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Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4+ T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4+ T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration-approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4+ T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4+ T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4+ T cells as a target for HIV-1 therapy.
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Linfocitos T CD4-Positivos/virología , Genómica , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Metaboloma , Metabolómica , Fosforilación Oxidativa , Proteoma , Transcriptoma , Replicación Viral , Animales , Antivirales/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Células HEK293 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/metabolismo , Interacciones Huésped-Patógeno , Humanos , Células Jurkat , Masculino , Metformina/farmacología , Ratones , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Proteómica , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Carga Viral , Replicación Viral/efectos de los fármacosRESUMEN
TANK-binding kinase 1 (TBK1) is a potential therapeutic target in multiple cancers, including clear cell renal cell carcinoma (ccRCC). However, targeting TBK1 in clinical practice is challenging. One approach to overcome this challenge would be to identify an upstream TBK1 regulator that could be targeted therapeutically in cancer specifically. In this study, we perform a kinome-wide small interfering RNA (siRNA) screen and identify doublecortin-like kinase 2 (DCLK2) as a TBK1 regulator in ccRCC. DCLK2 binds to and directly phosphorylates TBK1 on Ser172. Depletion of DCLK2 inhibits anchorage-independent colony growth and kidney tumorigenesis in orthotopic xenograft models. Conversely, overexpression of DCLK2203, a short isoform that predominates in ccRCC, promotes ccRCC cell growth and tumorigenesis in vivo. Mechanistically, DCLK2203 elicits its oncogenic signaling via TBK1 phosphorylation and activation. Taken together, these results suggest that DCLK2 is a TBK1 activator and potential therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinogénesis/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Quinasas Similares a Doblecortina , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismoRESUMEN
Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases.
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Diferenciación Celular/genética , Proteínas Activadoras de GTPasa/genética , Células Th17/citología , Células Th17/metabolismo , Células Th2/citología , Células Th2/metabolismo , Animales , Autoinmunidad , Biomarcadores , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Proteínas Activadoras de GTPasa/metabolismo , Expresión Génica , Inmunofenotipificación , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Ratones , Proteolisis , ARN Mensajero , Células Th17/inmunología , Células Th2/inmunologíaRESUMEN
The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells1,2. It consists of an innate immune receptor/sensor, pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1ß and IL-18 in myeloid cells3-6. Here we show that the DNA-binding inflammasome receptor AIM27-10 has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (Treg) cells. AIM2 is highly expressed by both human and mouse Treg cells, is induced by TGFß, and its promoter is occupied by transcription factors that are associated with Treg cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in Treg cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of Treg cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of Treg cells.
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Autoinmunidad/inmunología , Proteínas de Unión al ADN/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Proteínas Adaptadoras de Señalización CARD/deficiencia , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Glucólisis , Humanos , Inflamasomas , Inflamación/inmunología , Ratones , Fosforilación Oxidativa , Fosforilación , Proteína Fosfatasa 2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores de Cinasa C Activada/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador betaRESUMEN
BACKGROUND: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. METHODS: Systems analyses integrating single-cell RNA sequencing and complementary immunologic approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming were assessed by integrated biochemical and genetic approaches. The intercellular propagation of homeostasis resolution was evaluated by coculture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high-fat diet-fed ApoE-/- mouse model with IP 4-PBA administration. Furthermore, the selective efficacy of 4-PBA-trained monocytes was examined by IV transfusion of ex vivo trained monocytes by 4-PBA into recipient high-fat diet-fed ApoE-/- mice. RESULTS: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 (intercellular adhesion molecule 1) via reducing peroxisome stress and attenuating SYK (spleen tyrosine kinase)-mTOR (mammalian target of rapamycin) signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPARγ (peroxisome proliferator-activated receptor γ) neddylation mediated by TOLLIP (toll-interacting protein). 4-PBA-trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA-trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. CONCLUSIONS: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.
