bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of perception by visual, auditory, and audiovisual reward predicting cues
Authors: Antono Jessica Emily , Pooresmaeili Arezoo
Published: February 2023

Rewards 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

Immune 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

The 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

Loss 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

Motivation

Accurate 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.

Results

To 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.

Availability

Implementation 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

Loss 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

Mass 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

The 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

Motivation

Knowing 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.

Results

In 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.

Availability

https://github.com/kbiharie/TACTiCS

Contact

a.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

Vertebrates 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 Summary

A. 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.

Anthropogenic 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

Sweetpotato,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

Plants 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
Humans, rats and mice show species-specific adaptations to sensory statistics in categorisation behaviour
Authors: Pedrosa Victor , Menichini Elena , Pajot-Moric Quentin , Vincent Peter , Zhou Liang , Teachen Lillianne , Latham Peter , Akrami Athena
Published: February 2023

One key aspect of animal intelligence is the ability to find, represent and update knowledge of statistical regularities in the sensory environment, in service of adaptive behaviour. This allows animals to build appropriate priors, in order to disambiguate noisy inputs, make predictions and act more efficiently. Here, we compare human, rat, and mouse performance on a 2-alternative-forced-choice sound categorisation task. Importantly, we manipulate the stimulus statistics without affecting the overall weight of each category, and we investigate decision-making in such distinct ‘statistical contexts’ associated with different stimulus prior probabilities. Humans, rats, and mice develop a sensory-dependent bias that increases reward to a near-optimal level. We also explore how flexible animals are in learning different types of statistics, without any explicit cue, when switching from one prior probability to another. All species can adapt to a new underlying distribution by gradually shifting their psychometric behaviour after the switch to a new statistical context, with mice showing the slowest rate of adaptation. Despite the overall sensory-dependent bias that is similar across species, humans versus rodents show distinct trial-to-trial learning updates. Rodents show an overall win-stay choice bias, with rats incorporating decision confidence more strongly than mice. Humans, on the other hand, show a more complex learning update, and more indicative of utilising detailed sensory statistics. We propose two classes of computational models, a boundary learning (discriminative) and a stimulus-category learning (generative) model. We show how they can account for the optimal exploitation of the sensory statistics, and predict the observed species-specific trial-to-trial updates.
Mangrove propagules are limited in their capacity to disperse across long distances
Authors: Granville Natasha R. , Banks-Leite Cristina
Published: February 2023

Mangroves are subject to rapid and large-scale habitat changes which threaten their unique genetic diversity and provision of critically important ecosystem services. Habitat fragmentation reduces connectivity which can impair dispersal and lead to genetic isolation. However, it is unclear whether fragmentation could impact mangrove genetic isolation, as mangrove propagules can disperse long distances. Here, we conducted a meta-analysis of studies reporting a correlation between geographic distance and genetic distance in mangrove plants. From the 22 studies that met the inclusion criteria, we found a significant isolation-by-distance effect; geographic distance was significantly associated with Nei’s genetic distance and FST. Our results show that mangrove propagules may be limited in their capacity to disperse across long distances, which highlights the importance of maintaining close proximity between habitat patches and reducing habitat fragmentation.
Analysis of the Distal Urinary Tract in Larval and Adult Zebrafish Reveals Unrecognized Homology to the Human System
Authors: Jubber Ibrahim , Morhardt Duncan R , Griffin Jonathan , Cumberbatch Marcus , Glover Maggie , Zheng Yang , Rehman Ishtiaq , Loynes Catherine , Hussain Syed A , Renshaw Stephen A , Leach Steven D , Cunliffe Vincent T , Catto James WF
Published: February 2023

