bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strigolactones optimise plant water usage by modulating vessel formation
Authors: Zhao Jiao , Shi Dongbo , Kaeufer Kiara , Song Changzheng , Xu Xiaocai , Luzzietti Laura , Bennett Tom , Kaufmann Kerstin , Greb Thomas 
Published: April 2023

AbstractWood formation is fundamental for the remarkable growth of plant bodies by continuously providing cells for long-distance transport of water and nutrients1–3. Vessel elements, the water transporting units within woody tissues, are generated from a cylindrical domain of cambium stem cells (CSCs) producing different vascular cell types in a bidirectional manner4–6. However, knowledge on the regulation of CSC activity is limited with unclear cell fate trajectories as the most obscure aspect in this context. Here, via revealing transcriptome signatures of CSCs and their derivatives with single cell resolution inArabidopsis thaliana, we discover that the strigolactone (SL) signalling pathway modulates cell type composition in vascular tissues and thereby increases drought resistance. In particular, we find that SL signalling negatively regulates vessel element formation and thereby plant water usage. SL signalling is generally associated with differentiating vascular tissues but low in developing vessels and in CSCs implying a local role during fate decisions in CSC-derived cells. Highlighting the importance of vascular tissue composition for the overall plant water balance, alteration of vessel element formation has a direct impact on transpiration rates through leaf stomata. Our results demonstrate the importance of structural alignment of water transporting tissues to unstable water regimes and provide perspectives for a long-term modulation of drought resistance in plants.
In plantaexploitation of leaf apoplastic compounds: a window of opportunity for spatiotemporal studies of apoplastic metabolites, hormones and physiology
Authors: Franzisky Bastian L. , Sölter Jakob , Xue Cheng , Harter Klaus , Stahl Mark , Geilfus Christoph-Martin 
Published: April 2023

AbstractProcesses in the leaf apoplast are relevant for development, cell wall rheological properties, plant nutrition, sink-source portioning, microbe-host plant-interactions or intercellular information exchange and signaling and are therefore regulated or influenced by the composition of the leaf apoplastic solute.In contrast to the traditional methods for the extraction of apoplastic solutes that are more or less destructive, we propose a new method that allows extraction of leaf apoplastic solutes (i) non-invasively and, thus, (ii) over time. Moreover, the method has (iii) a high spatial resolution that allows identification of solute-microdomains in the leaf apoplast. The method was established forArabidopsis thalianaandVicia fabaleaves but should also be applicable to other plants species with similar leaf morphologies. It is based on the infiltration of an aqueous extraction solution into the apoplast followed by its recovery seconds later, both through the stomata. By this, the apoplast (and its solutes) of an identical leaf can be sampled on successive days with negligible symplastic contamination.A spatiotemporal mapping of leaf apoplastic ion and metabolite patterns within the identical leaf opens a window of opportunity for understanding apoplast biology. As for example, the existence of apoplastic abscisic acid gradients within a leaf in response to salinity was witnessed in this study, as was the unsuspected accumulation of kaempferol glycosides in the leaf apoplast.The presented method is relevant for plant developmental biologists, phytopathologists, plant physiologists, plant nutritionists and others that need to integrate apoplast biology into their research approaches.
Discovery of a novel drug using lipid-based formulation targeting G12D-mutated KRAS4B through non-covalent bonds
Authors: Lu Huixia , Hu Zheyao , Faraudo Jordi , Martí Jordi 
Published: April 2023

AbstractOne of the most common drivers in human cancer is KRAS4B. In recent years, the promising KRAS targeted drug development has attracted significant new research interest and reignited the field of RAS therapeutics. To signal, oncogenic KRAS4B not only requires a sufficient nucleotide exchange, but also needs to recruit effectors by exposing its effector-binding sites while anchoring to plasma membrane where KRAS4B-mediated signaling events occur. Phosphodiesterase-δplays an important role in sequestering KRAS4B from the cytoplasm and targeting it to cellular membranes. In this work, we have designed a drug LIG1 using lipid-based formulation to directly target both the switch-IIpocket of KRAS4B-G12D and phosphodiesterase-δ. LIG1 was found to lock KRAS4B in its GDP-bound state while the effector-binding domain is blocked by the interface of the plasma membrane which hinders the nucleotide exchange while simultaneously it can affect the GTP-bound KRAS4B to shift from an active state to its inactive state. LIG1 is also observed to stably accommodate itself in the prenyl-binding pocket of phosphodiesterase-δwhich impairs KRAS4B enrichment at the membrane and suppress the proliferation of KRAS4B-dependent cancer cells. In this work we report a drug based on lipid-based formulation that can foster drug discovery efforts for the targeting of oncogenes of the RAS family and beyond.
Questioning Neanderthal admixture: on models, robustness and consensus in human evolution
Authors: Tournebize Rémi , Chikhi Lounès 
Published: April 2023

