bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of perception by visual, auditory, and audiovisual reward predicting cues
Authors: Antono Jessica Emily , Pooresmaeili Arezoo 
Published: February 2023

AbstractRewards influence information processing in the primary sensory areas specialized to process stimuli from a specific sensory modality. In real life situations, we receive sensory inputs not only from one single modality, but stimuli are often multisensory. It is however not known whether the reward-driven modulation of perception follows the same principles when reward is cued through a single or multiple sensory modalities. We previously showed that task-irrelevant reward cues modulate perception both intra- as well as cross-modally, likely through a putative enhancement in the integration of the stimulus parts into a coherent object. In this study, we explicitly test this possibility by assessing whether reward enhances the integration of unisensory components of a multisensory object in accordance with thesupra-additiveprinciple of multisensory integration. Towards this aim, we designed a simple detection task using reward predicting cues that were either unisensory (auditory or visual, both above the detection threshold) or multisensory (audiovisual). We conducted two experiments, behavioral (experiment 1) and simultaneous behavioral and neuroimaging testing (experiment 2). We expected that reward speeds up reaction times in response to all stimulus configurations, and that additionally the reward effects in multisensory cues fulfill thesupra-additiveprinciple of multisensory integration. We observed that reward decreased response times in both experiments with the strongest effect found for the multisensory stimuli in experiment 1. However, this behavioral effect did not fulfill thesupra-additiveprinciple. Neuroimaging results demonstrated sensory supra-additivity at the classical areas involved in multisensory integration such as the Superior Temporal areas (STS), while reward modulation was found in the midbrain and fronto-parietal areas, reflecting the typical areas that receive dopaminergic projections. However, reward did not enhance thesupra-additivityin the STS compared to a no reward condition. Instead, we observed that some of the reward-related areas showed asub-additivemodulation by rewards and areas exhibiting a weakersupra-additiveresponse to audiovisual stimuli, namely the fusiform gyrus, were modulated by rewards of audiovisual stimuli as measured by a conjunction analysis. Overall, our results indicate that reward does not enhance the multisensory integration through asupra-additiverule. These findings inspire a model where reward and sensory integration processes are regulated by two independent mechanisms, where sensory information is integrated at an early stage in asupra-additivemanner, while reward modulates perception at a later stagesub-additively. Moreover, an associative area in the Fusiform gyrus exhibits a convergence of both reward and multisensory integration signals, indicating that it may be ahubto integrate different types of signals including rewards to disambiguate the information from different sensory modalities.
Distribution-modeling quantifies collective Th cell decision circuits in chronic inflammation
Authors: Burt Philipp , Thurley Kevin 
Published: February 2023

AbstractImmune responses are tightly regulated by a diverse set of interacting immune cell populations. Alongside decision-making processes such as differentiation into specific effector cell types, immune cells initiate proliferation at the beginning of an inflammation, forming two layers of complexity. Here, we developed a general mathematical framework for the data-driven analysis of collective immune-cell dynamics. We identified qualitative and quantitative properties of generic network motifs, and we specified differentiation dynamics by analysis of kinetic transcriptome data. Further, we derived a specific, data-driven mathematical model for Th1 vs. Tfh cell fate-decision dynamics in acute and chronic LCMV infections in mice. The model recapitulates important dynamical properties without model fitting, and solely by employing measured response-time distributions. Model simulations predict different windows of opportunity for perturbation in acute and chronic infection scenarios, with potential implications for optimization of targeted immunotherapy.
LTK and ALK regulate neuronal polarity and cortical migration by modulating IGF1R activity
Authors: Christova Tania , Ho Stephanie , Liu Ying , Gill Mandeep , Attisano Liliana 
Published: February 2023

