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1.
Cell ; 180(6): 1144-1159.e20, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32169217

RESUMO

In eukaryotic cells, organelle biogenesis is pivotal for cellular function and cell survival. Chloroplasts are unique organelles with a complex internal membrane network. The mechanisms of the migration of imported nuclear-encoded chloroplast proteins across the crowded stroma to thylakoid membranes are less understood. Here, we identified two Arabidopsis ankyrin-repeat proteins, STT1 and STT2, that specifically mediate sorting of chloroplast twin arginine translocation (cpTat) pathway proteins to thylakoid membranes. STT1 and STT2 form a unique hetero-dimer through interaction of their C-terminal ankyrin domains. Binding of cpTat substrate by N-terminal intrinsically disordered regions of STT complex induces liquid-liquid phase separation. The multivalent nature of STT oligomer is critical for phase separation. STT-Hcf106 interactions reverse phase separation and facilitate cargo targeting and translocation across thylakoid membranes. Thus, the formation of phase-separated droplets emerges as a novel mechanism of intra-chloroplast cargo sorting. Our findings highlight a conserved mechanism of phase separation in regulating organelle biogenesis.


Assuntos
Arabidopsis/metabolismo , Transporte Proteico/fisiologia , Sistema de Translocação de Argininas Geminadas/metabolismo , Proteínas de Cloroplastos/metabolismo , Cloroplastos/metabolismo , Membranas Intracelulares/metabolismo , Proteínas de Membrana/metabolismo , Biogênese de Organelas , Organelas/metabolismo , Transição de Fase , Proteínas de Plantas/metabolismo , Tilacoides/metabolismo , Sistema de Translocação de Argininas Geminadas/fisiologia
2.
Cell ; 182(3): 563-577.e20, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32615086

RESUMO

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.


Assuntos
Adipogenia/genética , Tecido Adiposo Bege/metabolismo , Metabolismo Energético/genética , Quinase 1 de Adesão Focal/metabolismo , Transdução de Sinais/genética , Células-Tronco/metabolismo , Tetraspanina 28/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/crescimento & desenvolvimento , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Ataxina-1/metabolismo , Feminino , Fibronectinas/farmacologia , Quinase 1 de Adesão Focal/genética , Humanos , Inflamação/genética , Inflamação/metabolismo , Resistência à Insulina/genética , Integrinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , RNA-Seq , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Células-Tronco/citologia , Tetraspanina 28/genética
3.
Immunity ; 57(1): 106-123.e7, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38159573

RESUMO

When the filtrate of the glomerulus flows through the renal tubular system, various microscopic sediment particles, including mineral crystals, are generated. Dislodging these particles is critical to ensuring the free flow of filtrate, whereas failure to remove them will result in kidney stone formation and obstruction. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we found that the juxtatubular macrophages in the renal medulla constitutively formed transepithelial protrusions and "sampled" urine contents. They efficiently sequestered and phagocytosed intraluminal sediment particles and occasionally transmigrated to the tubule lumen to escort the excretion of urine particles. Mice with decreased renal macrophage numbers were prone to developing various intratubular sediments, including kidney stones. Mechanistically, the transepithelial behaviors of medulla macrophages required integrin ß1-mediated ligation to the tubular epithelium. These findings indicate that medulla macrophages sample urine content and remove intratubular particles to keep the tubular system unobstructed.


Assuntos
Cálculos Renais , Rim , Camundongos , Animais , Macrófagos
4.
Nature ; 609(7925): 151-158, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35978186

RESUMO

Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3-8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.


