfluorocarbon liquid core can be acoustically vaporized into echogenic microbubbles for ultrasound imaging. Packaging the microbubble in its condensed liquid state provides distinct advantages, includingin situactivation of the acoustic signal, longer circulation persistence, and the advent of expanded diagnostic and therapeutic applications in pathologies which exhibit compromised vasculature. One obstacle to clinical translation is the inability of the limited surfactant present on the nanodrop to encapsulate the greatly expanded microbubble interface, resulting in ephemeral microbubbles with limited utility. In this study, we examine a biomimetic approach to stabilizing an expanding gas surface by employing the lung surfactant replacement, Beractant. Lung surfactant contains a suite of lipids and surfactant proteins that provides efficient shuttling of material from bilayer folds to the monolayer surface. We therefore hypothesized that Beractant would improve stability of acoustically vaporized microbubbles. To test this hypothesis, we characterized Beractant surface dilation mechanics and revealed a novel biophysical phenomenon of rapid interfacial melting, spreading and re-solidification. We then harnessed this unique spreading capability to increase the stability and echogenicity of microbubbles produced after acoustic droplet vaporization forin vivoultrasound imaging. Such biomimetic lung surfactant-stabilized nanodrops may be useful for applications in ultrasound imaging and therapy.Graphical Abstract
Long-range gene regulation network of theMGMTenhancer in modulating glioma cell sensitivity to temozolomide
Authors: He Anshun , Chen Bohan , Bi Jinfang , Wang Wenbin , Chen Jun , Qian Yuyang , Shi Tengfei , Zhao Zhongfang , Shi Jiandang , Yang Hongzhen , Zhang Lei , Lu Wange 
Published: November 2020

AbstractAcquired resistance to temozolomide (TMZ) is a major obstacle in glioblastoma treatment. MGMT, a DNA repair protein, and the methylation at its gene promoter, plays an important role in TMZ resistance. However, some evidences have suggested a MGMT-independent mechanisms underlying TMZ resistance. Here, we usedMGMTenhancer as a model and discovered that its deletion in glioma cells of lowMGMTexpression induced increased sensitivity to temozolomide. Analysis of a combination of RNA-seq and Capture Hi-C further suggested multiple long-range target genes regulated by theMGMTenhancer and that interactions may play important roles in glioma cell sensitivity to TMZ. This study reveals a novel mechanism of regulation of TMZ sensitivity in glioma cells.
Feedback inhibition of AMT1 NH4+-transporters mediated by CIPK15 kinase
Authors: Chen Hui-Yu , Chen Yen-Ning , Wang Hung-Yu , Liu Zong-Ta , Frommer Wolf B. , Ho Cheng-Hsun 
Published: November 2020

SUMMARYAmmonium (NH4+), a key nitrogen form, becomes toxic when it accumulates to high levels. Ammonium transporters (AMTs) are the key transporters responsible for NH4+uptake. AMT activity is under allosteric feedback control, mediated by phosphorylation of a threonine in the cytosolic C-terminus (CCT). However, the kinases responsible for the NH4+-triggered phosphorylation remain unknown. In this study, a functional screen identified protein kinaseCBL-InteractingProteinKinase15 (CIPK15) as a negative regulator of AMT1;1 activity. CIPK15 was able to interact with several AMT1 paralogs at the plasma membrane. Analysis of AmTryoshka, an NH4+transporter activity sensor for AMT1;3 in yeast, and a two-electrode-voltage-clamp (TEVC) of AMT1;1 inXenopusoocytes showed that CIPK15 inhibits AMT activity. CIPK15 transcript levels increased when seedlings were exposed to elevated NH4+levels. Notably,cipk15knockout mutants showed higher15NH4+uptake and accumulated higher amounts of NH4+compared to the wild-type. Consistently,cipk15was hypersensitive to both NH4+and methylammonium but not nitrate (NO3−). Taken together, our data indicate that feedback inhibition of AMT1 activity is mediated by the protein kinase CIPK15 via phosphorylation of residues in the CCT to reduce NH4+-accumulation.
Environmental DNA as a management tool for tracking artificial waterhole use in savanna ecosystems
Authors: Farrell Maxwell J. , Govender Danny , Hajibabaei Mehrdad , van der Bank Michelle , Davies T. Jonathan 
Published: November 2020

