bluuebunny/crossref_metadata_2025_split huggingface dataset:
Audiovisual cues must be predictable and win-paired to drive risky choice
Authors: Hathaway Brett A. , Kim Dexter R. , Malhas Salwa B. A. , Hrelja Kelly M. , Kerker Lauren , Hynes Tristan J. , Harris Celyn , Langdon Angela J. , Winstanley Catharine A. 
Published: September 2022

AbstractRisky or maladaptive decision making is thought to be central to the etiology of both drug and gambling addiction. Salient audiovisual cues paired with rewarding outcomes, such as the jackpot sound on a win, can enhance disadvantageous, risky choice in both rats and humans, yet it is unclear which aspects of the cue-reward contingencies drive this effect. Here, we implemented six variants of the rat Gambling Task (rGT), in which animals can maximise their total sugar pellet profits by avoiding options paired with higher per-trial gains but disproportionately longer and more frequent time-out penalties. When audiovisual cues were delivered concurrently with wins, and scaled in salience with reward size, significantly more rats preferred the risky options as compared to the uncued rGT. Similar results were observed when the relationship between reward size and cue complexity was inverted, and when cues were delivered concurrently with all outcomes. Conversely, risky choice did not increase when cues occurred randomly on 50% of trials, and decision making actually improved when cues were coincident with losses alone. As such, cues do not increase risky choice by simply elevating arousal, or amplifying the difference between wins and losses. It is instead important that the cues are reliably associated with wins; presenting the cues on losing outcomes as well as wins does not diminish their ability to drive risky choice. Computational analyses indicate reductions in the impact of losses on decision making in all rGT variants in which win-paired cues increased risky choice. These results may help us understand how sensory stimulation can increase the addictive nature of gambling and gaming products.
VASH1/2 inhibition accelerates functional recovery of injured nerves
Authors: Gobrecht Philipp , Gebel Jeannette , Hilla Alexander , Gisselmann Günter , Fischer Dietmar 
Published: September 2022

AbstractTreatments accelerating axon regeneration in the nervous system are still unavailable in the clinic. However, in culture, parthenolide markedly promotes adult sensory neurons’ axon growth by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration, while the knockdown of vasohibins or their enhancer SVBP abolishes parthenolide’s effects, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-amino-parthenolide (DMAPT) markedly facilitates regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves and accelerates functional re-covery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT promising drugs for curing nerve injury.
Climate influences bill shape diversification in cavity-excavating birds
Authors: Chhaya Vaibhav , Reddy Sushma , Krishnan Anand 
Published: September 2022

ABSTRACTThe remarkable structural and functional diversity of the avian bill serves as an ideal system to understand how ecological and environmental factors influence morphological diversification under physically demanding tasks. For example, in cavity-excavating birds where the bill experiences tremendous physical stresses, climate and habitat affect the mechanical properties of available nesting substrates and therefore can potentially influence the shape and performance of bills. Few studies have focused on the entire avian bill, a complex structure consisting of the rhamphotheca and bony core of the upper and lower mandibles, which may evolve as independent modules or as a single integrated unit. Here, we examined patterns and drivers of bill shape diversification in barbets using micro-computed tomography of museum study skins. We employed landmark-based geometric morphometrics and phylogenetic comparative methods to study the influence of climatic conditions, integration and phylogenetic constraints on bill shape diversification. Asian and African barbets have explored distinct maxillary shape spaces without corresponding change in mandibular shape after correcting for phylogenetic non-independence. Additionally, maxillary shape for both rhamphotheca and bony components was significantly correlated with climate variables and exhibited signatures of allometric scaling. All four bill components, however, covaried with each other and have evolved in a gradual and integrated fashion, exhibiting late-stage shape disparity. Through these findings, our study offers crucial insights into how ecological behaviors impact morphological evolution of complex, multifunctional features.
Finding the right balance of conservation effort in cultivated grasslands: A modelling study on protecting dispersers in a climatically changing and anthropogenically disturbed environment
Authors: Leins Johannes A. 
Published: September 2022

