bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Dct-/- mouse model to unravel retinogenesis misregulation in patients with albinism
Authors: Tingaud-Sequeira Angèle , Mercier Elina , Michaud Vincent , Pinson Benoît , Gazova Ivet , Gontier Etienne , Decoeur Fanny , McKie Lisa , Jackson Ian J. , Arveiler Benoît , Javerzat Sophie 
Published: May 2022

AbstractWe have recently identified DCT encoding dopachrome tautomerase (DCT) as the 8th gene for oculocutaneous albinism (OCA). Patients with loss of function of DCT suffer from eye hypopigmentation and retinal dystrophy. Here we investigate the eye phenotype in Dct-/- mice. We show that their retinal pigmented epithelium (RPE) is severely hypopigmented from early stages contrasting with the darker melanocytic tissues. Multimodal imaging reveals specific RPE cellular defects. Melanosomes are fewer with correct subcellular localization but disrupted melanisation. RPE cell size is globally increased and heterogeneous. P-cadherin labeling of Dct-/- newborn RPE reveals a defect in adherens junctions similar to what has been described in tyrosinase-deficient Tyrc/c embryos. The first intermediate of melanin biosynthesis, dihydroxyphenylalanine (L-Dopa), which is thought to control retinogenesis, is detected in substantial yet significantly reduced amounts in Dct-/- postnatal mouse eyecups. L-Dopa synthesis in the RPE alone remains to be evaluated during the critical period of retinogenesis. The Dct-/- mouse should prove useful in understanding the molecular regulation of retinal development and aging of the hypopigmented eye. This may guide therapeutic strategies to prevent vision deficits in patients with albinism.
Store-Operated Ca2+ Channels Mediate Microdomain Ca2+ Signals and Amplify Gq-Coupled Ca2+ Elevations in Capillary Pericytes
Authors: Phillips Braxton , Clark Jenna , Martineau Éric , Rungta Ravi L. 
Published: May 2022

AbstractPericytes are multifunctional cells of the vasculature that are vital to brain homeostasis, yet many of their fundamental physiological properties remain unexplored. Ca2+ is a ubiquitous second messenger across cell-types, where it mediates diverse functions such as contractility and gene transcription. It is therefore important to understand the cellular mechanisms underlying Ca2+ signalling in capillary pericytes. Here, we performed pharmacological and ion substitution experiments to investigate the mechanisms underlying pericyte Ca2+ signaling in acute cortical brain slices of PDGFRβ-GCaMP6f mice. We report that in mid-capillary bed pericytes (≥ 4th branch order), spontaneous microdomain Ca2+ signals are dependent on extracellular Ca2+, but largely independent of depolarization, L- and T-type voltage-gated calcium channels (VGCCs), and TRPC3/6 channels. In contrast, these microdomain signals were inhibited by multiple Orai channel blockers, including the specific antagonist GSK-7975A. Furthermore, capillary pericytes exhibited classical store operated calcium entry (SOCE) following store depletion that was sensitive to GSK-7975A and required for amplification of intracellular Ca2+ increases evoked by the vasoconstrictor endothelin-1. These results suggest that Orai SOCE mediates microdomain Ca2+ signals at rest and amplifies Gq-GPCR coupled Ca2+ elevations in capillary pericytes. Thus, SOCE is a major regulator of pericyte Ca2+ and a target for manipulating their function in health and disease.
Gene losses resulting in specialized metabolism in the earliest divergent symbiotic Frankia clade can be linked to its low saprotrophic capabilities
Authors: Berckx Fede , Van Nguyen Thanh , Hilker Rolf , Wibberg Daniel , Battenberg Kai , Kalinowski Jörn , Berry Alison , Pawlowski Katharina 
Published: May 2022

SummaryFrankia cluster-2 are diazotrophs that engage in root nodule symbiosis with host plants of the Cucurbitales and the Rosales. They are rarely found in the soil in the absence of their hosts. Previous studies have shown that an assimilated nitrogen source, presumable arginine, is exported to the host in nodules of Datisca glomerata (Cucurbitales), but not in the nodules of Ceanothus thyrsiflorus (Rosales). To investigate if an assimilated nitrogen form is commonly exported by cluster-2 strains, and which nitrogen source would then be exported to C. thyrsiflorus, gene expression levels, metabolite profiles and enzyme activities were analysed.We found that the export of assimilated nitrogen in symbiosis is a common feature for Frankia cluster-2 strains, but which source is host-plant dependent. We also identified several gene losses.The ammonium assimilation via the GS/GOGAT cycle for export to the host, entails a high demand of 2-oxoglutarate from the TCA cycle. This specialised metabolism seems to have led to genome reduction: we show that Frankia cluster-2 strains have lost the glyoxylate shunt and succinate semialdehyde dehydrogenase, leading to a linearization of the TCA cycle. This could explain the low saprotrophic potential of Frankia cluster-2.
The repetitive DNA sequence landscape and DNA methylation in chromosomes of an apomictic tropical forage grass,Cenchrus ciliaris
Authors: Rathore Priyanka , Schwarzacher Trude , Heslop-Harrison J.S. (Pat) , Bhat Vishnu , Tomaszewska Paulina 
Published: May 2022

