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1.
Cell ; 185(17): 3124-3137.e15, 2022 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-35944541

RESUMEN

During development, melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) become light sensitive much earlier than rods and cones. IpRGCs project to many subcortical areas, whereas physiological functions of these projections are yet to be fully elucidated. Here, we found that ipRGC-mediated light sensation promotes synaptogenesis of pyramidal neurons in various cortices and the hippocampus. This phenomenon depends on activation of ipRGCs and is mediated by the release of oxytocin from the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) into cerebral-spinal fluid. We further characterized a direct connection between ipRGCs and oxytocin neurons in the SON and mutual projections between oxytocin neurons in the SON and PVN. Moreover, we showed that the lack of ipRGC-mediated, light-promoted early cortical synaptogenesis compromised learning ability in adult mice. Our results highlight the importance of light sensation early in life on the development of learning ability and therefore call attention to suitable light environment for infant care.


Asunto(s)
Oxitocina , Células Ganglionares de la Retina , Animales , Encéfalo/metabolismo , Humanos , Ratones , Células Ganglionares de la Retina/fisiología , Opsinas de Bastones/metabolismo
2.
Cell ; 173(7): 1716-1727.e17, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29779945

RESUMEN

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.


Asunto(s)
Encéfalo/efectos de la radiación , Ácido Glutámico/biosíntesis , Aprendizaje/efectos de la radiación , Memoria/efectos de la radiación , Rayos Ultravioleta , Animales , Encéfalo/metabolismo , Encéfalo/patología , Cromatografía Líquida de Alta Presión , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/fisiología , Técnicas de Placa-Clamp , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Espectrometría de Masas en Tándem , Urocanato Hidratasa/antagonistas & inhibidores , Urocanato Hidratasa/genética , Urocanato Hidratasa/metabolismo , Ácido Urocánico/sangre , Ácido Urocánico/metabolismo
3.
Nature ; 623(7989): 964-971, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38030779

RESUMEN

Plasmas can generate ultra-high-temperature reactive environments that can be used for the synthesis and processing of a wide range of materials1,2. However, the limited volume, instability and non-uniformity of plasmas have made it challenging to scalably manufacture bulk, high-temperature materials3-8. Here we present a plasma set-up consisting of a pair of carbon-fibre-tip-enhanced electrodes that enable the generation of a uniform, ultra-high temperature and stable plasma (up to 8,000 K) at atmospheric pressure using a combination of vertically oriented long and short carbon fibres. The long carbon fibres initiate the plasma by micro-spark discharge at a low breakdown voltage, whereas the short carbon fibres coalesce the discharge into a volumetric and stable ultra-high-temperature plasma. As a proof of concept, we used this process to synthesize various extreme materials in seconds, including ultra-high-temperature ceramics (for example, hafnium carbonitride) and refractory metal alloys. Moreover, the carbon-fibre electrodes are highly flexible and can be shaped for various syntheses. This simple and practical plasma technology may help overcome the challenges in high-temperature synthesis and enable large-scale electrified plasma manufacturing powered by renewable electricity.

4.
PLoS Biol ; 22(6): e3002666, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38905316

RESUMEN

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.


Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Histonas , Animales , Femenino , Humanos , Ratones , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Histonas/metabolismo , L-Lactato Deshidrogenasa/metabolismo , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5/metabolismo , Lactato Deshidrogenasa 5/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Metástasis de la Neoplasia , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Pronóstico , Regulación hacia Arriba/genética
5.
Cell ; 151(6): 1283-95, 2012 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-23217710

RESUMEN

Hair cells are mechanosensors for the perception of sound, acceleration, and fluid motion. Mechanotransduction channels in hair cells are gated by tip links, which connect the stereocilia of a hair cell in the direction of their mechanical sensitivity. The molecular constituents of the mechanotransduction channels of hair cells are not known. Here, we show that mechanotransduction is impaired in mice lacking the tetraspan TMHS. TMHS binds to the tip-link component PCDH15 and regulates tip-link assembly, a process that is disrupted by deafness-causing Tmhs mutations. TMHS also regulates transducer channel conductance and is required for fast channel adaptation. TMHS therefore resembles other ion channel regulatory subunits such as the transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) of AMPA receptors that facilitate channel transport and regulate the properties of pore-forming channel subunits. We conclude that TMHS is an integral component of the hair cell's mechanotransduction machinery that functionally couples PCDH15 to the transduction channel.


