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1.
EMBO J ; 43(7): 1301-1324, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38467834

RESUMEN

Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.


Asunto(s)
Telomerasa , Humanos , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Telomerasa/genética , Ubiquitinación , Replicación del ADN , Telómero/genética , Telómero/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Daño del ADN
2.
EMBO J ; 41(16): e108791, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35811497

RESUMEN

TGF-ß signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-ß/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-ß receptor TßRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-ß/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TßRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-ß/SMAD signaling, and reduces TßRII stability and the number of TßRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.


Asunto(s)
Vesículas Extracelulares , Neoplasias , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Ubiquitina Tiolesterasa , Linfocitos T CD8-positivos/metabolismo , Endopeptidasas/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Ubiquitina Tiolesterasa/metabolismo
3.
Plant Cell ; 35(6): 2271-2292, 2023 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-36916511

RESUMEN

Ethylene induces anthocyanin biosynthesis in most fruits, including apple (Malus domestica) and plum (Prunus spp.). By contrast, ethylene inhibits anthocyanin biosynthesis in pear (Pyrus spp.), but the underlying molecular mechanism remains unclear. In this study, we identified and characterized an ethylene-induced ETHYLENE RESPONSE FACTOR (ERF) transcription factor, PpETHYLENE RESPONSE FACTOR9 (PpERF9), which functions as a transcriptional repressor. Our analyses indicated PpERF9 can directly inhibit expression of the MYB transcription factor gene PpMYB114 by binding to its promoter. Additionally, PpERF9 inhibits the expression of the transcription factor gene PpRELATED TO APETALA2.4 (PpRAP2.4), which activates PpMYB114 expression, by binding to its promoter, thus forming a PpERF9-PpRAP2.4-PpMYB114 regulatory circuit. Furthermore, PpERF9 interacts with the co-repressor PpTOPLESS1 (PpTPL1) via EAR motifs to form a complex that removes the acetyl group on histone H3 and maintains low levels of acetylated H3 in the PpMYB114 and PpRAP2.4 promoter regions. The resulting suppressed expression of these 2 genes leads to decreased anthocyanin biosynthesis in pear. Collectively, these results indicate that ethylene inhibits anthocyanin biosynthesis by a mechanism that involves PpERF9-PpTPL1 complex-mediated histone deacetylation of PpMYB114 and PpRAP2.4. The data presented herein will be useful for clarifying the relationship between chromatin status and hormone signaling, with implications for plant biology research.


Asunto(s)
Malus , Pyrus , Pyrus/genética , Pyrus/metabolismo , Factores de Transcripción/metabolismo , Antocianinas/metabolismo , Histonas/metabolismo , Regulación de la Expresión Génica de las Plantas , Etilenos/metabolismo , Frutas/metabolismo , Malus/genética , Malus/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
4.
Nat Mater ; 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664497

RESUMEN

In situ tailoring of two-dimensional materials' phases under external stimulus facilitates the manipulation of their properties for electronic, quantum and energy applications. However, current methods are mainly limited to the transitions among phases with unchanged chemical stoichiometry. Here we propose on-device phase engineering that allows us to realize various lattice phases with distinct chemical stoichiometries. Using palladium and selenide as a model system, we show that a PdSe2 channel with prepatterned Pd electrodes can be transformed into Pd17Se15 and Pd4Se by thermally tailoring the chemical composition ratio of the channel. Different phase configurations can be obtained by precisely controlling the thickness and spacing of the electrodes. The device can be thus engineered to implement versatile functions in situ, such as exhibiting superconducting behaviour and achieving ultralow-contact resistance, as well as customizing the synthesis of electrocatalysts. The proposed on-device phase engineering approach exhibits a universal mechanism and can be expanded to 29 element combinations between a metal and chalcogen. Our work highlights on-device phase engineering as a promising research approach through which to exploit fundamental properties as well as their applications.