AbstractCenchrus ciliarisis an apomictic, allotetraploid pasture grass widely distributed in tropical and subtropical regions of Africa and Asia. In this work, we aim to investigate the genomic organization and characterize the nature of repetitive DNA sequences in this species. Because of the apomictic propagation, various aneuploid genotypes are found and we analysed here a 2n=4×+3=39 accession. The physical mapping of Ty1-copiaand Ty3-gypsyretroelements through fluorescencein situhybridization with global assessment of 5-methylcytosine DNA methylation through immunostaining revealed the genome-wide distribution pattern of retroelements and their association with DNA methylation. About a third of Ty1-copiasites overlapped or spanned centromeric DAPI positive heterochromatin, while the centromeric regions and arms of some chromosomes were labeled with Ty3-gypsy. Most of the retroelement sites overlapped with 5-methycytosine signals, except some Ty3-gypsyon the arms of chromosomes which did not overlap with anti-5-mC signals. Universal retrotransposon probes did not distinguish genomes ofC. ciliarisshowing signals in pericentromeric regions of all 39 chromosomes, unlike highly abundant repetitive DNA motifs found in survey genome sequences ofC. ciliarisusing graph-based clustering. Probes developed from RepeatExplorer clusters gave strong signals mostly in pericentromeric regions of about half of the chromosomes, and we suggested that they differentiate the two ancestral genomes in the allotetraploidC. ciliarislikely having different repeat sequence variants amplified before the genome came together in the tetraploid.
Low alcohol preferring mice have reduced task engagement during a waiting task for alcohol, which is enhanced by intermittent alcohol drinking
Authors: Starski Phillip , Maulucci Danielle , Mead Hunter , Hopf Frederic 
Published: May 2022

ABSTRACTAlcohol use disorder (AUD) is related to excessive binge alcohol consumption, and there is considerable interest in associated factors that promote intake. AUD has many behavioral facets that enhance inflexibility toward alcohol consumption, including impulsivity, motivation, and attention. Thus, it is important to understand how these factors might promote responding for alcohol and can change after protracted alcohol intake. Previous studies have explored such behavioral factors using responding for sugar in the 5-Choice Serial Reaction Time Task (5-CSRTT), which allows careful separation of impulsivity, attention, and motivation. Importantly, our studies uniquely focus on using alcohol as the reward throughout training and testing sessions, which is critical for beginning to answer central questions relating to behavioral engagement for alcohol. Alcohol preference and consumption in C57BL/6 mice were determined from the first 9 sessions of 2-hour alcohol drinking which were interspersed among 5-CSRTT training. Interestingly, alcohol preference but not consumption level significantly predicted 5-CSRTT responding for alcohol. In contrast, responding for strawberry milk was not related to alcohol preference. Moreover, high-preference (HP) mice made more correct alcohol-directed responses than low-preference (LP) during the first half of each session and had more longer reward latencies in the second half, with no differences when performing for strawberry milk, suggesting that HP motivation for alcohol may reflect “front-loading.” Mice were then exposed to an Intermittent Access to alcohol paradigm and retested in 5-CSRTT. While both HP and LP mice increased 5-CSRTT responding for alcohol, but not strawberry milk, LP performance rose to HP levels, with a greater change in correct and premature responding in LP versus HP. Overall, this study provides three significant findings: 1) alcohol was a suitable reward in the 5-CSRTT, allowing dissection of impulsivity, attention, and motivation in relation to alcohol drinking, 2) alcohol preference was a more sensitive indicator of mouse 5-CSRTT performance than consumption, and 3) chronic alcohol drinking promoted behavioral engagement with alcohol, especially for individuals with less initial engagement.
Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins
Authors: Zhang Fengwen , Zang Trinity , Stevenson Eva M. , Lei Xiao , Copertino Dennis C. , Mota Talia M. , Boucau Julie , Garcia-Beltran Wilfredo F. , Jones R. Brad , Bieniasz Paul D. 
Published: May 2022

AbstractViruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I downregulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I downregulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single-amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8+ T-cells. Speficially, ORF7a prevented the assembly of the MHC-I peptide loading complex and causing retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.
Genomic signatures associated with transitions to viviparity in Cyprinodontiformes
Authors: Yusuf Leeban H. , Lemus Yolitzi Saldívar , Thorpe Peter , Garcia Constantino Macías , Ritchie Michael G. 
Published: May 2022