Little is known about the distal excretory component of the urinary tract inDanio rerio(zebrafish). This component is affected by many human diseases and disorders of development. Here, we undertook multi-level analyses to determine the structure and composition of the distal urinary tract in the zebrafish.In silicosearches identifieduroplakin 1a, 2-likeand3-likegenes in the zebrafish genome (orthologues to genes that encode proteins that characterise the urothelium in humans).In situhybridization demonstrateduroplakin-1aexpression in the zebrafish pronephros and cloaca from 96 hours post-fertilisation. H&E sectioning of adult zebrafish demonstrated two mesonephric ducts uniting into a urinary bladder which leads to a distinct urethral opening. Immunohistochemistry identified Uroplakin 1a and 2 expression within the urothelial luminal surface and Gata3 expression in cell layers that match human urothelial expression. Fluorescent dye injections demonstrated urinary bladder function, including urine storage, intermittent micturition, and a urethral orifice separate from the larger anal canal and rectum. Our findings reveal homology between the urinary tracts of zebrafish and humans and offer the former as a model system to study disease.

Summary Statement

The excretory components of the distal urinary tract in larval and adult zebrafish have been incompletely evaluated. Here, we demonstrate close homology in urinary tract anatomy between zebrafish and human, including the presence of a distinct adult urinary bladder capable of periodic micturition
Hypermetabolism in mice carrying a near complete human chromosome 21
Authors: Sarver Dylan C. , Xu Cheng , Rodriguez Susana , Aja Susan , Jaffe Andrew E. , Gao Feng J. , Delannoy Michael , Periasamy Muthu , Kazuki Yasuhiro , Oshimura Mitsuo , Reeves Roger H. , Wong G. William
Published: February 2023

The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are due to sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle. This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health.
Why do young readers vary in reading fluency? The impact of word length and frequency in French 6th graders
Authors: Lubineau Marie , Watkins Cassandra Potier , Glasel Hervé , Dehaene Stanislas
Published: February 2023

Purpose

Which processes induce variations in reading speed in young readers with the same amount of education, but different levels of reading fluency? Here, we tested a prediction of the dual-route model: as fluency increases, these variations may reflect a decreasing reliance on decoding and an increasing reliance on the lexical route.

Method

1,500 French 6thgraders passed a one-minute speeded reading-aloud task evaluating fluency, and a 10-minute computerized lexical decision task evaluating the impact of word length, word frequency and pseudoword type.

Results

As predicted, the word length effect varied dramatically with reading fluency, with the least fluent group showing a length effect even for frequent words. The frequency effect also varied, but solely in proportion to overall slowness, suggesting that frequency affects the decision stage in all readers, while length impacts poor readers disproportionately. Response times and errors were also affected by pseudoword type (e.g. letter substitutions or transpositions), but these effects did not vary much with fluency. Overall, lexical decision variables were excellent predictors of reading fluency (r=0.62).

Conclusion

Our results call attention to middle-school reading difficulties and encourage the use of lexical decision as a test of students’ mental lexicon and the automatization of reading.
A Novel Approach to T-Cell Receptor Beta Chain (TCRB) Repertoire Encoding Using Lossless String Compression
Authors: Konstantinovsky Thomas , Yaari Gur
Published: February 2023

T-cell diversity is crucial for producing effective receptors that can recognize the pathogens encountered throughout life. A stochastic biological process known as VDJ recombination accounts for the high diversity of these receptors, making their analysis challenging. We present a new approach to sequence encoding and analysis, based on the Lempel-Ziv 76 algorithm (LZ-76). By creating a graph-like model, we identify specific sequence features and produce a new encoding approach to an individual’s repertoire. We demonstrate that this repertoire representation allows for various applications, such as generation probability inference, informative feature vector derivation, sequence generation, and a new measure for diversity estimation.
TGF-β downregulates antigen processing and presentation genes and MHC I surface expression through a Smad3-dependent mechanism
Authors: Berglund Alix K. , Hinson Anna L. , Schnabel Lauren V.
Published: February 2023

