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Antarctic krill (Euphausia superba) is Earth's most abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research.
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Euphausiacea , Genoma , Animales , Relojes Circadianos/genética , Ecosistema , Euphausiacea/genética , Euphausiacea/fisiología , Genómica , Análisis de Secuencia de ADN , Elementos Transponibles de ADN , Evolución Biológica , Adaptación FisiológicaRESUMEN
In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (µ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine.
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Estimulación Encefálica Profunda/métodos , Optogenética/métodos , Animales , Encéfalo/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ratones , Sondas Moleculares , Tecnología InalámbricaRESUMEN
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.
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Antidepresivos , Depresión , Habénula , Ketamina , Receptores de N-Metil-D-Aspartato , Animales , Ratones , Antidepresivos/administración & dosificación , Antidepresivos/metabolismo , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Depresión/metabolismo , Habénula/efectos de los fármacos , Habénula/metabolismo , Semivida , Ketamina/administración & dosificación , Ketamina/metabolismo , Ketamina/farmacocinética , Ketamina/farmacología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de Tiempo , Unión ProteicaRESUMEN
The neocortex consists of a vast number of diverse neurons that form distinct layers and intricate circuits at the single-cell resolution to support complex brain functions1. Diverse cell-surface molecules are thought to be key for defining neuronal identity, and they mediate interneuronal interactions for structural and functional organization2-6. However, the precise mechanisms that control the fine neuronal organization of the neocortex remain largely unclear. Here, by integrating in-depth single-cell RNA-sequencing analysis, progenitor lineage labelling and mosaic functional analysis, we report that the diverse yet patterned expression of clustered protocadherins (cPCDHs)-the largest subgroup of the cadherin superfamily of cell-adhesion molecules7-regulates the precise spatial arrangement and synaptic connectivity of excitatory neurons in the mouse neocortex. The expression of cPcdh genes in individual neocortical excitatory neurons is diverse yet exhibits distinct composition patterns linked to their developmental origin and spatial positioning. A reduction in functional cPCDH expression causes a lateral clustering of clonally related excitatory neurons originating from the same neural progenitor and a significant increase in synaptic connectivity. By contrast, overexpression of a single cPCDH isoform leads to a lateral dispersion of clonally related excitatory neurons and a considerable decrease in synaptic connectivity. These results suggest that patterned cPCDH expression biases fine spatial and functional organization of individual neocortical excitatory neurons in the mammalian brain.
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Regulación de la Expresión Génica , Neocórtex , Protocadherinas , Animales , Ratones , Interneuronas/metabolismo , Neocórtex/anatomía & histología , Neocórtex/citología , Neocórtex/metabolismo , Neuronas/metabolismo , Protocadherinas/genética , Protocadherinas/metabolismo , Sinapsis/metabolismo , Transmisión SinápticaRESUMEN
Diamond color centers have proven to be versatile quantum emitters and exquisite sensors of stress, temperature, electric and magnetic fields, and biochemical processes. Among color centers, the silicon-vacancy (SiV[Formula: see text]) defect exhibits high brightness, minimal phonon coupling, narrow optical linewidths, and high degrees of photon indistinguishability. Yet the creation of reliable and scalable SiV[Formula: see text]-based color centers has been hampered by heterogeneous emission, theorized to originate from surface imperfections, crystal lattice strain, defect symmetry, or other lattice impurities. Here, we advance high-resolution cryo-electron microscopy combined with cathodoluminescence spectroscopy and 4D scanning transmission electron microscopy (STEM) to elucidate the structural sources of heterogeneity in SiV[Formula: see text] emission from nanodiamond with sub-nanometer-scale resolution. Our diamond nanoparticles are grown directly on TEM membranes from molecular-level seedings, representing the natural formation conditions of color centers in diamond. We show that individual subcrystallites within a single nanodiamond exhibit distinct zero-phonon line (ZPL) energies and differences in brightness that can vary by 0.1 meV in energy and over 70% in brightness. These changes are correlated with the atomic-scale lattice structure. We find that ZPL blue-shifts result from tensile strain, while ZPL red shifts are due to compressive strain. We also find that distinct crystallites host distinct densities of SiV[Formula: see text] emitters and that grain boundaries impact SiV[Formula: see text] emission significantly. Finally, we interrogate nanodiamonds as small as 40 nm in diameter and show that these diamonds exhibit no spatial change to their ZPL energy. Our work provides a foundation for atomic-scale structure-emission correlation, e.g., of single atomic defects in a range of quantum and two-dimensional materials.