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Aterosclerosis , Inflamación , Monocitos , Fenilbutiratos , Animales , Aterosclerosis/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/patología , Aterosclerosis/prevención & control , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Ratones , Inflamación/metabolismo , Fenilbutiratos/farmacología , Ratones Endogámicos C57BL , Humanos , Masculino , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Ratones Noqueados para ApoE , PPAR gamma/metabolismo , Reprogramación Celular/efectos de los fármacos , Células Cultivadas , Antiinflamatorios/farmacologíaRESUMEN
Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues1-4. H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca2+ increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/enzimología , Peróxido de Hidrógeno/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Calcio/metabolismo , Canales de Calcio/metabolismo , Señalización del Calcio , Cisteína/química , Cisteína/metabolismo , Activación Enzimática , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Mutación , Oxidación-Reducción , Células Vegetales/metabolismo , Dominios Proteicos , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
Starch synthesis in maize endosperm adheres to the basipetal sequence from the apex downwards. However, the mechanism underlying nonuniformity among regions of the endosperm in starch accumulation and its significance is poorly understood. Here, we examined the spatiotemporal transcriptomes and starch accumulation dynamics in apical (AE), middle (ME), and basal (BE) regions of endosperm throughout the filling stage. Results demonstrated that the BE had lower levels of gene transcripts and enzymes facilitating starch synthesis, corresponding to incomplete starch storage at maturity, compared with AE and ME. Contrarily, the BE showed abundant gene expression for genetic processing and slow progress in physiological development (quantified by an index calculated from the expression values of development progress marker genes), revealing a sustained cell vitality of the BE. Further analysis demonstrated a significant parabolic correlation between starch synthesis and physiological development. An in-depth examination showed that the BE had more active signaling pathways of IAA and ABA than the AE throughout the filling stage, while ethylene showed the opposite pattern. Besides, SNF1-related protein kinase1 (SnRK1) activity, a regulator for starch synthesis modulated by trehalose-6-phosphate (T6P) signaling, was kept at a lower level in the BE than the AE and ME, corresponding to the distinct gene expression in the T6P pathway in starch synthesis regulation. Collectively, the findings support an improved understanding of the timing of starch synthesis and cell vitality in regions of the endosperm during development, and potential regulation from hormone signaling and T6P/SnRK1 signaling.
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Two-dimensional materials have emerged as an important research frontier for overcoming the challenges in nanoelectronics and for exploring new physics. Among them, black phosphorus, with a combination of a tunable bandgap and high mobility, is one of the most promising systems. In particular, black phosphorus nanoribbons show excellent electrostatic gate control, which can mitigate short-channel effects in nanoscale transistors. Controlled synthesis of black phosphorus nanoribbons, however, has remained an outstanding problem. Here we report large-area growth of black phosphorus nanoribbons directly on insulating substrates. We seed the chemical vapour transport growth with black phosphorus nanoparticles and obtain uniform, single-crystal nanoribbons oriented exclusively along the [100] crystal direction. With comprehensive structural calculations, we discover that self-passivation at the zigzag edges holds the key to the preferential one-dimensional growth. Field-effect transistors based on individual nanoribbons exhibit on/off ratios up to ~104, confirming the good semiconducting behaviour of the nanoribbons. These results demonstrate the potential of black phosphorus nanoribbons for nanoelectronic devices and also provide a platform for investigating the exotic physics in black phosphorus.
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Although copper oxide high-temperature superconductors constitute a complex and diverse material family, they all share a layered lattice structure. This curious fact prompts the question of whether high-temperature superconductivity can exist in an isolated monolayer of copper oxide, and if so, whether the two-dimensional superconductivity and various related phenomena differ from those of their three-dimensional counterparts. The answers may provide insights into the role of dimensionality in high-temperature superconductivity. Here we develop a fabrication process that obtains intrinsic monolayer crystals of the high-temperature superconductor Bi2Sr2CaCu2O8+δ (Bi-2212; here, a monolayer refers to a half unit cell that contains two CuO2 planes). The highest superconducting transition temperature of the monolayer is as high as that of optimally doped bulk. The lack of dimensionality effect on the transition temperature defies expectations from the Mermin-Wagner theorem, in contrast to the much-reduced transition temperature in conventional two-dimensional superconductors such as NbSe2. The properties of monolayer Bi-2212 become extremely tunable; our survey of superconductivity, the pseudogap, charge order and the Mott state at various doping concentrations reveals that the phases are indistinguishable from those in the bulk. Monolayer Bi-2212 therefore displays all the fundamental physics of high-temperature superconductivity. Our results establish monolayer copper oxides as a platform for studying high-temperature superconductivity and other strongly correlated phenomena in two dimensions.