5.
Nucleic Acids Res ; 51(9): e50, 2023 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-36938898

RESUMEN

Genetic screening based on the clustered regularly interspaced palindromic repeat (CRISPR) system has been indicated to be a powerful tool for identifying regulatory genes or cis-elements. However, when applying CRISPR screens to pinpoint functional elements at particular loci, a large number of guide RNA (gRNA) spacers may be required to achieve saturated coverage. Here, we present a controlled template-dependent elongation (CTDE) method relying on reversible terminators to synthesize gRNA libraries with genomic regions of interest. By applying this approach to H3K4me3 chromatin immunoprecipitation (ChIP)-derived DNA of mammalian cells, mega-sized gRNA libraries were synthesized in a tissue-specific manner, with which we conducted screening experiments to annotate essential sites for cell proliferation. Additionally, we confirmed that an essential site within the intron of LINC00339 regulates its own mRNA and that LINC00339 is a novel regulator of the cell cycle that maintains HepG2 proliferation. The CTDE method has the potential to be automated with high efficiency at low cost, and will be widely used to identify functional elements in mammalian genomes.


Asunto(s)
Biblioteca de Genes , Genoma , Histonas , Mamíferos , ARN Guía de Sistemas CRISPR-Cas , Animales , Humanos , Proliferación Celular , Inmunoprecipitación de Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Sistemas CRISPR-Cas , ADN/genética , Genoma/genética , Genómica , Células Hep G2 , Histonas/genética , Mamíferos/genética , Especificidad de Órganos , Ciclo Celular/genética , Automatización
6.
Proc Natl Acad Sci U S A ; 119(38): e2210769119, 2022 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-36095215

RESUMEN

Nanobodies and chemical cross-linking were used to gain information on the identity and positions of flexible domains of PI3Kα. The application of chemical cross-linking mass spectrometry (CXMS) facilitated the identification of the p85 domains BH, cSH2, and SH3 as well as their docking positions on the PI3Kα catalytic core. Binding of individual nanobodies to PI3Kα induced activation or inhibition of enzyme activity and caused conformational changes that could be correlated with enzyme function. Binding of nanobody Nb3-126 to the BH domain of p85α substantially improved resolution for parts of the PI3Kα complex, and binding of nanobody Nb3-159 induced a conformation of PI3Kα that is distinct from known PI3Kα structures. The analysis of CXMS data also provided mechanistic insights into the molecular underpinning of the flexibility of PI3Kα.


Asunto(s)
Dominio Catalítico , Fosfatidilinositol 3-Quinasa Clase I , Fosfatidilinositol 3-Quinasa Clase Ia , Fosfatidilinositol 3-Quinasa Clase I/química , Fosfatidilinositol 3-Quinasa Clase Ia/química , Humanos , Espectrometría de Masas/métodos , Anticuerpos de Dominio Único
7.
Eur Radiol ; 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38913243

RESUMEN

OBJECTIVES: To establish normative values and identify potential factors influencing pancreatic iodine uptake using dual-energy CT (DECT). MATERIALS AND METHODS: This retrospective study included participants without pancreatic diseases undergoing DECT at two institutions with different platforms. Their protocols both included arterial phase (AP), portal venous phase (PP), and equilibrium phase (EP), defined as 35 s-40 s, 60 s-70 s, and 150 s-180 s after injection of contrast agent, respectively. Both iodine concentration (IC) and normalised IC (NIC) were measured. Demographic features, local measurements of the pancreas and visceral fat area (VFA) were considered as potential factors influencing iodine uptake using multivariate linear regression analyses. RESULTS: A total of 562 participants (median age 58 years [interquartile range: 47-67], with 282 men) were evaluated. The mean IC differed significantly between two institutions (all p < 0.001) across three contrast-enhanced phases, while the mean NIC showed no significant differences (all p > 0.05). The mean values of NIC were 0.22 at AP, 0.43 at PP and 0.45 at EP. NICAP was independently affected by VFA (ß = 0.362, p < 0.001), smoking (ß = -0.240, p = 0.001), and type-II diabetes (ß = -0.449, p < 0.001); NICPP by VFA (ß = -0.301, p = 0.017) and smoking (ß = -0.291, p < 0.001); and NICEP by smoking (ß = -0.154, p = 0.10) and alcohol consumption (ß = -0.350, p < 0.001) with statistical power values over 0.81. CONCLUSION: NIC values were consistent across institutions. Abdominal obesity, smoking, alcohol consumption, and diabetes are independent factors influencing pancreatic iodine uptake. CLINICAL RELEVANCE STATEMENT: This study has provided reference normative values, influential factors and effective normalisation methods of pancreatic iodine uptake in multiphase dual-energy CT for future studies in this area as a new biological marker. KEY POINTS: Evaluation of pancreatic iodine uptake measured by dual-energy CT is a promising method for future studies. Abdominal obesity, smoking, alcohol consumption, diabetes, and sex are independent factors influencing pancreatic iodine uptake. Utility of normalised iodine concentration is necessary to ensure the consistency across different institutions.