Asunto(s)
Células Ciliadas Auditivas/metabolismo , Audición , Mecanotransducción Celular , Proteínas de la Membrana/metabolismo , Animales , Proteínas Relacionadas con las Cadherinas , Cadherinas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/ultraestructura , Ratones , Ratones Noqueados , Precursores de Proteínas/metabolismo , Estereocilios/metabolismo
6.
Nature ; 597(7878): 655-659, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34588672

RESUMEN

In 1878, Lord Rayleigh observed the highly celebrated phenomenon of sound waves that creep around the curved gallery of St Paul's Cathedral in London1,2. These whispering-gallery waves scatter efficiently with little diffraction around an enclosure and have since found applications in ultrasonic fatigue and crack testing, and in the optical sensing of nanoparticles or molecules using silica microscale toroids. Recently, intense research efforts have focused on exploring non-Hermitian systems with cleverly matched gain and loss, facilitating unidirectional invisibility and exotic characteristics of exceptional points3,4. Likewise, the surge in physics using topological insulators comprising non-trivial symmetry-protected phases has laid the groundwork in reshaping highly unconventional avenues for robust and reflection-free guiding and steering of both sound and light5,6. Here we construct a topological gallery insulator using sonic crystals made of thermoplastic rods that are decorated with carbon nanotube films, which act as a sonic gain medium by virtue of electro-thermoacoustic coupling. By engineering specific non-Hermiticity textures to the activated rods, we are able to break the chiral symmetry of the whispering-gallery modes, which enables the out-coupling of topological 'audio lasing' modes with the desired handedness. We foresee that these findings will stimulate progress in non-destructive testing and acoustic sensing.

7.
Nature ; 595(7869): 718-723, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34082438

RESUMEN

Resistance represents a major challenge for antibody-based therapy for COVID-191-4. Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern-B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)-and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19.


Asunto(s)
COVID-19/prevención & control , COVID-19/virología , Inmunoglobulina M/administración & dosificación , Inmunoglobulina M/inmunología , SARS-CoV-2/clasificación , SARS-CoV-2/inmunología , Administración Intranasal , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/metabolismo , COVID-19/inmunología , Relación Dosis-Respuesta Inmunológica , Femenino , Humanos , Inmunoglobulina A/genética , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/efectos adversos , Inmunoglobulina M/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ingeniería de Proteínas , Receptores Virales/antagonistas & inhibidores , Receptores Virales/metabolismo , SARS-CoV-2/genética , Tratamiento Farmacológico de COVID-19
8.
Nature ; 599(7886): 673-678, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34732895

RESUMEN

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.


Asunto(s)
Colágeno/metabolismo , Receptor con Dominio Discoidina 1/metabolismo , Matriz Extracelular/metabolismo , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Escape del Tumor , Animales , Línea Celular Tumoral , Receptor con Dominio Discoidina 1/antagonistas & inhibidores , Receptor con Dominio Discoidina 1/deficiencia , Receptor con Dominio Discoidina 1/genética , Modelos Animales de Enfermedad , Matriz Extracelular/inmunología , Femenino , Eliminación de Gen , Técnicas de Inactivación de Genes , Humanos , Inmunocompetencia/inmunología , Inmunoterapia , Ratones , Linfocitos T/citología , Linfocitos T/inmunología , Neoplasias de la Mama Triple Negativas/terapia
9.
Proc Natl Acad Sci U S A ; 121(10): e2309656121, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38408254

RESUMEN

Inner ear hair cells are characterized by the F-actin-based stereocilia that are arranged into a staircase-like pattern on the apical surface of each hair cell. The tips of shorter-row stereocilia are connected with the shafts of their neighboring taller-row stereocilia through extracellular links named tip links, which gate mechano-electrical transduction (MET) channels in hair cells. Cadherin 23 (CDH23) forms the upper part of tip links, and its cytoplasmic tail is inserted into the so-called upper tip-link density (UTLD) that contains other proteins such as harmonin. The Cdh23 gene is composed of 69 exons, and we show here that exon 68 is subjected to hair cell-specific alternative splicing. Tip-link formation is not affected in genetically modified mutant mice lacking Cdh23 exon 68. Instead, the stability of tip links is compromised in the mutants, which also suffer from progressive and noise-induced hearing loss. Moreover, we show that the cytoplasmic tail of CDH23(+68) but not CDH23(-68) cooperates with harmonin in phase separation-mediated condensate formation. In conclusion, our work provides evidence that inclusion of Cdh23 exon 68 is critical for the stability of tip links through regulating condensate formation of UTLD components.


