Biology subjects

Xue, J.

Publications and source records attributed to Xue, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Gut Microbiota and Derived Metabolites Mediate Obstructive Sleep Apnea Induced Atherosclerosis

BackgroundObstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. ResultsAtherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) ApoE-/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF ApoE-/- mice markedly reduced atherosclerotic formation relative to SPF ApoE-/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. ConclusionsIn summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

microbiology↗

bioRxiv2024

Heat Acclimation in Mice Requires Preoptic BDNF Neurons and Postsynaptic Potentiation

Heat acclimation (HA) is a key adaptive response in mammals to repeated heat exposure, essential for fitness and survival1-3. HA improves cardiovascular function, thermal comfort, and exercise capacity4, 5. However, the lack of a genetically tractable model has hindered understanding of the molecular and neural mechanisms underlying HA. Here, we show that 10 days of daily 38{degrees}C exposure lowers core body temperature (Tcore) and reduces anxiety during subsequent heat exposures in mice. HA increases brain-derived neurotrophic factor (BDNF) expression in the medial preoptic area (MPO). BDNF-expressing MPO neurons (MPOBDNF) show increased intrinsic heat sensitivity after HA. These neurons orchestrate downstream targets in the dorsomedial hypothalamus (DMH) and rostral raphe pallidus (rRPa) to mediate HA effects. BDNF, acting through its receptor tropomyosin-related kinase B (TrkB) in the DMH, facilitates the anxiolytic effect of HA by enhancing excitatory synaptic connections between MPOBDNF and DMH neurons. This study provides new insights into HA mechanisms, setting the stage for future research on heat stress reduction and exercise optimization.

neuroscience↗

bioRxiv2024

Computer prediction and genetic analysis identifies retinoic acid modulation as a driver of conserved longevity pathways in genetically-diverse Caenorhabditis nematodes

Aging is a pan-metazoan process with significant consequences for human health and society--discovery of new compounds that ameliorate the negative health impacts of aging promise to be of tremendous benefit across a number of age-based comorbidities. One method to prioritize a testable subset of the nearly infinite universe of potential compounds is to use computational prediction of their likely anti-aging capacity. Here we present a survey of longevity effects for 16 compounds suggested by a previously published computational prediction set, capitalizing upon the comprehensive, multi-species approach utilized by the Caenorhabditis Intervention Testing Program (CITP). While eleven compounds (aldosterone, arecoline, bortezomib, dasatinib, decitabine, dexamethasone, erlotinib, everolimus, gefitinib, temsirolimus, and thalidomide) either had no effect on median lifespan or were toxic, five compounds (all-trans retinoic acid, berberine, fisetin, propranolol, and ritonavir) extended lifespan in Caenorhabditis elegans. These computer predictions yield a remarkable positive hit rate of 30%. Deeper genetic characterization of the longevity effects of one of the most efficacious compounds, the endogenous signaling ligand all-trans retinoic acid (atRA, designated tretinoin in medical products), which is widely prescribed for treatment of acne, skin photoaging and acute promyelocytic leukemia, demonstrated a requirement for the regulatory kinases AKT-1 and AKT-2. While the canonical Akt-target FOXO/DAF-16 was largely dispensable, other conserved Akt-targets (Nrf2/SKN-1 and HSF1/HSF-1), as well as the conserved catalytic subunit of AMPK AAK-2, were all necessary for longevity extension by atRA. Evolutionary conservation of retinoic acid as a signaling ligand and the structure of the downstream effector network of retinoic acid combine to suggest that the all-trans retinoic acid pathway is an ancient metabolic regulatory system that can modulate lifespan. Our results highlight the potential of combining computational prediction of longevity interventions with the power of nematode functional genetics and underscore that the manipulation of a conserved metabolic regulatory circuit by co-opting endogenous signaling molecules is a powerful approach for discovering aging interventions.

genetics↗

bioRxiv2024

Cryo-EM structural insights into Vγ9Vδ2 TCR activation via multiple butyrophilins