AbstractThe establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning and formation of neuronal circuitry. Here, we demonstrate that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, loss of Ltk and/or Alk yields a striking multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk results in a delay in neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and there is a disruption of the axon tracts in the corpus callosum. Mechanistically, we show that loss of Alk and Ltk increases cell surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which acts to activate downstream PI3 kinase signalling to drive the excess axon phenotype. Thus, our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioural abnormalities.
Antimicrobial overproduction sustains intestinal inflammation by inhibitingEnterococcuscolonization
Authors: Jang Kyung Ku , Heaney Thomas , London Mariya , Ding Yi , Yeung Frank , Ercelen Defne , Chen Ying-Han , Axelrad Jordan , Gurunathan Sakteesh , Marijke Keestra-Gounder A. , Griffin Matthew E. , Hang Howard C. , Cadwell Ken 
Published: February 2023

SUMMARYLoss of antimicrobial proteins such as REG3 family members compromises the integrity of the intestinal barrier. Here, we demonstrate that overproduction of REG3 proteins can also be detrimental by reducing a protective species in the microbiota. Patients with inflammatory bowel disease (IBD) experiencing flares displayed heightened levels of secreted REG3 proteins that mediated depletion ofEnterococcus faecium(Efm) from the gut microbiota.Efminoculation of mice ameliorated intestinal inflammation through activation of the innate immune receptor NOD2, which was associated with the bacterial DL-endopeptidase SagA. Microbiota sensing by NOD2 in myeloid cells mediated IL-1β secretion and increased the proportion of IL-22-producing CD4+T helper cells and innate lymphoid cells. Finally,Efmwas unable to protect mice carrying aNOD2gene variant commonly found in IBD patients. Our findings demonstrate that inflammation self-perpetuates by causing aberrant antimicrobial activity that disrupts symbiotic relationships with gut microbes.
MHCnvex: Likelihood-based model for calling the copy number variations and loss of heterozygosity in MHC class I and II locus
Authors: Hosseini Noshad , Mumphrey Michael B. , Cieslik Marcin 
Published: February 2023

MotivationAccurate detection of copy number variation (CNV) and loss of heterozygosity (LOH) in the major histocompatibility complex (MHC) locus is of great significance to both clinicians and researchers since it has the potential to inform treatment decisions, particularly in the context of immunotherapy. However, due to the high level of polymorphism in this region, calling copy number variations is a challenging task and requires special methodology. To address this challenge, we have developed a tool with a wide range of applicability to call CNV and LOH in the MHC region.ResultsTo address the challenge mentioned above, we have developed MHCnvex, an algorithm that accurately calls haplotype level CNVs for the genes in the MHC class I and II locus. MHCnvex presents a novel approach based on likelihood models for detecting CNVs at haplotype level. Additionally, this method integrates the MHC locus with other adjacent loci from the short arm of chromosome 6 to enhance the accuracy of the calls. The incorporation of a statistical approach and the examination of the broader chromosome 6 region, rather than just the MHC locus alone, make MHCnvex less vulnerable to local coverage biases (commonly associated with MHC locus). The performance of MHCnvex has been evaluated according to different measures including concordance with MHC flanking regions and changes in the allelic expression of MHC genes due to alteration. MHCnvex has also shown to significantly reduce the variability of calculated coverage for CNV analysis.AvailabilityImplementation of MHCnvex algorithm is available as an R package at:https://github.com/NoshadHo/MHCnvex
HLAProphet: Personalized allele-level quantification of the HLA proteins
Authors: Mumphrey Michael B. , Li Ginny Xiaohe , Hosseini Noshad , Nesvizhskii Alexey , Cieslik Marcin 
Published: February 2023

AbstractLoss of HLA expression in tumor cells is a commonly observed phenotype that is known to be associated with T-cell evasion. Proteogenomic characterizations of the molecular mechanisms underpinning this loss of HLA expression are hindered by the polymorphic nature of the HLA proteins, with most individuals having germline HLA sequences that are highly divergent from the sequences found in standard reference databases. To address this issue, we have developed HLAProphet, an algorithm that utilizes HLA types from paired DNA sequencing data to provide personalized allele-level quantification of the HLA proteins from TMT mass spectrometry data. We show that HLAProphet triples the number of tryptic peptide identifications made by standard reference based approaches, and produces protein expression values that have high concordance with RNA expression and known loss of heterozygosity events.
Charge-State-Dependent Collision-Induced Dissociation Behaviors of RNA Oligonucleotides via High-Resolution Mass Spectrometry
Authors: Sun Rui-Xiang , Zuo Mei-Qing , Zhang Ji-Shuai , Dong Meng-Qiu 
Published: February 2023