Asunto(s)
Sordera , Pérdida Auditiva , Ratones , Animales , Pérdida Auditiva/genética , Pérdida Auditiva/metabolismo , Células Ciliadas Auditivas/fisiología , Sordera/genética , Células Ciliadas Auditivas Internas/metabolismo , Cadherinas/metabolismo , Exones/genética
10.
Plant Cell ; 35(5): 1334-1359, 2023 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-36691724

RESUMEN

Gynandropsis gynandra (Cleomaceae) is a cosmopolitan leafy vegetable and medicinal plant, which has also been used as a model to study C4 photosynthesis due to its evolutionary proximity to C3 Arabidopsis (Arabidopsis thaliana). Here, we present the genome sequence of G. gynandra, anchored onto 17 main pseudomolecules with a total length of 740 Mb, an N50 of 42 Mb and 30,933 well-supported gene models. The G. gynandra genome and previously released genomes of C3 relatives in the Cleomaceae and Brassicaceae make an excellent model for studying the role of genome evolution in the transition from C3 to C4 photosynthesis. Our analyses revealed that G. gynandra and its C3 relative Tarenaya hassleriana shared a whole-genome duplication event (Gg-α), then an addition of a third genome (Th-α, +1×) took place in T. hassleriana but not in G. gynandra. Analysis of syntenic copy number of C4 photosynthesis-related gene families indicates that G. gynandra generally retained more duplicated copies of these genes than C3T. hassleriana, and also that the G. gynandra C4 genes might have been under positive selection pressure. Both whole-genome and single-gene duplication were found to contribute to the expansion of the aforementioned gene families in G. gynandra. Collectively, this study enhances our understanding of the polyploidy history, gene duplication and retention, as well as their impact on the evolution of C4 photosynthesis in Cleomaceae.


Asunto(s)
Arabidopsis , Brassicaceae , Magnoliopsida , Duplicación de Gen , Magnoliopsida/genética , Brassicaceae/genética , Arabidopsis/genética , Fotosíntesis/genética , Evolución Molecular
11.
Nat Chem Biol ; 20(7): 835-846, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38287154

RESUMEN

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.


Asunto(s)
Lesión Renal Aguda , Ferroptosis , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/tratamiento farmacológico , Ferroptosis/efectos de los fármacos , Animales , Ratones , Ratones Endogámicos C57BL , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Factor de Activación Plaquetaria/metabolismo , Ratones Noqueados , Humanos , Masculino
12.
Chem Rev ; 124(5): 2512-2552, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38416701

RESUMEN

Molecular polaritons are quasiparticles resulting from the hybridization between molecular and photonic modes. These composite entities, bearing characteristics inherited from both constituents, exhibit modified energy levels and wave functions, thereby capturing the attention of chemists in the past decade. The potential to modify chemical reactions has spurred many investigations, alongside efforts to enhance and manipulate optical responses for photonic and quantum applications. This Review centers on the experimental advances in this burgeoning field. Commencing with an introduction of the fundamentals, including theoretical foundations and various cavity architectures, we discuss outcomes of polariton-modified chemical reactions. Furthermore, we navigate through the ongoing debates and uncertainties surrounding the underpinning mechanism of this innovative method of controlling chemistry. Emphasis is placed on gaining a comprehensive understanding of the energy dynamics of molecular polaritons, in particular, vibrational molecular polaritons─a pivotal facet in steering chemical reactions. Additionally, we discuss the unique capability of coherent two-dimensional spectroscopy to dissect polariton and dark mode dynamics, offering insights into the critical components within the cavity that alter chemical reactions. We further expand to the potential utility of molecular polaritons in quantum applications as well as precise manipulation of molecular and photonic polarizations, notably in the context of chiral phenomena. This discussion aspires to ignite deeper curiosity and engagement in revealing the physics underpinning polariton-modified molecular properties, and a broad fascination with harnessing photonic environments to control chemistry.