Human V{gamma}9V{delta}2 T cells detect cancerous and pathogen-infected cells through an "inside-out" mechanism wherein intracellular domains of butyrophilin (BTN) proteins recognize phosphoantigens (pAgs) to prime BTN ectodomains to engage with the T cell receptor (TCR) to activate V{gamma}9V{delta}2 T cells. Here, we present cryo-electron microscopy (cryo-EM) structures, including the full-length BTN3A1-BTN3A2-BTN2A1 complex stabilized by the pAg HMBPP and an HMBPP-primed BTN multimer complex engaged with the V{gamma}9V{delta}2 TCR. The HMBPP-primed BTN3A1-BTN3A2-BTN2A1 complex confirms that this pAg bridges the intracellular B30.2 domains of BTN3A1 and BTN2A1, while also revealing an association of the ectodomains of BTN3A2 and BTN2A1. Upon TCR engagement, the TCR undergoes a substantial conformational change and BTN3A2-BTN2A1 ectodomain interaction dissociates, allowing BTN2A1 to bind to the lateral surface of the V{gamma}9 chain, while BTN3A2 binds to the apical surface of the V{delta}2 chain. Beyond demonstrating that BTN3A2 as a bona fide TCR ligand, this dissociation/binding sequence suggests a "pliers-like gripping" mechanism for TCR activation. We also obtained cryo-EM structures of BTN proteins in complex with functional antibodies, further elucidating the overall V{gamma}9V{delta}2 T cell activation process. Thus, our structural insights into how BTN proteins sense antigens and drive TCR activation lay the groundwork for developing targeted {gamma}{delta} T cell immunotherapies.

immunology↗

bioRxiv2024

S-RNase Evolution in Self-Incompatibility: Phylogenomic Insights into Synteny with S-Like Genes

S-RNases are essential in the gametophytic self-incompatibility (GSI) system of many flowering plants, where they act as stylar-S determinants. Despite their significance, the syntenic genomic origin and evolutionary trajectory of S-RNase genes in eudicots have remained largely unclear. Here, we performed large-scale phylogenetic and microsynteny network analyses of RNase T2 genes across 130 angiosperm genomes, encompassing 35 orders and 56 families. Based on the connections observed in the synteny network, particularly the persisting synteny block in none-SI Cucurbitaceae species, we infer that well-characterized S-RNase genes (Class III-A RNase genes) were duplicated and evolved from Class I S-like RNase genes, possibly as a result of the gamma triplication event shared by core eudicots. Additionally, we identified frequent lineage-specific gene transpositions of S-RNase genes across diverse angiosperm lineages, including Rosaceae, Solanaceae, and Rutaceae families, accompanied by a significant increase in transposable element (TE) activity near these genes. Our findings delineate the precise genomic origin and evolutionary path of eudicot S-RNase genes, enhancing our understanding of the evolution of the S-RNase-based GSI system.

evolutionary biology↗

bioRxiv2024

Semantic Influences on Object Detection: Drift Diffusion Modeling Provides Insights Regarding Mechanism

AbstractResearch shows that semantics, activated by words, impacts object detection. Skocypec & Peterson (2022) indexed object detection via correct reports of where figures lie in bipartite displays depicting familiar objects on one side of a border. They reported 2 studies with intermixed Valid and Invalid labels shown before test displays and a third, control, study. Valid labels denoted display objects. Invalid labels denoted unrelated objects in a different or the same superordinate-level category in studies 1 & 2, respectively. We used drift diffusion modeling (DDM) to elucidate the mechanisms of their results. DDM revealed that, following Valid labels, drift rate toward the correct decision increased, i.e., SNR increased. Following Invalid labels, SNR was lower only for upright displays in study 2. Thresholds were higher in studies 1 & 2 than in control. That more evidence must be accumulated from displays that follow labels implies that familiar object detection entails semantic activation. Threshold was even higher following Invalid labels in study 2, suggesting that more evidence from the display is needed to resolve within- category conflicts. These results support the view that semantic networks are engaged in object detection.