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Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions. The core of our innovation lies in the strategic engagement of Z-form DNA with ADAR1 and its degradation is achieved by leveraging a VHL ligand conjugated to Z-form DNA to recruit the E3 ligase. This ingenious construct engendered a series of Z-PROTACs, which we utilized to selectively degrade the Z-DNA-binding protein ADAR1, a molecule that is frequently overexpressed in cancer cells. This meticulously orchestrated approach triggers a cascade of PANoptotic events, notably encompassing apoptosis and necroptosis, by mitigating the blocking effect of ADAR1 on ZBP1, particularly in cancer cells compared with normal cells. Moreover, the Z-PROTAC design exhibits a pronounced predilection for ADAR1, as opposed to other Z-DNA readers, such as ZBP1. As such, Z-PROTAC likely elicits a positive immunological response, subsequently leading to a synergistic augmentation of cancer cell death. In summary, the Z-DNA-based PROTAC (Z-PROTAC) approach introduces a modality generated by the conformational change from B- to Z-form DNA, which harnesses the structural specificity intrinsic to potentiate a selective degradation strategy. This methodology is an inspiring conduit for the advancement of PROTAC-based therapeutic modalities, underscoring its potential for selectivity within the therapeutic landscape of PROTACs to target undruggable proteins.
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ADN de Forma Z , Quimera Dirigida a la Proteólisis , Proteolisis , Adenosina Desaminasa/metabolismo , ARN/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Unión al ADN/metabolismoRESUMEN
Deubiquitinase-targeting chimeras (DUBTACs) have been recently developed to stabilize proteins of interest, which is in contrast to targeted protein degradation (TPD) approaches that degrade disease-causing proteins. However, to date, only the OTUB1 deubiquitinase has been utilized to develop DUBTACs via an OTUB1 covalent ligand, which could unexpectedly compromise the endogenous function of OTUB1 owing to its covalent nature. Here, we show for the first time that deubiquitinase USP7 can be harnessed for DUBTAC development. Based on a noncovalent ligand of USP7, we developed USP7-based DUBTACs that stabilized the ΔF508-CFTR mutant protein as effectively as the previously reported OTUB1-based DUBTAC. Importantly, using two different noncovalent ligands of USP7, we developed the first AMPK DUBTACs that appear to selectively stabilize different isoforms of AMPKß, leading to elevated AMPK signaling. Overall, these results highlight that, in addition to OTUB1, USP7 can be leveraged to develop DUBTACs, thus significantly expanding the limited toolbox for targeted protein stabilization and the development of novel AMPK DUBTACs as potential therapeutics.
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BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Ftalazinas , Piperidinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Anciano , Adulto , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Ftalazinas/uso terapéutico , Ftalazinas/administración & dosificación , Indazoles/uso terapéutico , Indazoles/administración & dosificación , Proteína BRCA1/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Anciano de 80 o más Años , Platino (Metal)/uso terapéutico , Platino (Metal)/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteína BRCA2/genética , Supervivencia sin Progresión , AzetidinasRESUMEN
Friedreich's ataxia (FA) is an autosomal recessive disorder caused by a deficiency in frataxin (FXN), a mitochondrial protein that plays a critical role in the synthesis of iron-sulfur clusters (Fe-S), vital inorganic cofactors necessary for numerous cellular processes. FA is characterized by progressive ataxia and hypertrophic cardiomyopathy, with cardiac dysfunction as the most common cause of mortality in patients. Commonly used cardiac-specific mouse models of FA use the muscle creatine kinase (MCK) promoter to express Cre recombinase in cardiomyocytes and striated muscle cells in mice with one conditional Fxn allele and one floxed-out/null allele. These mice quickly develop cardiomyopathy that becomes fatal by 9-11 wk of age. Here, we generated a cardiac-specific model with floxed Fxn allele homozygosity (MCK-Fxnflox/flox). MCK-Fxnflox/flox mice were phenotypically normal at 9 wk of age, despite no detectable FXN protein expression. Between 13 and 15 wk of age, these mice began to display progressive cardiomyopathy, including decreased ejection fraction and fractional shortening and increased left ventricular mass. MCK-Fxnflox/flox mice began to lose weight around 16 wk of age, characteristically associated with heart failure in other cardiac-specific FA models. By 18 wk of age, MCK-Fxnflox/flox mice displayed elevated markers of Fe-S deficiency, cardiac stress and injury, and cardiac fibrosis. This modified model reproduced important pathophysiological and biochemical features of FA over a longer timescale than previous cardiac-specific mouse models, offering a larger window for studying potential therapeutics.NEW & NOTEWORTHY Previous cardiac-specific frataxin knockout models exhibit rapid and fatal cardiomyopathy by 9 wk of age. This severe phenotype poses challenges for the design and execution of intervention studies. We introduce an alternative cardiac-specific model, MCK-Fxnflox/flox, with increased longevity and delayed onset of all major phenotypes. These phenotypes develop to the same severity as previous models. Thus, this new model provides the same cardiomyopathy-associated mortality with a larger window for potential studies.
