bluuebunny/crossref_metadata_2025_split huggingface dataset:
Automatic cell type harmonization and integration across Human Cell Atlas datasets
Authors: Xu Chuan , Prete Martin , Webb Simone , Jardine Laura , Stewart Benjamin J. , Hoo Regina , He Peng , Meyer Kerstin , Teichmann Sarah A. 
Published: May 2023

SummaryHarmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here we present CellHint, a predictive clustering tree-based tool to resolve cell type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with ∼3.7 million cells and various machine learning models for automatic cell annotation across human tissues.
Beyond Alternans: Detection of Higher-Order Periodicity in Ex-Vivo Human Ventricles Before Induction of Ventricular Fibrillation
Authors: Iravanian Shahriar , Uzelac Ilija , Shah Anand D , Toye Mikael J , Lloyd Michael S. , Burke Michael A. , Daneshmand Mani A , Attia Tamer S , Vega J David , Merchant Faisal M. , Cherry Elizabeth M , Bhatia Neal K. , Fenton Flavio H. 
Published: May 2023

AbstractBackgroundRepolarization alternans, defined as period-2 oscillation in the repolarization phase of the action potentials, is one of the cornerstones of cardiac electrophysiology as it provides a mechanistic link between cellular dynamics and ventricular fibrillation (VF). Theoretically, higher-order periodicities (e.g., period-4, period-8,…) are expected but have very limited experimental evidence.MethodsWe studied explanted human hearts, obtained from the recipients of heart transplantation at the time of surgery, using optical mapping technique with transmembrane voltage-sensitive fluorescent dyes. The hearts were stimulated at an increasing rate until VF was induced. The signals recorded from the right ventricle endocardial surface just before the induction of VF and in the presence of 1:1 conduction were processed using the Principal Component Analysis and a combinatorial algorithm to detect and quantify higher-order dynamics.ResultsA prominent and statistically significant 1:4 peak (corresponding to period-4 dynamics) was seen in three of the six studied hearts. Local analysis revealed the spatiotemporal distribution of higher-order periods. Period-4 was localized to temporally stable islands. Higher-order oscillations (period-5, 6, and 8) were transient and primarily occurred in arcs parallel to the activation isochrones.DiscussionWe present evidence of higher-order periodicities and the co-existence of such regions with stable non-chaotic areas in ex-vivo human hearts before VF induction. This result is consistent with the period-doubling route to chaos as a possible mechanism of VF initiation, which complements the concordant to discordant alternans mechanism. The presence of higher-order regions may act as niduses of instability that can degenerate into chaotic fibrillation.
Pannexin 1 modulates angiogenic activities of human endothelial colony-forming cells through IGF-1 mechanism and is a marker of senescence
Authors: Tien Ting-Yi , Wu Yih-Jer , Su Cheng-Huang , Hsieh Chin-Ling , Wang Bo-Jeng , Lee Yi-Nan , Su Yeu , Yeh Hung-I 
Published: May 2023

