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Type I CRISPR systems feature a sequential dsDNA target searching and degradation process, by crRNA-displaying Cascade and nuclease-helicase fusion enzyme Cas3, respectively. Here we present two cryo-EM snapshots of the Thermobifida fusca type I-E Cascade: (1) unwinding 11 bp of dsDNA at the seed-sequence region to scout for sequence complementarity, and (2) further unwinding of the entire protospacer to form a full R-loop. These structures provide the much-needed temporal and spatial resolution to resolve key mechanistic steps leading to Cas3 recruitment. In the early steps, PAM recognition causes severe DNA bending, leading to spontaneous DNA unwinding to form a seed-bubble. The full R-loop formation triggers conformational changes in Cascade, licensing Cas3 to bind. The same process also generates a bulge in the non-target DNA strand, enabling its handover to Cas3 for cleavage. The combination of both negative and positive checkpoints ensures stringent yet efficient target degradation in type I CRISPR-Cas systems.
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Actinobacteria/genética , Actinobacteria/ultraestructura , Sistemas CRISPR-Cas , Hibridación de Ácido Nucleico , Actinobacteria/química , Actinobacteria/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Secuencia de Bases , Proteínas Asociadas a CRISPR/química , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/ultraestructura , Microscopía por Crioelectrón , Modelos Moleculares , ARN Bacteriano/química , ARN Bacteriano/metabolismo , ARN Pequeño no Traducido/química , ARN Pequeño no Traducido/metabolismoRESUMEN
The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy1,2. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance2-4. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.
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Células Supresoras de Origen Mieloide , Neoplasias , Neutrófilos , Receptores Inmunológicos , Animales , Humanos , Ratones , Sistemas CRISPR-Cas , Progresión de la Enfermedad , Edición Génica , Inmunoterapia , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Neoplasias/inmunología , Neoplasias/patología , Neutrófilos/inmunología , Neutrófilos/patología , Receptores Inmunológicos/inmunología , Análisis de Supervivencia , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T/patología , Microambiente Tumoral , Activación de LinfocitosRESUMEN
The NLRP3 inflammasome, a pivotal component of innate immunity, has been implicated in various inflammatory disorders. The ubiquitin-editing enzyme A20 is well known to regulate inflammation and maintain homeostasis. However, the precise molecular mechanisms by which A20 modulates the NLRP3 inflammasome remain poorly understood. Here, our study revealed that macrophages deficient in A20 exhibit increased protein abundance and elevated mRNA level of NIMA-related kinase 7 (NEK7). Importantly, A20 directly binds with NEK7, mediating its K48-linked ubiquitination, thereby targeting NEK7 for proteasomal degradation. Our results demonstrate that A20 enhances the ubiquitination of NEK7 at K189 and K293 ubiquitinated sites, with K189 playing a crucial role in the binding of NEK7 to A20, albeit not significantly influencing the interaction between NEK7 and NLRP3. Furthermore, A20 disrupts the association of NEK7 with the NLRP3 complex, potentially through the OTU domain and/or synergistic effect of ZnF4 and ZnF7 motifs. Significantly, NEK7 deletion markedly attenuates the activation of the NLRP3 inflammasome in A20-deficient conditions, both in vitro and in vivo. This study uncovers a mechanism by which A20 inhibits the NLRP3 inflammasome.
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Inflamasomas , Quinasas Relacionadas con NIMA , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Ubiquitinación , Quinasas Relacionadas con NIMA/metabolismo , Quinasas Relacionadas con NIMA/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Inflamasomas/metabolismo , Animales , Ratones , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Humanos , Macrófagos/metabolismo , Macrófagos/inmunología , Células HEK293 , Ratones Noqueados , Unión ProteicaRESUMEN
Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.