AbstractGenomic and ancient DNA data have revolutionized palaeoanthropology and our vision of human evolution, with indisputable landmarks like the sequencing of Neanderthal and Denisovan genomes. Yet, using genetic data to identify, date and quantify evolutionary events—like ancient bottlenecks or admixture—is not straightforward, as inferences may depend on model assumptions. In the last two decades, the idea that Neanderthals and members of theHomo sapienslineage interbred has gained momentum. From the status of unlikely theory, it has reached consensus among human evolutionary biologists. This theory is mainly supported by statistical approaches that depend on demographic models minimizing or ignoring population structure, despite its widespread occurrence and the fact that when ignored, population structure can lead to infer spurious demographic events. We simulated genomic data under a structured and admixture-free model of human evolution, and found that all the tested admixture approaches identified long Neanderthal fragments in our simulated genomes and an admixture event that never took place. We also observed that several published admixture models failed to predict important empirical diversity or admixture statistics, and that our model was best at predicting these statistics jointly. Our results suggest that models accounting for population structure are fundamental to improve our understanding of human evolution, and that admixture between Neanderthals andHomo sapiensneeds to be re-evaluated in the light of structured models. Beyond the Neanderthal case, we argue that ancient hybridization events, which are increasingly documented in many species, including with other hominins, may also benefit from such reevaluation.Significance statementThe idea that Neanderthals and some ancestralHomo sapienspopulations interbred has gained momentum in the last two decades. Yet, this theory is mainly supported by statistical approaches that assume highly simplified models of hominin evolution. A major issue is that these methods have been poorly tested in the context of population structure, despite its widespread occurrence in many vertebrate species. We simulated data under a structured model and found that all tested methods identified spurious admixture events, suggesting a lack of robustness to population structure. Besides, our structured model was better at predicting several key genomic statistics than the tested admixture models. This suggests that admixture should be re-evaluated in the light of population structure, in hominins and beyond.
Human motor neurons are rare and can be transcriptomically divided into known subtypes
Authors: Gautier Olivia , Blum Jacob A. , Maksymetz James , Chen Derek , Schweingruber Christoph , Mei Irene , Hermann Anita , Hackos David H. , Hedlund Eva , Ravits John , Gitler Aaron D. 
Published: April 2023

AbstractWe performed single-nucleus RNA-sequencing on adult human spinal cord using a neuronal nuclei enrichment strategy. We obtained transcriptomic profiles of >14,000 spinal neurons, including a small population of motor neurons that shares similarities with mouse motor neurons and can be subdivided into alpha and gamma subtypes. We sought to compare our results to those from a recent study by Yadav and colleagues, which provides a single-nucleus transcriptomic atlas of the human spinal cord. While most neuronal nuclei from both studies share similar features, our results from motor neurons differ substantially. We reanalyzed their RNA-sequencing data and provide evidence that the authors incorrectly identified cholinergic cellular debris as motor neuron nuclei in their dataset, raising doubts about their conclusions regarding motor neurons. Our findings underscore the challenges associated with transcriptionally profiling motor neurons from the spinal cord because of their rarity. We propose specific enrichment strategies and recommend important quality control measures for future transcriptional profiling studies involving human spinal cord tissue and rare cell types.
Host-cell Interactions of Engineered T cell Micropharmacies
Authors: Bourne Christopher M. , Wallisch Patrick , Dacek Megan , Gardner Thomas , Pierre Stephanie , Vogt Kristen , Corless Broderick C. , Bah Mamadou A. , Pichardo Jesus Romero , Charles Angel , Kurtz Keifer G. , Tan Derek S. , Scheinberg David A. 
Published: April 2023

AbstractGenetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration
Authors: Leibinger Marco , Zeitler Charlotte , Paulat Miriam , Gobrecht Philipp , Hilla Alexander , Andreadaki Anastasia , Guthoff Rainer , Fischer Dietmar 
Published: April 2023

AbstractInjured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of PTEN or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and PTEN knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) enables axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.Significance statementInjured axons in the CNS usually fail to regenerate, causing permanent disabilities. No clinically approved drugs are currently available to improve or accelerate axon regeneration. We demonstrate that pro-regenerative treatments’ induced tubulin detyrosination in axonal growth cones limits axon growth. Hence, cotreatment with parthenolide, a compound blocking detyrosination, synergistically accelerates neurite growth of primary murine and, demonstrated for the first time,humanretinal ganglion cells. Furthermore, systemic application of the parthenolide’s prodrug DMAPT accelerates hIL-6-mediated optic nerve regeneration and locomotor recovery after severe spinal cord injury. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a potential (adjuvant) drug candidate for treating CNS injuries.
Metformin regulates bone marrow stromal cells to accelerate bone healing in diabetic mice
Authors: Guo Yuqi , Wei Jianlu , Liu Chuanju , Li Xin , Yan Wenbo 
Published: April 2023

AbstractDiabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type-2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in T2D mice in all the three injury models. The proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from WT and T2D mice treated with or without metformin were comparedin vitroandin vivoby assessing the subcutaneous ossicle formation of the BMSC implants in recipient T2D mice.In vivotreatment with metformin to T2D mice could effectively rescue the impaired differentiation potential and detrimental lineage commitment of BMSCs, caused by the hyperglycemic conditions. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in T2D mice receiving metformin treatment. The chondrocyte transcript factor SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, bone formation and chondrogenesis in T2D mouse models.
Deep Learning Enhanced Fast Fluorescence Lifetime Imaging with A Few Photons
Authors: Xiao Dong , Sapermsap Natakorn , Chen Yu , Day-Uei Li David 
Published: April 2023

AbstractWe present a deep learning (DL) framework, which we term FPFLI (Few-PhotonFluorescenceLifetimeImaging), for fast analyzing fluorescence lifetime imaging (FLIM) data under highly low-light conditions with only a few photon-per-pixels (PPPs). FPFLI breaks the conventional pixel-wise lifetime analysis paradigm and fully exploits the spatial correlation and intensity information of fluorescence lifetime images to estimate lifetime images, pushing the photon budget to an unprecedented low level. The DL framework can be trained by synthetic FLIM data and easily adapted to various FLIM systems. FPFLI can effectively and robustly estimate FLIM images within seconds using synthetic and experimental data. The fast analysis of low-light FLIM images made possible by FPFLI will promise a broad range of potential applications.
Patient-derived glioblastoma neurosphere cultures differentially express nicotinic acetylcholine receptors depending on ambient choline
Authors: Gondarenko Elena A. , Mazur Diana V. , Masliakova Marina , Ryabukha Yana A. , Kasheverov Igor E. , Tsetlin Victor I. , Kudryavtsev Denis S. , Antipova Nadine V. 
Published: April 2023

ABSTRACTGlioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a poor prognosis. GBM cells, developing in the environment of neural tissue, often exploit neurotransmitters and their receptors to promote their growth and invasion. Nicotinic acetylcholine receptors (nAChRs) play a crucial role in the central nervous system signal transmission, are widely represented in the brain, the GBM cells expressing several subtypes of nAChRs which are suggested to transmit signals from neurons, thus promoting tumor invasion and growth. Functional α1*, α7 and α9 nAChRs are demonstrated on several patient-derived GBM neurosphere cultures and U87MG cell line using neurotoxins and fluorescent calcium assay. Selective α1*, α7 and α9 nAChR antagonists stimulated cell growth in presence of nicotinic agonists. Choline, normally present in blood, is capable of activating α1*, α7 and α9 nAChR subtypes, mediates the antagonist’s influence on cell proliferation. Several cultivating conditions have been shown to directly change sensitivity of primary GBM lines to nAChR ligands. Thus, results ofin vitrotesting of nAChR ligands on GBM lines should be interpreted and reviewed in cell culture conditions-aware manner.
Cell division can accelerate the loss of a heteroplasmic mitochondrial DNA mutation in a mouse model of mitochondrial disease
Authors: Su Tianhong , Bernardino Gomes Tiago M , Smith Anna L M , Whitehall Julia C , Blain Alasdair P , Simard Marie-Lune , Scholten Louisa , Stewart James B , Turnbull Doug M , Lawless Conor , Greaves Laura C 
Published: April 2023