neuroscience↗

bioRxiv2024

Multiomics analyses decipher intricate changes in the cellular and metabolic landscape of steatotic livers upon dietary restriction and sleeve gastrectomy

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic, progressive liver disease that encompasses a spectrum of steatosis, steatohepatitis (or MASH), and fibrosis. Evidence suggests that dietary restriction (DR) and sleeve gastrectomy (SG) can lead to remission of hepatic steatosis and inflammation through weight loss, but it is unclear whether these procedures induce distinct metabolic or immunological changes in MASLD livers. This study aims to elucidate the intricate hepatic changes following DR, SG or sham surgery in rats fed a high-fat diet as a model of obesity-related MASLD, in comparison to a clinical cohort of patients undergoing SG. Single-cell and single-nuclei transcriptome analysis, spatial metabolomics, and immunohistochemistry revealed the liver landscape, while circulating biomarkers were measured in serum samples. Artificial intelligence (AI)-assisted image analysis characterized the spatial distribution of hepatocytes, myeloid cells and lymphocytes. In patients and experimental MASLD rats, SG improved BMI, circulating liver injury biomarkers and triglyceride levels. Both DR and SG attenuated liver steatosis and fibrosis in rats. Metabolism-related genes (Ppara, Cyp2e1 and Cyp7a1) were upregulated in hepatocytes upon DR and SG, while SG broadly upregulated lipid metabolism on cholangiocytes, monocytes, macrophages, and neutrophils. Furthermore, SG promoted myeloid cell accumulation in the liver not only ameliorating inflammation but activating liver repair processes. Regions with potent myeloid infiltration were marked with enhanced metabolic capacities upon SG. Additionally, a disruption of periportal hepatocyte functions was observed upon DR. In conclusion, this study indicates a dynamic cellular crosstalk in steatotic livers undergoing SG. Notably, PPAR- and gut-liver axis-related processes, and metabolically-active myeloid cell infiltration indicate intervention-related mechanisms supporting SG for the treatment of MASLD.

bioinformatics↗

bioRxiv2024

Mechanical cues of extracellular matrix determines tumor innervation

Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, {beta}1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin {beta}1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin {beta}1/YAP1-dependent mechanotransduction may counteract TIN.

neuroscience↗

bioRxiv2024

Spatiotemporal Mapping and Molecular Basis of Whole-brain Circuit Maturation

Brain development is highly dynamic and asynchronous, marked by the sequential maturation of functional circuits across the brain. The timing and mechanisms driving circuit maturation remain elusive due to an inability to identify and map maturing neuronal populations. Here we create DevATLAS (Developmental Activation Timing-based Longitudinal Acquisition System) to overcome this obstacle. We develop whole-brain mapping methods to construct the first longitudinal, spatiotemporal map of circuit maturation in early postnatal mouse brains. Moreover, we uncover dramatic impairments within the deep cortical layers in a neurodevelopmental disorders (NDDs) model, demonstrating the utility of this resource to pinpoint when and where circuit maturation is disrupted. Using DevATLAS, we reveal that early experiences accelerate the development of hippocampus-dependent learning by increasing the synaptically mature granule cell population in the dentate gyrus. Finally, DevATLAS enables the discovery of molecular mechanisms driving activity-dependent circuit maturation.

neuroscience↗

bioRxiv2023

NASTRA: Innovative Short Tandem Repeat Analysis through Cluster-Based Structure-Aware Algorithm in Nanopore Sequencing Data

