bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional and cell type profiles of cortical brain regions showing ultradian cortisol rhythm dependent responses to emotional face stimulation
Authors: Habets Philippe C , Kalafatakis Konstantinos , Dzyubachyk Oleh , van der Werff Steven J.A. , Keo Arlin , Thakrar Jamini , Mahfouz Ahmed , Pereira Alberto M , Russell Georgina M , Lightman Stafford L , Meijer Onno C 
Published: January 2022

AbstractThe characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling – the ANXA1 gene and retrograde endocannabinoid signaling – show top differential expression and the most significant enrichment. Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies.
Relaxed risk of predation drives parallel evolution of stickleback behaviour
Authors: Fraimout Antoine , Päiviö Elisa , Merilä Juha 
Published: January 2022

AbstractThe occurrence of similar phenotypes in multiple independent populations (viz. parallel evolution) is a testimony of evolution by natural selection. Parallel evolution implies that populations share a common phenotypic response to a common selection pressure associated with habitat similarity. Examples of parallel evolution at the genetic and phenotypic levels are fairly common, but the driving selective agents often remain elusive. Similarly, the role of phenotypic plasticity in facilitating early stages of parallel evolution is unclear. We investigated whether the relaxation of predation pressure associated with the colonization of freshwater ponds by nine-spined sticklebacks (Pungitius pungitius) likely explains the divergence in complex behaviours between marine and pond populations, and whether this divergence is parallel. Using laboratory-raised individuals exposed to different levels of perceived predation risk, we calculated vectors of phenotypic divergence for four behavioural traits between habitats and predation risk treatments. We found a significant correlation between the directions of evolutionary divergence and phenotypic plasticity, suggesting that habitat divergence in behaviour is aligned with the response to relaxation of predation pressure. Finally, we show that this alignment is found across multiple pairs of populations, and that the relaxation of predation pressure has likely driven parallel evolution of behaviour in this species.
Characterization of alveolar epithelial lineage heterogeneity during the late pseudoglandular stage of mouse lung development
Authors: Jones Matthew R. , Chong Lei , Limgapally Arun Reddy , Wilhem Jochen , Ansari Meshal , Schiller Herbert B. , Carraro Gianni , Bellusci Saverio 
Published: January 2022

AbstractThe specification, characterization, and fate of alveolar type 1 and type 2 (AT1 and 2) progenitors during embryonic lung development remains mostly elusive. In this paper, we build upon our previously published work on the regulation of airway epithelial progenitors by fibroblast growth factor receptor 2b (Fgfr2b) signalling during early (E12.5) and mid (E14.5) pseudoglandular lung development. Here, we looked at the regulation by Fgfr2b signalling on alveolar progenitors during late pseudoglandular/early canalicular (E14.5-E16.5) development. Using a dominant negative mouse model to conditionally inhibit Fgfr2b ligands at E16.5, we used gene array analyses to characterize a set of potential direct targets of Fgfr2b signalling. By mining published single-cell RNA sequence (scRNAseq) datasets, we showed that these Fgfr2b signature genes narrow on a discreet subset of AT2 cells at E17.5 and in adult lungs. Furthermore, we demonstrated that Fgfr2b signalling is lost in AT2 cells in their transition to AT1 cells during repair after injury.We also used CreERT2-based mouse models to conditionally knock-out the Fgfr2b gene in AT2 and in AT1 progenitors, as well as lineage label these cells. We found, using immunofluorescence, that in wildtype controls AT1 progenitors labeled at E14.5-E15.5 contribute a significant proportion to AT2 cells at E18.5; while AT2 progenitors labeled at the same time contribute significantly to the AT1 lineage. We show, using immunofluorescence and FACS-based analysis, that knocking out of Fgfr2b at E14.5-E15.5 in AT2 progenitors leads to an increase in lineage-labeled AT1 cells at E18.5; while the reverse is true in AT1 progenitors. Furthermore, we demonstrate that increased Fgfr signalling in AT2 progenitors reduces their contribution to the AT1 pool.Taken together, our results suggest that a significant proportion of AT2 and AT1 progenitors are cross-lineage committed during late pseudoglandular development, and that lineage commitment is regulated in part by Fgfr2b signalling. We have characterized a set of direct Fgfr2b targets at E16.5 which are likely involved in alveolar lineage formation. These signature genes concentrate on a subpopulation of AT2 cells later in development, and are downregulated in AT2 cells transitioning to the AT1 lineage during repair after injury in adults.Our findings highlight the extensive heterogeneity of alveolar cells by elucidating the role of Fgfr2b signalling in these cells during early alveolar lineage formation, as well as during repair after injury.
Full Spectrum Flow Cytometry for High-Dimensional Immunophenotyping of Mouse Innate Lymphoid Cells
Authors: Mincham Kyle T. , Snelgrove Robert J. 
Published: January 2022