13.
Proc Natl Acad Sci U S A ; 120(1): e2206062120, 2023 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-36574657

RESUMEN

In this study, the "particle in a box" idea, which was broadly developed in semiconductor quantum dot research, was extended into mid-infrared (IR) cavity modes by applying lateral confinement in an optical cavity. The discrete cavity modes hybridized with molecular vibrational modes, resulting in a quartet of polariton states that can support multiple coherence states in the IR regime. We applied tailored pump pulse sequences to selectively prepare these coherences and verified the multi-coherence existence. The simulation based on Lindblad equation showed that because the quartet of polariton states resided in the same cavity, they were specifically robust toward decoherence caused by fluctuations in space. The multiple robust coherences paved the way for entangled states and coherent interactions between cavity polaritons, which would be critical for advancing polariton-based quantum information technology.


Asunto(s)
Ciencia de la Información , Puntos Cuánticos , Simulación por Computador , Tecnología de la Información , Semiconductores
14.
Ann Neurol ; 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39039739

RESUMEN

Endovascular thrombectomy (EVT) safety and efficacy in patients with large core infarcts receiving oral anticoagulants (OAC) are unknown. In the SELECT2 trial (NCT03876457), 29 of 180 (16%; vitamin K antagonists 15, direct OACs 14) EVT, and 18 of 172 (10%; vitamin K antagonists 3, direct OACs 15) medical management (MM) patients reported OAC use at baseline. EVT was not associated with better clinical outcomes in the OAC group (EVT 6 [4-6] vs MM 5 [4-6], adjusted generalized odds ratio 0.89 [0.53-1.50]), but demonstrated significantly better outcomes in patients without OAC (EVT 4 [3-6] vs MM 5 [4-6], adjusted generalized odds ratio 1.87 [1.45-2.40], p = 0.02). The OAC group had higher comorbidities, including atrial fibrillation (70% vs 17%), congestive heart failure (28% vs 10%), and hypertension (87% vs 72%), suggesting increased frailty. However, the results were consistent after adjustment for these comorbidities, and was similar regardless of the type of OACs used. Whereas any hemorrhage rates were higher in the OAC group receiving EVT (86% in OAC vs 70% in no OAC), no parenchymal hemorrhage or symptomatic intracranial hemorrhage were observed with OAC use in both the EVT and MM arms. Although we did not find evidence that the effect was due to excess hemorrhage or confounded by underlying cardiac disease or older age, OAC use alone should not exclude patients from receiving EVT. Baseline comorbidities and ischemic injury extent should be considered while making individualized treatment decisions. ANN NEUROL 2024.

15.
Int Immunol ; 36(6): 303-316, 2024 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-38387051

RESUMEN

Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for l-selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double-knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced. To determine whether 6-sulfo sLeX could serve as a target for MS, we also examined the effects of anti-glycan monoclonal antibody (mAb) SF1 against 6-sulfo sLeX in EAE. Administration of mAb SF1 significantly reduced EAE symptoms and the numbers of antigen-specific effector T cells in the dLN and SC in association with suppression of critical genes including Il17a and Il17f that are involved in the pathogenesis of EAE. Taken together, these results suggest that 6-sulfo sLeX glycan would serve as a novel target for MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Ratones Noqueados , Antígeno Sialil Lewis X , Antígeno Sialil Lewis X/análogos & derivados , Células Th17 , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Ratones , Células Th17/inmunología , Antígeno Sialil Lewis X/metabolismo , Polisacáridos/metabolismo , Interleucina-17/metabolismo , Interleucina-17/inmunología , Oligosacáridos , Carbohidrato Sulfotransferasas , Células TH1/inmunología , Sulfotransferasas/metabolismo , Sulfotransferasas/genética , Sulfotransferasas/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Femenino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Médula Espinal/inmunología , Médula Espinal/metabolismo , Movimiento Celular/inmunología
16.
J Allergy Clin Immunol ; 153(2): 447-460.e9, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37922997