8.
Soft Matter ; 20(20): 4136-4142, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38726867

RESUMEN

Wound dressings can generally complete hemostasis and provide temporary protection after skin damage. Herein, a MXene-based hydrogel was prepared from MXene, gelatin, poly(ethylene glycol)diacrylate (PEGDA) and N,N'-methylenebis(acrylamide) (HEAA) to prepare wound-dressing hydrogels for skin repair. HEAA and PEGDA crosslink polymerization formed the first layer of the network. Hydrogen bonds between MXene, PHEAA, and gelatin formed the second layer of the network. To make the hydrogel more suitable for skin repair, the mechanical properties of the hybrid hydrogel were adjusted. The MXene-based hydrogel could recover its original shape in 16 s upon immersion in water or for a few minutes under light irradiation. The obtained hydrogel showed good photothermal properties upon light irradiation (808 nm, 1 W cm-2) for 20 s, and its temperature on the surface could reach 86.4 °C. Due to its good photothermal properties, this MXene-based hydrogel was suitable for skin repair.


Asunto(s)
Hidrogeles , Piel , Cicatrización de Heridas , Hidrogeles/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Humanos , Polietilenglicoles/química , Materiales Inteligentes/química , Ratones
9.
Prev Med ; 180: 107893, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38342383

RESUMEN

PURPOSE: The association between sleep and myopia in children and adolescents has been reported, yet it remains controversial and inconclusive. This study aimed to investigate the influence of different sleep traits on the risk of myopia using meta-analytical and Mendelian randomization (MR) techniques. METHODS: The literature search was performed in August 31, 2023 based on PubMed, Embase, Web of Science, and Cochrane library. The meta-analysis of observational studies reporting the relationship between sleep and myopia was conducted. MR analyses were carried out to assess the causal impact of genetic pre-disposition for sleep traits on myopia. RESULTS: The results of the meta-analysis indicated a significant association between the risk of myopia and both short sleep duration [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.42, P = 0.003] and long sleep duration (OR = 0.75, 95% CI = 0.66-0.86, P < 0.001). MR analyses revealed no significant causal associations of genetically determined sleep traits with myopia, including chronotype, sleep duration, short sleep duration and long sleep duration (all P > 0.05). CONCLUSIONS: No evidence was found to support a causal relationship between sleep traits and myopia. While sleep may not independently predict the risk of myopia, the potential impact of sleep on the occurrence and development of myopia cannot be disregarded.


Asunto(s)
Análisis de la Aleatorización Mendeliana , Miopía , Niño , Adolescente , Humanos , Sueño/genética , Miopía/epidemiología , Miopía/genética , Oportunidad Relativa , Fenotipo , Estudio de Asociación del Genoma Completo
10.
Value Health ; 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38677363