AbstractManaging cultivated grasslands in a sustainable way is controversial, because it often goes along with economical loss and additional effort for local farmers. On the plus side, such a management could permit inhabiting species not only to survive but to thrive and expand their range. In order to satisfy both aspects, it can be helpful to minimize conservation effort to a degree that is still ecologically beneficial but intervenes as little as possible with regional land-use customs. Computer simulations are a useful tool to find such compromises prior to implementing management strategies. We simulated the population development of the large marsh grasshopper, a grassland species with limited dispersal abilities, in a disturbed and climatically changing environment of Germany up to the year 2080. Our results show that - in a spatially aggregated landscape - adapting the harvesting schedule in a relatively low number ≤ 7 % of (in)directly connected yet otherwise intensively managed grasslands suffices for species preservation and even expansion to some extent. The effect on dispersal success of additional conservation effort above this 7 % threshold is significantly lower than it is below the threshold. In terms of population size, however, every additional refuge benefits the grasshopper. Climate change enhances the positive effects on the target species even further. A higher level of fragmentation, however, requires a substantially larger conservation effort in terms of protected grassland proportion. Therefore, it is recommended and more effective to focus on the implementation of protected areas within spatially aggregated grasslands. Stakeholders should additionally be aware of the fact that it can take several years for a conservation effort to become apparent and measurable, especially if the goal is to support an isolated or reintroduced species in expanding into unpopulated territories.
Asymmetric inheritance of centrosomes maintains stem cell properties in human neural progenitor cells
Authors: Royall Lars N. , Denoth-Lippuner Annina , Jessberger Sebastian 
Published: September 2022

AbstractDuring human forebrain development, neural progenitor cells (NPCs) in the ventricular zone (VZ) undergo asymmetric cell divisions to produce a self-renewed progenitor cell, maintaining the potential to go through additional rounds of cell divisions, and differentiating daughter cells, populating the developing cortex. Previous work in the embryonic rodent brain suggested that the preferential inheritance of the pre-existing (older) centrosome to the self-renewed progenitor cell is required to maintain stem cell properties, ensuring proper neurogenesis. If asymmetric segregation of centrosomes occurs in NPCs of the developing human brain, which depends on unique molecular regulators and species-specific cellular composition, remains unknown. Using a novel, recombination-induced tag exchange (RITE)-based genetic tool to birthdate and track the segregation of centrosomes over multiple cell divisions in human embryonic stem cell (hESC)-derived regionalized forebrain organoids, we show the preferential inheritance of the older mother centrosome towards self-renewed NPCs. Aberration of asymmetric segregation of centrosomes by genetic manipulation of the centrosomal, microtubule-associated protein Ninein alters fate decisions of NPCs and their maintenance in the VZ of human cortical organoids. Thus, the data described here use a novel genetic approach to birthdate centrosomes in human cells and identify asymmetric inheritance of centrosomes as a mechanism to maintain self-renewal properties and to ensure proper neurogenesis in human NPCs.Impact StatementGenetic birthdating in forebrain organoids shows asymmetric inheritance of centrosomes in human neural progenitor cells, required for proper human neurogenesis.
Comprehensive characterization of multi-omic landscapes between gut-microbiota metabolites and the G-protein-coupled receptors in Alzheimer’s disease
Authors: Qiu Yunguang , Hou Yuan , Zhou Yadi , Xu Jielin , Bykova Marina , Leverenz James B. , Pieper Andrew A. , Nussinov Ruth , Caldwell Jessica Z.K. , Brown J. Mark , Cheng Feixiong 
Published: September 2022