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The recent advances of single-cell RNA sequencing (scRNA-seq) have enabled reliable profiling of gene expression at the single-cell level, providing opportunities for accurate inference of gene regulatory networks (GRNs) on scRNA-seq data. Most methods for inferring GRNs suffer from the inability to eliminate transitive interactions or necessitate expensive computational resources. To address these, we present a novel method, termed GMFGRN, for accurate graph neural network (GNN)-based GRN inference from scRNA-seq data. GMFGRN employs GNN for matrix factorization and learns representative embeddings for genes. For transcription factor-gene pairs, it utilizes the learned embeddings to determine whether they interact with each other. The extensive suite of benchmarking experiments encompassing eight static scRNA-seq datasets alongside several state-of-the-art methods demonstrated mean improvements of 1.9 and 2.5% over the runner-up in area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). In addition, across four time-series datasets, maximum enhancements of 2.4 and 1.3% in AUROC and AUPRC were observed in comparison to the runner-up. Moreover, GMFGRN requires significantly less training time and memory consumption, with time and memory consumed <10% compared to the second-best method. These findings underscore the substantial potential of GMFGRN in the inference of GRNs. It is publicly available at https://github.com/Lishuoyy/GMFGRN.
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Benchmarking , Redes Reguladoras de Genes , Área Bajo la Curva , Aprendizaje , Redes Neurales de la ComputaciónRESUMEN
Reactive oxygen species (ROS) play an essential role in plant growth and responses to environmental stresses. Plant cells sense and transduce ROS signaling directly via hydrogen peroxide (H2O2)-mediated posttranslational modifications (PTMs) on protein cysteine residues. Here, we show that the H2O2-mediated cysteine oxidation of NAC WITH TRANS-MEMBRANE MOTIF1-LIKE 1 (GmNTL1) in soybean (Glycine max) during salt stress promotes its release from the endoplasmic reticulum (ER) membrane and translocation to the nucleus. We further show that an oxidative posttranslational modification on GmNTL1 residue Cys-247 steers downstream amplification of ROS production by binding to and activating the promoters of RESPIRATORY BURST OXIDASE HOMOLOG B (GmRbohB) genes, thereby creating a feed-forward loop to fine-tune GmNTL1 activity. In addition, oxidation of GmNTL1 Cys-247 directly promotes the expression of CATION H+ EXCHANGER 1 (GmCHX1)/SALT TOLERANCE-ASSOCIATED GENE ON CHROMOSOME 3 (GmSALT3) and Na+/H+ Antiporter 1 (GmNHX1). Accordingly, transgenic overexpression of GmNTL1 in soybean increases the H2O2 levels and K+/Na+ ratio in the cell, promotes salt tolerance, and increases yield under salt stress, while an RNA interference-mediated knockdown of GmNTL1 elicits the opposite effects. Our results reveal that the salt-induced oxidation of GmNTL1 promotes its relocation and transcriptional activity through an H2O2-mediated posttranslational modification on cysteine that improves resilience of soybean against salt stress.