Forensic short-tandem repeats (STR) genetic markers are multi-allelic and widely utilized for individual identification, kinship testing, and cell-line authentication. Nanopore sequencing, known for its portability, is emerging as a promising approach for STR typing, facilitating real-time and in-field testing. However, its efficacy is often hampered by sequencing noise. Previous methods rely on alignment-based genotyping, necessitating known alleles, which limits their applicability to unknown alleles. Here, we introduced NASTRA, an innovative allele reference-free tool for precise germline analysis of STR genetic markers. NASTRA incorporates a recursive algorithm to infer repeat structures of allele sequences using only known repeat motifs. Our tests, conducted on 80 individual samples and 8 DNA standards, have demonstrated NASTRAs exceptional 100% accuracy in genotyping nearly all diploid STRs across various multiplex kits and flow cells. It surpasses alignment-based methods in accuracy and speed. In a paternity testing case study, NASTRA accurately identified three relationships among six individuals within an 18-minute sequencing duration. These results underscore NASTRAs ability to perform STR analysis on both NGS and nanopore sequencing platforms, significantly enhancing the utility of nanopore sequencing in relevant applications. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/565630v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@296e89org.highwire.dtl.DTLVardef@180b6forg.highwire.dtl.DTLVardef@96bf21org.highwire.dtl.DTLVardef@de1b1d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Dynamin 1xA interacts with Endophilin A1 via its spliced long C-terminus for ultrafast endocytosis

Dynamin 1 (Dyn1) has two major splice variants, xA and xB, with unique C-terminal extensions of 20 and 7 amino acids, respectively. Of these, only Dyn1xA is enriched at endocytic zones and accelerates vesicle fission during ultrafast endocytosis. Here, we report that the long tail variant, Dyn1xA, achieves this localization by preferentially binding to Endophilin A through a newly defined Class II binding site overlapping with its extension, at a site spanning the splice boundary. Endophilin binds this site at higher affinity than the previously reported site, and this affinity is determined by amino acids outside the binding sites acting as long distance elements within the xA tail. Their interaction is regulated by the phosphorylation state of two serine residues specific to the xA variant. Dyn1xA and Endophilin colocalize in patches near the active zone of synapses. Mutations selectively disrupting Endophilin binding to the long extension cause Dyn1xA mislocalization along axons. In these mutants, endocytic pits are stalled on the plasma membrane during ultrafast endocytosis. These data suggest that the specificity for ultrafast endocytosis is defined by the phospho-regulated interaction of Endophilin A through a newly identified site of Dyn1xAs long tail.

cell biology↗

bioRxiv2023

Multilevel regulation of NF-kappa B signaling by NSD2 suppresses Kras-driven pancreatic tumorigenesis

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase which has been reported to play a crucial role in promoting tumorigenesis. Here, we demonstrate that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. Low level of NSD2 indicates aggressive feature of PDAC. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of I{kappa}B, which inhibits the phosphorylation of p65 and NF-{kappa}B nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-{kappa}B transcriptional activity. Furthermore, inhibition of NF-{kappa}B signaling relieves the symptoms of Nsd2-deficient mice. Together, our study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study contributes to understanding the pathogenesis of pancreatic tumorigenesis and identifies a novel negative regulator of NF-{kappa}B signaling.

cancer biology↗

bioRxiv2023

T2T-YAO: a Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese

Since its initial release in 2001, the human reference genome has been continuously improved in both continuity and accuracy, and the recently-released telomere-to-telomere version--T2T-CHM13--reaches its top quality after 20 years of effort. However, T2T-CHM13 does not represent an authentic diploid human genome, but rather one derived from a simplified, nearly homozygous genome of a hydatidiform mole cell line. To address this limitation and provide an alternative pertinent to the Chinese population, the largest ethnic group in the world, we have assembled a complete diploid human genome of a male Han Chinese, T2T-YAO, which includes telomere-to-telomere assemblies for all the 22+X+M and 22+Y chromosomes in his two haploids inherited separately from his parents. Both haplotypes contain no artificial sequences or model nucleotides and possess a high quality comparable to CHM13, with fewer than one error per [~]14 Mb. Derived from the individual who lives in the aboriginal region of Han Chinese, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors of the Han population. Each haplotype of T2T-YAO possesses [~]340 Mb exclusive sequences and [~]3100 unique genes as compared to CHM13, and their genome sequences show greater genetic distance to CHM13 than to each other in terms of nucleotide polymorphism and structural variations. The construction of T2T-YAO would serve as a high-quality diploid reference that enables precise delineation of genomic variations in a haplotype-sensitive manner, which could advance our understandings in human evolution, hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

genetics↗

bioRxiv2023

Single-cell landscape reveals NAMPT mediated macrophage polarization that regulate smooth muscle cell phenotypic switch in pulmonary arterial hypertension