Regulation of MHC I surface expression by TGF-β is important for controlling cell-mediated immune responses, but how TGF-β downregulates MHC I is unknown. We investigated this mechanism using flow cytometry and RNA-sequencing to identify the major TGF-β signaling pathway and target genes involved. All three isoforms of TGF-β were found to have similar abilities to downregulate constitutive MHC I surface expression. Inhibiting the type I TGF-β receptor, ALK5, as well the canonical TGF-β signaling molecule Smad3, prevented TGF-β from downregulating MHC I surface expression. RNA-sequencing from horse and human mesenchymal stem cells revealed that multiple genes associated with antigen processing and presentation were downregulated in TGF-β-treated cells with B2M and ERAP1 being downregulated in both species. While downregulation of MHC I surface expression a slow process that continued past 24 hours after TGF-β treatment, downregulation of gene expression of ERAP1 occurred within 12 hours after treatment. B2M expression was not consistently downregulated until after 24 hours and TAP2 expression was inconsistent over a 72-hour period, although it was significantly downregulated at 12 hours after TGF-β treatment. This data supports that TGF-β downregulates antigen processing and presentation genes resulting in decreased surface expression of MHC I through a Smad3-dependent mechanism.
A compact multifunctional model of the rabbit atrioventricular node with dual pathways
Authors: Ryzhii Maxim , Ryzhii Elena
Published: February 2023

The atrioventricular node (AVN) is considered a “black box”, and the functioning of its dual pathways remains controversial and not fully understood. In contrast to numerous clinical studies, there are only a few mathematical models of the node. In this paper, we present a compact, computationally lightweight multi-functional rabbit AVN model based on the Aliev-Panfilov two-variable cardiac cell model. The AVN model includes fast (FP) and slow (SP) pathways, primary pacemaking in the sinoatrial node, subsidiary pacemaking in the SP, and takes into account the asymmetry of coupling between model cells. At the same time, the model is accompanied by a visualization of electrical conduction in the AVN, revealing the interaction between SP and FP in the form of ladder diagrams. The AVN model demonstrates broad functionality, including normal sinus rhythm, AVN automaticity, filtering of high-rate atrial rhythms during atrial fibrillation and atrial flutter with Wenckebach periodicity, direction-dependent properties, and realistic anterograde and retrograde conduction curves in the control case and the cases of FP and SP ablation. To show the validity of the proposed model, we compare the simulation results with the available experimental data. Despite its simplicity, the proposed model can be used both as a stand-alone module and as a part of complex three-dimensional atrial or whole heart simulation systems and can help to understand some puzzling functions of AVN.
The plasma degradome reflects later development of NASH fibrosis after liver transplant
Authors: Li Jiang , Sato Toshifumi , Hernández-Tejero María , Beier Juliane I. , Sayed Khaled , Benos Panayiotis V , Wilkey Daniel W , Humar Abhinav , Merchant Michael L , Duarte-Rojo Andres , Arteel Gavin E
Published: February 2023

Although liver transplantation (LT) is an effective therapy for cirrhosis, the risk of post-LT NASH is alarmingly high and is associated with accelerated progression to fibrosis/cirrhosis, cardiovascular disease, and decreased survival. Lack of risk stratification strategies hamper liver undergoes significant remodeling during inflammatory injury. During such remodeling, degraded peptide fragments (i.e., ‘degradome’) of the ECM and other proteins increase in plasma, making it a useful diagnostic/prognostic tool in chronic liver disease. To investigate whether inflammatory liver injury caused by post-LT NASH would yield a unique degradome profile, predictive of severe post-LT NASH fibrosis, we performed a retrospective analysis of 22 biobanked samples from the Starzl Transplantation Institute (12 with post-LT NASH after 5 years and 10 without). Total plasma peptides were isolated and analyzed by 1D-LC-MS/MS analysis using a Proxeon EASY-nLC 1000 UHPLC and nanoelectrospray ionization into an Orbitrap Elite mass spectrometer. Qualitative and quantitative peptide features data were developed from MSn datasets using PEAKS Studio X (v10). LC-MS/MS yielded ∼2700 identifiable peptide features based on the results from Peaks Studio analysis. Several peptides were significantly altered in patients that later developed fibrosis and heatmap analysis of the top 25 most significantly-changed peptides, most of which were ECM-derived, clustered the 2 patient groups well. Supervised modeling of the dataset indicated that a fraction of the total peptide signal (∼15%) could explain the differences between the groups, indicating a strong potential for representative biomarker selection. A similar degradome profile was observed when the plasma degradome patterns were compared being obesity sensitive (C57Bl6/J) and insensitive (AJ) mouse strains. Both The plasma degradome profile of post-LT patients yields stark difference based on later development of post-LT NASH fibrosis. This approach could yield new “fingerprints” that can serve as minimally-invasive biomarkers of negative outcomes post-LT.
Smartwatch-based prediction of single-stride and stride-to-stride gait outcomes using regression-based machine learning
Authors: Bailey Christopher A. , Mir-Orefice Alexandre , Uchida Thomas K. , Nantel Julie , Graham Ryan B.
Published: February 2023

