bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete sequences of six Major Histocompatibility Complex haplotypes, including all the major MHC class II structures
Authors: Houwaart Torsten , Scholz Stephan , Pollock Nicholas R , Palmer William H. , Kichula Katherine M. , Strelow Daniel , Le Duyen B , Belick Dana , Lautwein Tobias , Wachtmeister Thorsten , Henrich Birgit , Köhrer Karl , Parham Peter , Guethlein Lisbeth A , Norman Paul J , Dilthey Alexander T 
Published: May 2022

AbstractAccurate and comprehensive immunogenetic reference panels are key to the successful implementation of population-scale immunogenomics. The 5Mbp Major Histocompatibility Complex (MHC) is the most polymorphic region of the human genome and associated with multiple immune-mediated diseases, transplant matching and therapy responses. Analysis of MHC genetic variation is severely complicated by complex patterns of sequence variation, linkage disequilibrium and a lack of fully resolved MHC reference haplotypes, increasing the risk of spurious findings on analyzing this medically important region. Integrating Illumina and ultra-long Nanopore sequencing as well as bespoke bioinformatics, we completed five of the alternative MHC reference haplotypes of the current (B38) build of the human reference genome and added one other. The six assembled MHC haplotypes encompass the DR1 and DR4 haplotype structures in addition to the previously completed DR2 and DR3, as well as six distinct classes of the structurally variable C4 region. Analysis of the assembled haplotypes showed that MHC class II sequence structures, including repeat element positions, are generally conserved within the DR haplotype supergroups, and that sequence diversity peaks in three regions around HLA-A, HLA-B+C, and the HLA class II genes. Demonstrating the potential for improved short-read analysis, the number of proper read pairs recruited to the MHC was found to be increased by 0.32% – 0.69% in a 1000 Genomes Project read re-mapping experiment with seven diverse samples. Furthermore, the assembled haplotypes can serve as references for the community and provide the basis of a structurally accurate genotyping graph of the complete MHC region.
Developmental changes of opsin gene expression in ray-finned fishes (Actinopterygii)
Authors: Lupše Nik , Kłodawska Monika , Truhlářová Veronika , Košátko Prokop , Kašpar Vojtěch , Bitja Nyom Arnold Roger , Musilova Zuzana 
Published: May 2022

AbstractFish often change their habitat and trophic preferences during development. Dramatic functional differences between embryos, larvae, juveniles and adults also concern sensory systems, including vision. Here we focus on the photoreceptors (rod and cone cells) in the retina and their gene expression profiles during the development. Using comparative transcriptomics on 63 species, belonging to 23 actinopterygian orders, we report general developmental patterns of opsin expression, mostly suggesting an increased importance of the rod opsin (RH1) gene and the long-wavelength sensitive (LWS) cone opsin, and a decreasing importance of the shorter wavelength sensitive cone opsin throughout development. Furthermore, we investigate in detail ontogenetic changes in 14 selected species (from Polypteriformes, Acipenseriformes, Cypriniformes, Aulopiformes and Cichliformes), and we report examples of expanded cone opsin repertoires, cone opsin switches (mostly within RH2) and increasing rod:cone ratio as evidenced by the opsin and phototransduction cascade genes. Our findings provide molecular support for developmental stage-specific visual palettes of ray-finned fishes and shifts between, which most likely arose in response to ecological, behavioural and physiological factors.
A novel computational approach to identify cancer cells in scRNA-seq data
Authors: Gasper William , Rossi Francesca , Ligorio Matteo , Ghersi Dario 
Published: May 2022

AbstractSingle-cell RNA-seq is an invaluable research tool that allows for the investigation of gene expression in heterogeneous cancer cell populations in ways that bulk RNA-seq cannot. However, normal (i.e., non tumor) cells in cancer samples have the potential to confound the downstream analysis of single-cell RNA-seq data. Several existing methods for identifying tumor cells use copy number variation inference. This work aims to extend existing approaches for identifying cancer cells in single-cell RNA-seq samples by incorporating putative driver alterations. We found that putative driver alterations can be detected in single-cell RNA-seq data and that a subset of cells in tumor samples are enriched in putative driver alterations as compared to normal cells. Furthermore, we show that the number of putative driver alterations and inferred copy number variation are not correlated in all samples. Taken together, our findings suggest that combining copy number variation inference with putative driver mutation load can augment the number of tumor cells that can be confidently included in downstream analyses of single-cell RNA-seq datasets.
Sex-Specific Effects of Psychedelic Drug Exposure on Central Amygdala Reactivity and Behavioral Responding
Authors: Effinger DP , Quadir SG , Ramage MC , Cone MG , Herman MA 
Published: May 2022