Assuntos
Tecido Adiposo Bege , Proteínas de Ligação a DNA , Fatores de Transcrição , Animais , Camundongos , Adipócitos Bege/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Proteínas Culina , Proteínas de Ligação a DNA/metabolismo , Dislipidemias , Intolerância à Glucose , Resistência à Insulina , Obesidade , Estabilidade Proteica , Termogênese/fisiologia , Fatores de Transcrição/metabolismo , Ubiquitinação
5.
Nature ; 609(7929): 925-930, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36171386

RESUMO

The paradigmatic example of a topological phase of matter, the two-dimensional Chern insulator1-5, is characterized by a topological invariant consisting of a single integer, the scalar Chern number. Extending the Chern insulator phase from two to three dimensions requires generalization of the Chern number to a three-vector6,7, similar to the three-dimensional (3D) quantum Hall effect8-13. Such Chern vectors for 3D Chern insulators have never been explored experimentally. Here we use magnetically tunable 3D photonic crystals to achieve the experimental demonstration of Chern vectors and their topological surface states. We demonstrate Chern vector magnitudes of up to six, higher than all scalar Chern numbers previously realized in topological materials. The isofrequency contours formed by the topological surface states in the surface Brillouin zone form torus knots or links, whose characteristic integers are determined by the Chern vectors. We demonstrate a sample with surface states forming a (2, 2) torus link or Hopf link in the surface Brillouin zone, which is topologically distinct from the surface states of other 3D topological phases. These results establish the Chern vector as an intrinsic bulk topological invariant in 3D topological materials, with surface states possessing unique topological characteristics.

6.
Nature ; 609(7927): 479-484, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36104555

RESUMO

Studying strong electron correlations has been an essential driving force for pushing the frontiers of condensed matter physics. In particular, in the vicinity of correlation-driven quantum phase transitions (QPTs), quantum critical fluctuations of multiple degrees of freedom facilitate exotic many-body states and quantum critical behaviours beyond Landau's framework1. Recently, moiré heterostructures of van der Waals materials have been demonstrated as highly tunable quantum platforms for exploring fascinating, strongly correlated quantum physics2-22. Here we report the observation of tunable quantum criticalities in an experimental simulator of the extended Hubbard model with spin-valley isospins arising in chiral-stacked twisted double bilayer graphene (cTDBG). Scaling analysis shows a quantum two-stage criticality manifesting two distinct quantum critical points as the generalized Wigner crystal transits to a Fermi liquid by varying the displacement field, suggesting the emergence of a critical intermediate phase. The quantum two-stage criticality evolves into a quantum pseudo criticality as a high parallel magnetic field is applied. In such a pseudo criticality, we find that the quantum critical scaling is only valid above a critical temperature, indicating a weak first-order QPT therein. Our results demonstrate a highly tunable solid-state simulator with intricate interplay of multiple degrees of freedom for exploring exotic quantum critical states and behaviours.

7.
Mol Cell ; 80(3): 525-540.e9, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33068521

RESUMO

Well-balanced and timed metabolism is essential for making a high-quality egg. However, the metabolic framework that supports oocyte development remains poorly understood. Here, we obtained the temporal metabolome profiles of mouse oocytes during in vivo maturation by isolating large number of cells at key stages. In parallel, quantitative proteomic analyses were conducted to bolster the metabolomic data, synergistically depicting the global metabolic patterns in oocytes. In particular, we discovered the metabolic features during meiotic maturation, such as the fall in polyunsaturated fatty acids (PUFAs) level and the active serine-glycine-one-carbon (SGOC) pathway. Using functional approaches, we further identified the key targets mediating the action of PUFA arachidonic acid (ARA) on meiotic maturation and demonstrated the control of epigenetic marks in maturing oocytes by SGOC network. Our data serve as a broad resource on the dynamics occurring in metabolome and proteome during oocyte maturation.


Assuntos
Meiose/fisiologia , Oócitos/metabolismo , Animais , Epigênese Genética/genética , Ácidos Graxos Insaturados/metabolismo , Feminino , Metaboloma/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Oogênese/genética , Oogênese/fisiologia , Proteoma/metabolismo , Proteômica
8.
Development ; 150(22)2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37882745