AbstractGame parks are the last preserve of many large mammals, and in savanna ecosystems, management of surface waters poses a conservation challenge. In arid and semi-arid regions, water can be a scarce resource during dry seasons and drought. Artificial waterholes are common in parks and reserves across Africa, but can alter mammal community composition by favoring drought intolerant species, with consequences for disease dynamics, and population viability of drought-tolerant species. Analysis of waterborne environmental DNA (eDNA) is increasingly used to inform conservation of rare and invasive species, and conduct large-scale biodiversity assessments. To explore the reliability of eDNA as an indicator of mammal waterhole use in savannas, we compare eDNA metabarcoding and camera traps for documenting artificial waterhole use in the Kruger National Park, South Africa, a global hotspot for mammal diversity. We show that eDNA metabarcoding can recover the majority of mammal species detected by camera traps, including a number of endangered species, but DNA signatures of mammal visitation are temporally limited, with best performance when tracking water-dependent large bodied mammals visiting within two days of sampling. Our results highlight limitation of eDNA based monitoring in these systems, including the lack of long-term eDNA persistence in small and highly utilized waterholes, and variability in detection rates among species. However, we demonstrate that eDNA-based approaches can be used to track mammals of conservation concern, and reflect patterns of recent waterhole use and co-occurrence across water-dependent species, both of which are crucial for making evidence-based decisions regarding water management and provisioning.
The translational landscape of SARS-CoV-2 and infected cells
Authors: Puray-Chavez Maritza , Lee Nakyung , Tenneti Kasyap , Wang Yiqing , Vuong Hung R. , Liu Yating , Horani Amjad , Huang Tao , Gunsten Sean P. , Case James B. , Yang Wei , Diamond Michael S. , Brody Steven L. , Dougherty Joseph , Kutluay Sebla B. 
Published: November 2020

AbstractSARS-CoV-2 utilizes a number of strategies to modulate viral and host mRNA translation. Here, we used ribosome profiling in SARS-CoV-2 infected model cell lines and primary airway cells grown at the air-liquid interface to gain a deeper understanding of the translationally regulated events in response to virus replication. We find that SARS-CoV-2 mRNAs dominate the cellular mRNA pool but are not more efficiently translated than cellular mRNAs. SARS-CoV-2 utilized a highly efficient ribosomal frameshifting strategy in comparison to HIV-1, suggesting utilization of distinct structural elements. In the highly permissive cell models, although SARS-CoV-2 infection induced the transcriptional upregulation of numerous chemokines, cytokines and interferon stimulated genes, many of these mRNAs were not translated efficiently. Impact of SARS-CoV-2 on host mRNA translation was more subtle in primary cells, with marked transcriptional and translational upregulation of inflammatory and innate immune responses and downregulation of processes involved in ciliated cell function. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.
Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets
Authors: de Vries Rory D. , Schmitz Katharina S. , Bovier Francesca T. , Noack Danny , Haagmans Bart L. , Biswas Sudipta , Rockx Barry , Gellman Samuel H. , Alabi Christopher A. , de Swart Rik L. , Moscona Anne , Porotto Matteo 
Published: November 2020

AbstractContainment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed a dimeric lipopeptide fusion inhibitor that blocks this critical first step of infection for emerging coronaviruses and document that it completely prevents SARS-CoV-2 infection in ferrets. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and non-toxic and thus readily translate into a safe and effective intranasal prophylactic approach to reduce transmission of SARS-CoV-2.One-sentence summaryA dimeric form of a SARS-CoV-2-derived lipopeptide is a potent inhibitor of fusion and infectionin vitroand transmissionin vivo.
The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis
Authors: Deruelle Vincent , Bouillot Stéphanie , Job Viviana , Taillebourg Emmanuel , Fauvarque Marie-Odile , Attrée Ina , Huber Philippe 
Published: November 2020

AbstractPseudomonas aeruginosais a causative agent in nosocomial infections, notably in ventilated or cystic fibrosis patients.P. aeruginosaisolates expressing the phospholipase ExoU, an effector of the type III secretion system, are the most pathogenic in clinics. Here, using a genome-wide screen, we discovered that ExoU toxicity requires DNAJC5, a host chaperone, to exert its necrotic activity. DNAJC5 is involved in an unconventional secretory pathway for misfolded proteins involving anterograde vesicular trafficking. DNAJC5-deficient human cells orDrosophilaflies knocked-down for the DNAJC5 orthologue were largely resistant to ExoU virulence. ExoU colocalized with DNAJC5-positive vesicles in the host cytoplasm. DNAJC5 mutations preventing vesicle trafficking - identified in adult neuronal ceroid lipofuscinosis, a human congenital disease - inhibited ExoU-dependent cell lysis. These results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where its phospholipase activity is triggered by binding to PI(4,5)P2.
CaveThiovulaceaediffer metabolically and genomically from marine species
Authors: Bizic Mina , Brad Traian , Ionescu Danny , Barbu-Tudoran Lucian , Aerts Joost , Popa Radu , Zoccarato Luca , Ody Jessica , Flot Jean-François , Tighe Scott , Vellone Daniel , Sarbu Serban M. 
Published: November 2020