RationalePulmonary arterial hypertension (PAH) is a progressive and lethal disease that leads to elevated pulmonary vascular resistance and right ventricular failure. The phenotypic switching of pulmonary arterial smooth muscle cells (SMCs) plays a crucial role in the pathological progression of PAH. However, the underlying mechanism of SMC phenotypic modulation remains unclear. ObjectivesWe aim to provide a comprehensive understanding of SMC phenotypes and regulatory networks by analyzing hypertensive and non-diseased pulmonary arteries. MethodsWe performed single-cell RNA sequencing (scRNA-seq) on pulmonary arteries obtained from patients with PAH and healthy donors. This was followed by bioinformatics analyses, mouse models, and in vitro studies to construct a normal pulmonary artery atlas, characterize SMC phenotypes, investigate intercellular communication, and explore the molecular mechanisms underlying SMC phenotypic switching. Measurements and Main ResultsOur scRNA-seq analysis identified specific activation of vascular cells, including myofibrocytes, macrophage M2 polarization, endothelial-mesenchymal transition, and chondroid-like SMCs in healthy pulmonary arteries. In PAH pathology, there was an enhanced phenotypic switch of SMCs from contractile to fibroblast-like. Intercellular communication revealed increased M1 macrophage-SMC crosstalk in PAH, which was facilitated by NAMPT. Using a cellular co-culture system, we found that NAMPT-mediated M1 macrophage polarization induced fibroblast-like phenotypic switching in SMCs via the CCR2/CCR5 axis. ConclusionsOur findings provide a comprehensive cell atlas of healthy human pulmonary arteries and demonstrate that NAMPT-driven M1 macrophage polarization plays a critical role in the fibroblast-like phenotypic switching of SMCs through CCR2/CCR5 cellular crosstalk in PAH.

molecular biology↗

bioRxiv2023

Mammalian PIWI-piRNA-target complexes reveal features for broad and efficient target-silencing

The PIWI-interacting RNA (piRNA) pathway is an adaptive defense system wherein piRNAs guide PIWI-family Argonaute proteins to recognize and silence ever-evolving selfish genetic elements and ensure genome integrity. Driven by this intensive host-pathogen arms race, piRNA pathway and its targeted transposons have co-evolved rapidly in a species-specific manner, but how the piRNA pathway specifically adapts to target silencing in mammals remains elusive. Here, we show that mouse MILI and human HILI piRISCs bind and cleave targets more efficiently than their invertebrate counterpart from sponge Ephydatia fluviatilis. The inherent functional differences comport with structural features identified by cryo-EM studies of piRISCs. In the absence of target, MILI and HILI piRISCs adopt a wider nucleic-acid-binding channel and display an extended prearranged piRNA seed as compared to EfPiwi piRISC, consistent with their ability to capture targets more efficiently than EfPiwi piRISC. In the presence of target, the seed gate--which enforces seed-target fidelity in microRNA RISC--adopts a relaxed state in mammalian piRISC, revealing how MILI and HILI tolerate seed-target mismatches to broaden the target spectrum. A vertebrate-specific lysine distorts the piRNA seed, shifting the trajectory of the piRNA-target duplex out of the central cleft and toward the PAZ lobe. Functional analyses reveal that this lysine promotes target binding and cleavage. Our study therefore provides a molecular basis for the piRNA targeting mechanism in mouse and human, and suggests that mammalian piRNA machinery can achieve broad target silencing using a limited supply of piRNA species.