AbstractThe transition from oviparity to viviparity has occurred independently over a hundred times across vertebrates, presenting a compelling case of phenotypic convergence. However, whether repeated, independent evolution of viviparity is driven by redeployment of similar genetic mechanisms and whether these leave a common genetic signature in genomic divergence remains unknown. Whilst investigations into the evolution of viviparity have demonstrated striking similarity among the genes and pathways involved across vertebrate groups, quantitative tests for genome-wide convergence provide ambivalent answers. Here, we investigate molecular convergence during independent transitions to viviparity across an order of ray-finned freshwater fish (Cyprinodontiformes). We assembledde novoand publicly-available genomes of viviparous and oviparous species to quantify molecular convergence across coding and non-coding regions. We found no evidence for an excess of molecular convergence in amino acid substitutions and rates of sequence divergence, implying independent genetic changes are associated with these transitions. However, statistical power and biological confounds (hemiplasy and introgression) could constrain our ability to detect correlated evolution. We therefore also identified candidate genes with potential signatures of molecular convergence in viviparousCyprinodontiformeslineages. While we detected no evidence of positive or relaxed selection for these genes in branches associated with the evolution of viviparity inCyprinodontiformes, motif-enrichment and gene ontology analyses suggest transcriptional changes associated with early morphogenesis, brain development and immunity occurred alongside the evolution of viviparity. Overall, our findings indicate that an excess of molecular convergence, at any level, is not strongly associated with independent transitions to viviparity in these fish.
Basal Ganglia Neurons in Healthy and Parkinsonian Primates Generate Recurring Sequences of Spikes
Authors: Galvan Adriana , Wichmann Thomas 
Published: May 2022

AbstractThe spiking activity of basal ganglia neurons can be characterized by summary statistics such as the average firing rate, or by measures of firing patterns, such as burst discharges, or oscillatory fluctuations of firing rates. Many of these features are altered by the presence of parkinsonism. This study examined another distinct attribute of firing activity, i.e., the occurrence of repeating sequences of inter-spike intervals. We studied this feature in extracellular electrophysiologic recordings that were made in the basal ganglia of Rhesus monkeys, before and after they had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phyl-1,2,3,6-tetrahydropyridine (MPTP). Neurons in both pallidal segments and in the subthalamic nucleus tended to fire in repeating sequences, typically 2 ISIs long (i.e., involving three spikes). In recordings that were 5000 inter-spike intervals long, 20-40% of spikes participated in one of many sequences with each ISI replicating the sequence pattern with a timing error of ≤1%. Compared to similar analyses in shuffled representations of the same data, sequences were more common in the original representation of ISIs in the subthalamic nucleus and the external pallidal segment. Induction of parkinsonism reduced the proportion of sequence spikes in the external pallidum but increased it in the subthalamic nucleus. We found no relation between the sequence generation and the firing rate of neurons, and, at most, a weak correlation between sequence generation and the incidence of bursts. We conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.
Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants
Authors: Roy Urmi 
Published: May 2022

AbstractAmong the multiple SARS-CoV-2 variants recently reported, the Delta variant has generated most perilous and widespread effects. Another variant, Omicron, has been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations and in numbers much larger than those of its predecessor variants. In this report we discuss some essential structural aspects and time-based structure changes of a selected set of spike protein mutations within the Delta and Omicron variants. The expected impact of multiple-point mutations within the spike protein’s receptor-binding domain (RBD) and S1 of these variants are examined. Additionally, RBD of the more recently emerged subvariants BA.4, BA.5 and BA.2.12.1 are discussed. Within the latter group, BA.5 represents globally, the most prevalent form of SARS-CoV-2 at the present time. Temporal mutation profile for the subvariant BF.7 and currently circulating variants of interest (VOI) and variants under monitoring (VUMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB and XBF are computationally explored here briefly with the expectation that these structural data will be helpful to identify drug targets and to neutralize antibodies for the evolving variants/subvariants of SARS-CoV-2.
A Van Gogh/Vangl tyrosine phosphorylation switch regulates its interaction with core Planar Cell Polarity factors Prickle and Dishevelled
Authors: Humphries Ashley C. , Hazelett C. Clayton , Molina-Pelayo Claudia , Devenport Danelle , Mlodzik Marek 
Published: May 2022