RESUMO

Primitive erythropoiesis serves a vital role in embryonic development, generating primitive red blood cells responsible for transportation of oxygen throughout the body. Although diverse niche factors are known to function in definitive hematopoiesis, the microenvironment contributing to primitive hematopoiesis remains largely elusive. Here, we report that platelet-derived growth factor (PDGF) signaling is required for erythroid progenitor differentiation in zebrafish. Ablating pdgfαa (also known as pdgfaa) and pdgfαb (also known as pdgfab) or blocking PDGF signaling with an inhibitor impairs erythroid progenitor differentiation, thus resulting in a significant decrease in the number of erythrocytes. We reveal that pdgfαb is expressed in sclerotomal cells, and that its receptor genes, pdgfra and pdgfrb, are expressed in the adjacent erythroid progenitor cells. Sclerotome-specific overexpression of pdgfαb effectively restores primitive erythropoiesis in pdgfαa-/-;pdgfαb-/- mutant embryos. In addition, we have defined ERK1/2 signaling as a downstream pathway of PDGF signaling during embryonic erythropoiesis. Taken together, our findings indicate that PDGF signaling derived from sclerotome functions as a niche cue for primitive erythropoiesis.


Assuntos
Eritropoese , Fator de Crescimento Derivado de Plaquetas , Animais , Eritropoese/genética , Peixe-Zebra , Sinais (Psicologia) , Diferenciação Celular/genética , Desenvolvimento Embrionário
9.
PLoS Genet ; 19(11): e1011052, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37976306

RESUMO

Rapid and uniform seed germination is required for modern cropping system. Thus, it is important to optimize germination performance through breeding strategies in maize, in which identification for key regulators is needed. Here, we characterized an AP2/ERF transcription factor, ZmEREB92, as a negative regulator of seed germination in maize. Enhanced germination in ereb92 mutants is contributed by elevated ethylene signaling and starch degradation. Consistently, an ethylene signaling gene ZmEIL7 and an α-amylase gene ZmAMYa2 are identified as direct targets repressed by ZmEREB92. OsERF74, the rice ortholog of ZmEREB92, shows conserved function in negatively regulating seed germination in rice. Importantly, this orthologous gene pair is likely experienced convergently selection during maize and rice domestication. Besides, mutation of ZmEREB92 and OsERF74 both lead to enhanced germination under cold condition, suggesting their regulation on seed germination might be coupled with temperature sensitivity. Collectively, our findings uncovered the ZmEREB92-mediated regulatory mechanism of seed germination in maize and provide breeding targets for maize and rice to optimize seed germination performance towards changing climates.


Assuntos
Germinação , Oryza , Germinação/genética , Amido/genética , Amido/metabolismo , Zea mays/metabolismo , Sementes/genética , Sementes/metabolismo , Melhoramento Vegetal , Etilenos/metabolismo , Regulação da Expressão Gênica de Plantas , Oryza/metabolismo
10.
Mol Biol Evol ; 41(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38768215

RESUMO

High mountains harbor a considerable proportion of biodiversity, but we know little about how diverse plants adapt to the harsh environment. Here we finished a high-quality genome assembly for Dasiphora fruticosa, an ecologically important plant distributed in the Qinghai-Tibetan Plateau and lowland of the Northern Hemisphere, and resequenced 592 natural individuals to address how this horticulture plant adapts to highland. Demographic analysis revealed D. fruticosa underwent a bottleneck after Naynayxungla Glaciation. Selective sweep analysis of two pairs of lowland and highland populations identified 63 shared genes related to cell wall organization or biogenesis, cellular component organization, and dwarfism, suggesting parallel adaptation to highland habitats. Most importantly, we found that stronger purging of estimated genetic load due to inbreeding in highland populations apparently contributed to their adaptation to the highest mountain. Our results revealed how plants could tolerate the extreme plateau, which could provide potential insights for species conservation and crop breeding.