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Glycine max , Tolerancia a la Sal , Glycine max/genética , Tolerancia a la Sal/genética , Peróxido de Hidrógeno/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cisteína/metabolismo , Estrés Fisiológico/genética , Plantas Modificadas Genéticamente/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
There has been increased awareness of the linkage between environmental exposures and cardiovascular health and disease. Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting millions of people worldwide and contributing to substantial morbidity and mortality. Although numerous studies have explored the role of genetic and lifestyle factors in the development and progression of atrial fibrillation, the potential impact of environmental determinants on this prevalent condition has received comparatively less attention. This review aims to provide a comprehensive overview of the current evidence on environmental determinants of atrial fibrillation, encompassing factors such as air pollution, temperature, humidity, and other meteorologic conditions, noise pollution, greenspace, and the social environment. We discuss the existing evidence from epidemiological and mechanistic studies, critically evaluating the strengths and limitations of these investigations and the potential underlying biological mechanisms through which environmental exposures may affect atrial fibrillation risk. Furthermore, we address the potential implications of these findings for public health and clinical practice and identify knowledge gaps and future research directions in this emerging field.
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Contaminación del Aire , Fibrilación Atrial , Sistema Cardiovascular , Exposoma , Humanos , Fibrilación Atrial/epidemiología , Fibrilación Atrial/etiología , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
Degradable polymer matrices and porous scaffolds provide powerful mechanisms for passive, sustained release of drugs relevant to the treatment of a broad range of diseases and conditions. Growing interest is in active control of pharmacokinetics tailored to the needs of the patient via programmable engineering platforms that include power sources, delivery mechanisms, communication hardware, and associated electronics, most typically in forms that require surgical extraction after a period of use. Here we report a light-controlled, self-powered technology that bypasses key disadvantages of these systems, in an overall design that is bioresorbable. Programmability relies on the use of an external light source to illuminate an implanted, wavelength-sensitive phototransistor to trigger a short circuit in an electrochemical cell structure that includes a metal gate valve as its anode. Consequent electrochemical corrosion eliminates the gate, thereby opening an underlying reservoir to release a dose of drugs by passive diffusion into surrounding tissue. A wavelength-division multiplexing strategy allows release to be programmed from any one or any arbitrary combination of a collection of reservoirs built into an integrated device. Studies of various bioresorbable electrode materials define the key considerations and guide optimized choices in designs. In vivo demonstrations of programmed release of lidocaine adjacent the sciatic nerves in rat models illustrate the functionality in the context of pain management, an essential aspect of patient care that could benefit from the results presented here.
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Implantes Absorbibles , Sistemas de Liberación de Medicamentos , Ratas , Animales , Electrónica , PolímerosRESUMEN
Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the largest comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the first supervised tissue deconvolution approach, a deep-learning-powered model, cfSort, for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, cfSort showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of cfSort with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from cfSort reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and cfSort enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.
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Ácidos Nucleicos Libres de Células , Aprendizaje Profundo , Humanos , Ácidos Nucleicos Libres de Células/genética , Metilación de ADN , Biomarcadores , Regiones Promotoras Genéticas , Biomarcadores de Tumor/genéticaRESUMEN
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.
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Dinoprostona , Transducción de Señal , Dinoprostona/metabolismo , Transducción de Señal/fisiología , Receptores de Prostaglandina/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hormonas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E/metabolismoRESUMEN
The interplay between microRNAs (miRNAs) and phytohormones allows plants to integrate multiple internal and external signals to optimize their survival of different environmental conditions. Here, we report that miR394 and its target gene LEAF CURLING RESPONSIVENESS (LCR), which are transcriptionally responsive to BR, participate in BR signaling to regulate hypocotyl elongation in Arabidopsis thaliana. Phenotypic analysis of various transgenic and mutant lines revealed that miR394 negatively regulates BR signaling during hypocotyl elongation, whereas LCR positively regulates this process. Genetically, miR394 functions upstream of BRASSINOSTEROID INSENSITIVE2 (BIN2), BRASSINAZOLEs RESISTANT1 (BZR1), and BRI1-EMS-SUPPRESSOR1 (BES1), but interacts with BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1 SUPRESSOR PROTEIN (BSU1). RNA-sequencing analysis suggested that miR394 inhibits BR signaling through BIN2, as miR394 regulates a significant number of genes in common with BIN2. Additionally, miR394 increases the accumulation of BIN2 but decreases the accumulation of BZR1 and BES1, which are phosphorylated by BIN2. MiR394 also represses the transcription of PACLOBUTRAZOL RESISTANCE1/5/6 and EXPANSIN8, key genes that regulate hypocotyl elongation and are targets of BZR1/BES1. These findings reveal a new role for a miRNA in BR signaling in Arabidopsis.