ABSTRACTMass spectrometry (MS)-based analysis of RNA oligonucleotides (oligos) plays an increasingly important role in the development of RNA therapeutics and in epitranscriptomic studies. However, MS fragmentation behaviors of RNA oligos are understood insufficiently. In this study, we characterized the negative-ion-mode fragmentation behaviors of 26 synthetic RNA oligos of four to eight nucleotides (nt) in length by collision-induced dissociation (CID) using a high-resolution, accurate-mass instrument. We find that in the CID spectra acquired under the normalized collisional energy of 35%, ∼70% of the total peak intensity belonged to sequencing ions (a-B, a, b, c, d, w, x, y, z), ∼25% belonged to precursor ions with either complete or partial loss of a nucleobase in the form of a neutral or an anion, and the remainder were internal ions and anionic nucleobases. Of the sequencing ions, the most abundant species werey, c, w, a-B, andaions. The charge state of the RNA precursor ions strongly affected their fragmentation behaviors. As the precursor charge increased from -1 to -5, the fractional intensity of sequencing ions in the CID spectra decreased, whereas the fractional intensity of precursor ions with neutral and/or charged losses of a nucleobase increased. Moreover, RNA oligos containing U, especially at the 3′ terminus, tended to produce precursors that lost HNCO and/or NCO-, which presumably corresponded to isocyanic acid and cyanate anion, respectively. These findings build a strong foundation for mechanistic understanding of RNA fragmentation by MS/MS, contributing to future automated identification of RNA oligos from their CID spectra in a more efficient way.
p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells
Authors: Majewska Julia , Agrawal Amit , Mayo Avi , Roitman Lior , Chatterjee Rishita , Kralova Jarmila , Landsberger Tomer , Katzenelenbogen Yonatan , Meir-Salame Tomer , Hagai Efrat , Stanojevic Nemanja , Amit Ido , Alon Uri , Krizhanovsky Valery 
Published: February 2023

AbstractThe accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.
Cell type matching across species using protein embeddings and transfer learning
Authors: Biharie Kirti , Michielsen Lieke , Reinders Marcel J.T. , Mahfouz Ahmed 
Published: February 2023

AbstractMotivationKnowing the relation between cell types is crucial for translating experimental results from mice to humans. Establishing cell type matches, however, is hindered by the biological differences between the species. A substantial amount of evolutionary information between genes that could be used to align the species is discarded by most of the current methods since they only use one-to-one orthologous genes. Some methods try to retain the information by explicitly including the relation between genes, however, not without caveats.ResultsIn this work, we present a model to Transfer and Align Cell Types in Cross-Species analysis (TACTiCS). First, TACTiCS uses a natural language processing model to match genes using their protein sequences. Next, TACTiCS employs a neural network to classify cell types within a species. Afterwards, TACTiCS uses transfer learning to propagate cell type labels between species. We applied TACTiCS on scRNA-seq data of the primary motor cortex of human, mouse and marmoset. Our model can accurately match and align cell types on these datasets. Moreover, at a high resolution, our model outperforms the state-of-the-art method SAMap. Finally, we show that our gene matching method results in better matches than BLAST, both in our model and SAMap.Availabilityhttps://github.com/kbiharie/TACTiCSContacta.mahfouz@lumc.nl
Structures ofArabidopsis thalianaMDL Proteins and Synergistic Effects with the Cytokine MIF on Human Receptors
Authors: Spiller Lukas , Manjula Ramu , Leissing Franz , Basquin Jerome , Bourilhon Priscila , Sinitski Dzmitry , Brandhofer Markus , Levecque Sophie , Sabelleck Björn , Feederle Regina , Flatley Andrew , Panstruga Ralph , Bernhagen Jürgen , Lolis Elias 
Published: February 2023