Purpose and appropriate sample typesThis 25-parameter, 22-colour full spectrum flow cytometry panel was designed and optimised for the comprehensive enumeration and functional characterisation of innate lymphoid cell (ILC) subsets in mouse tissues (Table 1). The panel presented here allows the discrimination of ILC progenitors (ILCP), ILC1, ILC2, NCR+ILC3, NCR−ILC3, CCR6+lymphoid tissue-inducer (LTi)-like ILC3 and mature natural killer (NK) cell populations. Further characterisation of ILC and NK cell functional profiles in response to stimulation is provided by the inclusion of subset-specific cytokine markers, and proliferation markers. Development and optimisation of this panel was performed on freshly isolated cells from adult BALB/c lungs and small intestine lamina propria, andex vivostimulation with phorbol 12-myrisate 13-acetate, ionomycin and pro-ILC activating cytokines.Ethical compliance statementAll mouse experiments were performed in accordance with the recommendations in the Guide for the Use of Laboratory Animals of Imperial College London, with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. All animal procedures and care conformed strictly to the UK Home Office Guidelines under the Animals (Scientific Procedures) Act 1986, and the protocols were approved by the Home Office of Great Britain.
Investigating the NRAS 5’ UTR as a Target for Small Molecules
Authors: Balaratnam Sumirtha , Torrey Zachary R. , Calabrese David R. , Banco Michael T. , Yazdani Kamyar , Liang Xiao , Ferré-D’Amaré Adrian R. , Incarnato Danny , Schneekloth John S. 
Published: January 2022

AbstractNeuroblastoma RAS (NRAS) is an oncogene that is deregulated and highly mutated in cancers including melanomas and acute myeloid leukemias. Constitutively activated NRAS induces the MAPK and AKT signaling pathways and leads to uncontrolled proliferation and cell growth, making it an attractive target for small molecule inhibition. Like all RAS-family proteins, it has proven difficult to identify small molecules that directly inhibit the protein. An alternative approach would involve targeting the NRAS mRNA. The 5′ untranslated region (5′ UTR) of the NRAS mRNA is reported to contain a G-quadruplex (G4) that regulates translation ofNRASmRNA. Stabilizing the G4 structure with small molecules could reduce NRAS protein expression in cancer cells by impacting translation. Here we report a novel class of small molecule that binds to the G4 structure located in the 5′ UTR of the NRAS mRNA. We used a small molecule microarray (SMM) screen to identify molecules that selectively bind to the NRAS-G4. Biophysical studies demonstrated that compound18binds reversibly to the NRAS-G4 structure with submicromolar affinity. A Luciferase based reporter assay indicated that18inhibits the translation of NRAS via stabilizing the NRAS-G4in vitrobut showed only moderate effects on the NRAS levelsin cellulo. Rapid Amplification of cDNA Ends (RACE), RT-PCR analysis on 14 differentNRAS-expressing cell lines, coupled with analysis of publicly available CAGE seq experiments, revealed that predominant NRAS transcript does not possess the G4 structure. Further analysis of published rG4 and G4 sequencing data indicated the presence of G4 structure in the promoter region ofNRASgene (DNA) but not in the mRNA. Thus, although manyNRAStranscripts lack a G4 in many cell lines the broader concept of targeting folded regions within 5’ UTRs to control translation remains a highly attractive strategy and this work represents an intriguing example of transcript heterogeneity impacting targetability.
Injury suppresses Ras cell competitive advantage through enhanced wild-type cell proliferation
Authors: Gallini Sara , Rahman Nur-Taz , Annusver Karl , Gonzalez David G. , Yun Sangwon , Matte-Martone Catherine , Xin Tianchi , Lathrop Elizabeth , Suozzi Kathleen C. , Kasper Maria , Greco Valentina 
Published: January 2022