ABSTRACTPsilocybin, and its active metabolite psilocin, have been shown to elicit rapid and long-lasting symptom improvements in a variety of affective psychiatric illnesses. However, the region-specific alterations underlying these therapeutic effects remain relatively unknown. The central amygdala (CeA) is a primary output region within the extended amygdala that is dysregulated in affective psychiatric disorders. Here, we measured CeA activity using the activity marker c-Fos and CeA reactivity using fiber photometry paired with an aversive air-puff stimulus. We found that psilocin administration acutely increased CeA activity in both males and females and increased stimulus specific CeA reactivity in females, but not males. In contrast, psilocin produced time-dependent decreases in reactivity in males, but not females as early as 2-days and lasting to 28-days post administration. We also measured behavioral responses to the air-puff stimulus and found sex-dependent changes in threat responding but not exploratory behavior or general locomotion. Repeated presentations of the auditory component of the air-puff were also performed and sex-specific effects of psilocin on CeA reactivity to the auditory-alone stimulus were also observed. This study provides new evidence that a single dose of psilocin produces sex-specific, time-dependent, and enduring changes in CeA reactivity and behavioral responding to specific components of an aversive stimulus.
A Unifying Statistical Framework to Discover Disease Genes from GWAS
Authors: McManus Justin N.J. , Lovelett Robert J. , Lowengrub Daniel , Christensen Sarah 
Published: May 2022

ABSTRACTGenome-wide association studies (GWAS) identify genomic loci associated with complex traits, but it remains an open challenge to identify the genes underlying the association signals. Here, we extend the equations of statistical fine-mapping, to compute the probability that each gene in the human genome is targeted by a causal variant, given a particular trait. Our computations are enabled by several key innovations. First, we partition the genome into optimal linkage disequilibrium blocks, enabling genome-wide detection of trait-associated genes. Second, we unveil a comprehensive mapping that associates genetic variants to the target genes they affect. The combined performance of the map on high-throughput functional genomics and eQTL datasets supersedes the state of the art. Lastly, we describe an algorithm which learns, directly from GWAS data, how to incorporate prior knowledge into the statistical computations, significantly improving their accuracy. We validate each component of the statistical framework individually and in combination. Among methods to identify genes targeted by causal variants, this paradigm rediscovers an unprecedented proportion of known disease genes. Moreover, it establishes human genetics support for many genes previously implicated only by clinical or preclinical evidence, and it discovers an abundance of novel disease genes with compelling biological rationale.
Divergence of trafficking and polarization mechanisms for PIN auxin transporters during land plant evolution
Authors: Tang Han , Lu Kuan-Ju , Zhang YuZhou , Cheng You-Liang , Tu Shih-Long , Friml Jiří 
Published: May 2022

AbstractThe phytohormone auxin and its directional transport through tissues play a fundamental role in development of higher plants. This polar auxin transport predominantly relies on PIN-FORMED (PIN) auxin exporters. Hence, PIN polarization is crucial for development, but its evolution during the rise of morphological complexity in land plants remains unclear. Here, we performed a cross-species investigation by observing the trafficking and localization of endogenous and xenologous PINs in two bryophytes,Physcomitrium patensandMarchantia polymorpha, and in the flowering plantArabidopsis thaliana. We confirmed that the GFP fusion did not compromise the auxin export function of all examined PINs by using radioactive auxin export assay and by observing the phenotypic changes in transgenic bryophytes. Endogenous PINs polarize to filamentous apices, while xenologous Arabidopsis PINs distribute symmetrically on the membrane in both bryophytes. In Arabidopsis root epidermis, bryophytic PINs show no defined polarity. Pharmacological interference revealed a strong cytoskeleton dependence of bryophytic but not Arabidopsis PIN polarization. The divergence of PIN polarization and trafficking is also observed within the bryophyte clade and between tissues in individual species. These results collectively reveal a divergence of PIN trafficking and polarity mechanisms throughout land plant evolution and a co-evolution of PIN sequence-based and cell-based polarity mechanisms.
Regenerating axolotl retinas regrow diverse cell types with modulation by Notch signaling and reconnect to the brain
Authors: Yandulskaya Anastasia S. , Miller Melissa N. , Ansaripour Ronak , Carrier Rebecca L. , Monaghan James R. 
Published: May 2022