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Proteínas de Arabidopsis , Arabidopsis , Brasinoesteroides , Regulación de la Expresión Génica de las Plantas , Hipocótilo , MicroARNs , Transducción de Señal , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Brasinoesteroides/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Hipocótilo/crecimiento & desarrollo , Hipocótilo/genética , Hipocótilo/metabolismo , Plantas Modificadas Genéticamente , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Proteínas QuinasasRESUMEN
Brassinosteroids (BRs) are phytohormones that regulate stomatal development. In this study, we report that BR represses stomatal development in etiolated Arabidopsis (Arabidopsis thaliana) cotyledons via transcription factors BRASSINAZOLE RESISTANT 1 (BZR1) and bri1-EMS SUPPRESSOR1 (BES1), which directly target MITOGEN-ACTIVATED PROTEIN KINASE KINASE 9 (MKK9) and FAMA, 2 important genes for stomatal development. BZR1/BES1 bind MKK9 and FAMA promoters in vitro and in vivo, and mutation of the BZR1/BES1 binding motif in MKK9/FAMA promoters abolishes their transcription regulation by BZR1/BES1 in plants. Expression of a constitutively active MKK9 (MKK9DD) suppressed overproduction of stomata induced by BR deficiency, while expression of a constitutively inactive MKK9 (MKK9KR) induced high-density stomata in bzr1-1D. In addition, bzr-h, a sextuple mutant of the BZR1 family of proteins, produced overabundant stomata, and the dominant bzr1-1D and bes1-D mutants effectively suppressed the stomata-overproducing phenotype of brassinosteroid insensitive 1-116 (bri1-116) and brassinosteroid insensitive 2-1 (bin2-1). In conclusion, our results revealed important roles of BZR1/BES1 in stomatal development, and their transcriptional regulation of MKK9 and FAMA expression may contribute to BR-regulated stomatal development in etiolated Arabidopsis cotyledons.
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Proteínas de Arabidopsis , Arabidopsis , Brasinoesteroides , Cotiledón , Proteínas de Unión al ADN , Regulación de la Expresión Génica de las Plantas , Proteínas Nucleares , Estomas de Plantas , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Brasinoesteroides/metabolismo , Estomas de Plantas/crecimiento & desarrollo , Estomas de Plantas/genética , Estomas de Plantas/efectos de los fármacos , Cotiledón/genética , Cotiledón/crecimiento & desarrollo , Cotiledón/metabolismo , Cotiledón/efectos de los fármacos , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Mutación/genética , Regiones Promotoras Genéticas/genética , Etiolado , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Unión Proteica/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/genéticaRESUMEN
Increasing attention is being paid to the mechanistic investigation of exercise-associated chronic inflammatory disease improvement. Ulcerative colitis (UC) is one type of chronic inflammatory bowel disease with increasing incidence and prevalence worldwide. It is known that regular moderate aerobic exercise (RMAE) reduces the incidence or risk of UC, and attenuates disease progression in UC patients. However, the mechanisms of this RMAE's benefit are still under investigation. Here, we revealed that ß-hydroxybutyrate (ß-HB), a metabolite upon prolonged aerobic exercise, could contribute to RMAE preconditioning in retarding dextran sulfate sodium (DSS)-induced mouse colitis. When blocking ß-HB production, RMAE preconditioning-induced colitis amelioration was compromised, whereas supplementation of ß-HB significantly rescued impaired ß-HB production-associated defects. Meanwhile, we found that RMAE preconditioning significantly caused decreased colonic Th17/Treg ratio, which is considered to be important for colitis mitigation; and the downregulated Th17/Treg ratio was associated with ß-HB. We further demonstrated that ß-HB can directly promote the differentiation of Treg cell rather than inhibit Th17 cell generation. Furthermore, ß-HB increased forkhead box protein P3 (Foxp3) expression, the core transcriptional factor for Treg cell, by enhancing histone H3 acetylation in the promoter and conserved noncoding sequences of the Foxp3 locus. In addition, fatty acid oxidation, the key metabolic pathway required for Treg cell differentiation, was enhanced by ß-HB treatment. Lastly, administration of ß-HB without exercise significantly boosted colonic Treg cell and alleviated colitis in mice. Together, we unveiled a previously unappreciated role for exercise metabolite ß-HB in the promotion of Treg cell generation and RMAE preconditioning-associated colitis attenuation.