AbstractAccumulating evidence suggests that gut-microbiota metabolites contribute to human disease pathophysiology, yet the host receptors that sense these metabolites are largely unknown. Here, we developed a systems pharmacogenomics framework that integrates machine learning (ML), AlphaFold2-derived structural pharmacology, and multi-omics to identify disease-relevant metabolites derived from gut-microbiota with non-olfactory G-protein-coupled receptors (GPCRome). Specifically, we evaluated 1.68 million metabolite-protein pairs connecting 408 human GPCRs and 516 gut metabolites using an Extra Trees algorithm-improved structural pharmacology strategy. Using genetics-derived Mendelian randomization and multi-omics (including transcriptomic and proteomic) analyses, we identified likely causal GPCR targets (C3AR, FPR1, GALR1 and TAS2R60) in Alzheimer’s disease (AD). Using three-dimensional structural fingerprint analysis of the metabolite-GPCR complexome, we identified over 60% of the allosteric pockets of orphan GPCR models for gut metabolites in the GPCRome, including AD-related orphan GPCRs (GPR27, GPR34, and GPR84). We additionally identified the potential targets (e.g., C3AR) of two AD-related metabolites (3-hydroxybutyric acid and Indole-3-pyruvic acid) and four metabolites from AD-related bacterium Eubacterium rectale, and also showed that tridecylic acid is a candidate ligand for orphan GPR84 in AD. In summary, this study presents a systems pharmacogenomics approach that serves to uncover the GPCR molecular targets of gut microbiota in AD and likely many other human diseases if broadly applied.
The chromodomain proteins, Cbx1 and Cbx2 have distinct roles in the regulation of heterochromatin and virulence in the fungal wheat pathogen, Zymoseptoria tritici
Authors: Fraser Callum J. , Rutherford Julian C. , Rudd Jason J. , Whitehall Simon K. 
Published: September 2022

SUMMARYHeterochromatin is characterized by specific histone post-translational modifications such as the di- and tri-methylation of histone H3 on lysine 9 (H3K9me2/3), which direct the recruitment of ‘reader’ proteins to chromatin. In the fungal phytopathogen, Zymoseptoria tritici, deletion of the H3K9 methyltransferase gene kmt1, results in a global increase in the expression of transposable elements (TEs), genome instability and loss of virulence. Here we have identified two Z. tritici chromodomain proteins, Cbx1 and Cbx2, that recognise H3K9me modifications. Cbx1 is a Heterochromatin Protein 1 homolog that binds H3K9me2/3 in vitro and associates with heterochromatic loci in vivo. Transcriptomic analysis also indicates that Cbx1 and Kmt1 regulate overlapping sets of protein-encoding genes. However, unlike Δkmt1 mutants, Δcbx1 strains do not exhibit a global increase in TE expression and have only a partial reduction in virulence, suggesting the existence of additional H3K9me reader proteins. Accordingly, we have identified a fungal-specific chromodomain protein, Cbx2, that binds H3K9me3 in vitro. Strikingly, the growth defects of Δcbx1 Δcbx2 double mutants closely resemble those of Δkmt1 consistent with Cbx1 and Cbx2 playing redundant roles in gene silencing. Overall, the data suggest that key functions of H3K9me modifications are mediated by a combination of Cbx1 and Cbx2.
From motor protein to toxin: Mutations in the zonula occludens toxin (Zot) of Vibrio cholerae phage CTXϕ suggest a loss of phage assembly function
Authors: Ma Long , Roux Simon , Hua Xiaoting , Wang Yong , Loh Belinda , Leptihn Sebastian 
Published: September 2022

AbstractProphages, i.e. dormant viruses residing in bacterial cells, are not just passive passengers in the bacterial host. Several prophage-encoded genes have been shown to be contributors to bacterial virulence by mediating antimicrobial resistance or by providing toxins. Other prophage genes exhibit beneficial effects on the host by modulating e.g. motility or biofilm formation. In this study, we used an in vivo phage assembly assay and tested an extensive array of single point mutations or their combinations found in Zot, the zonula occludens toxin encoded by the Vibrio cholerae phage CTXϕ. The assay makes use of the highly homologous Zot-like protein g1p of the filamentous Coliphage M13, a motor protein that mediates the trans-envelope assembly and secretion of filamentous phages. We also measured the in vitro ATP hydrolysis of purified proteins, and quantified virus production in V. cholerae mediated by Zot or the Zot-like protein of the two Vibrio phages CTXϕ and VFJϕ. In addition, we investigated sequence variations of the Walker motifs in Vibrio species using bioinformatics method, and revealed the molecular basis of ATP binding using molecular docking and molecular dynamics simulation based on the structure predicted by AlphaFold2. Our data indicates that g1p proteins in Vibrio can easily accumulate deleterious mutations and likely lose the ability to efficiently hydrolyse ATP, while the CTXϕ Zot was further exapted to now act as an auxiliary toxin during the infection by Vibrio cholerae.
SARS-CoV-2 Sublingual Vaccine with RBD Antigen and Poly(I:C) Adjuvant: Preclinical Study in Cynomolgus Macaques
Authors: Yamamoto Tetsuro , Tanji Masanori , Mitsunaga Fusako , Nakamura Shin 
Published: September 2022