AbstractBACKGROUNDWe examined the role of pannexins in human endothelial progenitor cell (EPC) senescence.METHODSYoung and replication-induced senescent endothelial colony-forming cells (ECFCs) derived from human circulating EPCs were used to examine cellular activities and senescence-associated indicators after transfection of siRNA specific to Panx1 or lentivirus-mediated Panx1 overexpression. Hindlimb ischemia mice were used asin vivoangiogenesis model. Protein and phospho-kinase arrays were used to determine underlying mechanisms.RESULTSPanx1 was the predominant pannexin isoform in human ECFCs and up-regulated in both replication-induced senescent ECFCs and circulating EPCs from aged mice and humans. Cellular activities of the young ECFCs were enhanced by Panx1 down-regulation, but attenuated by its up-regulation. In addition, reduction of Panx1 in the senescent ECFCs could rejuvenate cellular activities with reduced senescence-associated indicators, including senescence-associated β-galactosidase activity, p16INK4a, p21, acetyl-p53, and phospho-Histone H2A.X. In mouse ischemic hindlimbs injected senescent ECFCs, blood perfusion ratio, salvaged limb outcome, and capillary density were all improved by Panx1 knockdown. Insulin-like growth factor 1 (IGF-1) was significantly increased in the supernatant from senescent ECFCs after Panx1 knockdown. The enhanced activities and paracrine effects of Panx1 knockdown senescent ECFCs were completely inhibited by anti-IGF-1 antibodies. FAK, ERK and STAT3 were activated in senescent ECFCs with Panx1 knockdown, in which the intracellular calcium level was reduced, and the activation was inhibited by supplemented calcium. The increased IGF-1 in Panx1-knockdown ECFCs was abrogated respectively by inhibitors of FAK (PF562271), ERK (U0126), and STAT3 (NSC74859), and supplemented calcium.CONCLUSIONSPanx1 expression is up-regulated in human ECFCs/EPCs with replication-induced senescence and during aging. Angiogenic potential of senescent ECFCs is improved by Panx1 reduction through increased IGF-1 production via activation of FAK-ERK axis following calcium influx reduction. Our findings provide new strategies to evaluate EPC activities and rejuvenate senescent EPCs for therapeutic angiogenesis.
The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis
Authors: Hazari Younis , Urra Hery , Garcia Lopez Valeria A. , Diaz Javier , Tamburini Giovanni , Milani Mateus , Pihan Philippe , Durand Sylvere , Aprahamia Fanny , Baxter Reese , Huang Menghao , Dong X Charlie , Vihinen Helena , Batista-Gonzalez Ana , Godoy Patricio , Criollo Alfredo , Ratziu Vlad , Foufelle Fabienne , Hengstler Jan G. , Jokitalo Eija , Bailly-maitre Beatrice , Maiers Jessica L , Plate Lars , Kroemer Guido , Hetz Claudio 
Published: May 2023

AbstractCollagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.
A unique C-terminal domain contributes to the molecular function of restorer-of-fertility proteins in plant mitochondria
Authors: Huynh Sang Dang , Melonek Joanna , Colas des Francs-Small Catherine , Bond Charles S. , Small Ian 
Published: May 2023

SummaryRestorer-of-fertility(Rf) genes have practical applications in hybrid seed production as a means to control self-pollination. They encode pentatricopeptide repeat (PPR) proteins that are targeted to mitochondria where they specifically bind to transcripts that induce cytoplasmic male sterility and repress their expression. In searching for a molecular signature unique to this class of proteins, we found that a majority of known Rf proteins have a unique domain, which we called RfCTD (Restorer-of-fertility C-terminal domain), and its presence correlates with the ability to induce cleavage of the mitochondrial RNA target. We constructed a sequence profile that can quickly and accurately identify RfCTD sequences in plant genomes or transcriptomes. We screened 219 angiosperm genomes from 123 genera and found that each diploid genome encodes, on average, 25 Rf-like (RFL) proteins, of which approximately 55% contain the C-terminal signature domain. This screen also revealed considerable variation in RFL gene numbers across flowering plants. We observed that plant genera with bisexual flowers have significantly higher numbers of RFL genes compared to those with unisexual flowers, consistent with a role of these proteins in restoration of male fertility.Finally, we show that removing the RfCTD from the RFL protein RNA PROCESSING FACTOR 2-nad6prevented cleavage of its RNA target, thenad6transcript, inArabidopsis thalianamitochondria. This research provides a simple way of identifying putativeRfcandidates in genome sequences, new insights into the molecular mode of action of Rf proteins in plant mitochondria and expands our understanding of the evolution of fertility restoration in flowering plants.
The astrocyte α1-adrenoreceptor is a key component of the neuromodulatory system in mouse visual cortex
Authors: Wahis Jérôme , Akkaya Cansu , Kirunda Andre M. , Mak Aline , Zeise Karen , Verhaert Jens , Gasparyan Hayk , Hovhannisyan Sargis , Holt Matthew G. 
Published: May 2023