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Colitis Ulcerosa , Colitis , Humanos , Ratones , Animales , Linfocitos T Reguladores/metabolismo , Ácido 3-Hidroxibutírico/farmacología , Ácido 3-Hidroxibutírico/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Diferenciación Celular , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Células Th17/metabolismo , Sulfato de Dextran/toxicidad , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Transient electronic systems represent an emerging class of technology that is defined by an ability to fully or partially dissolve, disintegrate, or otherwise disappear at controlled rates or triggered times through engineered chemical or physical processes after a required period of operation. This review highlights recent advances in materials chemistry that serve as the foundations for a subclass of transient electronics, bioresorbable electronics, that is characterized by an ability to resorb (or, equivalently, to absorb) in a biological environment. The primary use cases are in systems designed to insert into the human body, to provide sensing and/or therapeutic functions for timeframes aligned with natural biological processes. Mechanisms of bioresorption then harmlessly eliminate the devices, and their associated load on and risk to the patient, without the need of secondary removal surgeries. The core content focuses on the chemistry of the enabling electronic materials, spanning organic and inorganic compounds to hybrids and composites, along with their mechanisms of chemical reaction in biological environments. Following discussions highlight the use of these materials in bioresorbable electronic components, sensors, power supplies, and in integrated diagnostic and therapeutic systems formed using specialized methods for fabrication and assembly. A concluding section summarizes opportunities for future research.
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Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.
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Artritis Reumatoide , Proteína Disulfuro Isomerasas , Factor de Transcripción STAT1 , Proteína Disulfuro Isomerasas/metabolismo , Proteína Disulfuro Isomerasas/genética , Humanos , Artritis Reumatoide/metabolismo , Ratones , Animales , Factor de Transcripción STAT1/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Transporte Activo de Núcleo Celular , Proteínas Portadoras/metabolismo , Transducción de Señal , Proteínas de Unión a Hormona Tiroide , Factores de Transcripción NFATC/metabolismo , Activación de Linfocitos , Hormonas Tiroideas/metabolismo , Regulación de la Expresión Génica , Células Th17/metabolismo , Células Th17/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Modelos Animales de Enfermedad , Piruvato QuinasaRESUMEN
The c-axis piezoresistivity is a fundamental and important parameter of graphite, but its value near zero pressure has not been well determined. Herein, a new method for studying the c-axis piezoresistivity of van der Waals materials near zero pressure is developed on the basis of in situ scanning electron microscopy and finite element simulation. The c-axis piezoresistivity of microscale highly oriented pyrolytic graphite (HOPG) is found to show a large value of 5.68 × 10-5 kPa-1 near zero pressure and decreases by 2 orders of magnitude to the established value of â¼10-7 kPa-1 when the pressure increases to 200 MPa. By modulating the serial tunneling barrier model on the basis of the stacking faults, we describe the c-axis electrical transport of HOPG under compression. The large c-axis piezoresistivity near zero pressure and its large decrease in magnitude with pressure are attributed to the rapid stiffening of the electromechanical properties under compression.