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Cardiomiopatías , Ataxia de Friedreich , Humanos , Ratones , Animales , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Alelos , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Modelos Animales de Enfermedad , Frataxina , Miocitos Cardíacos/metabolismoRESUMEN
Additive engineering is widely utilized to optimize film morphology in active layers of organic solar cells (OSCs). However, the role of additive in film formation and adjustment of film morphology remains unclear at the molecular level. Here, taking high-efficiency Y6-based OSC films as an example, this work thus employs all-atom molecular-dynamics simulations to investigate how introduction of additives with different π-conjugation degree thermodynamically and dynamically impacts nanoscale molecular packings. These results demonstrate that the van der Waals (vdW) interactions of the Y6 end groups with the studied additives are strongest. The larger the π-conjugation degree of the additive molecules, the stronger the vdW interactions between additive and Y6 molecules. Due to such vdW interactions, the π-conjugated additive molecules insert into the neighboring Y6 molecules, thus opening more space for relaxation of Y6 molecules to trigger more ordered packing. Increasing the interactions between the Y6 end groups and the additive molecules not only accelerates formation of the Y6 ordered packing, but also induces shorter Y6-intermolecular distances. This work reveals the fundamental molecular-level mechanism behind film formation and adjustment of film morphology via additive engineering, providing an insight into molecular design of additives toward optimizing morphologies of organic semiconductor films.
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Organic single crystals possess distinct advantages due to their highly ordered molecular structures, resulting in improved stability, enhanced carrier mobility, and superior optical characteristics. However, their mechanical rigidity and brittleness impede the applications in flexible and wearable optoelectronic devices. Here, photoluminescence (PL) emission from 2,6-diphenylanthracene (DPA) single crystals is studied under tensile strain, which shows PL enhancement by more than two times with a strain of ≈1.42%. Such a tension induced PL enhancement is reversible, exhibiting no clear optical degradations during 100 cycles of bending and recovery processes. Theoretical calculations reveal that the deformation of molecular structure under strain induces a decrease of the dihedral between anthracene and benzene moieties in DPA molecules. Further, the increased molecular conjugation enhances the molecular oscillator strength, leading to the brightened PL emission. Meanwhile, with the decreased dihedral, the molecular vibrations in DPA crystals are suppressed, which can reduce the non-radiative decay rate. In contrast, no tension induced PL enhancement is observed in polycrystalline DPA thin films as the strain can be released via the grain boundaries. This study highlights the superior optical performance of DPA single crystals under strain field, which will provide new possibilities for DPA-based flexible devices.
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The commercialization of lithium-sulfur (Li-S) battery is seriously hindered by the shuttle behavior of lithium (Li) polysulfide, slow conversion kinetics, and Li dendrite growth. Herein, a novel hierarchical p-type iron nitride and n-type vanadium nitride (p-Fe2N/n-VN) heterostructure with optimal electronic structure, confined in vesicle-like N-doped nanofibers (p-Fe2N/n-VNâPNCF), is meticulously constructed to work as "one stone two birds" dual-functional hosts for both the sulfur cathode and Li anode. As demonstrated, the d-band center of high-spin Fe atom captures more electrons from V atom to realize more π* and moderate σ* bond electron filling and orbital occupation; thus, allowing moderate adsorption intensity for polysulfides and more effective d-p orbital hybridization to improve reaction kinetics. Meanwhile, this unique structure can dynamically balance the deposition and transport of Li on the anode; thereby, more effectively inhibiting Li dendrite growth and promoting the formation of a uniform solid electrolyte interface. The as-assembled Li-S full batteries exhibit the conspicuous capacities and ultralong cycling lifespan over 2000 cycles at 5.0 C. Even at a higher S loading (20 mg cm-2) and lean electrolyte (2.5 µL mg-1), the full cells can still achieve an ultrahigh areal capacity of 16.1 mAh cm-2 after 500 cycles at 0.1 C.
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Nickel oxide (NiOx) is a promising hole transport layer (HTL) to fabricate efficient and large-scale inverted perovskite solar cells (PSCs) due to its low cost and superior chemical stability. However, inverted PSCs based on NiOx are still lagging behind that of other HTL because of the poor quality of buried interface contact. Herein, a bidentate ligand, 4,6-bis (diphenylphosphino) phenoxazine (2DPP), is used to regulate the NiOx surface and perovskite buried interface. The diphosphine Lewis base in the 2DPP molecule can coordinate both with NiOx and lead ions at NiOx/perovskite interface, leading to high-quality perovskite films with minimized defects. It is found that the inverted PSCs with 2DPP-modified buried interface exhibit double advantages of being both fast charge extraction and reduced nonradiative recombination, which is a combination of multiple factors including favorable energetic alignment, improved interface contact and strong binding between NiOx/2DPP and perovskite. The optimal PSC based on 2DPP modification yields a champion power conversion efficiency (PCE) of 21.9%. The unencapsulated PSC maintains above 75% of its initial PCE in the air with a relative humidity (RH) of 30-40% for 1000 h.