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Aparato de Golgi , Herpesvirus Humano 8 , Lipoilación , Proteínas Virales , Virión , Replicación Viral , Herpesvirus Humano 8/fisiología , Herpesvirus Humano 8/metabolismo , Aparato de Golgi/metabolismo , Aparato de Golgi/virología , Humanos , Virión/metabolismo , Proteínas Virales/metabolismo , Proteínas Virales/genética , Replicación Viral/fisiología , Células HEK293RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells1,2. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
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Anticuerpos Antivirales/inmunología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/inmunología , Neumonía Viral/prevención & control , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , COVID-19 , Vacunas contra la COVID-19 , Humanos , Macaca mulatta/inmunología , Macaca mulatta/virología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Animales , Modelos Moleculares , Dominios Proteicos , SARS-CoV-2 , Suero/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T/inmunología , VacunaciónRESUMEN
The peptidoglycan (PG) cell wall produced by the bacterial division machinery is initially shared between the daughters and must be split to promote cell separation and complete division. In gram-negative bacteria, enzymes that cleave PG called amidases play major roles in the separation process. To prevent spurious cell wall cleavage that can lead to cell lysis, amidases like AmiB are autoinhibited by a regulatory helix. Autoinhibition is relieved at the division site by the activator EnvC, which is in turn regulated by the ATP-binding cassette (ABC) transporter-like complex called FtsEX. EnvC is also known to be autoinhibited by a regulatory helix (RH), but how its activity is modulated by FtsEX and the mechanism by which it activates the amidases have remained unclear. Here, we investigated this regulation by determining the structure of Pseudomonas aeruginosa FtsEX alone with or without bound ATP, in complex with EnvC, and in a FtsEX-EnvC-AmiB supercomplex. In combination with biochemical studies, the structures reveal that ATP binding is likely to activate FtsEX-EnvC and promote its association with AmiB. Furthermore, the AmiB activation mechanism is shown to involve a RH rearrangement. In the activated state of the complex, the inhibitory helix of EnvC is released, freeing it to associate with the RH of AmiB, which liberates its active site for PG cleavage. These regulatory helices are found in many EnvC proteins and amidases throughout gram-negative bacteria, suggesting that the activation mechanism is broadly conserved and a potential target for lysis-inducing antibiotics that misregulate the complex.
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Proteínas de Escherichia coli , Escherichia coli , Hidrólisis , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , Amidohidrolasas/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Pared Celular/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Peptidoglicano/metabolismo , Endopeptidasas/metabolismo , Proteínas de Escherichia coli/metabolismoRESUMEN
Congenital human cytomegalovirus (HCMV) infection causes severe damage to the fetal brain, and the underlying mechanisms remain elusive. Cytokine signaling is delicately controlled in the fetal central nervous system to ensure proper development. Here we show that suppressor of cytokine signaling 3 (SOCS3), a negative feedback regulator of the IL-6 cytokine family signaling, was upregulated during HCMV infection in primary neural progenitor cells (NPCs) with a biphasic expression pattern. From viral protein screening, pUL97 emerged as the viral factor responsible for prolonged SOCS3 upregulation. Further, by proteomic analysis of the pUL97-interacting host proteins, regulatory factor X 7 (RFX7) was identified as the transcription factor responsible for the regulation. Depletion of either pUL97 or RFX7 prevented the HCMV-induced SOCS3 upregulation in NPCs. With a promoter-luciferase activity assay, we demonstrated that the pUL97 kinase activity and RFX7 were required for SOCS3 upregulation. Moreover, the RFX7 phosphorylation level was increased by either UL97-expressing or HCMV-infection in NPCs, suggesting that pUL97 induces RFX7 phosphorylation to drive SOCS3 transcription. We further revealed that elevated SOCS3 expression impaired NPC proliferation and migration in vitro and caused NPCs migration defects in vivo. Taken together, these findings uncover a novel regulatory mechanism of sustained SOCS3 expression in HCMV-infected NPCs, which perturbs IL-6 cytokine family signaling, leads to NPCs proliferation and migration defects, and consequently affects fetal brain development.
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Infecciones por Citomegalovirus , Citomegalovirus , Humanos , Citomegalovirus/fisiología , Interleucina-6/metabolismo , Proteómica , Factores de Transcripción/metabolismo , Células Madre , Proteína 3 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention.