AbstractMitochondrial DNA (mtDNA) mutations accumulate in both mitotic and post-mitotic somatic tissues of normal individuals with age. They clonally expand within individual cells and cause mitochondrial dysfunction. In contrast, in patients with inherited disease-causing mtDNA mutations the mutation load decreases in mitotic tissues over time, whereas the mutations load in post-mitotic tissues remains relatively stable. The mechanisms underlying this decrease in mitotic tissues, and whether mitochondrial function is restored at the tissue level are unknown. Here, using a combination of homogenate tissue and single crypt/muscle fibre pyrosequencing we have shown a decrease in the mutation load of the germline heteroplasmic m.5024C>T mutation in multiple mitotic tissues of a mouse model of inherited mitochondrial disease (C5024T mice). We have then usedin silicopredictions to model the cellular dynamics of mtDNA mutation load in mitotic and post mitotic tissues. We demonstrate that: (1) the rate of m.5024C>T decrease correlates with the rate of tissue turnover; (2) the mutation load decrease is not associated with changes in overall cellular proliferation and apoptosis within the mitotic colonic epithelium; instead, it could be due to an upper limit of m.5024C>T load in stem cell populations; (3) the m.5024C>T mutation load is maintained in post-mitotic tissues over time with a consistent load amongst individual muscle fibres; (4)in silicomodelling supports a scenario where genetic drift is accelerated in mitotic tissues by high levels of mtDNA replication coupled with mtDNA segregation at cell division. This study has advanced our understanding of the dynamics of mtDNA mutations and phenotype development in patients with mtDNA disease.Author SummaryHealthy individuals randomly accumulate pathogenic mtDNA mutations with age in dividing cells, causing mitochondrial dysfunction. Interestingly, patients with mitochondrial disease show a relative decrease in the loads of inherited mtDNA mutations in some dividing cells over time. The mechanisms underlying this decrease are unknown. Here we show a decrease in the load of the germline heteroplasmic m.5024C>T mutation in dividing cells and tissues of a mouse model of mitochondrial disease. In contrast, the mutation load in non-dividing cells and tissue remains stable. Our data are consistent with the hypothesis that a higher frequency of mtDNA replication in dividing cells, coupled with stem cells having an upper tolerance limit for m.5024C>T, causes an overall decrease in m.5024C>T load at the tissue level.
Influences of persona self on luxury brand attachment in the Metaverse context
Authors: Kim Juran , Bae Joonheui 
Published: April 2023

PurposeThis study aims to examine the effect of actual and persona self-congruence on luxury brand attachment and the effects of luxury brand attachment on attitude toward luxury brands and purchase intentions using empirical data on Metaverse users.Design/methodology/approachThe authors recruited 300 Metaverse users from South Korea to participate in the survey. Participants were asked whether the participants had experienced Metaverse, including Roblox and Zepeto, before participating in the survey. The Gucci Garden was suggested as a luxury brand in the Metaverse for the participants.FindingsThe findings clarify the concept of persona self-congruence and support the congruence's effects on luxury brand attachment in the Metaverse context. This study found a positive relationship between persona self-congruence and luxury brand attachment that influences attitude and purchase intentions in the context of Metaverse, contributing to the theoretical and practical implications for luxury brand management.Research limitations/implicationsThis study contributes to luxury brand marketing in the Metaverse context by clarifying the concept of persona self-congruence and articulating the congruence's effects on luxury brand attachment in the context of the Metaverse.Practical implicationsIn the post-pandemic world, this study offers luxury brand practitioners new insights to help the practitioners develop and manage luxury brand strategies by understanding the influence of persona self-congruence and luxury brand attachment on luxury brand evaluation in the Metaverse context.Originality/valueThis study addresses an innovative and practical issue related to the impact of persona self-congruence on luxury brand attachment in the Metaverse, offering new insights for luxury brand management in the post-pandemic world.