ABSTRACTNoradrenaline (norepinephrine) is known to modulate many physiological functions and behaviors. In this study, we tested to what extent astrocytes, a type of glial cell, participate in noradrenergic signaling in mouse primary visual cortex (V1). Astrocytes are essential partners of neurons in the central nervous system. They are central to brain homeostasis, but also dynamically regulate neuronal activity, notably by relaying and regulating neuromodulator signaling. Indeed, astrocytes express receptors for multiple neuromodulators, including noradrenaline, but the extent to which astrocytes are involved in noradrenergic signaling remains unclear. To test whether astrocytes are involved in noradrenergic neuromodulation in mice, we knocked down the major noradrenaline receptor in astrocytes, the α1A- adrenoreceptor. Using this model, we found that the α1A-adrenoreceptor is involved in triggering intracellular calcium transients in astrocytes, which are generally thought to underlie astrocyte function. To test if impaired α1A-adrenoreceptor signaling in astrocytes affected the function of neuronal circuits in V1, we used electrophysiological measurements and found that noradrenergic signaling through astrocyte α1A-adrenoreceptor controls the basal level of inhibition and regulates plasticity in V1 by potentiating synaptic responses in circuits involved in visual information processing.MAIN POINTSThe α1A-adrenoreceptor (α1A-NAR) is the major α1-NAR in primary visual cortex (V1)α1A-NAR signaling triggers astrocyte Ca2+responses in V1.Astrocyte α1A-NARs play a key role in regulating basal inhibitory transmission and are crucial for LTP induction in V1
Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain
Authors: Simard Sophie , Rahimian Reza , Davoli Maria Antonietta , Théberge Stéphanie , Matosin Natalie , Turecki Gustavo , Nagy Corina , Mechawar Naguib 
Published: May 2023

ABSTRACTUsing spatial transcriptomics and FISH, we detected very few cells expressing neural stem cell- and proliferation-specific genes in the human dentate gyrus (DG) from childhood to middle age. However, we observed at all ages a significant number of DG cells expressing the immature neuronal markerDCX. Across ages, the majority of these cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature.
NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+T cells
Authors: Zeeshan Chaudhry M. , Borkner Lisa , Berberich-Siebelt Friederike , Cicin-Sain Luka 
Published: May 2023

ABSTRACTCytomegalovirus (CMV) induces a unique T-cell response, where antigen-specific populations do not contract, but rather inflate during viral latency. It has been proposed that subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells by intermittently engaging T-cell receptors (TCRs), but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1 and NFATc2 signal downstream of TCR in mature T lymphocytes. We show selective impacts of NFATc1 and/or NFATc2 genetic ablations on the long-term inflation of MCMV-specific CD8 T-cell responses despite largely maintained responses to acute infection. NFATc1 ablation elicited robust phenotypes in isolation, but the strongest effects were observed when both NFAT genes were missing. CMV control was impaired only when both NFATs were deleted in CD8 T cells used in adoptive immunotherapy of immunodeficient mice. Transcriptome analyses revealed that T-cell intrinsic NFAT is not necessary for CD8 T-cell priming, but rather for their maturation towards effector-memory and in particular the effector cells, which dominate the pool of inflationary cells.
Navigating sex and sex roles: deciphering sex-biased gene expression in a species with sex-role reversal (Syngnathus typhle)
Authors: Pappert Freya A. , Dubin Arseny , Torres Guillermo , Roth Olivia 
Published: May 2023