ABSTRACTLife in Movile Cave (Romania) relies entirely on carbon fixation by bacteria. The microbial community in the surface water of Movile Cave’s hypoxic air bells is dominated by large spherical-ovoid bacteria we identified asThiovulumsp. (Campylobacterota). These form a separate phylogenetic cluster within theThiovulaceae, consisting mostly of freshwater cave bacteria. We compared the closed genome of thisThiovulumto that of the marine strainThiovulumES, and to a genome we assembled from public data from the sulfidic Frasassi caves. The Movile and FrasassiThiovulumwere very similar, differing greatly from the marine strain. Based on their genomes, caveThiovulumcan switch between aerobic and anaerobic sulfide oxidation using O2and NO3-as electron acceptors, respectively. NO3-,is likely reduced to NH3via dissimilatory nitrate reduction to ammonia using periplasmic nitrate reductase (Nap) and hydroxylamine oxidoreductase. Thus,Thiovulum, is likely important to both S and N cycles in sulfidic subterranean aquatic ecosystems. Additionally, we suggest that the short peritrichous flagella-like structures typical ofThiovulumare type IV pili, for which genes were found in allThiovulumgenomes. These pili may play a role in veil formation, connecting adjacent cells and the exceptionally fast swimming of these bacteria.
Developmental Regulation of Mitotic Chromosome Formation Revealed by Condensin Reporter Mice
Authors: Taylor Gillian C A , Macdonald Lewis A , Bui Matilda , Scott Lucy , Christodoulou Ioannis , Bukowski-Wills Jimi , Papadopoulos Dimitrios K , Wood Andrew J 
Published: November 2020

Withdrawal Note:The authors have withdrawn their manuscript due to the discovery of artifacts that call into question key findings from the study. Both artifacts originate from cell-type differences that arose during sample processing, creating the impression that non-SMC subunits of condensin proteins were present at substantially higher levels in thymic T cells compared to bone marrow B cells or erythroblast cells. Based on data collected since the preprint was submitted, we no longer believe this to be true. The experimental artifacts do not affect the data contributed by the Papadopoulos laboratory (Figure 4).The authors wish to make it clear that all data and experimental protocols in the original manuscript were accurately reported, and that the experimental artifacts which affect data interpretation were discovered during internal review, independently of peer review, and are being reported at the authors’ own instigation. They do not, to our knowledge, affect the interpretation of data from any other published work.Due to the issues outlined above, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Human-specific expansion of 22q11.2 low copy repeats
Authors: Vervoort Lisanne , Dierckxsens Nicolas , Pereboom Zjef , Capozzi Oronzo , Rocchi Mariano , Shaikh Tamim H. , Vermeesch Joris R. 
Published: November 2020

AbstractSegmental duplications or low copy repeats (LCRs) constitute complex regions interspersed in the human genome. They have contributed significantly to human evolution by stimulating neo- or sub-functionalization of duplicated transcripts. The 22q11.2 region carries eight LCRs (LCR22s). One of these LCR22s was recently reported to be hypervariable in the human population. It remains unknown whether this variability exists also in non-human primates. To assess the inter- and intra-species variability, wede novoassembled the region in non-human primates by a combination of optical mapping techniques. Orangutan carries three LCR22-mediated inversions of which one is the ancient haplotype since it is also present in macaque. Using fiber-FISH, lineage-specific differences in LCR22 composition were mapped. The smallest and likely ancient haplotype is present in the chimpanzee, bonobo and rhesus macaque. The absence of intra-species variation in chimpanzee indicates the LCR22-A expansion to be unique to the human population. Further, we demonstrate that LCR22-specific genes are expressed in both human and non-human primate neuronal cell lines and show expression of several primate LCR22 transcripts for the first time. The human-specificity of the expansions suggest an important role for the region in human evolution and adaptation.Author summaryLow copy repeats or segmental duplications are DNA segments composed of various subunits which are duplicated across the genome. Due to the high level of sequence identity between these segments, homologous regions can misalign, resulting in reciprocal deletions and duplications, classified as genomic disorders. These regions are subject to structural variation in the human population. We recently detected extreme structural variation in one of the most complex segmental duplication regions of the human genome, the low copy repeats on chromosome 22 (LCR22s). Rearrangements between the LCR22s result in the 22q11.2 deletion/duplication syndrome, the most common human genomic disorder. However, it remains unknown whether this variability is human-specific. In this study, we investigated those LCR22s in several individuals of the different great apes and macaque. We show only the smallest haplotype is present without any intra-species variation in thePangenus, our closest ancestors. Hence, LCR22 expansions are human-specific, suggesting a role of these LCR22s in human evolution and adaptation and hypothesize the region contributes to the 22q11.2 deletion syndrome inter-patient phenotypic variability.