AbstractVertebrates have developed effective immune mechanisms to fight microbial attacks, relying on a sophisticated network of innate and adaptive responses, a circulatory system, and numerous orchestrating soluble mediators such as cytokines. Mammalian macrophage migration inhibitory factor (MIF) and its paralog D-dopachrome tautomerase (D-DT/MIF-2) are multifunctional inflammatory cytokines with chemokine-like properties that modulate immunity. Plants possess orthologous MIF/D-DT-like (MDL) proteins, whose function is largely unexplored. Driven by the previous discovery of cross-kingdom mimicry of plant (Arabidopsis thaliana) MDL proteins and human MIF receptor signaling, we here characterized the structures of the threeA. thalianaMDLs by X-ray crystallography and explored the mechanism underlying the interplay between plant MDLs, human MIF, and its receptors. We obtained high-resolution structures at 1.56 Å, 1.40 Å, and 2.00 Å resolution for MDL1, MDL2, and MDL3, respectively, revealing a typical trimeric assembly and a high three-dimensional similarity to human MIF. Although residues at the catalytic site of the three MDLs show high identity to human MIF, the proteins showed low tautomerase activity for the substrate 4-hydroxyphenylpyruvate (HPP). Structural differences likely explain the enzymatic inactivity of plant MDLs for HPP. Strikingly, employingin vitro, in vivo,andin plantatest systems, we found that MIF and MDL proteins interact with each other and have the capacity to form hetero-oligomeric complexes. The functional consequences of this interaction were demonstrated applying a yeast-based reporter system specific for the MIF chemokine receptors CXCR2 and CXCR4. MDLs not only triggered receptor signaling on their own, but exhibited pronounced synergism regarding the activation of the CXCR2- and CXCR4-dependent signaling pathways, when co-applied with MIF. These findings were substantiated by the co-administration of pharmacological inhibitors that either disrupt MIF receptor binding or block the catalytic cavity. Moreover, biochemical and biophysical experiments using an allosteric oligomer-specific MIF inhibitor established hexa-oligomer formation between MIF and MDLs as the putative basis for the synergistic effect. Our results are the starting point for a mechanistic understanding of the immunomodulatory activity of a family of highly conserved plant proteins.One Sentence SummaryA. thalianaMDLs and human macrophage inhibitory factor interact with each other and induce synergistic effects in activating CXCR2 and CXCR4.
Sustainable land management enhances ecological and economic multifunctionality under ambient and future climate
Authors: Scherzinger Friedrich , Schädler Martin , Reitz Thomas , Yin Rui , Auge Harald , Merbach Ines , Roscher Christiane , Harpole Stan , Berger Sigrid , Blagodatskaya Evgenia , Siebert Julia , Ciobanu Marcel , Eisenhauer Nico , Quaas Martin 
Published: February 2023

1.AbstractAnthropogenic activity is threatening ecosystem multifunctionality, i.e. the ability of ecosystems to provide multiple functions and services which are vital for human well-being. Here we assess how multifunctionality of agroecosystems in Central Germany depends on land-use type and climate change. Our analysis included 13 ecosystem functions in a large-scale field experiment with five different land-use types (three grassland and two farmland types either sustainably or intensively managed) under two different climate scenarios (ambient and future climate). We consider ecological measures of multifunctionality using averaging approaches with different weights, i.a. reflecting preferences of farmers and environmentalists, and assess an economic multifunctionality measure based on the total value of ecosystem services. Results show that intensive management and future climate decrease ecological multifunctionality for multiple weighting scenarios in both grassland and farmland. Only under a weighting according to farmers’ preferences, intensively-managed grassland shows higher multifunctionality as compared to sustainably-managed grassland. The economic multifunctionality measure, which includes economic benefits for society at large, reveals a multifunctionality about ∼1.7 times higher for sustainable compared to intensive management for both grassland and farmland. Above-belowground biodiversity correlates positively with ecosystem multifunctionality and is expected to be one of its main drivers. Based on these findings, we suggest to promote and economically incentivise sustainable land management that enhances both ecological and economic multifunctionality, also under future climatic conditions.
Identification of genes associated with abiotic stress tolerance in sweetpotato using weighted gene co-expression network analysis
Authors: Kitavi Mercy , Gemenet Dorcus C. , Wood Joshua C. , Hamilton John P. , Wu Shan , Fei Zhangjun , Khan Awais , Buell C. Robin 
Published: February 2023