AbstractSome species successfully repair retinal injuries in contrast to non-regenerative mammalian retina. We show here that the Mexican axolotl salamander regrows its excised retina even in adulthood. During early regeneration, cell proliferation occurred in the retinal pigment epithelium (RPE). All dividing cells expressed Vimentin, and some also expressed Müller glia and neural progenitor cell marker Glast (Slc1a3), suggesting that regeneration is driven by RPE-derived retinal progenitor cells. Bulk RNA sequencing showed that genes associated with the extracellular matrix and angiogenesis were upregulated in early-to-mid retinal regeneration. The fully regenerated retina re-established nerve projections to the brain and contained all the original retinal cell types, including Müller glia. Regeneration of cellular diversity may be modulated by Notch signaling, as inhibiting Notch signaling in early regeneration promoted production of rod photoreceptors. Our study highlights the axolotl salamander as an advantageous model of adult tetrapod retinal regeneration and provides insights into its mechanisms.SummaryWe demonstrate that adult Mexican axolotl salamanders regenerate retinas after a retinectomy. We also show some cellular and molecular mechanisms that drive axolotl retinal regeneration.
Smoke exposed roots causes reduced whole-plant vascular sectoriality
Authors: Benoit Mary , Waller Spenser , Wilder Stacy L. , Schueller Michael J. , Ferrieri Richard A. 
Published: May 2022

AbstractWhile photosynthates are partitioned by the relative strength of young developing leaves and roots as sinks for carbon-based resources, many plants also show a close relationship between partitioning, phyllotaxy and vascular connectivity, yielding sectorial patterns of allocation. We examined whether smoke influences phloem vascular sectoriality in a model plant, sunflower (Helianthis annuus L.). Using radioactive 11CO2 administered to single photosynthetically active source leaves, we examined the transport behavior and allocation patterns of 11C-photosynthates using gamma counting and autoradiography. Soil treated with liquid smoke caused significant reductions in phloem sectoriality involving young sink leaves and roots. The resulting increase in vascular connectivity could benefit young plant performance by allowing a more uniform allocation of nutrients and/or stress signal molecules at a critical time of their growth.One-Sentence SummarySmoke-exposed roots exhibit a significant reduction in phloem sectoriality involving carbon transport to young sink leaves and roots.
Actin-regulated Siglec-1 nanoclustering influences HIV-1 capture and virus-containing compartment formation in dendritic cells
Authors: Gutiérrez-Martínez Enric , Benet Susana , Mateos Nicolas , Erkizia Itziar , Nieto-Garai Jon Ander , Lorizate Maier , Manzo Carlo , Campelo Felix , Izquierdo-Useros Nuria , Martinez-Picado Javier , Garcia-Parajo Maria F. 
Published: May 2022