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Infecciones por Citomegalovirus , Glioblastoma , Receptor EphA2 , Humanos , Proteínas del Envoltorio Viral/metabolismo , Glioblastoma/genética , Citomegalovirus/fisiología , Receptor EphA2/genéticaRESUMEN
The presence of human cytomegalovirus (HCMV) in glioblastoma (GBM) and improved outcomes of GBM patients receiving therapies targeting the virus have implicated HCMV in GBM progression. However, a unifying mechanism that accounts for the contribution of HCMV to the malignant phenotype of GBM remains incompletely defined. Here we have identified SOX2, a marker of glioma stem cells (GSCs), as a key determinant of HCMV gene expression in gliomas. Our studies demonstrated that SOX2 downregulated promyelocytic leukemia (PML) and Sp100 and consequently facilitated viral gene expression by decreasing the amount of PML nuclear bodies in HCMV-infected glioma cells. Conversely, the expression of PML antagonized the effects of SOX2 on HCMV gene expression. Furthermore, this regulation of SOX2 on HCMV infection was demonstrated in a neurosphere assay of GSCs and in a murine xenograft model utilizing xenografts from patient-derived glioma tissue. In both cases, SOX2 overexpression facilitated the growth of neurospheres and xenografts implanted in immunodeficient mice. Lastly, the expression of SOX2 and HCMV immediate early 1 (IE1) protein could be correlated in tissues from glioma patients, and interestingly, elevated levels of SOX2 and IE1 were predictive of a worse clinical outcome. These studies argue that HCMV gene expression in gliomas is regulated by SOX2 through its regulation of PML expression and that targeting molecules in this SOX2-PML pathway could identify therapies for glioma treatment.
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Glioma , Proteínas Inmediatas-Precoces , Animales , Humanos , Ratones , Citomegalovirus/fisiología , Regulación hacia Abajo , Expresión Génica , Glioma/genética , Glioma/patología , Proteínas Inmediatas-Precoces/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Auxin inactivation is critical for plant growth and development. To develop plant growth regulators functioning in auxin inactivation pathway, we performed a phenotype-based chemical screen in Arabidopsis and identified a chemical, nalacin, that partially mimicked the effects of auxin. Genetic, pharmacological, and biochemical approaches demonstrated that nalacin exerts its auxin-like activities by inhibiting indole-3-acetic acid (IAA) conjugation that is mediated by Gretchen Hagen 3 (GH3) acyl acid amido synthetases. The crystal structure of Arabidopsis GH3.6 in complex with D4 (a derivative of nalacin) together with docking simulation analysis revealed the molecular basis of the inhibition of group II GH3 by nalacin. Sequence alignment analysis indicated broad bioactivities of nalacin and D4 as inhibitors of GH3s in vascular plants, which were confirmed, at least, in tomato and rice. In summary, our work identifies nalacin as a potent inhibitor of IAA conjugation mediated by group II GH3 that plays versatile roles in hormone-regulated plant development and has potential applications in both basic research and agriculture.
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Arabidopsis , Ligasas , Arabidopsis/genética , Ácidos Indolacéticos/farmacología , Fenómenos Químicos , Reguladores del Crecimiento de las Plantas/farmacología , Pruebas GenéticasRESUMEN
Assembling active materials into dense electrodes is a promising way to obtain high-volumetric-capacitance supercapacitors, but insufficient ion channels in the dense structure lead to a low rate capability. Herein, a dense and robust wood electrode with a large MXene volumetric mass loading (1.25 g cm-3) and abundant ion diffusion channels is designed via a facile capillary-force-driven self-densification strategy. Specifically, MXene is assembled onto a wood cell wall, endowing the wood electrode with good electrical conductivity (86 S cm-1) and high electrochemical activity (5.9 F cm-2 at 1 mA cm-2). Notably, the oriented channels along with spaces between adjacent microfibrils recast after densification ensure efficient ion transport for the wood electrode, achieving an excellent rate capability with a high capacitance retention of 77% from 1 to 20 mA cm-2. Meanwhile, the capillary force induces self-densification on the softened wood cell wall, resulting in a highly compact and robust structure for the wood electrode.
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The shrinkage and collapse of wood cell walls during carbonization make it challenging to control the size and shape of carbonized wood (CW) through pre- or postprocessing (e.g., sawing, cutting, and milling). Herein, a shape-adaptive MXene shell (MS) is created on the surface of the wood cell walls. The MS limits the deformation of wood cell walls by spatial confinement and traction effects, which is supported by the inherent dimensional stability of the MS and the formation of new C-O-Ti covalent bonds between the wood cell wall and MS. Consequently, the volumetric shrinkage ratio of CW encapsulated by the MS (CW-MS) is significantly reduced from 54.8% for CW to 2.6% for CW-MS even at 800 °C. The harnessing of this collapse enables the production of CW-MS with prolonged stability and high electric conductivity (384 S m-1). These properties make CW-MS suitable for energy storage devices with various designed shapes, matching the increasingly compact and complex structures of electronic devices.