AbstractSexual dimorphism, the divergence in morphological traits between males and females of the same species, is often accompanied by sex-biased gene expression. However, the majority of research has focused on species with conventional sex roles, where females have the highest energy burden with both egg production and parental care, neglecting the diversity of reproductive roles found in nature. We investigated sex-biased gene expression in the broadnosed pipefish (Syngnathus typhle), a sex-role reversed species with male pregnancy, allowing us to separate these two female traits. Employing RNA sequencing, we examined gene expression across organs (brain, head kidney, gonads) at various life stages, encompassing differences in age, sex, and reproductive status. While some gene groups were more strongly associated with sex roles, such as stress resistance and immune defence, others were driven by biological sex, such as energy and lipid storage regulation in an organ- and age-specific manner. By investigating how genes regulate and are regulated by changing reproductive roles and resource allocation in a model system with unconventional life-history strategy, we aim to enhance our understanding of the importance of sex and sex role in regulating gene expression patterns, broadening the scope of this discussion to encompass a wide range of organisms.
Habitat fragmentation selects for low dispersal in an ant species
Authors: Finand Basile , Loeuille Nicolas , Bocquet Céline , Fédérici Pierre , Ledamoisel Joséphine , Monnin Thibaud 
Published: May 2023

ABSTRACTIncreased habitat fragmentation is one of the major global changes affecting biodiversity. It is characterised by a decrease in habitat availability and by an increase in the isolation of suitable habitat patches. The dispersal capacities of species may evolve in response to increased habitat fragmentation. Spatial heterogeneities and/or costs of dispersal, which are directly linked to habitat fragmentation, tend to select for lower dispersal abilities. We studied the effects of habitat fragmentation on dispersal using an ant species that exhibits a marked dispersal polymorphism.Myrmecina graminicolaproduces winged queens dispersing by flight over long distances, or apterous queens dispersing on foot over short distances. We sampled queens in 24 forests around Paris and 25 parks within Paris, representing varied levels of habitat fragmentation and habitat size. We identified the queen morphotypes in each environment and used it as a proxy of dispersal. Winged queens predominated in both environments. However, apterous queens were comparatively more common in parks than in forests, suggesting that high fragmentation counterselects dispersal in this species. We argue that this is because dispersing within urban environments is very costly and discuss the factors favouring each queen morph or resulting in their co-occurrence (maintenance of polymorphism).
The adaptive stochasticity hypothesis: modelling equifinality, multifinality and adaptation to adversity
Authors: Carozza Sofia , Akarca Danyal , Astle Duncan 
Published: May 2023

ABSTRACTNeural phenotypes are the result of probabilistic developmental processes. This means that stochasticity is an intrinsic aspect of the brain as it self-organizes over a protracted period. In other words, while both genomic and environmental factors shape the developing nervous system, another significant—though often neglected—contributor is the randomness introduced by probability distributions. Using generative modelling of brain networks, we provide a framework for probing the contribution of stochasticity to neurodevelopmental diversity. To mimic the prenatal scaffold of brain structure set by activity-independent mechanisms, we start our simulations from the medio-posterior neonatal rich-club (Developing Human Connectome Project;dHCP, n= 630). From this initial starting point, models implementing Hebbian-like wiring processes generate variable yet consistently plausible brain network topologies. By analyzing repeated runs of the generative process (> 107simulations), we identify critical determinants and effects of stochasticity. Namely, we find that stochastic variation has a greater impact on brain organization when networks develop under weaker constraints. This heightened stochasticity makes brain networks more robust to random and targeted attacks, but more often results in non-normative phenotypic outcomes. To test our framework empirically, we evaluated whether stochasticity varies according to the experience of early-life deprivation using a cohort of neurodiverse children (Centre for Attention, Learning and Memory;CALM n= 357). We show that low socioeconomic status predicts more stochastic brain wiring. We conclude that stochasticity may be an unappreciated contributor to relevant developmental outcomes, and make specific predictions for future research.
Tet Controls Axon Guidance in Early Brain Development through Glutamatergic Signaling
Authors: Tran Hiep , Le Le , Singh Badri Nath , Kramer Joseph , Steward Ruth 
Published: May 2023