AbstractHealthy skin is a tapestry of wild-type and mutant clones. Although injury can cooperate with Ras mutations to promote tumorigenesis, the consequences in genetically mosaic skin are unknown. Here, we show that wild-type cells prevent oncogenic Ras-induced aberrant growth after injury. Although HrasG12V/+and KrasG12D/+cells outcompete wild-type cells in uninjured, mosaic tissue, their competitive advantage is suppressed after injury due to a selective increase in wild-type cell proliferation. EGFR inhibition abolishes the competitive advantage of wild-type cells after injury of HrasG12V/+-mosaic skin. Global loss of the cell cycle inhibitor p21 increases wild-type cell proliferation even without injury, suppressing the competitive advantage of HrasG12V/+cells. Thus, injury plays an unanticipated role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.One sentence SummaryInjury-repair selectively induces wild-type cell proliferation to suppress oncogenic growth in Ras-mosaic skin epithelium.
Phosphate transporter PHT1;1 as a key determinant of phosphorus acquisition in Arabidopsis natural accessions
Authors: Chien Pei-Shan , Chao Ya-Ting , Chou Chia-Hui , Hsu Yu-Ying , Chiang Su-Fen , Tung Chih-Wei , Chiou Tzyy-Jen 
Published: January 2022

ABSTRACTTo understand the genetic basis in governing phosphorus (P) acquisition, we performed genome-wide association studies (GWAS) on a diversity panel of Arabidopsis thaliana by two primary determinants of P acquisition, phosphate (Pi)-uptake activity and PHOSPHATE TRANSPORTER 1 (PHT1) protein abundance. Association mapping revealed a shared significant peak on chromosome 5 (Chr5) where the PHT1;1/2/3 genes reside, suggesting a strong correlation between the regulation of Pi-uptake activity and PHT1 protein abundance. Genes encoding transcription factors, kinases, and a metalloprotease associated with both traits were also identified. Conditional GWAS followed by statistical analysis of genotype-dependent expression of PHT1;1 and transcription activity assays revealed an epistatic interaction between PHT1;1 and MYB DOMAIN PROTEIN 52 (MYB52) on Chr1. Analyses of F1 hybrids generated by crossing two subgroups of natural accessions carrying specific SNPs associated with PHT1;1 and MYB52 further revealed the strong effects of potential variants on PHT1;1 expression and Pi uptake activity. Notably, the soil P contents in A. thaliana habitats were found to coincide with PHT1;1 haplotype, underscoring how fine-tuning of the activity of P acquisition by natural variants allows plants to adapt to their environments. This study sheds light on the complex regulation of P acquisition and offers a framework to systematically assess the effectiveness of GWAS approaches in the study of quantitative traits.One sentence summaryStepwise GWAS analyses reveal insights into the genetic basis in regulating phosphorus acquisition and associations between the phosphate transporter PHT1;1 haplotype and Arabidopsis habitats.
Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons
Authors: Cadenas Lester Torres , Cheng Hui , Weisz Catherine J.C. 
Published: January 2022

AbstractThe descending auditory system modulates the ascending system at every level. The final descending, or efferent stage, is comprised of lateral olivocochlear (LOC) and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC-mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention, and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB-MOC synapses exhibit short-term depression, suggesting reduced MNTB-MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound-evoked activity in MNTB neurons in vivo, MNTB-MOC synapses may be tonically depressed. To probe this, we characterized short-term plasticity of MNTB-MOC synapses in mouse brain slices. We mimicked in vivo-like temperature and extracellular calcium conditions, and in vivo-like activity patterns of fast synaptic activation rates, sustained activation, and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, post-synaptic currents (PSCs) in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression.Key points summaryInhibitory synapses from MNTB onto MOC neurons exhibit short-term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperatureHigh rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB-MOC synapses that limits further synaptic inhibitionHigh rates of activity at MNTB-MOC synapses cause synaptic summation concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition
The neural dynamics associated with computational complexity
Authors: Franco Juan Pablo , Bossaerts Peter , Murawski Carsten 
Published: January 2022

AbstractMany everyday tasks require people to solve computationally complex problems. However, little is known about the effects of computational hardness on the neural processes associated with solving such problems. Here, we draw on computational complexity theory to address this issue. We performed an experiment in which participants solved several instances of the 0-1 knapsack problem, a combinatorial optimization problem, while undergoing ultra-high field (7T) functional magnetic resonance imaging (fMRI). Instances varied in two task-independent measures of intrinsic computational hardness: complexity and proof hardness. We characterise a network of brain regions whose activation was correlated with both measures but in distinct ways, including the anterior insula, dorsal anterior cingulate cortex and the intra-parietal sulcus/angular gyrus. Activation and connectivity changed dynamically as a function of complexity and proof hardness, in line with theoretical computational requirements. Overall, our results suggest that computational complexity theory provides a suitable framework to study the effects of computational hardness on the neural processes associated with solving complex cognitive tasks.
Simultaneous inference of parental admixture proportions and admixture times from unphased local ancestry calls
Authors: Avadhanam Siddharth , Williams Amy L. 
Published: January 2022