Assuntos
Genoma de Planta , Seleção Genética , Adaptação Fisiológica/genética , Altitude
11.
Hum Mol Genet ; 32(5): 764-772, 2023 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-36130215

RESUMO

Hereditary hearing loss is a highly genetically heterogeneous disorder. More than 150 genes have been identified to link to human non-syndromic hearing impairment. To identify genetic mutations and underlying molecular mechanisms in affected individuals and families with congenital hearing loss, we recruited a cohort of 389 affected individuals in 354 families for whole-exome sequencing analysis. In this study, we report a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in the OXR1 gene, which was identified in a 4-year-old girl with sensorineural hearing loss. OXR1 encodes Oxidation Resistance 1 and is evolutionarily conserved from zebrafish to human. We found that the ortholog oxr1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL) in zebrafish. Knockdown of oxr1b in zebrafish resulted in a significant developmental defect of SAG and pLL. This phenotype can be rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs. OXR1-associated pathway analysis revealed that mutations of TBC1D24, a TLDc-domain-containing homolog gene of OXR1, have previously been identified in patients with hearing loss. Interestingly, mutations or knockout of OXR1 interacting molecules such as ATP6V1B1 and ESR1 are also associated with hearing loss in patients or animal models, hinting an important role of OXR1 and associated partners in cochlear development and hearing function.


Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , ATPases Vacuolares Próton-Translocadoras , Animais , Feminino , Humanos , Pré-Escolar , Peixe-Zebra/genética , Perda Auditiva/genética , Surdez/genética , Perda Auditiva Neurossensorial/genética , Mutação , Linhagem , Proteínas Mitocondriais/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas Ativadoras de GTPase/genética
12.
EMBO J ; 40(13): e106742, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33855718

RESUMO

Fe-S clusters are ancient, ubiquitous and highly essential prosthetic groups for numerous fundamental processes of life. The biogenesis of Fe-S clusters is a multistep process including iron acquisition, sulfur mobilization, and cluster formation. Extensive studies have provided deep insights into the mechanism of the latter two assembly steps. However, the mechanism of iron utilization during chloroplast Fe-S cluster biogenesis is still unknown. Here we identified two Arabidopsis DnaJ proteins, DJA6 and DJA5, that can bind iron through their conserved cysteine residues and facilitate iron incorporation into Fe-S clusters by interactions with the SUF (sulfur utilization factor) apparatus through their J domain. Loss of these two proteins causes severe defects in the accumulation of chloroplast Fe-S proteins, a dysfunction of photosynthesis, and a significant intracellular iron overload. Evolutionary analyses revealed that DJA6 and DJA5 are highly conserved in photosynthetic organisms ranging from cyanobacteria to higher plants and share a strong evolutionary relationship with SUFE1, SUFC, and SUFD throughout the green lineage. Thus, our work uncovers a conserved mechanism of iron utilization for chloroplast Fe-S cluster biogenesis.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cloroplastos/metabolismo , Proteínas Ferro-Enxofre/metabolismo , Ferro/metabolismo , Enxofre/metabolismo , Fotossíntese/fisiologia
13.
Development ; 149(23)2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36468454

RESUMO

Developmentally, the great vessels of the heart originate from the pharyngeal arch arteries (PAAs). During PAA vasculogenesis, PAA precursors undergo sequential cell fate decisions that are accompanied by proliferative expansion. However, how these two processes are synchronized remains poorly understood. Here, we find that the zebrafish chemokine receptor Cxcr4a is expressed in PAA precursors, and genetic ablation of either cxcr4a or the ligand gene cxcl12b causes PAA stenosis. Cxcr4a is required for the activation of the downstream PI3K/AKT cascade, which promotes not only PAA angioblast proliferation, but also differentiation. AKT has a well-known role in accelerating cell-cycle progression through the activation of cyclin-dependent kinases. Despite this, we demonstrate that AKT phosphorylates Etv2 and Scl, the key regulators of angioblast commitment, on conserved serine residues, thereby protecting them from ubiquitin-mediated proteasomal degradation. Altogether, our study reveals a central role for chemokine signaling in PAA vasculogenesis through orchestrating angioblast proliferation and differentiation.