2.

Abstract and key terms

Spatiotemporal variability during gait is linked to fall risk and could be monitored using wearable sensors. Although many users prefer wrist-worn sensors, most applications position at other sites. We developed and evaluated an application using a consumer-grade smartwatch inertial measurement unit (IMU). Young adults (N = 41) completed seven-minute conditions of treadmill gait at three different speeds. Single-stride outcomes (stride time, length, width, and speed) and spatiotemporal variability (coefficient of variation of each single-stride outcome) were recorded using an optoelectronic system, while 232 single- and multi-stride IMU metrics were recorded using an Apple Watch Series 5. These metrics were input to train linear, ridge, support vector machine (SVM), random forest, and extreme gradient boosting (xGB) models of each spatiotemporal outcome. We conducted Model × Condition ANOVAs to explore model sensitivity to speed-related responses. xGB models were best for single-stride outcomes (relative mean absolute error [% error]: 7–11%; intraclass correlation coefficient [ICC2,1]: 0.60–0.86) and SVM models were best for spatiotemporal variability (% error: 18–22%; ICC2,1= 0.47–0.64). Spatiotemporal changes with speed were captured by these models (Condition: p < 0.00625). Results support the feasibility of monitoring multi-stride spatiotemporal parameters using a smartwatch IMU and machine learning.
Mesenchymal Stromal Cell secretome is affected by tissue source, donor age and sex
Authors: Turlo AJ , Hammond DE , Ramsbottom KA , Soul J , Gillen A , McDonald K , Peffers MJ , Clegg PD
Published: February 2023

Variation in Mesenchymal Stromal Cell (MSC) function depending on their origin is problematic, as it may confound clinical outcomes of MSC therapy. Current evidence suggests that the therapeutic benefits of MSCs is primarily attributed to secretion of various biologically active factors (secretome). However, the effect of donor characteristics on the MSC secretome composition remains largely unknown. Here, we examined the influence of donor age, sex and tissue source, on the protein profile of the equine MSC secretome. Initially, we used dynamic metabolic labelling with stable isotopes combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify secreted proteins in MSC conditioned media (CM). Seventy proteins were classified as classically-secreted based on the rate of isotope label incorporation into newly synthesised proteins released into the extracellular space. Next, we analysed CM of bone marrow- (n = 14) and adipose-derived MSCs (n = 16) with label-free LC-MS/MS proteomics. Clustering analysis of 314 proteins detected across all samples identified tissue source as the main factor driving variability in MSC CM proteomes. Linear modelling applied to the subset of 70 secreted proteins identified tissue-related difference in the abundance of 23 proteins. There was an age-related decrease in the abundance of two proteins (CTHRC1, LOX), which has been validated with western blot and enzymatic activity assay. There was limited evidence of sex-related differences in protein abundance. In conclusion, this study provides evidence that tissue source and donor age contribute to heterogeneity in the protein composition of MSC secretomes which may influence the effects of MSC-based cell therapy.