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BACKGROUND: Climate change is expected to alter the factors that drive changes in adaptive variation. This is especially true for species with long life spans and limited dispersal capabilities. Rapid climate changes may disrupt the migration of beneficial genetic variations, making it challenging for them to keep up with changing environments. Understanding adaptive genetic variations in tree species is crucial for conservation and effective forest management. Our study used landscape genomic analyses and phenotypic traits from a thorough sampling across the entire range of Quercus longinux, an oak species native to Taiwan, to investigate the signals of adaptation within this species. RESULTS: Using ecological data, phenotypic traits, and 1,933 single-nucleotide polymorphisms (SNPs) from 205 individuals, we classified three genetic groups, which were also phenotypically and ecologically divergent. Thirty-five genes related to drought and freeze resistance displayed signatures of natural selection. The adaptive variation was driven by diverse environmental pressures such as low spring precipitation, low annual temperature, and soil grid sizes. Using linear-regression-based methods, we identified isolation by environment (IBE) as the optimal model for adaptive SNPs. Redundancy analysis (RDA) further revealed a substantial joint influence of demography, geology, and environments, suggesting a covariation between environmental gradients and colonization history. Lastly, we utilized adaptive signals to estimate the genetic offset for each individual under diverse climate change scenarios. The required genetic changes and migration distance are larger in severe climates. Our prediction also reveals potential threats to edge populations in northern and southeastern Taiwan due to escalating temperatures and precipitation reallocation. CONCLUSIONS: We demonstrate the intricate influence of ecological heterogeneity on genetic and phenotypic adaptation of an oak species. The adaptation is also driven by some rarely studied environmental factors, including wind speed and soil features. Furthermore, the genetic offset analysis predicted that the edge populations of Q. longinux in lower elevations might face higher risks of local extinctions under climate change.
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Quercus , Humanos , Quercus/genética , Cambio Climático , Genómica , Frío , SueloRESUMEN
Although proton exchange membrane water electrolyzers (PEMWE) are considered as a promising technique for green hydrogen production, it remains crucial to develop intrinsically effective oxygen evolution reaction (OER) electrocatalysts with high activity and durability. Here, a flexible self-supporting electrode with nanoporous Ir/Ta2O5 electroactive surface is reported for acidic OER via dealloying IrTaCoB metallic glass ribbons. The catalyst exhibits excellent electrocatalytic OER performance with an overpotential of 218 mV for a current density of 10 mA cm-2 and a small Tafel slope of 46.1 mV dec-1 in acidic media, superior to most electrocatalysts. More impressively, the assembled PEMWE with nanoporous Ir/Ta2 O5 as an anode shows exceptional performance of electrocatalytic hydrogen production and can operate steadily for 260 h at 100 mA cm-2 . In situ spectroscopy characterizations and density functional theory calculations reveal that the modest adsorption of OOH* intermediates to active Ir sites lower the OER energy barrier, while the electron donation behavior of Ta2 O5 to stabilize the high-valence states of Ir during the OER process extended catalyst's durability.
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Human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Though the underlying mechanisms remain poorly characterized, mouse models of congenital CMV infection have demonstrated that the neuronal migration process is damaged. In this study, we evaluated the effects of HCMV infection on connexin 43 (Cx43), a crucial adhesion molecule mediating neuronal migration. We show in multiple cellular models that HCMV infection downregulated Cx43 posttranslationally. Further analysis identified the immediate early protein IE1 as the viral protein responsible for the reduction of Cx43. IE1 was found to bind the Cx43 C terminus and promote Cx43 degradation through the ubiquitin-proteasome pathway. Deletion of the Cx43-binding site in IE1 rendered it incapable of inducing Cx43 degradation. We validated the IE1-induced loss of Cx43 in vivo by introducing IE1 into the fetal mouse brain. Noteworthily, ectopic IE1 expression induced cortical atrophy and neuronal migration defects. Several lines of evidence suggest that these damages result from decreased Cx43, and restoration of Cx43 levels partially rescued IE1-induced interruption of neuronal migration. Taken together, the results of our investigation reveal a novel mechanism of HCMV-induced neural maldevelopment and identify a potential intervention target. IMPORTANCE Congenital CMV (cCMV) infection causes neurological sequelae in newborns. Recent studies of cCMV pathogenesis in animal models reveal ventriculomegaly and cortical atrophy associated with impaired neural progenitor cell (NPC) proliferation and migration. In this study, we investigated the mechanisms underlying these NPC abnormalities. We show that Cx43, a critical adhesion molecule mediating NPC migration, is downregulated by HCMV infection in vitro and HCMV-IE1 in vivo. We provide evidence that IE1 interacts with the C terminus of Cx43 to promote its ubiquitination and consequent degradation through the proteasome. Moreover, we demonstrate that introducing IE1 into mouse fetal brains led to neuronal migration defects, which was associated with Cx43 reduction. Deletion of the Cx43-binding region in IE1 or ectopic expression of Cx43 rescued the IE1-induced migration defects in vivo. Our study provides insight into how cCMV infection impairs neuronal migration and reveals a target for therapeutic interventions.