RESUMEN

OBJECTIVES: To develop the EQ-5D-5L (5L) population norms for China and to assess the relationship between various factors and 5L data. METHODS: This study used data derived from the Psychology and Behavior Investigation of Chinese Residents, a national sample survey of 21 909 representative participants aged 12 years and above. Participants' health-related quality of life (HRQoL) was measured by the 5L. Their socioeconomic characteristics, behavioral factors, and health conditions were also obtained from the survey. Norm scores were generated and compared for different socioeconomic variables. Multiple linear and logistic regressions were used to assess the relationships of the 3 kinds of variables with the 5L utility, visual analog scale (VAS) scores and 5L health problems. RESULTS: The mean (SD) age of participants was 39.4 (18.9) years, and 50.0% of them were female. The mean (SD) utility and VAS scores were 0.940 (0.138) and 73.4 (21.6), respectively. Participants reported considerably more problems in anxiety/depression (26.2%) and pain/discomfort (22.2%) dimensions. The gender difference in HRQoL is attenuated. The participants older than 75 years suffered from a sharp decline in HRQoL; the participants in Shanghai and Tibet provinces reported lower utility and VAS scores and more health problems. Those who were younger, with better socioeconomic status and healthier lifestyles, and without diseases tended to report higher utility and VAS scores and fewer health problems. CONCLUSIONS: This study derived the 5L population norms for China based on a representative population sample.

11.
Qual Life Res ; 33(5): 1335-1346, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38353890

RESUMEN

PURPOSE: The high prevalence of multimorbidity in aging societies has posed tremendous challenges to the healthcare system. The aim of our study was to comprehensively assess the association of multimorbidity patterns and health-related quality of life (HRQOL) among rural Chinese older adults. METHODS: This was a cross-sectional study. Data from 4,579 community-dwelling older adults aged 60 years and above was collected by the clinical examination and questionnaire survey. Information on 10 chronic conditions was collected and the 3-Level EQ-5D (EQ-5D-3L) was adopted to measure the HRQOL of older adults. An exploratory factor analysis was performed to determine multimorbidity patterns. Regression models were fitted to explore the associations of multimorbidity patterns with specific health dimensions and overall HRQOL. RESULTS: A total of 2,503 (54.7%) participants suffered from multimorbidity, and they reported lower HRQOL compared to those without multimorbidity. Three kinds of multimorbidity patterns were identified including cardiovascular-metabolic diseases, psycho-cognitive diseases and organic diseases. The associations between psycho-cognitive diseases/organic diseases and overall HRQOL assessed by EQ-5D-3L index score were found to be significant (ß = - 0.097, 95% CI - 0.110, - 0.084; ß = - 0.030, 95% CI - 0.038, - 0.021, respectively), and psycho-cognitive diseases affected more health dimensions. The impact of cardiovascular-metabolic diseases on HRQOL was largely non-significant. CONCLUSION: Multimorbidity was negatively associated with HRQOL among older adults from rural China. The presence of the psycho-cognitive diseases pattern or the organic diseases pattern contributed to worse HRQOL. The remarkable negative impact of psycho-cognitive diseases on HRQOL necessiates more attention and relevant medical assistance to older rural adults.


Asunto(s)
Vida Independiente , Multimorbilidad , Calidad de Vida , Población Rural , Humanos , Calidad de Vida/psicología , Anciano , Masculino , China/epidemiología , Femenino , Estudios Transversales , Población Rural/estadística & datos numéricos , Persona de Mediana Edad , Vida Independiente/psicología , Encuestas y Cuestionarios , Anciano de 80 o más Años , Enfermedad Crónica/psicología , Enfermedad Crónica/epidemiología , Estado de Salud
12.
Graefes Arch Clin Exp Ophthalmol ; 262(1): 121-132, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37401934

RESUMEN

PURPOSE: To assess the associations of corneal biomechanical properties as measured by the Corvis ST with refractive errors and ocular biometry in an unselected sample of young adults. METHODS: A total of 1645 healthy university students underwent corneal biomechanical parameters measurement by the Corvis ST. The refractive status of the participants was measured using an autorefractor without cycloplegia. Ocular biometric parameters were measured using the IOL Master. RESULTS: After adjusting for the effect of age, sex, biomechanical-corrected intraocular pressure and central corneal thickness, axial length was significantly associated with A1 velocity (A1v, ß = -10.47), A2 velocity (A2v, ß = 4.66), A2 deflection amplitude (A2DeflA, ß = -6.02), HC deflection amplitude (HC-DeflA, ß = 5.95), HC peak distance (HC-PD, ß = 2.57), deformation amplitude ratio max (DA Rmax, ß = -0.36), Ambrósio's relational thickness to the horizontal profile (ARTh, ß = 0.002). For axial length / corneal radius ratio, only A1v (ß = -2.01), A1 deflection amplitude (A1DeflA, ß = 2.30), HC-DeflA (ß = 1.49), HC-PD (ß = -0.21), DA Rmax (ß = 0.07), stress-strain index (SSI, ß = -0.29), ARTh (ß < 0.001) were significant associates. A1v (ß = 23.18), HC-DeflA (ß = -15.36), HC-PD (ß = 1.27), DA Rmax (ß = -0.66), SSI (ß = 3.53), ARTh (ß = -0.02) were significantly associated with spherical equivalent. CONCLUSION: Myopic eyes were more likely to have more deformable corneas and corneas in high myopia were easier to deform and were even softer compared with those in the mild/moderate myopia.