Significance statement

This research shows for the first time that donor age can influence the proteins secreted by mesenchymal stromal cells (MSC), which is considered the main mechanism through which they mediate their biological actions. This information may improve our understanding of the variable outcomes observed in MSC clinical studies, as well as identify optimal sources and donor selection for specific clinical applications.
Genetic diversity and population structure ofEpichloefungal pathogens of plants in natural ecosystems
Authors: Treindl Artemis D. , Stapley Jessica , Leuchtmann Adrian
Published: February 2023

Understanding the population genetic processes driving the evolution of plant pathogens is of central interest to plant pathologists and evolutionary biologists alike. However, most studies focus on host-pathogen associations in agricultural systems of high genetic and environmental homogeneity and less is known about the genetic structure of pathogen populations infecting wild plants in natural ecosystems. We performed parallel population sampling of two pathogenicEpichloespecies occurring sympatrically on different host grasses in natural and seminatural grasslands in Europe:E. typhinainfectingDactylis glomerataandE. clarkiiinfectingHolcus lanatus. We sequenced 422 haploid isolates and generated genome-wide SNP datasets to investigate genetic diversity and population structure. In both species geographically separated populations formed genetically distinct groups, however population separation was less distinct inE. typhinacompared toE. clarkii. The patterns of among population admixture also differed between species across the same geographic range: we found higher levels of population genetic differentiation and a stronger effect of isolation by distance inE. clarkiicompared toE. typhina, consistent with lower levels of gene flow in the former. This pattern may be explained by the different dispersal abilities of the two pathogens and is expected to be influenced by the genetic structure of host populations. In addition, genetic diversity was higher inE. typhinapopulations compared toE. clarkii, indicative of higher effective population size inE. typhina. These results suggest that the effect of genetic drift and the efficacy of selection may differ in the two species. Our study provides evidence of how ecologically similar species occupying the same geographical space can experience different evolutionary contexts, which could influence local adaptation and coevolutionary dynamics of these fungal pathogens.
Simultaneous Knockouts of the Oxytocin and Vasopressin 1b Receptors in Hippocampal CA2 Impair Social Memory
Authors: Cymerblit-Sabba Adi , Walsh Caroline , Duan Kai-Zheng , Song June , Holmes Oliver , Young W. Scott
Published: February 2023

Oxytocin (Oxt) and vasopressin (Avp) are two neuropeptides with many central actions related to social cognition. The oxytocin (Oxtr) and vasopressin 1b (Avpr1b) receptors are co-expressed in the pyramidal neurons of the hippocampal subfield CA2 and are known to play a critical role in social memory formation. How the neuropeptides perform this function in this region is not fully understood. Here, we report the behavioral effects of a life-long conditional removal (knockout, KO) of either the Oxtr alone or both Avpr1b and Oxtr from the pyramidal neurons of CA2 as well as the resultant changes in synaptic transmission within the different fields of the hippocampus. Surprisingly, the removal of both receptors results in mice that are unable to habituate to a familiar female presented for short duration over short intervals but are able to recognize and discriminate females when presented for a longer duration over a longer interval. Importantly, these double KO mice were unable to discriminate between a male littermate and a novel male. Synaptic transmission between CA3 and CA2 is enhanced in these mice, suggesting a compensatory mechanism is activated to make up for the loss of the receptors. Overall, our results demonstrate that co-expression of the receptors in CA2 is necessary to allow intact social memory processing.
Genomic vulnerability to climate change and mutation load are affected by past declines in effective population size in two sedentary arctic bird species
Authors: Rödin-Mörch Patrik , Squires Theodore , Magnússon Kristinn P. , Höglund Jacob
Published: February 2023

Using whole genome re-sequencing data we study the effects of climate influenced declines in effective population size on the accumulation of deleterious mutations and the response to future climate change in populations of cold-adapted avian sister species from the Holarctic: rock ptarmigan (Lagopus muta) and willow ptarmigan (Lagopus lagopus). We reconstruct the demographic histories of the populations and determine their nucleotide diversity, past and present inbreeding, and mutation load. Genomic vulnerability to future climate change scenarios (also known as offset) is predicted for the populations.. We show that relatively small and isolated populations have reduced nucleotide diversity, higher signatures of past and present inbreeding, and higher estimates of mutation load. Among the studied populations, the most vulnerable to a mismatch between current and predicted future environments are rock ptarmigan populations in East Greenland, Iceland, and Svalbard, while among willow ptarmigan, subspecies residing on the British Isles are the most vulnerable.