AbstractMucosal vaccine for sublingual route was prepared with recombinant SARS-CoV-2 spike protein receptor binding domain (RBD) antigen and poly(I:C) adjuvant components. The efficacy of this sublingual vaccine was examined using Cynomolgus macaques. Nine of the macaque monkeys were divided into three groups of three animals; control (just 400 μg poly(I:C) per head); low dose (30 μg RBD and 400 μg poly(I:C) per head); and high dose (150 μg RBD and 400 μg poly(I:C) per head), respectively. N-acetylcysteine (NAC), a mild reducing agent losing mucin barrier, was used to enhance vaccine delivery to mucosal immune cells. RBD-specific IgA antibody secreted in pituita was detected in two of three monkeys of the high dose group and one of three animals of the low dose group. RBD-specific IgG and/or IgA antibodies in plasma were also detected in these monkeys. These indicated that the sublingual vaccine stimulated mucosal immune response to produce antigen-specific secretory IgA antibodies in pituita and/or saliva. This sublingual vaccine also affected systemic immune response to produce IgG (IgA) in plasma. Little RBD-specific IgE was detected in plasma, suggesting no allergic antigenicity of this sublingual vaccine. Thus, SARS-CoV-2 sublingual vaccine consisting of poly(I:C) adjuvant showed reasonable efficacy in a non-human primate model.
Characterization of Plasmodium falciparum RAP domain proteins-RAP291 and RAP070, and their association with ribosomal RNAs
Authors: Akhtar Asif , Deshmukh Arunaditya , Panda Ashutosh , Saini Ekta , Pandey Rajan , Junaid Iqbal Taliy , Onchieku Noah Machuki , Parveen Sadaf , Singh Suneet Shekhar , Gupta Dinesh , Theisen Michael , Mohmmed Asif , Malhotra Pawan 
Published: September 2022

AbstractPlasmodium genomes encode multiple RAP (RNA-binding domain abundant in Apicomplexan) domain proteins that contain a conserved module of 56 to 73 amino acids. Here, we characterized two of the P. falciparum RAP domain proteins; PfRAP291 & PfRAP070, for their expression and role at asexual blood stages. RNA binding assays and high-throughput CLIP-seq analysis showed that these proteins mainly bind ribosome associated RNAs. Blue-native PAGE and protein-protein interaction studies suggested association of these proteins with MSP-1 complex. Anti-PfRAP291 and anti-PfRAP070 antibodies showed moderate inhibitions in in-vitro merozoite invasion assays. Together, these results suggest multiple roles of these proteins; PfRAP291 and PfRAP070, in merozoite invasion and in ribosome regulation during asexual stages of the parasite.
Cellular and molecular dynamics in the lungs of neonatal and juvenile mice in response to E. coli
Authors: McGrath-Morrow Sharon A. , Venezia Jarrett , Ndeh Roland , Singer Benjamin D. , Cimbro Raffaello , Soloski Mark , Scott Alan L. 
Published: September 2022