AbstractEpithelial tissues can be polarized along two axes, in addition to apical-basal polarity they are often also polarized within the plane of the epithelium, known as planar cell polarity (PCP). PCP depends upon the conserved Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl). Here, taking advantage of the complementary features of Drosophila wing and mouse skin PCP establishment, we dissect how Vang phosphorylation on a specific conserved tyrosine residue affects its interaction with two cytoplasmic core PCP factors, Dsh/Dvl and Pk. We demonstrate that Pk and Dsh/Dvl bind to Vang/Vangl in an overlapping region centered around this tyrosine. Strikingly, Vang/Vangl2 phosphorylation promotes its binding to Pk, a key effector of the Vang/Vangl complex, and inhibits its interaction with Dsh/Dvl, and thus phosphorylation of this tyrosine appears to promote the formation of the mature and stable Vang/Vangl-Pk complex during PCP establishment. Interestingly, as our single point mutations allow selective binding inhibition of either Dsh or Pk, we can demonstrate for the first time that Dsh interaction with Vang is physiologically important, as all single point mutations fail to rescue the Vang null mutant wing phenotype.
Space-Time Mapping Identifies Concerted Multicellular Patterns and Gene Programs in Healing Wounds and their Conservation in Cancers
Authors: Hu Kenneth H. , Kuhn Nicholas F. , Courau Tristan , Krummel Matthew F. 
Published: May 2022

AbstractTissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene expression profiles. We identified shared and prominent space-time patterns of cellular and gene expression enrichment: which we call multicellular ‘movements’ and which spanned multiple cell types. We validated some of the discovered space-time movements using large volume imaging of cleared wounds and demonstrated the value of this analysis to predict gene products made by macrophages or fibroblasts, which activated gene programs in the opposite cell type. Finally, using two different tumor models, we tested the hypothesis that tumors are like ‘wounds that never heal’ finding conserved wound healing movements in the tumor space, wherein some movements were preferentially used in one tumor versus another.Graphical Abstract
The ELT-3 GATA Factor Specifies Endoderm inCaenorhabditis angariain an ancestral gene network
Authors: Broitman-Maduro Gina , Maduro Morris F. 
Published: May 2022

AbstractEndoderm specification in the nematode,C. elegans, occurs through a well-characterized pathway that is initiated by maternally provided SKN-1/Nrf, and with additional input from POP-1/TCF, which activates the GATA factor cascade MED-1,2 → END-1,3 → ELT-2,7. Orthologues of the MED and END factors, and ELT-7, are found only among nematodes of the Elegans Supergroup consisting of species closely related toC. elegans, which raises the question of how gut is specified in their absence. In this work, we investigate gut specification outside the Elegans Supergroup. We find that theC. angariaandC. portoensisorthologues of theelt-3GATA factor gene are expressed in the early E lineage, just before theirelt-2orthologues. InC. angaria, bothCan-pop-1(RNAi)andCan-elt-3(RNAi)result in a penetrant ‘gutless’ phenotype.Can-pop-1is necessary forCan-elt-3activation, showing that it acts upstream. When introduced intoC. elegansas transgenes, overexpressedCan-elt-3is sufficient to specify gut, whileCan-elt-2can rescue gut differentiation under the control of its own promoter. Our results demonstrate an ancestral mechanism for gut specification and differentiation inCaenorhabditisinvolving a simplified gene network consisting of POP-1 → ELT-3 → ELT-2.Summary statementSpecification of the gut progenitor E in a distant relative ofC. elegansuses a different GATA factor, ELT-3, suggesting that the ancestral network was simpler.
Pseudotemporal whole blood transcriptional profiling of COVID-19 patients stratified by clinical severity reveals differences in immune responses and possible role of monoamine oxidase B
Authors: Broderick Claire , Calle Irene Rivero , Gómez Carballa Alberto , Gómez-Rial Jose , Li Ho Kwong , Mehta Ravi , Jackson Heather , Salas Antonio , Martinón-Torres Federico , Sriskandan Shiranee , Levin Michael , Kaforou Myrsini ,   the BioAID Consortium and GEN-COVID Study Group
Published: May 2022

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with highly variable clinical outcomes. Studying the temporal dynamics of host whole blood gene expression during SARS-CoV-2 infection can elucidate the biological processes that underlie these diverse clinical phenotypes. We employed a novel pseudotemporal approach using MaSigPro to model and compare the trajectories of whole blood transcriptomic responses in patients with mild, moderate and severe COVID-19 disease. We identified 5,267 genes significantly differentially expressed (SDE) over pseudotime and between severity groups and clustered these genes together based on pseudotemporal trends. Pathway analysis of these gene clusters revealed upregulation of multiple immune, coagulation, platelet and senescence pathways with increasing disease severity and downregulation of T cell, transcriptional and cellular metabolic pathways. The gene clusters exhibited differing pseudotemporal trends. Monoamine oxidase B was the top SDE gene, upregulated in severe>moderate>mild COVID-19 disease. This work provides new insights into the diversity of the host response to SARS-CoV-2 and disease severity and highlights the utility of pseudotemporal approaches in studying evolving immune responses to infectious diseases.