Assuntos
Região Branquial , Peixe-Zebra , Animais , Peixe-Zebra/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Artérias , Quimiocinas , Divisão Celular
14.
Development ; 149(11)2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35666088

RESUMO

The evolutionarily conserved C-terminal binding protein (CtBP) has been well characterized as a transcriptional co-repressor. Herein, we report a previously unreported function for CtBP, showing that lowering CtBP dosage genetically suppresses Polycomb group (PcG) loss-of-function phenotypes while enhancing that of trithorax group (trxG) in Drosophila, suggesting that the role of CtBP in gene activation is more pronounced in fly development than previously thought. In fly cells, we show that CtBP is required for the derepression of the most direct PcG target genes, which are highly enriched by homeobox transcription factors, including Hox genes. Using ChIP and co-IP assays, we demonstrate that CtBP is directly required for the molecular switch between H3K27me3 and H3K27ac in the derepressed Hox loci. In addition, CtBP physically interacts with many proteins, such as UTX, CBP, Fs(1)h and RNA Pol II, that have activation roles, potentially assisting in their recruitment to promoters and Polycomb response elements that control Hox gene expression. Therefore, we reveal a prominent activation function for CtBP that confers a major role for the epigenetic program of fly segmentation and development.


Assuntos
Proteínas de Drosophila , Genes Homeobox , Oxirredutases do Álcool , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Ligação Proteica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/genética
15.
Bioinformatics ; 40(1)2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38058211

RESUMO

MOTIVATION: Pediatric kidney disease is a widespread, progressive condition that severely impacts growth and development of children. Chronic kidney disease is often more insidious in children than in adults, usually requiring a renal biopsy for diagnosis. Biopsy evaluation requires copious examination by trained pathologists, which can be tedious and prone to human error. In this study, we propose an artificial intelligence (AI) method to assist pathologists in accurate segmentation and classification of pediatric kidney structures, named as AI-based Pediatric Kidney Diagnosis (APKD). RESULTS: We collected 2935 pediatric patients diagnosed with kidney disease for the development of APKD. The dataset comprised 93 932 histological structures annotated manually by three skilled nephropathologists. APKD scored an average accuracy of 94% for each kidney structure category, including 99% in the glomerulus. We found strong correlation between the model and manual detection in detected glomeruli (Spearman correlation coefficient r = 0.98, P < .001; intraclass correlation coefficient ICC = 0.98, 95% CI = 0.96-0.98). Compared to manual detection, APKD was approximately 5.5 times faster in segmenting glomeruli. Finally, we show how the pathological features extracted by APKD can identify focal abnormalities of the glomerular capillary wall to aid in the early diagnosis of pediatric kidney disease. AVAILABILITY AND IMPLEMENTATION: https://github.com/ChunyueFeng/Kidney-DataSet.


Assuntos
Inteligência Artificial , Insuficiência Renal Crônica , Adulto , Humanos , Criança , Rim/diagnóstico por imagem , Rim/patologia , Insuficiência Renal Crônica/patologia
16.
Arterioscler Thromb Vasc Biol ; 44(3): 698-719, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38205641

RESUMO

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHß antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3ß (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3ß/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Neoplasias da Próstata , Animais , Masculino , Camundongos , Antagonistas de Androgênios/efeitos adversos , Androgênios/deficiência , Aterosclerose/patologia , Endotélio/metabolismo , Hormônio Foliculoestimulante/genética , Hormônio Foliculoestimulante/metabolismo , Glicogênio Sintase Quinase 3 beta , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/fisiologia , Inflamação/etiologia , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Testosterona
17.
Cell ; 140(4): 529-39, 2010 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-20178745

RESUMO

A circadian clock coordinates physiology and behavior in diverse groups of living organisms. Another major cyclic cellular event, the cell cycle, is regulated by the circadian clock in the few cases where linkage of these cycles has been studied. In the cyanobacterium Synechococcus elongatus, the circadian clock gates cell division by an unknown mechanism. Using timelapse microscopy, we confirm the gating of cell division in the wild-type and demonstrate the regulation of cytokinesis by key clock components. Specifically, a state of the oscillator protein KaiC that is associated with elevated ATPase activity closes the gate by acting through a known clock output pathway to inhibit FtsZ ring formation at the division site. An activity that stimulates KaiC phosphorylation independently of the KaiA protein was also uncovered. We propose a model that separates the functions of KaiC ATPase and phosphorylation in cell division gating and other circadian behaviors.