RESUMEN

BACKGROUND: Whether IgE affects eosinophil migration in chronic rhinosinusitis with nasal polyps (CRSwNP) remains largely unclear. Moreover, our understanding of local IgE, eosinophils, and omalizumab efficacy in CRSwNP remains limited. OBJECTIVE: We investigated whether IgE acts directly on eosinophils and determined its role in omalizumab therapy. METHODS: Eosinophils and their surface receptors were detected by hematoxylin and eosin staining and flow cytometry. IgE and its receptors, eosinophil peroxidase (EPX), eosinophilic cationic protein, and CCR3 were detected by immunohistochemistry and immunofluorescence. Functional analyses were performed on blood eosinophils and polyp tissues. Logistic regression was performed to screen for risk factors. Receiver operating characteristic curve was generated to evaluate the accuracy. RESULTS: Both FcεRI and CD23 were expressed on eosinophils. The expression of FcεRI and CD23 on eosinophil in nasal polyp tissue was higher than in peripheral blood (both P < .001). IgE and EPX colocalized in CRSwNP. IgE directly promoted eosinophil migration by upregulating CCR3 in CRSwNP but not in healthy controls. Omalizumab and lumiliximab were found to be effective in restraining this migration, indicating CD23 was involved in IgE-induced eosinophil migration. Both IgE+ and EPX+ cells were significantly reduced after omalizumab treatment in those who experienced response (IgE+ cells, P = .001; EPX+ cells, P = .016) but not in those with no response (IgE+ cells, P = .060; EPX+ cells, P = .151). Baseline IgE+ cell levels were higher in those with response compared to those without response (P = .024). The baseline local IgE+ cell count predicted omalizumab efficacy with an accuracy of 0.811. CONCLUSIONS: IgE directly promotes eosinophil migration, and baseline local IgE+ cell counts are predictive of omalizumab efficacy in CRSwNP.


Asunto(s)
Pólipos Nasales , Rinitis , Rinosinusitis , Humanos , Eosinófilos , Omalizumab/farmacología , Omalizumab/uso terapéutico , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/metabolismo , Inmunoglobulina E , Enfermedad Crónica , Rinitis/tratamiento farmacológico , Rinitis/metabolismo , Receptores CCR3
17.
J Neurosci ; 43(18): 3219-3231, 2023 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-37001993

RESUMEN

The mechanoelectrical transduction (MET) protein complex in the inner-ear hair cells is essential for hearing and balance perception. Calcium and integrin-binding protein 2 (CIB2) has been reported to be a component of MET complex, and loss of CIB2 completely abolishes MET currents in auditory hair cells, causing profound congenital hearing loss. However, loss of CIB2 does not affect MET currents in vestibular hair cells (VHCs) as well as general balance function. Here, we show that CIB2 and CIB3 act redundantly to regulate MET in VHCs, as MET currents are completely abolished in the VHCs of Cib2/Cib3 double knock-out mice of either sex. Furthermore, we show that Cib2 and Cib3 transcripts have complementary expression patterns in the vestibular maculae, and that they play different roles in stereocilia maintenance in VHCs. Cib2 transcripts are highly expressed in the striolar region, and knock-out of Cib2 affects stereocilia maintenance in striolar VHCs. In contrast, Cib3 transcripts are highly expressed in the extrastriolar region, and knock-out of Cib3 mainly affects stereocilia maintenance in extrastriolar VHCs. Simultaneous knock-out of Cib2 and Cib3 affects stereocilia maintenance in all VHCs and leads to severe balance deficits. Taken together, our present work reveals that CIB2 and CIB3 are important for stereocilia maintenance as well as MET in mouse VHCs.SIGNIFICANCE STATEMENT Calcium and integrin-binding protein 2 (CIB2) is an important component of mechanoelectrical transduction (MET) complex, and loss of CIB2 completely abolishes MET in auditory hair cells. However, MET is unaffected in Cib2 knock-out vestibular hair cells (VHCs). In the present work, we show that CIB3 could compensate for the loss of CIB2 in VHCs, and Cib2/Cib3 double knock-out completely abolishes MET in VHCs. Interestingly, CIB2 and CIB3 could also regulate VHC stereocilia maintenance in a nonredundant way. Cib2 and Cib3 transcripts are highly expressed in the striolar and extrastriolar regions, respectively. Stereocilia maintenance and balance function are differently affected in Cib2 or Cib3 knock-out mice. In conclusion, our data suggest that CIB2 and CIB3 are important for stereocilia maintenance and MET in mouse VHCs.