AbstractThe immunoglobulin-like lectin receptor CD169 (Siglec-1) mediates the capture of HIV-1 by activated dendritic cells (DC) through binding to sialylated ligands. These interactions result in a more efficient virus capture as compared to resting DCs, although the underlying mechanisms are poorly understood. Using a combination of super-resolution microscopy, single particle tracking and biochemical perturbations we studied the nanoscale organization of Siglec-1 on activated DCs and its impact on viral capture and its trafficking to a single viral-containing compartment. We found that activation of DCs leads to Siglec-1 basal nanoclustering at specific plasma membrane regions where receptor diffusion is constrained by Rho-ROCK activation and formin-dependent actin polymerization. Using liposomes with varying ganglioside concentrations, we further demonstrate that Siglec-1 nanoclustering enhances the receptor avidity to limiting concentrations of gangliosides carrying sialic ligands. Binding to either HIV-1 particles or ganglioside-bearing liposomes lead to enhanced Siglec-1 nanoclustering and global actin rearrangements characterized by a drop in RhoA activity, facilitating the final accumulation of viral particles in a single sac-like compartment. Overall, our work provides new insights on the role of the actin machinery of activated DCs in regulating the formation of basal Siglec-1 nanoclustering, being decisive for the capture and actin-dependent trafficking of HIV-1 into the virus-containing compartment.
Partial refuges from biological control due to intraspecific variation in protective host traits: a case study with the egg parasitoidTrissolcus japonicus
Authors: Abram Paul K. , Haye Tim , Clarke Peggy , Grove Emily , Thiessen Jason , Gariepy Tara D. 
Published: May 2022

AbstractPredicting how much of a host or prey population may be attacked by their natural enemies is fundamental to several subfields of applied ecology, particularly biological control of pest organisms. Hosts or prey can occupy refuges from natural enemy attack, but habitat or ecological refuges are challenging or impossible to predict in a laboratory setting – which is often where efficacy and specificity testing of candidate biological control agents is done. Here we explore how intraspecific variation in continuous traits that confers some protection from natural enemy attack – even after the natural enemy has encountered the prey – could provide partial refuges. The size of these trait-based refuges should depend on the relationship between trait values and host/prey susceptibility to natural enemy attack, and on how common different trait values are within a host/prey population. These can be readily estimated in laboratory testing of natural enemy impact on target or non-target prey or hosts as long as sufficient host material is available. We provide a general framework for how intraspecific variation in protective host traits could be integrated into biological control research, specifically with reference to non-target testing as part of classical biological control programs. As a case study, we exposed different host clutch sizes of target (pest) and non-target (native species) stink bug (Hemiptera: Pentatomidae) species to a well-studied exotic biocontrol agent, the egg parasitoidTrissolcus japonicus(Hymenoptera: Scelionidae). Although we observed several behavioural and reproductive responses to variation in host egg mass size byT. japonicus, they did not translate to increases in predicted refuge size (proportion host survival) large enough to change the conclusions of non-target testing. We encourage researchers to investigate intraspecific variation in a wider variety of protective host and prey traits and their consequences for refuge size.
Sorting single T cells based on secreted cytokines and surface markers using hydrogel nanovials
Authors: Koo Doyeon , Dimatteo Robert , Lee Sohyung , de Rutte Joseph , Di Carlo Dino 
Published: May 2022

AbstractImmune cell function is intrinsically linked to secreted factors which enable cells to communicate with neighboring or distant cells to coordinate a response. The ability to secrete cytokines also can help define the population of cells with therapeutic potential in emerging cell therapies, such as chimeric antigen receptor (CAR)-T cell therapies. Polyfunctional cells that can secrete more than one cytokine have been found to play an outsized role in therapeutic efficacy. While there are a variety of techniques to analyze cellular secretions from individual polyfunctional cells, there are no widely-available approaches to sort viable cells based on this phenotype. Here, we apply lab on a particle technology to the analysis and sorting of T cells based on a combination of secreted factors, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α) and interleukin 2 (IL-2) and surface markers (CD8+ and CD4+). Cells are selectively loaded into the antibody-functionalized cavity of micro-hydrogel particles, called nanovials, where secreted cytokines are captured and fluorescently stained. By leveraging standard fluorescence activated cell sorters and using fluorescence pulse area/height information we can distinguish between fluorescence signals on the nanovial cavities and on cells, and are able to process greater than 1 million nanovials in one hour of sorting. The frequency of multi-cytokine secreting cells was correlated with surface marker expression, and biased towards CD4+ T cells. CD8+ cells that secreted more than one cytokine, were biased towards IFN-γ and TNF-α with fewer CD8+ cells secreting IL-2. The majority of cells with a polyfunctional phenotype that were sorted remained viable and regrew following sorting. This nanovial cytokine secretion assay can be applied to sort antigen-specific T cells or CAR-T cells based on their functional engagement with cognate antigens or peptide-major histocompatibility complexs (MHCs), enabling discovery of functional CARs or T cell receptors and deeper investigation into the molecular underpinnings of single T cell function.
BMAL1 loss in oligodendroglial lineage cells dysregulates myelination and sleep
Authors: Rojo Daniela , Badner Anna , Dal Cengio Louisa , Kim Samuel , Sakai Noriaki , Greene Jacob , Eisinger Ella , Arellano-Garcia Caroline , Mehl Lindsey C. , Gumma Mohammad E. , Soyk Rebecca L. , Ransom Julia , Weigel Maya K. , Yalçın Belgin , Jones Samuel E. , Ollila Hanna M. , Nishino Seiji , Gibson Erin M. 
Published: May 2022