AbstractSweetpotato,Ipomoea batatas(L.), a key food security crop, is negatively impacted by heat, drought, and salinity stress. We exposed the orange-fleshed cultivar ‘Beauregard’ to 24 and 48 hours of heat and salt stresses to identify differentially expressed genes (DEGs) in leaves. Analysis revealed both shared and unique sets of up-regulated (650 for heat; 287 for salt) and down-regulated (1,249 for heat; 793 for salt) DEGs suggesting common, yet stress-specific transcriptional responses to these two abiotic stressors. Gene Ontology analysis of downregulated DEGs common to both heat and salt stress revealed enrichment of terms associated with ‘cell population proliferation’ suggestive of an impact on the cell cycle by the heat stress. To identify shared and unique gene coexpression networks under multiple abiotic stress conditions, weighted gene co-expression network analysis was performed using gene expression profiles from heat, salt, and drought stress treated ‘Beauregard’ leaves yielding 18 coexpression modules. One module was enriched for ‘response to water deprivation’, ‘response to abscisic acid’, and ‘nitrate transport’ indicating synergetic crosstalk between nitrogen, water and phytohormones with genes encoding osmotin, cell expansion, and cell wall modification proteins present as key hub genes in this drought-associated module. This research lays the background for future research in mediating abiotic stress tolerance in sweetpotato.
Two splice forms ofOsbZIP1, a homolog ofAtHY5, function to regulate skoto- and photo-morphogenesis in rice
Authors: Bhatnagar Akanksha , Burman Naini , Sharma Eshan , Tyagi Akhilesh , Khurana Paramjit , Khurana Jitendra P. 
Published: February 2023

AbstractPlants possess well-developed light sensing mechanisms and signal transduction systems for regulating photomorphogenesis. ELONGATED HYOCOTYL 5 (HY5), a basic leucine zipper transcription factor, has been extensively characterized in dicot plants. In this study, we have shown thatOsbZIP1is a functional homolog ofArabidopsis HY5 (AtHY5)and is important for light-mediated regulation of seedling and mature plant development in rice. Ectopic expression ofOsbZIP1in rice reduces plant height and leaf length without affecting plant fertility, which is in contrast toOsbZIP48, another HY5 homolog we characterised earlier.OsbZIP1is alternatively spliced and the isoform OsbZIP1.2 lacking COP1 binding domain regulates seedling development in dark; this is unique since AtHY5 lacking COP1 binding domain does not display such a phenotype. Rice seedlings overexpressingOsbZIP1were found to be shorter than vector control under white and monochromatic light conditions whereas RNAi seedlings displayed completely opposite phenotype. While OsbZIP1.1 is light regulated, OsbZIP1.2 shows similar protein profile in both light and dark conditions. Due to its interaction with OsCOP1, OsbZIP1.1 undergoes degradation via 26S proteasome under dark conditions. Also, OsbZIP1.1 interacts with CASEIN KINASE 2 (OsCK2ɑ3) and consequently undergoes phosphorylation. In comparison, OsbZIP1.2 did not show any interaction with COP1 and OsCK2ɑ3. We propose that OsbZIP1.1 most likely works under low fluence of blue light (15 μmol/m²/s) while OsbZIP1.2 becomes dominant as the fluence is increased to 30 μmol/m²/s. Data presented in this study reveal that AtHY5 homologs in rice have undergone neofunctionalization and alternative splicing (AS) ofOsbZIP1has increased the repertoire of its functions.One sentence summary:Alternative spliced forms ofOsbZIP1, anAtHY5homolog in rice, regulate seedling development in response to light and dark