AbstractBacterial pneumonias cause significantly higher morbidity and mortality in neonates compared to other age groups. To understand the immune mechanisms that underlie these age-related differences, we employed a mouse model of E. coli pneumonia to examine cellular and molecular dynamics in immune responsiveness in neonates (PND 3-5) and juveniles (PND 12-18) at 24, 48, and 72 hours. Cytokine gene expression from whole lung extracts was quantified using qRT-PCR. E. coli challenge resulted in rapid and significant increases in neutrophils, monocytes, and yδT cells and significant decreases in dendritic cells and alveolar macrophages for both neonates and juveniles. Juveniles had significant increases in interstitial macrophages and recruited monocytes that were not observed in neonatal lungs. Expression of IFNγ-responsive genes were positively correlated with the levels and dynamics of MHCII-expressing innate cells in neonatal and juvenile lungs. Several facets of the responses of wild-type neonates was recapitulated in juvenile MHCII-/- juveniles. Employing a pre-clinical model of E. coli pneumonia, we identified significant differences in the early cellular and molecular dynamics in the lungs that likely contribute to the elevated susceptibility of neonates to bacterial pneumonia and could represent targets for intervention to improve respiratory outcomes and survivability of neonates.
in vivo expression vector derived from anhydrobiotic tardigrade genome enables live imaging in Eutardigrada
Authors: Tanaka Sae , Aoki Kazuhiro , Arakawa Kazuharu 
Published: September 2022

SummaryWater is essential for life, but anhydrobiotic tardigrades can survive almost complete dehydration. Anhydrobiosis has been a biological enigma for more than a century with respect to how organisms sustain life without water, but the few choices of genetic toolkits available in tardigrade research have been a challenging circumstance. Here, we report the development of an in vivo expression system for tardigrades (the TardiVec system). TardiVec is based on a plasmid vector with promoters that originated from an anhydrobiotic tardigrade Ramazzottius varieornatus. It enables the introduction of GFP-fused proteins and genetically encoded indicators such as the Ca2+ indicator GCaMP into tardigrade cells; consequently, the dynamics of proteins and cells in tardigrades may be observed by fluorescence live imaging. This system is applicable for several tardigrades in the class Eutardigrada: the promoters of anhydrobiosis-related genes showed tissue-specific expression in this work. Surprisingly, promoters functioned similarly between multiple species, even for species with different modes of expression of anhydrobiosis-related genes, such as Hypsibius exemplaris, in which these genes are highly induced upon facing desiccation, and Thulinius ruffoi, which lacks anhydrobiotic capability. These results suggest that the highly dynamic expression changes in desiccation-induced species are regulated in trans. Tissue-specific expression of tardigrade-unique unstructured proteins also suggests differing anhydrobiosis machinery depending on the cell types. We believe that TardiVec opens up various experimental possibilities in tardigrade research, especially to explore anhydrobiosis mechanisms.
Hierarchical sequence-affinity landscapes shape the evolution of breadth in an anti-influenza receptor binding site antibody
Authors: Phillips Angela M. , Maurer Daniel P. , Brooks Caelan , Dupic Thomas , Schmidt Aaron G. , Desai Michael M. 
Published: September 2022

AbstractBroadly neutralizing antibodies (bnAbs) that neutralize diverse variants of a particular virus are of considerable therapeutic interest1. Recent advances have enabled us to isolate and engineer these antibodies as therapeutics, but eliciting them through vaccination remains challenging, in part due to our limited understanding of how antibodies evolve breadth2. Here, we analyze the landscape by which an anti-influenza receptor binding site (RBS) bnAb, CH65, evolved broad affinity to diverse H1 influenza strains3, 4. We do this by generating an antibody library of all possible evolutionary intermediates between the unmutated common ancestor (UCA) and the affinity-matured CH65 antibody and measure the affinity of each intermediate to three distinct H1 antigens. We find that affinity to each antigen requires a specific set of mutations – distributed across the variable light and heavy chains – that interact non-additively (i.e., epistatically). These sets of mutations form a hierarchical pattern across the antigens, with increasingly divergent antigens requiring additional epistatic mutations beyond those required to bind less divergent antigens. We investigate the underlying biochemical and structural basis for these hierarchical sets of epistatic mutations and find that epistasis between heavy chain mutations and a mutation in the light chain at the VH-VL interface is essential for binding a divergent H1. Collectively, this work is the first to comprehensively characterize epistasis between heavy and light chain mutations and shows that such interactions are both strong and widespread. Together with our previous study analyzing a different class of anti-influenza antibodies5, our results implicate epistasis as a general feature of antibody sequence-affinity landscapes that can potentiate and constrain the evolution of breadth.