AbstractMyelination depends on maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that the dynamic nature of oligodendroglia and myelination are regulated by the circadian transcription factor BMAL1. Bmal1 knockdown in OPCs during development – but not adulthood – decreases OPC proliferation, whereas BMAL1 regulates OPC morphology throughout life. OPC-specific Bmal1 deficiency impairs remyelination in an age-dependent manner, suggesting that age-associated decrements in circadian regulation of oligodendroglia may contribute to the deficient remyelination potential in demyelinating diseases like multiple sclerosis (MS). This oligodendroglial dysregulation and dysmyelination increase sleep fragmentation in OPC-specific Bmal1 knockout mice, and sleep fragmentation is causally associated with MS. These findings have broad mechanistic and therapeutic implications for numerous brain disorders that include both myelin and sleep phenotypes.One-Sentence SummaryBMAL1 regulates the homeostatic maintenance of oligodendroglia and myelin, that subsequently controls sleep architecture.
Hyperimmune bovine colostrum containing lipopolysaccharide antibodies (Imm124-E) has a non-detrimental effect on gut microbial communities in unchallenged mice
Authors: Gore Rachele , Mohsenipour Mitra , Wood Jennifer L , Balasuriya Gayathri K , Hill-Yardin Elisa L , Franks Ashley E 
Published: May 2022

1AbstractEnterotoxigenicEscherichia coli(ETEC) is a leading cause of bacterial diarrhea in travelers, military personnel and children in developing countries. Infection has the potential to cause long-term gastrointestinal dysfunction. Preventative treatments for ETEC-induced diarrhea exist, yet the effects of these treatments on gastrointestinal commensals in healthy individuals is unclear. Whether administration of a prophylactic preventative treatment for ETEC-induced diarrhea causes specific shifts in gut microbial populations in controlled environments is also unknown. Here we studied the effects of a hyperimmune bovine colostrum (IMM-124E) used in the manufacture of Travelan® (AUST L 106709) on gastrointestinal bacteria in healthy C57BL/6 mice. Using next generation sequencing, we aimed to test the onset and magnitude of potential changes to the mouse gut microbiome in response to the anti-diarrheagenic hyperimmune bovine colostrum product, rich in immunoglobulins against select ETEC strains (Travelan®, Immuron Ltd). We engineered changes in mouse fecal and cecal bacterial communities by delivering lipopolysaccharide (LPS) antibodies derived from bovine colostrum via dietary supplementation. Holstein Friesian and Jersey cows between 28- and 35-weeks’ gestation stimulated by subcutaneous delivery of three important pathogenic and antigenic determinants; LPS, flagella, and colonization factor antigen (CFA), produced a hyperimmune colostrum (IMM-124E) with demonstrated beneficial effects on health via modulation of metabolic pathways and immune function. We show that in mice administered colostrum containing LPS antibodies there was an increased abundance of potentially gut-beneficial bacteria, such asAkkermansiaandDesulfovibrio, without disrupting the underlying ecology of the gastrointestinal tract. Compared to controls, there was no difference in overall weight gain, body or cecal weights or small intestine length following LPS antibody colostrum supplementation. Overall, dietary supplementation with colostrum containing LPS antibodies produced subtle alterations in gut bacterial composition of mice. Primarily, Travelan® LPS antibody treatment decreased the ratio of Firmicutes/Bacteroidetes in gut microbial populations in unchallenged healthy mice. Further studies are required to examine the effect of Travelan® LPS antibody treatment to engineer the microbiome in a diseased state and during recovery.