molecular biology↗

bioRxiv2023

A cingulate-hippocampal circuit mediates early depressive symptoms in Alzheimer's disease

AbstractDepressive symptoms are prevalent and precedes cognitive decline in Alzheimers disease (AD), which worsen the clinical outcome and severely challenge the life quality of the patients. However, the neural circuitry mediating mood disturbance in AD remains elusive. Here we report that the glutamatergic projection from the anterior cingulate cortex (ACC) to the ventral hippocampal CA1 (vCA1) acts as the neural substrate of depressive symptoms in AD. We systemically mapped axonal projection in early stage of 5xFAD mice (3 months), which accompanies depressive- like behavior in these animals and identified reduced axonal projection from ACC to vCA1. This is in accordance with reduced axonal calcium signals detected with in vivo fiber photometry. Chemogenetic or optogenetic reversal of ACC-vCA1 circuitry activity efficiently ameliorated the depressive-like behaviors as well as cognitive impairment in 5xFAD mice. We further identified the synaptic molecules neuregulin-1 (Nrg1) as one vital signal regulating the synaptic glutamate transmission from the ACC to the vCA1. Collectively, these results indicated ACC-vCA1 as a critical pathway that regulates emotional states in Alzheimer disease. Targeting cingulate cortices with brain stimulation may treat depression in AD.

neuroscience↗

bioRxiv2023

Autophagy collaborates with apoptosis pathways to control myelination specificity and function

Oligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevates PUMA mRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number. HIGHLIGHTSO_LIAutophagy flux increases in the premyelinating and myelinating oligodendrocytes C_LIO_LIAutophagy promotes premyelinating oligodendrocyte (pre-OL) apoptosis to control myelination location and timing C_LIO_LIAutophagy acts in the TFEB-PUMA-Bax/Bak pathway and elevates PUMA mRNA levels to determine pre-OL fate C_LIO_LIAutophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath thickness and finetune nerve pulse propagation C_LI

neuroscience↗

bioRxiv2022

68Ga-Bisphosphonates for the Imaging of Extraosseous Calcification by Positron Emission Tomography

Radiolabelled bisphosphonates (BPs) and [18F]NaF (18F-fluoride) are the two types of radiotracers available to image calcium mineral in vivo (e.g. bone), yet only [18F]NaF has been widely explored for the non-invasive molecular imaging of extraosseous calcification (EC) using the highly sensitive nuclear imaging technique positron emission tomography (PET). These two radiotracers bind calcium mineral deposits via different mechanisms, with BPs chelating to calcium ions and thus being non-selective, and [18F]NaF being selective for hydroxyapatite (HAp) which is the main component of bone mineral. Taking into account that the composition of EC has been reported to include a diverse range of non-HAp calcium minerals, we hypothesised that BPs may be more sensitive for imaging EC due to their ability to bind to both HAp and non-HAp deposits. To test this hypothesis, we report a comparison between the 68Ga-labelled BP tracer [68Ga]Ga-THP-Pam and [18F]NaF for PET imaging in a rat model of EC that develops macro- and microcalcifications in several organs. The presence of macrocalcifications was identified using preclinical computed tomography (CT) and microcalcifications were identified using CT-based 3D X-ray histology (XRH) on isolated organs ex vivo. The morphological and mineral analysis of individual calcified deposits was performed using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The PET imaging and ex vivo analysis results demonstrated that while both radiotracers behave similarly for bone imaging, the BP-based radiotracer [68Ga]Ga-THP-Pam was able to detect EC more sensitively in several organs in which the mineral composition departs from that of HAp. We conclude that BP-based PET radiotracers such as [68Ga]Ga-THP-Pam have a particular advantage for the sensitive imaging and early detection of EC by being able to detect a wider array of relevant calcium minerals in vivo than [18F]NaF, and should be evaluated clinically for this purpose.

pharmacology and toxicology↗