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Epithelioid hemangioendothelioma (EHE) is a rare endothelial sarcoma associated with a high incidence of metastases and for which there are no standard treatment options. Based on disease-defining mutations, most EHEs are classified into two subtypes: WWTR1::CAMTA1-fused EHE or YAP1::TFE3-fused EHE. However, rare non-canonical fusions have been identified in clinical samples of EHE cases and are challenging to classify. In this study, we report the identification of a novel WWTR1::TFE3 fusion variant in an EHE patient using targeted RNA sequencing. Histologically, the tumor exhibited hybrid morphological characteristics between WWTR1::CAMTA1-fused EHE and YAP1::TFE3-fused EHE. In addition to the driver fusion, there were six additional secondary mutations identified, including a loss-of-function FANCA mutation. Furthermore, in vitro studies were conducted to investigate the tumorigenic function of the WWTR1::TFE3 fusion protein in NIH3T3 cells and demonstrated that WWTR1::TFE3 promotes colony formation in soft agar. Finally, as the wild-type WWTR1 protein relies on binding the TEAD family of transcription factors to affect gene transcription, mutation of the WWTR1 domain of the fusion protein to inhibit such binding abrogates the transformative effect of WWTR1::TFE3. Overall, we describe a novel gene fusion in EHE with a hybrid histological appearance between the two major genetic subtypes of EHE. Further cases of this very rare subtype of EHE will need to be identified to fully elucidate the clinical and pathological characteristics of this unusual subtype of EHE.
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Hemangioendotelioma Epitelioide , Transactivadores , Humanos , Ratones , Animales , Transactivadores/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patología , Células 3T3 NIH , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Fusión Génica , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZRESUMEN
Alfalfa, an essential forage crop known for its high yield, nutritional value, and strong adaptability, has been widely cultivated worldwide. The yield and quality of alfalfa are frequently jeopardized due to environmental degradation. Lignin, a constituent of the cell wall, enhances plant resistance to abiotic stress, which often causes osmotic stress in plant cells. However, how lignin responds to osmotic stress in leaves remains unclear. This study explored the effects of osmotic stress on lignin accumulation and the contents of intermediate metabolites involved in lignin synthesis in alfalfa leaves. Osmotic stress caused an increase in lignin accumulation and the alteration of core enzyme activities and gene expression in the phenylpropanoid pathway. We identified five hub genes (CSE, CCR, CADa, CADb, and POD) and thirty edge genes (including WRKYs, MYBs, and UBPs) by integrating transcriptome and metabolome analyses. In addition, ABA and ethylene signaling induced by osmotic stress regulated lignin biosynthesis in a contradictory way. These findings contribute to a new theoretical foundation for the breeding of high-quality and resistant alfalfa varieties.
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Lignina , Medicago sativa , Medicago sativa/genética , Lignina/metabolismo , Presión Osmótica , Fitomejoramiento , Perfilación de la Expresión Génica , Hojas de la Planta/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
MeDalphos Au(I) complexes featuring aryl, alkynyl, and alkyl groups readily react with electrophilic fluorinating reagents such as N-fluorobenzenesulfonimide and Selectfluor. The ensuing [(MeDalphos)Au(R)F]+ complexes have been isolated and characterized by multinuclear NMR spectroscopy as well as X-ray diffraction. They adopt a square-planar contra-thermodynamic structure, with F trans to N. DFT/IBO calculations show that the N lone pair of MeDalphos assists and directs the transfer of F+ to gold. The [(MeDalphos)Au(Ar)F]+ (Ar = Mes, 2,6-F2Ph) complexes smoothly engage in C-C cross-coupling with PhCCSiMe3 and Me3SiCN, providing direct evidence for the oxidative fluorination/transmetalation/reductive elimination sequence proposed for F+-promoted gold-catalyzed transformations. Moreover, direct reductive elimination to forge a C-F bond at Au(III) was explored and substantiated. Thermal means proved unsuccessful, leading mostly to decomposition, but irradiation with UV-visible light enabled efficient promotion of aryl-F coupling (up to 90% yield). The light-induced reductive elimination proceeds under mild conditions; it works even with the electron-deprived 2,6-difluorophenyl group, and it is not limited to the contra-thermodynamic form of the aryl Au(III) fluoride complexes.