Assuntos
Proteínas de Bactérias/metabolismo , Divisão Celular , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Ritmo Circadiano , Synechococcus/citologia , Synechococcus/fisiologia , Relógios Biológicos , Proteínas do Citoesqueleto/metabolismo , Regulação Bacteriana da Expressão Gênica , Fosforilação , Proteínas Quinases/metabolismo
18.
Nature ; 565(7738): 180-185, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568302

RESUMO

Environmental cues profoundly affect cellular plasticity in multicellular organisms. For instance, exercise promotes a glycolytic-to-oxidative fibre-type switch in skeletal muscle, and cold acclimation induces beige adipocyte biogenesis in adipose tissue. However, the molecular mechanisms by which physiological or pathological cues evoke developmental plasticity remain incompletely understood. Here we report a type of beige adipocyte that has a critical role in chronic cold adaptation in the absence of ß-adrenergic receptor signalling. This beige fat is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. We therefore refer to it as glycolytic beige fat. Mechanistically, we identify GA-binding protein α as a regulator of glycolytic beige adipocyte differentiation through a myogenic intermediate. Our study reveals a non-canonical adaptive mechanism by which thermal stress induces progenitor cell plasticity and recruits a distinct form of thermogenic cell that is required for energy homeostasis and survival.


Assuntos
Tecido Adiposo Bege/citologia , Tecido Adiposo Bege/metabolismo , Temperatura Baixa , Resposta ao Choque Frio , Glicólise , Desenvolvimento Muscular , Aclimatação , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Diferenciação Celular , Sobrevivência Celular , Metabolismo Energético , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Homeostase , Masculino , Camundongos , Proteína MyoD/metabolismo , Mioblastos/citologia , Receptores Adrenérgicos beta/metabolismo
19.
Nature ; 572(7771): 614-619, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31435015

RESUMO

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.


Assuntos
Tecido Adiposo Marrom/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Metabolismo Energético , Homeostase , Proteínas Mitocondriais/metabolismo , Proteínas Carreadoras de Solutos/metabolismo , Termogênese , Tecido Adiposo Marrom/citologia , Animais , Temperatura Baixa , Intolerância à Glucose/metabolismo , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Obesidade/metabolismo
20.
Cereb Cortex ; 34(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38584086

RESUMO

Machine learning is an emerging tool in clinical psychology and neuroscience for the individualized prediction of psychiatric symptoms. However, its application in non-clinical populations is still in its infancy. Given the widespread morphological changes observed in psychiatric disorders, our study applies five supervised machine learning regression algorithms-ridge regression, support vector regression, partial least squares regression, least absolute shrinkage and selection operator regression, and Elastic-Net regression-to predict anxiety and depressive symptom scores. We base these predictions on the whole-brain gray matter volume in a large non-clinical sample (n = 425). Our results demonstrate that machine learning algorithms can effectively predict individual variability in anxiety and depressive symptoms, as measured by the Mood and Anxiety Symptoms Questionnaire. The most discriminative features contributing to the prediction models were primarily located in the prefrontal-parietal, temporal, visual, and sub-cortical regions (e.g. amygdala, hippocampus, and putamen). These regions showed distinct patterns for anxious arousal and high positive affect in three of the five models (partial least squares regression, support vector regression, and ridge regression). Importantly, these predictions were consistent across genders and robust to demographic variability (e.g. age, parental education, etc.). Our findings offer critical insights into the distinct brain morphological patterns underlying specific components of anxiety and depressive symptoms, supporting the existing tripartite theory from a neuroimaging perspective.


Assuntos
Depressão , Substância Cinzenta , Humanos , Masculino , Feminino , Substância Cinzenta/diagnóstico por imagem , Depressão/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Ansiedade/diagnóstico por imagem , Ansiedade/psicologia , Afeto
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