Asunto(s)
Córnea , Miopía , Humanos , Adulto Joven , Refracción Ocular , Presión Intraocular , Tonometría Ocular , Miopía/diagnóstico , Fenómenos Biomecánicos
13.
BMC Ophthalmol ; 24(1): 59, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38342901

RESUMEN

BACKGROUND: Several studies have previously reported the normal values of corneal volume (CV) in various populations, whereas little is known about the CV distribution in healthy young Chinese adults. Our study aimed to investigate the distribution of CV and its relationships with other ocular biometric parameters among healthy young Chinese adults. METHODS: A total of 1645 eyes from 1645 students at Dali University in Yunnan Province, China, were analyzed. Pentacam was used to measure CV. Central corneal thickness (CCT) and biomechanically corrected intraocular pressure (bIOP) were evaluated by Corvis-ST. Other biometrical parameters, including axial length (AL), keratometry, and white-to-white (WTW) distance, were measured using IOL Master. RESULTS: The mean age of the study population was 19.01 ± 0.92 years, and 68.81% of them were women. The CV was normally distributed in the whole sample, with a mean value of 61.23 ± 3.22 mm3. CV and CCT were significantly smaller in the Yi ethnic group than in the Han ethnic group (p < 0.01). CCT (coefficient: 0.085; p < 0.001) and keratometry (coefficient: 0.422; p < 0.001) were positively correlated with CV, while AL (coefficient: -0.204; p < 0.001), WTW distance (coefficient: -0.236; p < 0.001) and bIOP (coefficient: -0.06; p < 0.001) were inversely associated with CV. CONCLUSIONS: Our study provides an age-specific distribution of CV among healthy young Chinese adults. CCT, keratometry, AL, WTW distance and bIOP were important factors associated with CV.


Asunto(s)
Córnea , Presión Intraocular , Adulto , Humanos , Femenino , Adolescente , Adulto Joven , Masculino , Estudios Transversales , China/epidemiología , Tonometría Ocular , Biometría
14.
J Public Health (Oxf) ; 46(1): 107-115, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38264954

RESUMEN

BACKGROUND: This study examined the moderating role of outdoor time on the relationship between overweight and myopia. METHODS: The data for this study was obtained from a prospective study in Shanghai, where non-myopic children wore wristwear and were followed up for 1 year. Eye examinations were performed at each visit. The modification effect was assessed on the additive scale using multivariable logistic regression, and relative excess risk due to interaction was used to calculate the modification effect. RESULTS: A total of 4683 non-myopic children were included with 32.20% being overweight at baseline. Following a 1-year period, 17.42% of children had myopia. When compared to those who spent <90 minutes outdoors, children who spent >120 had a relative risk of myopia onset that was reduced to 0.61. As time spent outdoors decreased, more risks of myopia onset were identified among overweight children than among normal children, the modification effect on the additive scale was -0.007, with ~70% of this effect attributed to the modifying influence of outdoor time. CONCLUSIONS: Increasing outdoor time can reduce myopia more among overweight children than normal. Future interventions should focus on outdoor activities among overweight children to reduce myopia risks.