AbstractMutations in human TET proteins have been found in individuals with neurodevelopmental disorders. Here we report a new function of Tet in regulatingDrosophilaearly brain development. We found that mutation in the Tet DNA-binding domain (TetAXXC) resulted in axon guidance defects in the mushroom body (MB). Tet is required in early brain development during the outgrowth of MB β axons. Transcriptomic study shows that glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly downregulated in theTetAXXCmutant brains. CRISPR/Cas9 mutagenesis or RNAi knockdown of Gs2 recapitulates theTetAXXCmutant phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in these cells rescues the axon guidance defects ofTetAXXC. TreatingTetAXXCwith the metabotropic glutamate receptor antagonist MPEP can rescue while treating with glutamate enhances the phenotype confirming Tet function in regulating glutamatergic signaling.TetAXXCand theDrosophilahomolog ofFragile X Messenger Ribonucleoprotein proteinmutant (Fmr13) have similar axon guidance defects and reduction in Gs2 mRNA levels. Interestingly, overexpression of Gs2 in the IPCs also rescues theFmr13phenotype, suggesting functional overlapping of the two genes. Our studies provide the first evidence that Tet can control the guidance of axons in the developing brain by modulating glutamatergic signaling and the function is mediated by its DNA-binding domain.
Mechanical regulation of substrate adhesion and de-adhesion drives a cell contractile wave during tissue morphogenesis
Authors: Collinet Claudio , Bailles Anaïs , Lecuit Thomas 
Published: May 2023

AbstractDuring morphogenesis tissue-scale forces drive large-scale deformations, yet how these forces arise from the local interplay between cellular contractility and adhesion is poorly understood. In the posterior endoderm ofDrosophilaembryos, a self-organized tissue-scale wave of actomyosin contractility and cell invagination is coupled with adhesion to the surrounding vitelline membrane to drive the polarized tissue deformation. We report here that this process emerges at the subcellular level from the mechanical coupling between Myosin-II activation and sequential adhesion/de-adhesion to the vitelline membrane. At the wavefront, integrin focal complexes anchor the actin cortex to the vitelline membrane and promote activation of Myosin-II, which in turn enhances adhesion in a positive feedback loop. Subsequently, upon detachment, cortex contraction and advective flow further amplify Myosin-II levels. Prolonged contact with the vitelline membrane increases the duration of the integrin-Myosin-II feedback, integrin adhesion and thus slows down cell detachment and wave propagation of the invagination. Finally, we show that the angle of cell detachment changes as a function of the strength of adhesion and modifies the tensile forces required for detachment to maintain wave propagation. This illustrates how the tissue-scale wave arises from subcellular mechanochemical feedbacks and tissue geometry.
Genome engineering allows selective conversions of terephthalaldehyde to multiple valorized products in bacterial cells
Authors: Dickey Roman M. , Jones Michaela A. , Butler Neil D. , Govil Ishika , Kunjapur Aditya M. 
Published: May 2023

AbstractDeconstruction of polyethylene terephthalate (PET) plastic waste generates opportunities for valorization to alternative products. We recently designed an enzymatic cascade that could produce terephthalaldehyde (TPAL) from terephthalic acid. Here, we showed that the addition of TPAL to growing cultures ofEscherichia coliwild-type strain MG1655 and an engineered strain for reduced aromaticaldehyderection (RARE) strain resulted in substantial reduction. We then investigated if we could mitigate this reduction using multiplex automatable genome engineering (MAGE) to create anE. colistrain with 10 additional knockouts in RARE. Encouragingly, we found this newly engineered strain enabled a 2.5-fold higher retention of TPAL over RARE after 24h. We applied this new strain for the production ofpara-xylylenediamine (pXYL) and observed a 6.8-fold increase in pXYL titer compared to RARE. Overall, our study demonstrates the potential of TPAL as a versatile intermediate in microbial biosynthesis of chemicals that derived from waste PET.