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Conexina 43 , Infecciones por Citomegalovirus , Citomegalovirus , Proteínas Inmediatas-Precoces , Animales , Humanos , Recién Nacido , Ratones , Conexina 43/genética , Conexina 43/metabolismo , Citomegalovirus/fisiología , Infecciones por Citomegalovirus/metabolismo , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Thymopoiesis depends on the recruitment and expansion of bone marrow-derived progenitor populations; tight regulation of these processes is required for maintenance of the homeostasis of the T lineage. Lyl-1, a transcription factor that regulates hematopoietic progenitors, is expressed in thymocyte progenitors until T cell commitment. Here we demonstrate a requirement for Lyl-1 in lymphoid specification and the maintenance of early T lineage progenitors (ETPs). Lyl-1 deficiency resulted in profound defects in the generation of lymphoid-primed multipotent progenitors (LMPPs), common lymphoid progenitors (CLPs) and ETPs. Lyl-1-deficient ETPs and thymocyte progenitors at the CD4(-)CD8(-) double-negative 2 (DN2) stage showed more apoptosis, blocked differentiation and impaired population expansion. We identified Gfi1 as a critical transcriptional target of Lyl-1-mediated lymphopoiesis of T cells. Thus, Lyl-1 is a pivotal component of a transcriptional program that controls the lymphoid specification and maintenance of ETPs.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Células Progenitoras Linfoides/fisiología , Linfopoyesis , Proteínas de Neoplasias/metabolismo , Linfocitos T/inmunología , Animales , Apoptosis/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Células de la Médula Ósea/fisiología , Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Linaje de la Célula , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Progenitoras Linfoides/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Linfocitos T/fisiología , Timocitos/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: A recurrence-free survival (RFS) prediction model was developed and validated for patients with locally advanced esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy (NCRT) in combination with surgery. PATIENTS AND METHODS: We included 282 patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy (NCRT) combined with surgery, constructed three models incorporating pathological factors, investigated the discrimination and calibration of each model, and compared the clinical utility of each model using the net reclassification index (NRI) and the integrated discrimination index (IDI). RESULTS: Multivariable analysis showed that pathologic complete response (pCR) and lymph node tumor regression grading (LN-TRG) (p < 0.05) were independent prognostic factors for RFS. LASSO regression screened six correlates of LN-TRG, vascular invasion, nerve invasion, degree of differentiation, platelet grade, and a total diameter of residual cancer in lymph nodes to build model three, which was consistent in terms of efficacy in the training set and validation set. Kaplan-Meier (K-M) curves showed that all three models were able to distinguish well between high- and low-risk groups (p < 0.01). The NRI and IDI showed that the clinical utility of model 2 was slightly better than that of model 1 (p > 0.05), and model 3 was significantly better than that of model 2 (p < 0.05). CONCLUSIONS: Clinical prediction models incorporating LN-TRG factors have high predictive efficacy, can help identify patients at high risk of recurrence after neoadjuvant therapy, and can be used as a supplement to the AJCC/TNM staging system while offering a scientific rationale for early postoperative intervention.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/terapia , Carcinoma de Células Escamosas de Esófago/patología , Terapia Neoadyuvante , Neoplasias Esofágicas/patología , Quimioradioterapia , Estadificación de Neoplasias , Estudios Retrospectivos , PronósticoRESUMEN
ConspectusThe invention of the laser is a pivotal milestone in the evolution of modern science and technology. Second-order nonlinear optical (NLO) crystals, which possess the ability to convert frequencies, have found widespread applications in laser science, information transmission, industrial Internet, and other cutting-edge fields within materials and optics. As modern science and technology continue to advance at a rapid pace, existing ultraviolet (UV) and deep ultraviolet (DUV) NLO crystals struggle to meet the ever-growing demands of various applications. Consequently, the development of novel UV and DUV NLO crystals has become an urgent necessity. For a UV NLO crystal to be considered outstanding in the UV/DUV range, it must exhibit three fundamental yet crucial properties: large second-order NLO coefficients, suitable birefringence, and short UV cutoff edge corresponding to a wide band gap. However, these key