Asunto(s)
Miopía , Obesidad Infantil , Niño , Humanos , Preescolar , Estudios de Seguimiento , Estudios Prospectivos , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Obesidad Infantil/epidemiología , Obesidad Infantil/etiología , Actividades Recreativas , China/epidemiología , Miopía/epidemiología , Miopía/etiología , Encuestas y Cuestionarios
15.
Nano Lett ; 23(21): 9928-9935, 2023 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-37862098

RESUMEN

Memristors have attracted considerable attention in the past decade, holding great promise for future neuromorphic computing. However, the intrinsic poor stability and large device variability remain key limitations for practical application. Here, we report a simple method to directly visualize the origin of poor stability. By mechanically removing the top electrodes of memristors operated at different states (such as SET or RESET), the memristive layer could be exposed and directly characterized through conductive atomic force microscopy, providing two-dimensional area information within memristors. Based on this technique, we observed the existence of multiple conducting filaments during the formation process and built up a physical model between filament numbers and the cycle-to-cycle variation. Furthermore, by improving the interface quality through the van der Waals top electrode, we could reduce the filament number down to a single filament during all switching cycles, leading to much controlled switching behavior and reliable device operation.

16.
Angew Chem Int Ed Engl ; 63(24): e202405139, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38588277

RESUMEN

It remains challenging to comprehensively understand the packing models of conjugated polymers, in which side chains play extremely critical roles. The side chains are typically flexible and non-conductive and are widely used to improve the polymer solubility in organic solutions. Herein, a buffer chain model is proposed to describe link between conjugated backbone and side chains for understanding the relationship of crystallization competition of conductive conjugated backbones and non-conductive side chains. A longer buffer chain is beneficial for alleviating such crystallization competition and further promoting the spontaneous packing of conjugated backbones, resulting in enhanced charge transport properties. Our results provide a novel concept for designing conjugated polymers towards ordered organization and enhanced electronic properties and highlight the importance of balancing the competitive interactions between different parts of conjugated polymers.

17.
Int J Cancer ; 152(10): 2174-2185, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-36629283

RESUMEN

Ovarian clear cell carcinoma (OCCC) is a distinct histotype of ovarian cancer, which usually presages a worse prognosis upon recurrence. Identifying patients at risk for relapse is an unmet need to improve outcomes. A retrospective cohort analysis of 195 early-stage OCCC patients diagnosed between January 2011 and December 2019 at National Taiwan University Hospital was conducted to identify prognostic factors for recurrence, progression-free survival (PFS) and overall survival (OS). Molecular profiling of tumors was performed in a case-controlled cohort matched for adjuvant therapy for biomarker discovery. Multivariate Cox proportional hazard model revealed that paclitaxel-based chemotherapy was associated with better PFS than nonpaclitaxel chemotherapy (HR = 0.19, P = .006). The addition of bevacizumab was associated with better PFS, compared to no bevacizumab (HR = 0.09, P = .02). Neither showed significant improvement in OS. Recurrence is associated with an Immune-Hot tumor feature (P = .03), the CTLA-4-high subtype (P = .01) and increased infiltration of immune cells in general. The Immune-Hot feature (HR = 3.39, P = .005) and the CTLA-4-high subtype (HR = 2.13, P = .059) were associated with worse PFS. Immune-Hot tumor features could prognosticate recurrence in early-stage OCCC.


Asunto(s)
Adenocarcinoma de Células Claras , Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Antígeno CTLA-4 , Estudios Retrospectivos , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Pronóstico , Carcinoma/patología , Adenocarcinoma de Células Claras/patología
18.
Biochem Biophys Res Commun ; 656: 16-22, 2023 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-36944284

RESUMEN

The estrogen-related receptor (ERR) family members are reported to bind DNA elements as either monomer or dimer. However, to date, only one solution NMR structure of ERRß in complex with a half-site DNA element has been reported. To better understand the DNA regulation mechanism, we determined the crystal structure of ERRγ-DBD bound to a natural DR1 element in Pla2g12b promoter to 2.2 Å resolution. Combined with biochemical assays, we show that ERRγ acts as a dimer and the C-terminal extension region undergoes conformational rearrangement when binding to the downstream DR1 element. In addition, the T-box region on the dimerization interface exhibits unique main-chain conformation. Thus, our structure presents a novel dimer interface for NR binding on DR1 DNA and provides a molecular basis for understanding the homodimer organization of ERR on DR1 elements.