Asunto(s)
Células Ciliadas Vestibulares , Animales , Ratones , Calcio/metabolismo , Células Ciliadas Vestibulares/metabolismo , Integrinas , Ratones Noqueados , Estereocilios/metabolismo
18.
J Proteome Res ; 23(5): 1859-1870, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38655723

RESUMEN

To understand how upregulated isoglutaminyl cyclase (isoQC) is involved in the initiation of diseases such as cancer, we developed a human KYSE30 carcinoma cell model in which isoQC was stably overexpressed. GO and KEGG analysis of the DEGs (228) and DEPs (254) respectively implicated isoQC on the proliferation invasion and metastasis of cells and suggested that isoQC might participate in the regulation of MAPK, RAS, circadian rhythm, and related pathways. At the functional level, isoQC-overexpressing KYSE30 cells showed enhanced proliferation, migration, and invasion capacity. Next, we decided to study the precise effect of isoQC overexpression on JNK, p-JNK, AKT, p-AKT, ERK, p-ERK, and PER2, as RNA levels of these proteins are significantly correlated with signal levels indicated in RNA-Seq analysis, and these candidates are the top correlated DEPs enriched in RT-qPCR analysis. We saw that only p-ERK expression was inhibited, while PER2 was increased. These phenotypes were inhibited upon exposure to PER2 inhibitor KL044, which allowed for the restoration of p-ERK levels. These data support upregulated isoQC being able to promote cancer cell proliferation and migration in vitro, likely by helping to regulate the MAPK and RAS signaling pathways, and the circadian protein PER2 might be a potential mediator.


Asunto(s)
Aminoaciltransferasas , Movimiento Celular , Proliferación Celular , Sistema de Señalización de MAP Quinasas , Humanos , Proliferación Celular/genética , Movimiento Celular/genética , Sistema de Señalización de MAP Quinasas/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Invasividad Neoplásica , Regulación hacia Arriba , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo
19.
Plant J ; 115(1): 108-126, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36987839

RESUMEN

Lactuca saligna L. is a wild relative of cultivated lettuce (Lactuca sativa L.), with which it is partially interfertile. Hybrid progeny suffer from hybrid incompatibility (HI), resulting in reduced fertility and distorted transmission ratios. Lactuca saligna displays broad-spectrum resistance against lettuce downy mildew caused by Bremia lactucae Regel and is considered a non-host species. This phenomenon of resistance in L. saligna is called non-host resistance (NHR). One possible mechanism behind this NHR is through the plant-pathogen interaction triggered by pathogen recognition receptors, including nucleotide-binding leucine-rich repeat (NLR) proteins and receptor-like kinases (RLKs). We report a chromosome-level genome assembly of L. saligna (accession CGN05327), leading to the identification of two large paracentric inversions (>50 Mb) between L. saligna and L. sativa. Genome-wide searches delineated the major resistance clusters as regions enriched in NLRs and RLKs. Three of the enriched regions co-locate with previously identified NHR intervals. RNA-seq analysis of Bremia-infected lettuce identified several differentially expressed RLKs in NHR regions. Three tandem wall-associated kinase-encoding genes (WAKs) in the NHR8 interval display particularly high expression changes at an early stage of infection. We propose RLKs as strong candidates for determinants of the NHR phenotype of L. saligna.


Asunto(s)
Lactuca , Oomicetos , Lactuca/genética , Genoma , Fenotipo , Enfermedades de las Plantas/genética
20.
J Cell Physiol ; 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38946173

RESUMEN

Amino acids are essential building blocks for proteins, crucial energy sources for cell survival, and key signaling molecules supporting the resistant growth of tumor cells. In tumor cells, amino acid metabolic reprogramming is characterized by the enhanced uptake of amino acids as well as their aberrant synthesis, breakdown, and transport, leading to immune evasion and malignant progression of tumor cells. This article reviews the altered amino acid metabolism in tumor cells and its impact on tumor microenvironment, and also provides an overview of the current clinical applications of amino acid metabolism. Innovative drugs targeting amino acid metabolism hold great promise for precision and personalized cancer therapy.

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