AbstractPopulation genetic analyses of local ancestry tracts routinely assume that the ancestral admixture process is identical for both parents of an individual, an assumption that may be invalid when considering recent admixture. Here we present Parental Admixture Proportion Inference (PAPI), a Bayesian tool for inferring the admixture proportions and admixture times for each parent of a single admixed individual. PAPI analyzes unphased local ancestry tracts and has two components models: a binomial model that exploits the informativeness of homozygous ancestry regions to infer parental admixture proportions, and a hidden Markov model (HMM) that infers admixture times from tract lengths. Crucially, the HMM employs an approximation to the pedigree crossover dynamics that accounts for unobserved within-ancestry recombination, enabling inference of parental admixture times. We compared the accuracy of PAPI’s admixture proportion estimates with those of ANCESTOR in simulated admixed individuals and found that PAPI outperforms ANCESTOR by an average of 46% in a representative set of simulation scenarios, with PAPI’s estimates deviating from the ground truth by 0.047 on average. Moreover, PAPI’s admixture time estimates were strongly correlated with the ground truth in these simulations (R = 0.76), but have an average downward bias of 1.01 generations that is partly attributable to inaccuracies in local ancestry inference. As an illustration of its utility, we ran PAPI on real African Americans from the PAGE study (N = 5, 786) and found strong evidence of assortative mating by ancestry proportion: couples’ ancestry proportions are closer to each other than expected by chance (P < 10−6), and are highly correlated (R = 0.87). We anticipate that PAPI will be useful in studying the population dynamics of admixture and will also be of interest to individuals seeking to learn about their personal genealogies.
Regulatory T-cells are central hubs for age-, sex- and severity-associated cellular networks during COVID-19
Authors: Søndergaard Jonas N. , Tulyeu Janyerkye , Edahiro Ryuya , Shira Yuya , Yamaguchi Yuta , Murakami Teruaki , Morita Takayoshi , Kato Yasuhiro , Hirata Haruhiko , Takeda Yoshito , Okuzaki Daisuke , Sakaguchi Shimon , Kumanogoh Atsushi , Okada Yukinori , Wing James B. 
Published: January 2022

AbstractUsing single-cell proteomics by mass cytometry, we investigate changes to a broad selection of over 10,000,000 immune cells in a cohort of moderate, severe, and critical Japanese COVID-19 patients and healthy controls with a particular focus on regulatory T-cells (Tregs). We find significant disruption within all compartments of the immune system and the emergence of atypical CTLA-4high CD4 T-cells and proliferating HLA-DRlowCD38high Tregs associated with critical patients. We also observed disrupted regulation of humoral immunity in COVID-19, with a loss of circulating T follicular regulatory T cells (Tfr) and altered T follicular helper (Tfh)/Tfr and plasma cell/Tfr ratios, all of which are significantly lower in male patients. Shifting ratios of CXCR4 and CXCR5 expression in B-cells provides further evidence of an autoimmune phenotype and dysregulated humoral immunity. These results suggest that Tregs are central to the changing cellular networks of a wide range of cells in COVID-19 and that sex specific differences to the balance of Tfr, Tfh and plasma cells may have important implications for the specificity of the humoral immune response to SARS-CoV-2.
Supplier change, market competition and enterprise innovation
Authors: Zu Yafei , Zhang Ruonan 
Published: January 2022

PurposeThe purpose of this paper is to study enterprise innovation in the perspective of external supplier relationship. On this purpose, this paper examines the impact of supplier change on enterprise innovation with the moderating role of market competition.Design/methodology/approachUsing 2012–2020 empirical data of Chinese listed manufacturing enterprises, this paper investigates the relationship among supplier change, market competition and enterprise innovation through a two-way interaction model.FindingsThe results show that supplier change has a negative impact on enterprise innovation. And market competition intensifies the negative relationship between supplier change and enterprise innovation. Additional analyses indicate that the main effect and the moderating effect are more significant when the enterprise is non-state-owned or has lower ownership concentration.Originality/valueThis paper studies enterprise innovation from the perspective of external stakeholders. It focuses on supplier relationship in a dynamic variation view, instead of the traditional static ones. Moreover, this paper explores the contingency effect of market competition and gives practical implications for managers to adjust innovation strategy flexibly.