RESUMEN
Although picornaviruses are conventionally considered 'nonenveloped', members of multiple picornaviral genera are released nonlytically from infected cells in extracellular vesicles. The mechanisms underlying this process are poorly understood. Here, we describe interactions of the hepatitis A virus (HAV) capsid with components of host endosomal sorting complexes required for transport (ESCRT) that play an essential role in release. We show release of quasi-enveloped virus (eHAV) in exosome-like vesicles requires a conserved export signal located within the 8 kDa C-terminal VP1 pX extension that functions in a manner analogous to late domains of canonical enveloped viruses. Fusing pX to a self-assembling engineered protein nanocage (EPN-pX) resulted in its ESCRT-dependent release in extracellular vesicles. Mutational analysis identified a 24 amino acid peptide sequence located within the center of pX that was both necessary and sufficient for nanocage release. Deleting a YxxL motif within this sequence ablated eHAV release, resulting in virus accumulating intracellularly. The pX export signal is conserved in non-human hepatoviruses from a wide range of mammalian species, and functional in pX sequences from bat hepatoviruses when fused to the nanocage protein, suggesting these viruses are released as quasi-enveloped virions. Quantitative proteomics identified multiple ESCRT-related proteins associating with EPN-pX, including ALG2-interacting protein X (ALIX), and its paralog, tyrosine-protein phosphatase non-receptor type 23 (HD-PTP), a second Bro1 domain protein linked to sorting of ubiquitylated cargo into multivesicular endosomes. RNAi-mediated depletion of either Bro1 domain protein impeded eHAV release. Super-resolution fluorescence microscopy demonstrated colocalization of viral capsids with endogenous ALIX and HD-PTP. Co-immunoprecipitation assays using biotin-tagged peptides and recombinant proteins revealed pX interacts directly through the export signal with N-terminal Bro1 domains of both HD-PTP and ALIX. Our study identifies an exceptionally potent viral export signal mediating extracellular release of virus-sized protein assemblies and shows release requires non-redundant activities of both HD-PTP and ALIX.
Asunto(s)
Complejos de Clasificación Endosomal Requeridos para el Transporte , Virus de la Hepatitis A , Animales , Proteínas de Unión al Calcio/metabolismo , Cápside/metabolismo , Proteínas de la Cápside/genética , Proteínas de la Cápside/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Virus de la Hepatitis A/genética , Virus de la Hepatitis A/metabolismo , Mamíferos , Proteínas Virales/metabolismoRESUMEN
Superelastic alloys used for stents, biomedical implants, and solid-state cooling devices rely on their reversible stress-induced martensitic transformations. These applications require the alloy to sustain high deformability over millions of cycles without failure. Here, we report an alloy capable of enduring 10×10^{7} tensile stress-induced phase transformations while still exhibiting over 2% recoverable elastic strains. After millions of cycles, the alloy is highly reversible with zero stress hysteresis. We show that the major martensite variant is reversible even after multimillions of cycles under tensile loadings with a highly coherent (11[over ¯]0)_{A} interface. This discovery provides new insights into martensitic transformation, and may guide the development of superelastic alloys for multimillion cycling applications.
RESUMEN
Porous thermosensitive hydrogels exhibit a more flexible strategy for freshwater capture compared to conventional hydrogels. This study employs molecular dynamics (MD) simulation to investigate the deswelling behavior of poly(N-isopropylacrylamide) (PNIPAM) grafted within the nanochannel, aiming to elucidate the deswelling elimination process at various temperatures. Notably, a distinct phase separation is observed at specific temperatures above the lower solution temperature (LCST). Furthermore, this study takes the effect of heat flux into account, wherein distinct heat fluxes lead to varying levels of phase separation between water and the polymer. Specifically, the number of hydrogen bonds, volume of polymer chains, and density distribution of water molecules are statistically analyzed to reveal the mechanism of phase separation in a thermosensitive hydrogel. These findings provide insight into the accelerated deswelling kinetics of the PNIPAM polymer chain, which has guiding significance for the field of water harvesting by the enhancement of the water release capacity in thermosensitive hydrogels.