factors often conflict with one another, making it challenging to achieve a harmonious balance within a single crystal. It is widely believed that these mutually constrained optical properties are codetermined by microscopic NLO-active units and macroscopic structure features. Therefore, how to design high performance UV NLO-active groups to balance these three key properties is an essential scientifically question and serious challenge. In this Account, we present three strategies for designing high-performance UV NLO-active groups: (1) The "tetrahedron partial substitution" strategy by employing various substituents to replace one or more atoms in the traditional nonpolar tetrahedral groups, might achieve the aim of increasing the polarizability anisotropy and hyperpolarizability of the newly formed polar tetrahedral functional groups, such as from SO4 to SO3NH2 or SO3CH3 groups. (2) The "structure-analogue" strategy to develop a range of organic functional groups exhibiting more strong polarizability anisotropy and hyperpolarizability by using inorganic π-conjugated groups, such as BO3 and B3O6 groups, as templates. (3) The "two in one" strategy for integrating groups featuring planar triangle configurations and tetrahedrons to create NLO-active functional groups possessing large band gaps, strong hyperpolarizability, and moderate polarizability anisotropy. These three strategies successfully guide us to design and explore various kinds of organic-inorganic composite NLO crystal materials with excellent performances, like Ba(SO3CH3)2, M(SO3NH2)2 (M = Sr, Ba), C(NH2)3SO3F, KLi(HC3N3O3)·2H2O, KLi(C3H2O4)·H2O, and so on. Finally, we briefly conclude these strategies and propose some prospects for exploring new excellent UV/DUV NLO materials with practical applications. These findings could inspire novel thoughts for researchers designing new UV/DUV NLO materials and providing abundant materials used in UV/DUV regions.
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Dissipative solitons (DSs), due to the complex interplay among dispersion, nonlinear, gain and loss, illustrate abundant nonlinear dynamics behaviors. Especially, dispersion plays an important role in the research of DS dynamics in ultrafast fiber lasers. Previous studies have mainly focused on the effect of even-order dispersion, i.e., group velocity dispersion (GVD) and fourth-order dispersion. In fact, odd-order dispersions, such as third-order dispersion (TOD), also significantly influences the dynamics of DSs. However, due to the lack of dispersion engineering tools, few experimental researches in this domain have been reported. In this work, by employing a pulse shaper in ultrafast fiber laser, an in-depth exploration of the DS dynamics influenced by TOD was conducted. With the increase of TOD value, the stable single DS undergoes a splitting into two solitons and then enters explosion state, and ultimately evolves into a chaotic state. The laser operation state is correlated to dispersion profile, which could be controlled by TOD. Here, the positive dispersion at long-wavelength side will be gradually shifted to negative dispersion by increasing the TOD, where soliton effect will drive the transitions. These findings offer valuable insights into the nonlinear dynamics of ultrafast lasers and may also foster applications involving higher-order dispersion.
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INTRODUCTION: Studies on the relationship between environmental tobacco smoke (ETS) and gestational diabetes mellitus (GDM) are limited. In this study, we aimed to clarify the association between ETS at different trimesters of pregnancy and the risk of GDM among non-smoking pregnant women. METHODS: A total of 16,893 non-smoking mothers from the Southwest Birth Cohort, China, were included in the final analyses. Exposure and outcome measures included self-reported ETS status at different trimesters of pregnancy and GDM diagnosis. Multivariable logistic regression models were constructed to estimate the association between ETS and GDM. RESULTS: The prevalence of ETS exposure was 25.7%. Compared with no ETS, ever ETS had an increased risk of GDM, with an adjusted odds ratio (95% confidence intervals) of 1.21 (1.09, 1.33). The association remained consistent at different trimesters of pregnancy ETS exposure. In the last trimester and with continuous ETS exposure, the risk of GDM increased significantly with the increase in the duration of the exposure. The risk of GDM associated with ever ETS during pregnancy significantly increased in mothers over 30 years old and pre-pregnancy overweight (P for interaction <0.05). CONCLUSIONS: ETS exposure at different trimesters of pregnancy was associated with an increased risk of GDM among non-smoking pregnant women. These findings emphasise the importance of preventing ETS exposure during pregnancy.