Asunto(s)
ADN , Receptores de Estrógenos , Dimerización , ADN/química , Conformación Proteica , Regiones Promotoras Genéticas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Sitios de Unión
19.
PLoS Pathog ; 17(8): e1009859, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34383852

RESUMEN

Wolbachia is a group of intracellular symbiotic bacteria that widely infect arthropods and nematodes. Wolbachia infection can regulate host reproduction with the most common phenotype in insects being cytoplasmic incompatibility (CI), which results in embryonic lethality when uninfected eggs fertilized with sperms from infected males. This suggests that CI-induced defects are mainly in paternal side. However, whether Wolbachia-induced metabolic changes play a role in the mechanism of paternal-linked defects in embryonic development is not known. In the current study, we first use untargeted metabolomics method with LC-MS to explore how Wolbachia infection influences the metabolite profiling of the insect hosts. The untargeted metabolomics revealed 414 potential differential metabolites between Wolbachia-infected and uninfected 1-day-old (1d) male flies. Most of the differential metabolites were significantly up-regulated due to Wolbachia infection. Thirty-four metabolic pathways such as carbohydrate, lipid and amino acid, and vitamin and cofactor metabolism were affected by Wolbachia infection. Then, we applied targeted metabolomics analysis with GC-MS and showed that Wolbachia infection resulted in an increased energy expenditure of the host by regulating glycometabolism and fatty acid catabolism, which was compensated by increased food uptake. Furthermore, overexpressing two acyl-CoA catabolism related genes, Dbi (coding for diazepam-binding inhibitor) or Mcad (coding for medium-chain acyl-CoA dehydrogenase), ubiquitously or specially in testes caused significantly decreased paternal-effect egg hatch rate. Oxidative stress and abnormal mitochondria induced by Wolbachia infection disrupted the formation of sperm nebenkern. These findings provide new insights into mechanisms of Wolbachia-induced paternal defects from metabolic phenotypes.


Asunto(s)
Infecciones Bacterianas/complicaciones , Drosophila melanogaster/metabolismo , Infertilidad Masculina/patología , Metaboloma , Fenotipo , Reproducción , Wolbachia/fisiología , Animales , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/microbiología , Femenino , Infertilidad Masculina/etiología , Infertilidad Masculina/metabolismo , Masculino
20.
Qual Life Res ; 32(11): 3279-3289, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37395987

RESUMEN

PURPOSE: Fall is a serious health hazard to older adults. The aim of our study was to investigate the relationship between falls and health-related quality of life (HRQOL) in mainland China. METHODS: Data from 4579 Chinese community-dwelling older adults was analyzed. Data of falls was self-reported by participants, the HRQOL of older adults was measured by the 3-Level EQ-5D (EQ-5D-3L, 3L). Regression models were built to explore the associations of falls (experience and frequency) with the 3L data (index score, EQ-VAS score and health problems). The potential interaction effects between falls and gender on HRQOL were assessed using a likelihood ratio test, sex-stratified analysis was also performed to separately investigate the associations in men and women. RESULTS: A total of 368 (8.0%) participants had the experience of fall during the last year. Falls (experience and frequency) were significantly related to EQ-5D-3L index and EQ-VAS scores, fall experience contributed to pain/discomfort and anxiety/depression problems, while fall frequency was associated with physical-related problems and pain/discomfort. Significant interactions between falls and sex in several EQ-5D measures were also observed, and men had lager magnitude of associations than women. CONCLUSION: Falls were negative associated with overall HRQOL as well as separate HRQOL dimensions among older adults. It also appears that the HRQOL influence on older men is more evident than older women.


Asunto(s)
Accidentes por Caídas , Vida Independiente , Calidad de Vida , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , China , Pueblos del Este de Asia , Estado de Salud , Dolor , Calidad de Vida/psicología , Encuestas y Cuestionarios , Accidentes por Caídas/prevención & control , Accidentes por Caídas/estadística & datos numéricos
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